Cu-Catalyzed Click Reaction in Carbohydrate Chemistry - Chemical

Review pubs.acs.org/CR

Cu-Catalyzed Click Reaction in Carbohydrate Chemistry Vinod K. Tiwari,*,† Bhuwan B. Mishra,†,§ Kunj B. Mishra,† Nidhi Mishra,† Anoop S. Singh,† and Xi Chen*,‡ †

Department of Chemistry, Centre of Advanced Study, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh-221005, India ‡ Department of Chemistry, One Shields Avenue, University of CaliforniaDavis, Davis, California 95616, United States ABSTRACT: Cu(I)-catalyzed azide−alkyne 1,3-dipolar cycloaddition (CuAAC), popularly known as the “click reaction”, serves as the most potent and highly dependable tool for facile construction of simple to complex architectures at the molecular level. Click-knitted threads of two exclusively different molecular entities have created some really interesting structures for more than 15 years with a broad spectrum of applicability, including in the fascinating fields of synthetic chemistry, medicinal science, biochemistry, pharmacology, material science, and catalysis. The unique properties of the carbohydrate moiety and the advantages of highly chemo- and regioselective click chemistry, such as mild reaction conditions, efficient performance with a wide range of solvents, and compatibility with different functionalities, together produce miraculous neoglycoconjugates and neoglycopolymers with various synthetic, biological, and pharmaceutical applications. In this review we highlight the successful advancement of Cu(I)-catalyzed click chemistry in glycoscience and its applications as well as future scope in different streams of applied sciences. 14.2. Triazole-Linked C-Glycocluster−Oligonucleotide Hybrids 14.3. Triazole-Linked Calix[4]arene S-Sialosides 14.4. Assembly via Thiol−Ene Coupling 15. Development of Graphene Nanosheets 16. Triazolyl Glycoconjugates as Enzyme Inhibitors 16.1. Glycosidase Inhibition Activities 16.2. Glycogen Phosphorylase Inhibitor 16.3. PTP1B Inhibitory Activities 16.4. Carbonic Anhydrase Inhibitor 16.5. Neuraminidase Inhibitors: Antiviral Activities 16.5.1. Zanamivir-Based Neuraminidase Inhibitors 16.5.2. DANA-Based Neuraminidase Inhibitors 16.5.3. Cholera Toxin Inhibitors 16.5.4. Trypanosoma cruzi trans-Sialidase (TcTS) Inhibitory Activities 16.5.5. Sialyltransferase Inhibitors 16.6. Anticancer Activities 16.7. Insecticidal Activity 16.8. Antifungal and Antibacterial Activity 16.9. Antitubercular Activities 16.10. Antileishmanial Activity 16.11. HIV-1 Inhibitors 16.12. Antiproliferative Activity 16.13. Potent Agonistic Antigen for T-Cell Receptors

CONTENTS 1. Introduction 2. Generalities on Click Chemistry 2.1. Catalysts, Solvents, and Additives 2.2. Mechanism 2.3. 1,2,3-Triazoles as Isosteres of Amides 2.4. Combination of Click Chemistry with Other Techniques 2.5. Azides and Alkyne Substrates: Benefit for Carbohydrates 3. Click-Chemistry-Inspired Synthesis of Diverse Triazolyl Glycoconjugates 4. Carbohydrate-Based Macrocycles Using Triazole as the Spacer 5. Glycopeptides and Protein Conjugates 6. Glycoclusters and Glycodendrimers 7. Glycopolymers 8. Click-Inspired Chemically Modified Nucleosides 9. “Carbo-Click” in Bioconjugation and Labeling 10. Carbohydrate Microarrays and Self-Assembled Monolayers 11. “Carbo-Click” in Sensing and Detection of Analytes 12. “Carbo-Click” in Lipid Functionalization 13. Application in the Glycosylation Reaction 13.1. Intermolecular Glycosylation 13.2. Intramolecular Glycosylation 14. Development of Calixarene Glycosides and Glycoclusters 14.1. Triazole-Linked Calix[4]arene C-Glycosides © 2016 American Chemical Society

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Received: July 15, 2015 Published: January 22, 2016 3086

DOI: 10.1021/acs.chemrev.5b00408 Chem. Rev. 2016, 116, 3086−3240

Chemical Reviews 16.14. Lectin Binding Activity 16.14.1. Galectin (S-Lectin) Inhibitory Activity 16.14.2. Selectin (C-Type Lectin) Binding Activity 16.15. Fucosyltransferase Inhibitors 16.16. Other Biologically Active Triazolyl Glycoconjugates 17. 18F-Labeling in “Carbo-Click” 18. Carbohydrate Click-to-Chelation 19. Carbohydrate Click-to-Catalysis 20. Conclusion and Future Perspective Author Information Corresponding Authors Present Address Notes Biographies Acknowledgments Abbreviations References

Review

etc.), (c) nucleophilic substitutions (e.g., nucleophilic opening of spring-loaded rings), and (d) carbonyl chemistry of non-aldoltype transformations (Scheme 1). The copper-catalyzed azide−alkyne cycloaddition (CuAAC) reaction satisfies all the stringent criteria of the Sharpless4 click chemistry concept, as this reaction is simple to perform, modular and wide in scope, highly efficient, high yielding, and regiospecific, creates no or inoffensive byproducts, requires readily available alkynes/azides as starting materials and reagents such as copper catalysts, and is conducted in easily removable or benign solvents (e.g., H2O). This reaction falls into the category of the ideal click reaction and is popularly known as Cu-catalyzed click chemistry (CuAAC or simply click chemistry) and is undoubtedly considered to have the largest number of applications known to date. Unlike the uncatalyzed cycloaddition of azides and alkynes which results in a mixture of 1,4- and 1,5triazole regioisomers at higher temperature, CuAAC unites organic azides 1 and terminal alkynes 2 in a regioselective way to afford the corresponding 1,4-disubstituted 1,2,3-triazoles 3 exclusively, under comparatively very moderate conditions (Scheme 2).6,7 The distinctive traits of thermodynamically piloted CuAAC, such as compatibility with a range of diverse functional groups, facile and gentle reaction conditions, wide pH range tolerance, and compatibility with a variety of solvents, including water, have framed this reaction as a potent technique to synthesize and modify complex organic scaffolds and biologically relevant molecules.9−62 In addition, azide and alkyne functionalities can be easily introduced into the organic moieties and remain considerably robust with other functional groups and common chemical reagents, which enhances the significance of the reaction. Another discovery in the field of click reactions came in 2005 with the ruthenium-catalyzed 1,3-dipolar azide−alkyne cycloaddition (RuAAC) reaction, which provided a regioisomer of the CuAAC product exclusively, i.e., 1,5-disubstituted triazoles 4. RuAAC tolerated a wide variety of functional groups. However, because of its greater sensitivity toward solvents and more stringent steric demand of the azide substituent than found for CuAAC, it could not be investigated extensively.63,64 The impact of click chemistry in different branches of science is increasing exponentially as evidenced from recent reviews available in the literature.9−62 Just a simple search in SciFinder (Chemical Abstract Service) using “click chemistry” as a keyword resulted in 12010 hits, which clearly confirms its importance in different fields of science where the number of publications, since just after its discovery in 2002, has increased exceedingly (Figure 1).65 When we move toward carbohydrate chemistry, the sugar moiety can be easily furnished with an alkyne or azide functionality with routine synthetic protocols that allow facile access to mono- as well as polyfunctionalized derivatives via CuAAC reaction. This convenient approach enables the rapid synthesis of carbohydrate conjugates in which the heterocyclic triazolyl ring serves as a shackle for joining the carbohydrate moiety to another biomolecule. In this review we summarize the widespread applications of Cu-catalyzed clicking of azides/ alkynes in carbohydrate chemistry for the generation of numerous glycoconjugates with simple to higher order molecular structures such as glycoproteins, neoglycoconjugates (poly(amino acid)s, oligomers, glycopolymers, glycoclusters, and glycol dendrimers), glycolipid conjugates, sugar-based macrocycles, calixarane glycoconjugates, glycopeptide conjugates,

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1. INTRODUCTION Huisgen’s 1,3-dipolar cycloaddition reaction of organic azides and alkynes, producing covalently linked molecules via a 1,2,3triazole, is among the paramount transformations in synthetic organic chemistry, as evidenced by the broad spectrum of targets that can be afforded by this methodology.1 Though the reaction was discovered in the dawn of the 20th century, it did not gain much attention until the 1960s when Huisgen et al. explored this reaction and carried out a comprehensive study to unveil the mechanism of the reaction.2−5 This reaction has an extremely high application potential due to the comparatively very facile functionalization of organic scaffolds with azides and alkynes which remain unaffected throughout subsequent transformations in the presence of immensely functionalized biomolecules, molecular oxygen, water, and other common synthesis conditions. Despite the high versatility of this reaction, it has endured several disadvantages for more than four decades, such as the requirement of heating and a long reaction time for completion, lack of product selectivity, and difficulty in the separation of the 1,4- and 1,5-linked regioisomers using classical chromatographic techinques.5 In 2002, the Meldal6 and Sharpless7 laboratories individually brought forward the ability of copper(I) salts in accelerating this cycloaddition at room temperature or with moderate heating, furnishing exclusively the 1,4-regioisomer with minimal workup and purification. The term “click chemistry” 8 was first introduced in 1999 by Barry Sharpless at the 217th American Chemical Society annual meeting, and it immediately became a very popular topic. Sharpless reported a set of stringent criteria to define a reaction as a “click” reaction. The reaction must be modular and broad in scope, must afford high to excellent reaction yields, must generate only inoffensive byproducts that can be removed by nonchromatographic methods, and must be stereospecific (but not necessarily enantioselective). The required process characteristics include simple reaction conditions, readily available starting materials and reagents, the use of no solvent or a solvent that is benign or easily removed, and simple product isolation.8 Click reactions can be classified into four major categories, including (a) cycloadditions (e.g., 1,3-dipolar or Huisgen’s cycloadditions, Diels−Alder cycloadditions, etc.), (b) additions to carbon−carbon multiple bonds (e.g., epoxidation, aziridination, dihydroxylation/aminohydroxylation, Michael addition, 3087


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reported the application of Cu(acac)2 as a useful catalyst for the development of 1,4-disubstituted triazole-containing disaccharides and trisaccharides from their corresponding glycosyl azides and terminal alkynes.74 To improve the reaction efficiency with these reagents, the assistance of some common bases, such as triethylamine (NEt3), 2,6-lutidine, diisopropylethylamine (DIPEA), and pyridine, has been reported. Interestingly, PhCOOH has been reported to facilitate the protonation of the copper triazolide intermediate and thus has been identified as a well-fitted additive for the clicking purpose.75,76 Although numerous catalysts are known to promote the azide−alkyne cycloaddition, there is a need to find an efficient, selective, and appropriate catalyst with several merits, including sufficient stability, low cost, heterogeneous nature, recyclability, reduced reaction time, and moreover low efficient loading. Due to the lack of sufficient stability of the catalyst in the reaction medium, a higher catalyst concentration throughout the reaction is mandatory. Alternatively, some ligands that stabilize the catalytic system have been used for further rate acceleration. Several phosphine-based complexes, including Cu(PPh3)2OAc,77 Cu(P(OMe)3)3Br,78 and Cu(PPh3)3Br, have shown good to excellent catalytic activity in azide−alkyne cycloaddition.79,80 Very recently, highly disperse copper particles immobilized on graphene and carbon nanotubes as a recyclable catalyst have been reported to catalyze the click reaction.81 On the other hand, a number of amine-based hard ligands, bound with different heterocyclic donors, for example, benzimidazole, benzothiazole, pyridyl, and the click-inspired triazole itself, have been sufficiently used for click purposes. All together, these ligands have offered unprecedented practicability to use such a clicking protocol in biological systems. Alternative strategies to overcome the problems related to catalyst toxicity have also been investigated. Toward this end, TBTA (5a), the leading common Cu(I)-stabilizing ligand, developed by the Sharpless group, has been successfully utilized for bioconjugation studies.82 Although TBTA shows a low water solubility, it is interestingly known to protect Cu(I) from oxidation and disproportionation, and thus enhances its catalytic activity to catalyze the click reaction. Ligand TTTA (5b) is also known to catalyze the click reaction under similar conditions. As a consequence, free Cu(I) ions that escape from the coordination of the ligand TBTA can initiate oxidative damage, also interfering with cellular metabolism.83 Another related ligand, THPTA (5c), was recently utilized for the development of virus-like particles such as Qβ conjugates, which are considered to be highly attractive platforms for the development of carbohydrate-based anticancer vaccines.84 In addition to ligands 5a−e, BTTES (6), which is nontoxic in nature, is also known to catalyze the click reaction (Figure 2).85 A very interesting sulfonated bathophenanthroline-based ligand (7) has been brought forward with wide applications particularly in bioconjugation, which is mainly due to its water solubility and exceptional reactivity.85 The Finn group optimized a protocol to reduce the generation of reactive oxygen species by using a ligand and copper in a 5:1 ratio. The authors underlined that aminoguanidine was a useful additive to capture ascorbate oxidation byproducts that can covalently modify proteins. This biocompatible catalyst allows noninvasive imaging of fucosylated glycans in a zebrafish model, signifying a promising method for a rapid in vivo imaging of biomolecules.86 An excellent rate acceleration was observed in the click protocol by using a number of tris(triazolyl)amine-based ligands, for example, tris(benzimidazolylmethyl)amines 8a,b.87,88 The

oligonucleotides, DNA−peptide conjugates having desired functionalities and applications in labeling, microarray constructions, triazolyl glycoconjugates in sensing, and promising enzyme inhibitors useful in drug discovery and development, click-to-chelation, and click-to-catalysis. Their future applications in diverse branches of science are also discussed. References for this review were collected up to May 2015. We apologize to the authors if their publications were not presented here due to the limitations of the search profiles and techniques employed.

2. GENERALITIES ON CLICK CHEMISTRY 2.1. Catalysts, Solvents, and Additives

The uncatalyzed alkyne−azide cycloaddition requires high temperatures and long reaction times and usually produces a mixture of both the 1,4- and 1,5-regioisomers of triazoles. In comparison, click-inspired CuAAC affords a single regioisomer, i.e., 1,4-disubstituted triazole, with an exceedingly high rate of reaction, likely 107 times faster than the reaction carried out in the absence of a catalyst. The three most common facile protocols for click conjugation include (i) direct utilization of a copper(I) source, (ii) alternative creation of copper(I) through the reduction of a copper(II) source, and (iii) finally oxidation of Cu(I) from the elemental form. All three protocols are widely employed to generate a number of clicked triazoles with a broad range of applications. However, the method which employs in situ formation of a copper(I) entity utilizing copper(II) salts such as CuSO4 and Cu(OAc)2 and other related compounds is known to be more practical because this catalytic system is unaffected by oxidizing as well as aqueous conditions, and also provides a high copper(I) concentration throughout the reaction process. Through the existing literature, it is easy to conclude that water is an appropriate choice of solvent for the CuSO4/sodium ascorbatecatalyzed click protocol which results in the formation of a clickinspired triazole product in high yields and with excellent regioselectivity. However, aerobic aqueous media normally require much larger quantities of CuSO4 and sodium ascorbate (NaAsc) due to the rapid oxidation of Cu(I) during the hour long reaction. Besides NaAsc, other reducing agents, such as hydrazine66 and tris(2-carboxyethyl)phosphine (TCEP),67 have also been applied with successful outcomes. However, use of salts with reducing tendencies (such as sodium ascorbate) for the clicking purpose in a biological system might sometimes be complicated because of possible reactions with protein chains67 which can alter the chemical structure of DNA.68 As a result, light-mediated in situ generation of a copper(I) system by means of photoinduced reduction of Cu(II) salts is an alternative protocol for the mandatory bioconjugation.69 Cu(0) in various forms, including Cu wire, CuNPs alone,70 or Cu nanoparticles adsorbed on activated carbon,71 has also been utilized in combination with an appropriate amine salt of Cu(II) or CuSO4 for triazole formation. Addition of copper(I) salts to the reaction medium in the absence of reducing agents provides an additional method to prompt the azide−alkyne cycloaddition. The protocol in essence requires deoxygenated conditions in the presence of mixed aprotic organic solvents such as THF, CH3CN, CH2Cl2, and toluene and other similar solvents. Various copper(I) salts, including copper iodide, copper bromide, copper chloride, and copper acetate, and coordination complexes such as CuOTf·C6H6, [Cu(NCCH3) 4][PF6], CuIP(OEt)3, CuBr(PPh3)4,72 and Cu{[(tris(2-(dioctadecylamino)ethyl]amine}Br73 have been used for click transformations.9 We recently 3088


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ligands, easy handling, etc. Interestingly, oxazoline-based alkyne 20 was successfully clicked with silica NP-based azide 19 under mild reaction conditions and afforded a high yield of nanocomposite 21 (Scheme 4).106 Fascinatingly, alkyne substrate 20 itself catalyzed the reaction. Moreover, the triazolyl nanocomposite product 21 was successfully used as a catalyst for the stereoselective benzoylation of geminal alcohols. Recently, the concept of chelation-assisted copper catalysis was implemented for the synthesis of organic azides bearing strong copper-chelating moieties that display unprecedented reactivity in click chemistry. Efficient ligation even at low concentration and the requirement of only 1.0 equiv of copper for the clicking of copper-chelating azides with terminal alkynes under diluted conditions make this protocol biocompatible, which can allow the localization of a pharmacologically active molecule inside living cells via fluorescence measurements.107 Apart from the Cu-catalyzed click reaction, some other catalysts, such as homogeneous silver(I) salts, were recently reported for the regioselective synthesis of a 1,4-disubstituted triazole through the cycloaddition of an azide with a terminal alkyne.108 However, this AgAAC has not gained popularity like CuAAC, possibly due to the high cost of the silver catalyst compared to that of the Cu catalyst.109 Other catalytic systems, such as zinc-mediated click,110 Ru-mediated click, and Pdcatalyzed click111 type protocols, are only little known, mainly due to poor regioselectivity and other reasons and could not be well explored in carbohydrate chemistry. This review will strictly focus on Cu-catalyzed click chemistry in glycoscience.

azide−alkyne click reaction, performed in the presence of other chelating heterocycles, 9a89 and 9b,90 afforded a good yield of the desired regioselective 1,4-disubstituted triazoles. In this case, the tertiary nitrogen center of the catalyst behaves as a donor to Cu(I) and also as a proton acceptor, and thus, another base is not required to bring the catalysis. The protocol utilizing such a chelating group is particularly valuable in bioconjugation. CuAAC reactions are efficiently operated using fine-tunable tris(triazolyl)methane ligands on a gram scale, where the ligands are converted to the Cu(I) complex form 10a−c (Figure 2) depending on the source of the copper catalyst. The author nicely demonstrated the selection of different media, e.g., H2O or other organic solvents, with the aid of selective tris(triazolyl)methane ligands 10a−c for the effective catalysis of the click reaction.91 A highly efficient isonitrile copper complex (12) has been reported for the clicking of an azide with alkyne under mild and aqueous reaction conditions.92 The heterogeneous nature and low loading efficiency are additional benefits related to the use of this catalyst. Furthermore, N-heterocyclic carbene (NHC)-based copper complexes, for example, triazolidine NHC ligands 11, are also well established and have emerged as a capable system to catalyze the click reactions in the presence of an aqueous−alcohol medium. The reactions require a comparatively elevated temperature and proceed with rapid rate acceleration, when carried out in the absence of solvent.93,94 Likewise, copper(I) complexes (for example, complex 13) have reportedly been found competent enough to click the sterically crowded starting materials (Figure 3).95 Bidentate S,N-ligand 14 was utilized to catalyze the click reaction between glucosyl azides and phenyl propargyl ethers for the synthesis of glycodendrimers, where the cycloaddition proceeds with 1 mol % catalyst in CH3CN at room temperature. Reaction under ordinary easy conditions and no requirement of an air-free atmosphere as well as additional base make the protocol more applicable.96 Recently, we reported the synthesis of copper(I) thiobenzoate complexes [CuSCOPh]x (15a), [Cu(dppf)(SCOPh)] (15b), and [Cu(bpy)(μ-SCOPh)] 2 (15c), and investigated their catalytic efficiency in the azide− alkyne cycloaddition reaction for the regioselective synthesis of a triazolyl glycoconjugate in good to excellent yields under click reaction conditions (Figure 4).97 Besides the high stability and inertness of click-inspired triazoles, generally the sulfonylated triazoles have been found to be labile, possibly because of the weak bond strength between N1 and N-2. These triazoles result in the corresponding N-acylated sulfonamides via ring−chain isomerization during the course of cycloaddition reaction and consequently complicate the click protocol.98,99 To defeat this trouble, a thiophene-2-carboxylate (CuTC)-based copper catalyst (17) has been introduced to click the sulfonyl azides 16 with various alkynes and afford the desired sulfonylated triazoles 18 in high yields under mild reaction conditions (Scheme 3).100 The sufficient stability of the CuTC catalyst, easy handling, remarkably high reaction yield, effectiveness in water as well as under anhydrous conditions, etc. make this catalyst interesting for wider applicability. A number of heterogeneous Cu catalysts are available to catalyze click-inspired triazole formation, including amberlyte resin-supported,101 polymer-supported,102 and zeolite-supported103,104 Cu catalysts which are applicable in conventional as well as green chemical reactions such as the ball-milling process.105 These catalysts have several merits, including their multiple recyclability, high reaction yield, no need for additives or

2.2. Mechanism

The CuAAC click reaction is considered to be a stepwise process, unlike the general [3 + 2]-cycloaddition reactions, which prefer a concerted mechanism. The stepwise mechanistic consideration is supported by the DFT calculations and kinetic evidence too.112−114 The experimental results also proposed an easygoing reaction that favors a more complicated mechanism, since the Cu(I) catalyst involves various additives of the reaction, such

Figure 1. Graphical representation of the numbers of publications dealing with click chemistry in 2002−2014.

as ligands, reactants, and solvents, etc., to form various complexes. This complexation of Cu(I) in the reaction medium leads to several equilibrium steps, including disproportionation of Cu(I) to Cu(0) and Cu(II) in a polar medium. By extensive study of the literature, two plausible pathways (I and II) are found to be best for click reactions as they are supported by DFT and kinetics (Scheme 5). Also recent reports showed that the triazole product might constitute one or two Cu species in the transition state. At the commencement of the reaction, Cu(I) undergoes complexation with a terminal alkyne to give a μ3089


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Figure 2. Potent polydentate nitrogen donors for the CuAAC reaction.

Figure 3. Effective catalysts and some coordination complexes for CuAAC catalysis.

coordinated aggregate, which in a protic medium deprotonates to give copper acetylides Ia and Ib. In the next step, Ia and Ib form complexes IIa and IIb respectively on reaction with an azide, which rearrange to metallacycles IIIa and IIIb, respectively, due to the nucleophilic nature of the terminal N-3 which favors attack of the C-4 position.115 The reaction proceeds through six-membered transition state IIIa, which is supported by Micouin and co-workers.116 The lone pair of N-1 in the metallacycle attacks at C-5, creating a facile ring contraction in the metallacycle and giving intermediate species IV. The presence of this Cu intermediate has already been supported by the isolation of cupper(I) triazolide using an NHC ligand.117 Lastly, base or solvent protonates IV, which finally gives the 1,4-

Figure 4. Effective copper(I) thiobenzoate complexes for the click reaction.

disubstituted 1,2,3-triazole product and also leads to easy dissociation of the copper complex, which could further attack the terminal alkyne and give copper acetylides Ia and Ib (Scheme 5). The stepwise mechanism of Sharpless, based on DFT studies, revealed the involvement of unprecedented metallacycle intermediates.113 Replacement of one of the ligands of copper 3090


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Scheme 1. General Classification of Click Reactions8

Scheme 2. Regioselective Comparison of Azide−Alkyne Cycloadditions in Different Reaction Catalytic Conditions

tionally found slightly exothermic (0.7 kcal/mol for the CH3CN ligand and 2.0 kcal/mol for H2O as the ligand). The next step, in which the C-2 carbon of the acetylide accepts an electron from N-3 of the azide in intermediate II, was found endothermic by 12.6 kcal/mol for the H2O ligand and by 8.2 kcal/mol for the CH3CN ligand. This step leads to the formation of six-membered copper(III) metallacycle III. The energy barrier calculated for this step, 14.9 kcal/mol for the acetonitrile ligand and 18.7 kcal/ mol for the water ligand, is much lower than that of the uncatalyzed reaction, i.e., 25.7 kcal/mol for the CH3CN ligand and 26.0 kcal/mol for the H2O ligand. This reveals the importance of Cu(I) catalysis in acceleration of the rate of reaction. Formation of triazolylcopper derivative IV from intermediate III via ring contraction is achieved through a very low energy barrier of 3.2 kcal/mol (for H2O as the ligand). The

Scheme 3. CuTC-Catalyzed Click Reaction of Alkynes with Sulfonyl Azides

acetylide I (formed by coordination of an alkyne to the Cu(I) species) by an azide leads to formation of intermediate II. The azide binds to the copper atom of the acetylide through the nitrogen atom proximal to the carbon. This step was computa3091


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Scheme 4. Click-Inspired Synthesis of Nanocomposite 21106

Figure 5. Energy profile diagram for CuAAC based on DFT studies (L = CH3CN or H2O) invented by K. B. Sharpless.113

acetylide I(Cu2) as a catalytically active complex instead of mononuclear I(Cu). The unusual stability of I(Cu2) and II(Cu2) unambiguously reveals that the biscopper pathway is kinetically more favored than the monocopper pathway. Kinetic studies of the Cu-catalyzed reaction of phenylacetylene with benzyl azide revealed that dinuclear complexes I(Cu2) and II(Cu2) are catalytically more active than their mononuclear counterparts I(Cu) and II(Cu). After an initiation period, the (CAAC)CuOTf complex adopts the dinuclear pathway.118

Sharpless energy profile diagram for Cu-catalyzed azide−alkyne cycloaddition using acetonitrile and water as the ligand was investigated on the basis of DFT studies (Figure 5).113 Although all these mechanistic studies gave agreeable ideas about the catalytic cycle of the Cu-catalyzed click reaction, the support of a direct observation of key components of the proposed mechanisms was missing. This gap was recently filled by the Bertrand research group. Very recently, this group reported the successful isolation of previously proposed π,σbiscopper acetylide I(Cu2) and a 3,5-bismetalated triazole complex, II(Cu2), which was never mentioned until now (Scheme 6).118 An interesting investigation that came into light through this report is the acceptance of σ-biscopper

2.3. 1,2,3-Triazoles as Isosteres of Amides

Amino acid scaffolds unite to give various proteins where the amide bond represents the key binding strategy. In fact, the composite and elaborate structures of these biological systems are solely influenced by amide linkages.119,120 The foundation laid by click chemistry instigated one of the best isosteres for

Scheme 5. Mechanism of Cu(I)-Catalyzed Azide−Alkyne Cycloaddition (CuAAC or Click Chemistry)113

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acceptor superiorly in comparison to amide linkages, and considerable imitation is achieved with respect to the peptide linkage. 1,4-Disubstituted triazoles are structurally different on account of the relative position of the substituents, as there are two atoms in the amide bond but three in triazole, which increases the distance (1.1 Å) between substituents in 1,4disubstituted triazoles. Similar discussions with structural similarity of 1,5-disubstituted 1,2,3-triazole to E-amide reveal that the relative positions of the substituents and sites for H donation and acceptance are the main responsible components for it, but as the electrophilic carbonyl carbon is replaced by a nitrogen atom with negative polarization, the polarization patterns of amide and triazole are dissimilar.

Scheme 6. Bertrand’s Conclusive Mechanism of CuAAC between Phenylacetylene and Benzyl Azide118,a

2.4. Combination of Click Chemistry with Other Techniques

The combination of click chemistry with other useful and quite popular techniques, such as microwave (MW) irradiation, ultrasound (US) irradiation, continuous flow conditions, aqueous media, solid supports, and room-temperature ionic liquids (RTILs), is considered a very successful and valuable protocol in synthetic chemistry.58 The advantages associated with MW irradiation, such as clean reaction, high yields, and shorter reaction time,122,123 have compelled the extension of the microwave-assisted alkyne−azide cycloaddition. The first examples of MW-assisted click reaction have been reported by Appukkuttan,124 where a variety of triazoles were developed by reacting the alkyl halides, alkynes, and NaN3 under one-pot MW irradiation for 15 min. Thus, clicking under MW irradiation conditions considerably reduces the time period (even up to 10 min of reaction time) and provides the desired click product in excellent yields.125 In addition to this, the methods utilizing US or US-induced MW for efficient click transformations have also been reported.126−128 The use of ultrasound, an alternative green source of energy, to promote chemical reactions allows a decrease in the reaction time and side reactions.129,130 The 1,3dipolar cycloaddition reaction was also investigated in flow using a meso flow reactor; however, further improvement in this direction is still mandatory. Smooth progress of the reaction at room temperature paves the way for performing similar

a Supported by successful isolation of intermediates I(Cu2) and II(Cu2) involved in “click chemistry”.

Figure 6. Assumption on isosteric similarities between triazoles and amides.

Scheme 7. US-Assisted Click Reaction in Carbohydrate Chemistry

amide linkages in the form of 1,2,3-triazoles. Their specific features, such as active participation in strong dipole−dipole interactions and hydrogen bonding, make them appropriate isosteres of amide. In addition to these, they hold superior properties in collation with amide linkages on account of their stability against hydrolysis and oxidative/reductive states (Figure 6). The triazoles exhibit remarkable isosteric similarity with E- and Z-amides on behalf of the motif of substitution. Experimentally reported peptidomimetic structures portray the mimicking nature of triazoles.121 Z-Amide is imitated by 1,4-disubstituted 1,2,3-triazoles which are prepared by CuAAC. These triazoles have a lone pair on N-3 which strongly resembles a carbonyl oxygen. The electron-deficient and polarized nature of C-4 exhibits a likeliness with a carbonyl carbon having electrophilic nature, whereas the hydrogen bond donor tendencies of the N− H amide bond are reflected by the polarized C-5−H of these triazoles. Along with these key similarities, the higher dipole moment of triazole (∼5.0 D) than amide (∼3.8 D) creates the basis for inert triazole linkages to act as a hydrogen donor and

reactions, where starting materials may be unstable under harsh reaction conditions (high temperature), consequently expanding the wide applications of click chemistry. Stefani et al. developed an effective US-supported protocol for the development of functionalized C-glycosyltriazoles 23 by reacting trimethylsilyl (TMS)-protected C-alkyne glycoside 22 with organic azides (Scheme 7).131 It was reported that the click reaction, accelerated by US irradiation, resulted in an increased yield (∼1.6-fold). The C-glycoside analogues are resistant to metabolic processes. In addition to their importance in medicinal chemistry, they have also been utilized as building blocks for the enantioselective synthesis of chiral compounds. 3093


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Recently, Jung et al. reported a flow procedure, utilizing a glass microchip (GMC) reactor functionalized with β-cyclodextrin, for the Cu-catalyzed clicking of terminal alkynes with aromatic azides to afford a high yield of the desired triazoles within a few minutes. Interestingly, the GMC surface was found to remain stable and could be further used for a number of cycles without loss of efficiency.143

The increased interest in performing reactions in aqueous media is due to the merits of water usage such as nontoxicity, safety, and above all having no cost at all.132 Click reactions tolerate a variety of solvents, including water. The click reactions which utilize metallic copper are preferably carried out in polar solvents, including THF, DMF, water, and/or aqueous alcohol (preferably a mixture of tert-butyl alcohol and water). Catalytic systems composed of Cu(0) and Cu(II) are even more useful for aqueous medium clicking in living systems. Since water is the recommended maximum support to distinguish the competing reactivities of “hard” (nonpolarizable) and “soft” (polarizable) species, numerous click reactions have frequently occurred superior in water than any other solvent. RTILs, in the presence of CuI and DIPEA, are also known to support the clicking of organic azides and glycosylalkynes to generate the triazolyl glycoconjugates. Since RTILs are superior solvents for the metal-catalyzed organic transformation, their function is beneficial, particularly where the click substrates have a solubility problem.133 Recently, Keshavarz et al. reported ([Cu(Im12)2]CuCl2-mediated clicking of organic azides and terminal alkynes in the presence of ILs such as [bmim]BF4 as green catalytic media. Starting from α-haloketones, a similar catalytic system was utilized to furnish a high yield of the desired triazoles. This catalytic system could be recycled five times without loss of its catalytic activity.134 With great motivation through light-induced reactions such as photosynthesis, chemists have applied the light-induced click reaction135 with varying exposure time, wavelength, and intensity to control the click reactions spatially and temporally.136,137 Tasdelen et al. reported the click reaction between benzylazide and simple alkynes in the presence of light as the activating agent (under irradiation at 350 nm) in the absence of a reducing agent.138 Sodium ascorbate, one of the most common reducing agents used in click chemistry, may react with protein side chains and lead to degradation of DNA. Therefore, performing such reactions in the absence of reducing agents allows this limitation to be overcome especially for bioconjugation applications, labeling of living organisms, carbohydrate microarrays, etc. The labeling of DNA, proteins, and glycans, both in vitro and within living cells, is now well established by click chemistry.139 The solid-supported click methodology is advantageous as the method is robust and insensitive to different conditions and permits the use of polar or nonpolar resin, solvents (THF, DMF, CH3CN), and catalysts (Cu(I) and in situ reduced Cu(II) salts).15 However, the possibility of homocoupling is still a practical inconvenience.140 The click protocol is now routinely applied on solid supports for different applications ranging from chemical biology to catalysis.141 The flow chemistry technique performs a chemical reaction in a continuously flowing stream in a network of interconnecting tubes. The reagents coming from different tubes are mixed together in the reactor to start the chemical reaction. The method is even more advantageous than the macroscopic batch reactor method, mainly due to the high surface/volume ratio, reduced utilization of reagents, and also better control over mass as well as heat transfer.58 Kappe et al. investigated the CuAAC reaction by ICP-MS analysis in the continuous flow mode. Employing a variety of copper metal sources as heterogeneous catalysts, including Cu/C, the authors scrutinized the outcome of copper leaching from the catalyst over the reaction time and also the composition of the reaction mixture. These studies established a “homogeneous” mechanism and suggested Cu2O as the active species in click chemistry involving copper.142

2.5. Azides and Alkyne Substrates: Benefit for Carbohydrates

The stereoelectronic effects of the substituents significantly influence the rate of reaction, but the Cu(I)-catalyzed click reaction is reasonably general with a wide array of terminal alkynes and organic azides.20 Matyjaszewski and co-workers presented the influence of the electronic and steric effects on the rate of the organic reaction. The authors conclusively reported that the azides which have electron-withdrawing substituents and also less steric congestion showed a faster reaction.144 The αcarbonylalkynes are more reactive than the alkylated alkynes, although the aromatic alkynes are similarly or marginally less reactive. The solubility of the reactants involved in the cycloaddition reaction is also considered a key requirement for a successful CuAAC reaction.145 The alkynes directly substituted on heteroatoms cause some unstability, mainly toward hydrolysis, but they do react with azides to afford triazoles under suitable reaction conditions. With increasing size of the alkyne and azide substrates, the extent of conversion has been noticed to decrease and was less than optimum.146 Several researchers have confirmed a significant rate enhancement in the formation of triazole as the click product, when azides are held in close proximity,147−149 even after being linked together on other molecular assemblies, including polymers,146 dendrimers, calixarenes,147 or other related scaffolds. In contrast, the rate enhancement effect is not that prominent if the alkynes are grouped together on a scaffold. Even with a high density of a particular alkyne when treated with the appropriate azide, a suppression of triazole formation was noticed.26 The presence of alkyne clusters on a scaffold possibly will saturate the coordination sphere of the catalytic Cu(I) complex. Bock et al. remarkably studied this effect from the mechanistic point of view and reported an outline of various methods of catalyst generation, solvent as well as substrate effects, and also choice of additives, bases, or ligands used in the click-inspired cycloaddition reactions.61 Iodoalkynes are sufficiently stable and were found to be even more reactive than terminal alkynes in the click reaction mediated by CuI in the presence of TBTA or TTTA. Also, the 5-iodo-substituted triazoles are amenable for their further interesting functionalizations of pharmaceutical importance.150 Despite the very high synthetic credentials of azides, their use is often limited, mainly because of their hazardous nature (particularly for the azides having a low molecular weight or especially those with multiazide functionalities) and often found dangerous to handle during scale-up in industry. In contrast, the glycosyl azides are in general extremely stable, and are also found inert toward a wide range of reaction conditions. Their use is ever increasing due to easy accessibility in corresponding diastereomerically pure form monosaccharides. The anomeric position is generally preferred for introduction of the connecting clickable azide group and also alkyne functionality, but the rest of the sugar ring positions are also used with a great ease through plenty of well-established high-yielding protection−deprotection synthetic steps.151 Hence, incorporation of an alkyne or azide 3094


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group into carbohydrates actually opens new doors for facile and successful construction of a wide range of well-defined molecular frameworks ranging from mono- to di- to polyfunctionalized derivatives that can be rationally used for the conjugation with other complementary functionalized scaffolds by means of their high-yielding intermolecular clicking protocol under mild reaction conditions.59 The glycosyl azides 25 are generally prepared by the reaction of glycosyl halides 24 with NaN3 in the

Scheme 10. Inversion of Configuration in Sugars by Introduction of an Azido Group

of glucoside 29 using NaN3 in DMF at elevated temperature (Scheme 10).161

Scheme 8. Synthesis of Glycosyl Azides 25 via SN2 Reaction

Scheme 11. Regio- and Stereoselective Epoxide Ring Opening in Compound 31

The reaction of sugar epoxides with NaN3, using DMF/H2O as the solvent system under heating conditions, causes opening of the epoxide ring via nucleophilic attack of azide ions, leading to the formation of diaxial products. This protocol provides another interesting methodology for generation of an azido group on carbohydrates.162 For example, 2-azido sugar 32 was prepared regioselectively from epoxide 31 by reaction with NaN3 (Scheme 11).163 The radical addition to glycals is also an interesting methodology for introduction of azides to carbohydrates. Lemieux et al. employed a classical azidonitration method for synthesis of 2-azido sugars, especially those which may serve as precursors to glycosamines but are inaccessible from nature.164 However, despite the high regioselectivity of this reaction, a mixture of epimers 34 and 35 was observed in varying ratios based on the employed glycal substrate 33 (Scheme 12).165 The prepared nitropyranoses 34 and 35 may find significance in preparation of numerous carbohydrate-based halides, thioglycosides, etc.166−170 Likewise, 2-azido sugars can also be prepared by azidochlorination,171 azidophenylselenation,172,173 and diazo transfer reaction.174 Apart from direct incorporation of an azido group, the diazo transfer reaction using triflyl azide involves the conversion of a N2 moiety to amine with retention of configuration. Vasella et al. used amino sugars for establishing diazo transfer,175 wherein the unprotected glycosamine 36 was treated with triflyl azide in the presence of a strong base, followed by acetylation to afford azido sugar 37 (Scheme 13). As a further expansion, CuSO4 was used as a catalyst, which furnished products reliably in a reduced reaction time.176,177 There are several reports regarding the significance of diazo transfer as a protecting strategy for amines.178−182 Azides, which can be structurally similar to diazoamines,151,183 were easily achieved using diazo transfer reaction from the corresponding amines. However, straightforward entry of an azide at the β-position of an α,β-unsaturated olefinic ester is not always easy. Quite a few conventional approaches for this purpose were not fruitful for several reasons, including harsh reaction conditions, elongated duration, and poor yields.184−186 Recently, we developed a one-pot synthetic protocol for an easy access of glycosyl β-azido ester from the corresponding α,βunsaturated olefinic ester utilizing diazo transfer reaction as the

presence of DMF as the reaction medium.152 However, synthesis of 25 under this condition requires substantial heat for the reaction to occur;153 therefore, phase-transfer catalysts are used to facilitate the reaction under milder conditions.154,155 A straightforward method that avoids the use of 24 for synthesis of clickable azides 25 involves the treatment of acetylated sugars with (TMS)N3 in the presence of SnCl4 at room temperature for 24 h (Scheme 8).156,157 Furthermore, 1,2-trans-azido sugars can be readily prepared from 1,2-cis-glycosyl halides, and vice versa, by reaction with NaN3 wherein the azide ion attacks as a nucleophile to facilitate an SN2 reaction.158,159 The functionalization of sugars with an azide substituent at the primary carbon was carried out readily via attaching a good Scheme 9. Azido Functionalization of Sugar Regioselectively at the Primary Carbon To Give 28

leaving group such as tosyl, mesyl, triflate, halides, and other similar groups. The protecting reagents, such as tosyl chloride (TsCl), selectively attack the hydroxyl group at the primary carbon, thus leaving secondary hydroxyl groups unaffected. For example, GlcNAc derivative 28 was prepared in good yields by conversion of compound 27 into a sulfonate derivative followed by subsequent SN2 reaction with sodium azide at elevated temperature (Scheme 9).160 The stereochemistry plays a crucial role in determining the reaction fate under SN2 reaction being carried out at a secondary carbon in carbohydrates. The neighboring substituents and groups, as well as the anomeric configuration of the sugar molecule, play a dynamic role in a successful outcome as evident from the example of synthesis of 4-azido galactoside 30 by SN2 displacement of the mesyl group (which results in inversion of configuration of the corresponding product) from the mesylate 3095


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Scheme 12. Regioselective Azidonitration of Glycal 33

cytidine 5′-monophosphate) leads to glycosyl donor 43, which is at last transferred to a wide range of appropriate acceptors 44 by using a suitable sialyl transferase (ST); for example, α-2,3- or α2,6-sialyl transferase leads to the formation of well-defined sialosides containing natural and non-natural functionalities, respectively, with the desired α-2,3 (45) or α-2,6 (46) linkages. The three-enzyme coupled synthesis of sialosides was successfully carried out in one pot without the necessity for the isolation of intermediates (Scheme 16).192 In a similar fashion, 5-azidomodified hexoses could successfully result in the corresponding 8-azidosialic acids of the desired Neisseria meningitidis α-2,3-ST or Photobacterium damsela α-2,6-ST sialyl trisaccharides, for example, Neu5Ac8N3 and other related azidosialosides useful for the click purpose.193 Recently, the same group extended the investigation and established a well-organized two-step multi-enzyme protocol for the synthesis of a series of GD3 ganglioside oligosaccharides and other interesting disialyl glycans of great chemotherapeutic potential.194 The truncated CstII mutant exhibits α-2,8-sialidase activity, catalyzes specific cleavage of the α-2,8-sialyl linkage of GD3-type oligosaccharides, and transfers a sialic acid from the GD3 oligosaccharide to a different GM3 oligosaccharide. Using the one-pot three-enzyme approach, α-2,3- or α-2,6-linked monosialylated oligosaccharides 45 or 46 were first synthesized and then used as acceptors for the α-2,8-sialyltransferase activity to produce oligosaccharides having two sialyl units, 47 (Scheme 17).194 Both the strategies were explored for different applications, which helps in the understanding of the biological significance of variable sialic acid residues on disialyl structures present in nature.195 Also, there is a great scope to click the constructed sialoside having an azide functionality with different sugars, peptides, lipids, and other alkynes using high-yielding Cucatalyzed click chemistry. In addition to these methods described for the introduction of an azide functionality onto a specific position of a carbohydrate for click chemistry, there are several protocols reported for the introduction of a terminal alkyne functionality in a wide range of organic scaffolds. The methods include the Pd-catalyzed Sonogashira reaction between a halogenated alkene of a 1,3conjugated system and a (trimethylsilyl)alkyne, Lewis acidmediated nucleophilic ring opening of an oxetane ring by trimethylsilane-linked acetylene, and peptide coupling between

Scheme 13. Synthesis of Azido Sugar 37 via Diazo Transfer in the Presence of CuSO4

key step under mild reaction conditions.187 The glycosyl β-amino ester, obtained by 1,4-conjugate addition of NH3 onto the glycosyl olefinic ester 38, on metal-catalyzed diazo transfer reaction, afforded the desired glycosyl azide 40 (Scheme 14).187 The best suitable conditions for the metal-catalyzed diazo transfer reaction are those in which the combination of imidazolyl-1-sulfonyl azide (39), K2CO3, and ZnCl2 afforded a high reaction yield with great ease. The structures of both the resulting diastereomeric azido esters (40a and 40b) were elucidated using single-crystal X-ray diffraction analysis. The authors presented a detailed mechanism of the metalcatalyzed diazo transfer reaction. Formation of a dianionic tetrazene intermediate was suggested during the reaction. The nucleophilic attack of amine complex A on the electrophilic imidazolyl-1-sulfonyl azide 39 followed by deprotonation resulted in Zn-stabilized mixed tetrazene intermediate B, which goes through cleavage possibly via retro 1,3-dipolar cycloaddition and thus affords clickable glycosyl β-azido ester in high yields (Scheme 15).187 Direct azidation at the specific position of sialic acid derivatives is not convenient like that of other five- or six-carbon sugars. Chemoenzymatic synthesis is a powerful approach to obtain a library of the complex sialic acid-containing carbohydrates. The one-pot three-enzyme chemoenzymatic protocol is considered to be the best choice to obtain a library of sialosides with the desired α-2,3 (45) or α-2,6 (46) linkages. The method is highly useful for the synthesis of sialic acid-containing complex structures, including the natural and non-natural sialic acid forms, through α-2,3- or α-2,6-sialyl linkages, and also diverse glycans that link to the sialic acid.188,189 In the first step, the reversible aldol cleavage of Neu5Ac or its derivative (42) to form pyruvate and ManNAc (41) is catalyzed by sialic acid aldolases/ N-acetylneuraminate lyases (NanAs).190,191 Then the subsequent activation by a CMP-sialic acid synthetase (CMP =

Scheme 14. Transformation of Olefinic Ester 38 to Glycosylated β-Azido Ester 40 under One-Pot Conditions

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Scheme 15. Diazo Transfer Reaction of Glycosylamine Using ImSO2N3a

a

Im = imidazolyl.

with hazardous glycosylation and also peptide coupling reagents. Moreover, purification is simple as in many cases column chromatography is not compulsory and pure product can be obtained merely by either precipitation or liquid−liquid extraction.90 Carbohydrates are the most abundant class of biomolecules; their importance can be viewed in terms of their crucial role in acting as structural building blocks of genetic materials in addition to serving as a vital source of energy.196 They play key roles in many cellular and intracellular interactions in the form of signaling molecules, cell surface receptors, and bacterial adhesives.197,198 Synthetic chemists are compelled to design facile ways to synthesize diverse glycoconjugates on account of their ability to act as pharmaceutical and diagnostic agents.199 The immense structural diversity in terms of functional groups, linkages, and numbers of rings makes them assets for the design and development of biologically active glycoconjugates. Besides being biologically active, carbohydrate-based entities also serve as valuable tools for development of molecular scaffolds based on their thorough chemical and biological investigations.200 Carbohydrate moieties are boon to any system because they impart crucial properties such as hydrophilicity, minimum toxicity, and optimum pharmacokinetics to the systems.196−201 Also, ready availability, high functional diversity, and the presence of several stereogenic centers and other fascinating structural aspects of the carbohydrate moiety make it a potent scaffold for chiral synthesis. A number of stereospecific transformations can be achieved by carbohydrate-based chiral molecules acting as chiral auxiliaries, chiral ligands, or asymmetric organocatalysts. The attuned character of click chemistry with carbohydrates has compelled researchers to exploit this protocol in the synthesis of interesting pharmacologically active sugar-based molecules ranging from simple to complex architectures, including diverse neoglycoconjugates, neoglycopolymers, and glycodendrimers. The versatility of the strategy allows the preparation of a wide variety of glycostructures that are not limited by the structural requirements of the target structures but

Scheme 16. One-Pot Three-Enzyme-Mediated Highly Expedient Synthesis of α-2,3-Linked Sialosides 45 and α-2,6Linked Sialosides 46

propargylamine and carboxylic acids, via the Bestmann reaction and also using nucleophilic displacement processes.15 Although these methods are applicable to introduce an alkyne functionality into the desired scaffolds, simple porpargylation of an orthogonally protected sugar using porpargyl bromide in basic conditions is exceedingly investigated in carbohydrate chemistry for Cu-catalyzed click purposes. The Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction utilizes low-cost and relatively less toxic solvents, thus alleviating the necessity of using expensive along

Scheme 17. Chemoenzymatic Protocol for Easy Access of GD3 Oligosaccharides Having an Azido Group for Click Purposes

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through filtration.204 In another example, (PPh3)3·CuBr was used instead of the CuSO4/ascorbic acid system to afford a trisaccharide carbohybrid, 52, with a 1,2,3-triazole linkage by clicking the azide 50 with bisalkyne 51 (Scheme 18).205 An expedient and high-yielding synthesis of triazole-linked glycopeptides from protected building blocks was reported by Rutjes and co-workers in 2004.206 A series of stable glycopeptides with both α- and β-triazole linkages (56) were efficiently prepared by clicking mono/disaccharide azides 53 with mono/ dipeptide alkynes 54 catalyzed by Cu(OAc)2/NaAsc in a water− tert-butyl alcohol system.206 In a reverse manner, mono/ disaccharide alkynes 56 were clicked in the same fashion with mono/dipeptide azides 57 to develop another series of glycopeptides (58) (Scheme 19).207 The authors further extended the work by application in the synthesis of glycosylated cyclic arginine−glycine−aspartate derivatives with a triazole linker. The linker c(RGDy-NTGA) was found to selectively target αvβ3 integrin.207 Tiwari and co-workers reported a high-yielding synthesis of numerous triazole-linked ethisterone glycoconjugates (61a−j) via CuAAC reaction of azido sugars with ethisterone (60), a 17αethynyl analogue of testosterone.208 The tactic involved the synthesis of 5-azido-3-O-benzyl-5-deoxy-1,2-O-isopropylideneα-D-xylofuranose (59a) readily prepared from D-xylose via consecutive steps of selective protection, O-tosylation, and

mainly by the creativity of the researchers, which is specifically discussed in the next section.

3. CLICK-CHEMISTRY-INSPIRED SYNTHESIS OF DIVERSE TRIAZOLYL GLYCOCONJUGATES The coupling of two molecular components with distinct properties to generate a new conjugate with collective properties of the parent entities has emerged as a rising technology in recent years.202,203 Numerous novel conjugates arising through such conjugation have been found to display unusual biological activities and other distinct properties as the dissimilar molecular segments act together. In this perspective, the Cu(I)-catalyzed azide−alkyne 1,3-dipolar cycloaddition (“click chemistry”) is a new, practically simple, and very reliable fast-growing approach for the development of pharmaceutically important drug-like molecules that can accelerate the drug discovery research for human use. Scheme 18. Clicking of a Glycosyl Azide with a Glycosylalkyne To Provide Regioselective 1,4-Disubstituted Triazolyl Glycoconjugates

Scheme 20. Synthesis of Ethisterone Glycoconjugate 61a via Cu-Catalyzed Click Chemistry

reaction with NaN3 in dry DMF at 80 °C under anhydrous conditions. Thus, clicking of an azido sugar (59a−j) with ethisterone (60), a naturally occurring steroid alkyne, in the presence of CuI and DIPEA in anhydrous dichloromethane afforded regioselectively 1-(3-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-D-xylofuranos-5-yl)-4-ethisterone-1,2,3-triazole (61a) in 90% yield. Following the established CuAAC reaction methodology, the authors successfully prepared a library of triazolylethisterone glycoconjugates (61a−j) by reaction of a

1-Azido-1-deoxy-2,3,4,6-tetra-O-acetyl-β- D-glucopyranose (25b), on treatment with 6-propargyl-1,2:3,4-di-O-ispropylidene-α-D-galactopyranose (48) in the presence of CuSO4/ ascorbic acid in water gives triazole-linked disaccharide analogue 49. The advantage of this reaction is that the resulting disaccharide can be easily isolated from the reaction mass simply

Scheme 19. Synthetic Strategy for Triazole-Linked Glycopeptides by Clicking Either a Sugar Azide with a Peptide Alkyne or a Sugar Alkyne with a Peptide Azide

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Figure 7. Structures of the other developed ethisterone glycoconjugates (61b−j) via click chemistry.

wide range of azido sugars with ethisterone (Scheme 20, Figure

The Tiwari group, further considering the importance of ethisterone, which is well identified to compete for androgen receptor (AR) binding and suppress the levels of AR transcriptional activation relative to dihydrotestosterone,209 reported the high-yielding synthesis of bis(triazolyl)ethisterone glycoconjugates 64a−i by means of a similar methodology from triazolyl azido alcohols 63a−i, obtained from the corresponding glycosylalkynes 62a−i using CuAAC (Scheme 21). The developed compounds are supposed to have applications in AR pharmacology and chemical biology.210 In addition, we considered the importance of the triazole− morpholine skeleton due to the associated enzyme inhibitory activities, such as those of glycosidase, galactosidase, sodium/ glucose cotransporter 2 (SGLT2), γ-secretase modulators, etc. 211,212 We have described a two-step protocol for straightforward access to a diverse range of morpholine-fused [5,1-c]triazoles from terminal sugar-based alkynes.213 The strategy involved the synthesis of triazolyl azido alcohols 63 from glycosylalkynes 62 via oxirane ring opening of epichlorohydrin followed by subsequent clicking with terminal alkynes. Then the subsequent azidation of chloro hydroxy triazoles under a one-pot methodology afforded the title compound. Epichlorohydrin is recognized as a valuable synthon in organic synthesis;214 however, we could not utilize the enantiomerically pure form of epichlorohydrin (R- or S-form) in our investigation. During the investigation, we noticed that bis(triazolyl) glycoconjugates 64 were obtained as side products in minor yields along with the desired azido hydroxyl triazoles 63. The developed 1-azido 2-hydroxyl triazoles 63 were further successfully utilized for the synthesis of morpholine-fused [5,1c]triazoles 65 in good yields ranging from 45% to 90% via Opropargylation using NaH in dry DMF at ambient temperature for 6−10 h, followed by metal-free intramolecular cyclization of

7). The yields of the click products were also evaluated under microwave irradiation where significant reduction of reaction time was observed in comparison to the reaction accomplished at room temperature. Scheme 21. Synthesis of Bis(triazolyl)ethistirone Glycoconjugates

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Scheme 22. Synthesis of Morpholine-Fused Triazolyl Glycoconjugates213

Table 1. Synthesis of Sugar-Based Terminal Alkynes 62a−h, Triazolyl Azido Alcohols 63a−h, and Morpholine-Fused Triazoles 65a−h213

a Conditions for one-pot synthesis of azido alcohols: glycosylalkynes, epichlorohydrin, NaN3 (1:2:4), CuSO4/NaAsc, at rt. bIsolated yield of triazolyl azido alcohols. cIsolated yield of sugar-based morpholine-fused triazoles by column chromatography (SiO2).

the intermediate azido alkynes in DMF at 100 °C for 2−4 h (Scheme 22).213 The structures of the reported triazolyl glycoconjugates are depicted in Table 1. The effects of the variants (alkynes) and weak interactions on the structural conformation of the developed compounds have also been investigated. These compounds, endowed with a triazolomorpholine scaffold,

could be potential antitumor agents, similar to other analogues recently reported in the literature;211,212 however, no similar biological data associated with morpholine-fused triazoles 65a−h have been reported to date. Alkaloids are the most potent and pharmaceutically interesting scaffolds that contribute a critical role in modern drug discovery and development.215 Noscapine, a phthaisoquinoline alkaloid, 3100


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Scheme 23. Synthesis of Noscapine Triazolyl Glycoconjugates 67 and 68217

Figure 8. Developed noscapine glycoconjugates.217

by propargylation of the parent noscapine, was reacted with various glycosyl azides 59 and azido alcohols 63 under click conditions (Scheme 23).217 We have developed a library of second-generation noscapine glycoconjugates 67 and 68 at the C-7 position of noscapine (Figure 8). Selective demethyaltion of noscapine following by its porpagylation and subsequent clicking separately with glycosyl azides 59 and glycosyl azido alcohols 63 is easy to carry out, and triazolyl glycoconjugates 67 and 68 were obtained in good to excellent yields.217 Although the role of weak interactions has

has been used as an antitussive agent since long back, and available reports suggest that the 7-hydroxyl compound and 7-Oalkylated derivatives have been found to be 100-fold more effective than noscapine.216 Thus, considering the multivalent nature of carbohydrates, which is often used to enhance the affinities of targets in diverse biological events, we recently developed the click-chemistry-inspired noscapine glycoconjugates to increase the therapeutic efficacy. The second-generation (C-7) noscapine analogue 66, having an alkyne functionality, obtained by selective demethylation using NaN3/NaI followed 3101


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Scheme 24. Click-Inspired Synthesis of C-5-Substituted Triazolylglucofuranose Derivatives187

Scheme 25. One-Pot Synthesis of a Divalent Glycoconjugate223

introduce an azido group at the β-position (C-5) of a glycosyl olefinic ester. Conjugate addition of ammonia to the olefinic ester followed by diazo transfer reaction led to the successful formation of the corresponding azido ester 40 in a one-pot fashion. Routine clicking of the resulting glycosyl β-azido esters 40a and 40b with different glycosylalkynes under catalysis of CuI/DIPEA in anhydrous dichloromethane or CuSO4/NaAsc in water afforded high yields of targated triazolyl glycoconjugates 69 and 70. A similar click reaction under MW irradiation was also carried out to afford the desired glycoconjugates (21 examples) in a short reaction time in high to excellent yield (Scheme 24).187 The Wittman group reported a one-pot reaction for Cu(II)catalyzed diazo transfer and Cu(I)-catalyzed azide−alkyne 1,3-

been correlated, no biological activity has been reported for these noscapine analogues. The methodology may be considered as efficient to prepare the modified noscapine conjugates to improve the chemotherapeutic efficacy and pharmacological activities. A series of glucofuranosides with C-5 amide functionalities were devevelped, and many of their library members are known to display significant biological activities, including antitubercular, antifungal, antifilarial, antimalarial, and α-glucosidase inhibitory activity.218−222 Attachment of a triazole skeleton at the C-5 position of monosaccharides and their derivatives is relatively well applicable, since triazoles are considered as the bioisosteres of peptides. For this purpose, it is necessary to 3102


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handling the carbohydrate scaffold or the limited number of scientists working in related fields. Mukherjee et al. utilized the one-pot multicomponent reaction for the development of biologically relevant furan-based glycoconjugates. One-pot three-component transformation of D-glucal to the corresponding furan-based hydroxy triazoles 82 has been accomplished through the sequential addition of reagents in the presence of Cu(OTf)2 and Cu powder as a suitable catalyst (Scheme 28).229 The authors claimed a high diastereomeric purity of glycoconjugates obtained by multicomponent cascade transformation of D-glucal. Sen et al. recently reported a useful one-pot strategy to generate a library of triazolyl N-carboxamides 84 using basic alumina as a solid support (Scheme 29).230 The method excludes the necessity of solvents, ligands, and bases, and thus would be interesting for pharmaceutical and industrial research. Also, a series of biologically significant unsymmetrical bis(1,2,3triazole)s were achieved by extending the protocol via a consecutive domino click reaction.231 The Dondoni group successfully attempted to introduce an azido group at the C-40 position of rapamycin, which was further used to synthesize a library of triazole-bridged rapamycin glycoconjugates (86a−l) by CuAAC reaction of the resulting azidorapamycin (85) with several propargylated O- and Sglycosides as well a C-ethynyl derivative (Scheme 30).232 Bera and co-workers used Cu-catalyzed click coupling for the synthesis of several disaccharide to oligosaccharide molecules with potential applications in chemical biology. Representative examples may include the click-inspired synthesis of disaccharide derivatives, including heparosan (87a) and chondroitin (87b), and also tetrasaccharides 88a and 88b having a triazole unit well utilized as an interglycosidic bridge (Figure 10).233 These unnatural, but very interesting, carbohydrate-based molecules, e.g., disaccharides and tetrasaccharides, were easily obtained in appreciable yields by clicking of an azidoglucuronic acid with propargylated GluNAc and propargylated GalNAc, respectively, under click reaction conditions. The clicking strategy may be extensively utilized for the construction of higher order oligosaccharides of potential interest. In addition, the Cu-catalyzed click reaction has delivered numerous interesting and important carbohydrate-based triazoles with medicinal and pharmacological applications. Some examples include glycoconjugates 89 (formed by CuAAC of lactosyl azide with N-Boc-protected propargylamine),234 90 (obtained by clicking ethyl 4-azido-6-O-acetoxy-2,3,4-trideoxyα- D -erythro-hex-2-enylpyranoside with 1,4-diethynylbenzene),235 91 (afforded by CuAAC of a galactose-derived azide and bromoalkyne amino acid),236 and 92 (formed by click reaction of a mannose-derived azide with propiolic acid).237 Glycoconjugates 89 and 92 have proven their activity as inhibitors of galectin and Leishmania, respectively (Figure 11). A pentadecasaccharide mimic containing two parallel maltoheptaosyl chains linked to a glucose core through a [1,2,3]triazole linkage was developed by Field et al. via the click reaction (Scheme 31). Cu(I)-catalyzed cycloaddition of azidosaccharide 93 and 4,6-di-O-propargylated methyl α-Dglucopyranoside using CuSO4/NaAsc as the Cu(I) source in water at 70 °C for 2 h afforded branched oligosaccharide mimic 94 in 89% yield.238 The click-inspired coupling of α-tocopherol azide 95 with glycosylalkynes was recently reported. The resulting triazolyl glycoconjugates of α-tocopherol (96) are stable and are found to have radical-scavenging activities comparable to those of α-

dipolar cycloaddition, where 1,4-disubstituted triazoles were obtained in excellent yields from a variety of readily available amines without the need for isolation of the azide intermediates. Reaction of diamine 71 with glycosylalkyne 72 in the presence of TfN3, CuSO4, and NaHCO3 at room temperature (rt) for 30 min followed by addition of NaAsc and TBTA (5a) under MWinduced click conditions at 80 °C for 20 min afforded triazolyl glycoconjugate 73 in 86% yield (Scheme 25).223 Molecules containing multiple azides are known to be comparatively unstable; thus, this reaction undoubtedly has a broad scope and could be useful to generate multivalent sugar-based structures. Scheme 26. Synthesis of Triazole-Linked Divalent Glycoamino Acid Mimics224

Sahoo et al. investigated the synthesis of triazole-linked divalent glycoconjugates which on selective deprotection and transformation of the nitro and cyano groups to α- or β-amines, respectively, can be incorporated in peptide synthesis to furnish unique divalent glycopeptide mimics with potential biological applications. The methodology involved the click reaction of alkyne-functionalized divalent building blocks 74a−c with perO-acetylated glycosyl azides or azidoacetamide to synthesize a diverse range of triazole-linked divalent glycoconjugates 75 (Scheme 26, Figure 9).224 Likewise, Mukherjee et al. synthesized C-spiro morpholinefused triazole-based glycoconjugates by modifying the C-spiro cyclopentenyl sugar.225 The authors first carried out allylation of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (76) under Barbier conditions to afford the C,C-diallyl sugar using Zn powder, allyl bromide, and (TMS)Cl in a molar ratio of 6:4:0.3. Compound 77 was subjected to intramolecular cyclization through ring-closing methathesis in the presence of the second-generation Grubbs catalyst and afforded a good yield of the desired C-spiro cyclopentenyl sugar derivative 78. The epoxidation of compound 78 by treatment with m-chloroperoxybenzoic acid (mCPBA) gave a β-epoxide, 79, which on further reaction with NaN3/ NH4Cl furnished azido alcohol 80 (in a 1:1 mixture). Compound 80 was then propargylated first using propargyl bromide, and the resulting azido alkyne thus obtained on treatment with CuI proceeded via intramolecular azide−alkyne cycloaddion reaction and afforded an 87% yield of the desired triazole-fused glycoconjugate 81 an an inseparable mixture of compounds 81a and 81b (Scheme 27).225 In addition to the straightforward Cu-catalyzed azide−alkyne click chemistry, several multicomponent condensation-based click reactions are also known under one-pot mild conditions.226−228 Surprisingly, out of these, very few are known in carbohydrate chemistry, probably due to the difficulty in 3103


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Figure 9. Developed triazole-linked divalent glycoamino acid mimics.

Scheme 27. Synthesis of C-Spiro Morpholine-Fused Triazolyl Glycoconjugate225

tocopherol with enhanced water solubility.239 Surprisingly, a

The synthesis of various pseudo-oligosaccharides and a series of amino acid-based glycoconjugates was achieved by utilizing accessible amino acid- and sugar-derived azide and alkyne building blocks.240 Ermolatev et al. nicely utilized 3-ethynyl2(1H)-pyrazinones for clicking with different glycosyl azides to

similar reaction of α-tocopherol alkyne 97 with a sugar azide affords air-sensitive and unstable glycoconjugate 98 under normal conditions (Scheme 32). 3104


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Scheme 28. Click-Inspired Cascade for Furan-Appended Triazolyl Glycoconjugate 82 from D-Glucal229

Scheme 29. Multicomponent Synthesis of Triazolyl N-Carboxamides 84230

carbohydrate interaction probably through the electrochemical biosensing techniques.245,246 The construction of the assembly of a densely decorated carbohydrate-containing scaffold is considered to have significant use for different purposes, mainly in supramolecular chemistry as the supramolecular interaction of triazole has been widely explored in recent years.247,248 Dondoni and Marra investigated click chemistry for the synthesis of triazole glycoclusters 102 with four triazoles having C-linked carbohydrate residues on a variety of scaffolds through clicking of suitably polyfunctionalized adamantane and arenes with ethynyl and azidomethyl Cglycosides by reaction with each other in the presence of CuI and DIPEA in anhydrous toluene at 80 °C for 18 h (Scheme 34).249 Debenzylation or deacetylation from the final polyfunctionalized glycoconjugates 102a and 102b was done satisfactorily to afford the scaffold 102c under well-established reaction conditions. Each click-inspired cycloaddition proceeds with an appreciable yield (up to 98%) and exclusively gives the desired 1,4-disubstituted triazoles. Considering the wide application of the calix[4]arene glycocluster,250 the highly efficient click protocol was successfully utilized to constitute a general way for an easy attachment of various carbohydrate units to the polyfunctionalized calixarane substrate, which is described in a separate section of this review.

afford a series of glycohybrid peptidomimetics containing triazole and pyrazinone heterocyclic skeletons, known to possess interesting pharmacological activities.241 Das et al. developed coumarin-based triazolyl glycoconjugates utilizing 3(azidomethyl)coumarin and sugar-based terminal acetylenic compounds via the Cu(I)-catalyzed click reaction. The authors calculated the geometry as well as frequency features of the reactants involved in the reaction, transition states, and products formed by utilizing the B3LYP/6-31G(d) level of theory. Also, 1,4-disubstituted triazoles were considered as thermodynamically more stable than the 1,5-triazoles, as evidenced through further computational investigation.242,243 Ferrocenyl glycoconjugates obtained with the aid of click chemistry have been recognized as interesting systems for electrochemical study.244 Thus, the easily accessible 1(azidomethyl)ferrocene and 1-ethynylferrocene on clicking with propargyl or 2-azidoethyl glycoside followed by the usual O-deprotection afforded the corresponding soluble metallocene conjugates 99 and 100 having promising binding sites for application in molecular recognition (Scheme 33). Although no biological data are available for the ferrocene glycoconjugates, their electrochemical behavior reveals that they exhibit reversible oxidation−reduction of the Fe2+ center.244 Also, the ferrocenyl glycoconjugate could be useful for the study of protein− 3105


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Scheme 30. Synthesis of Triazole-Bridged Rapamycin Glycoconjugates232

Figure 10. Structures of heparosan, chondroitin, and tetrasaccharide derivatives.

In another investigation, Ermolat et al. reported a simple and easy synthesis of furo[2,3-b]pyrazine nucleoside analogues 105, where this interesting heterocyclic skeleton was coupled via a 1,2,3-triazole linkage. The synthesis of the 1,2,3-triazole nucleoside was achieved in 91% yield by applying high-yielding

azide−alkyne click chemistry of glycofuranosyl azide 103 with pyrazine-based alkyne 104 under microwave irradiation at 90 °C for 5−10 min (Scheme 35).251 A similar protocol was extensively utilized in nucleic acid chemistry to construct a nucleic acid 3106


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Figure 11. Structures of click-inspired triazolyl glycoconjugate scaffolds.

Scheme 31. Synthesis of a Pentadecasaccharide Mimic Containing Two Parallel Maltoheptaosyl Chains Linked to a Glucose Core through Triazole as the Spacer

Scheme 33. Synthesis of Ferrocenyl Glycoconjugates 99 and 100 via Click Chemistry

modified both at the sugar component and at the nucleosidebased component.15 Scheme 32. Synthesis of an α-Tocopherol-Containing Glycoconjugate Using Triazole as the Linker

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link-spacer-controlled supramolecular chirality which was based on the self-assembly of the perylenebisimide glycoconjugates. A mannose-modified triazole-linked perylenebisimide derivative with triazole as the link spacer (108a) and another one with an amide-linked spacer in the bay position (108b) have been achieved in good yield using click chemistry (Figure 12).253 Interestingly, the conjugates having triazole as the linker exhibited right-handed chirality; however, the corresponding amide bond as the linker showed left-handed chirality in aqueous solution. The difference in their chirality transfer may possibly be due to the additional H-bonds of the concerned amides or could be induced by the dissimilar π−π stacking interactions. The different and opposite supramoloecular chiralities observed in the case of perylenebisimide glycoconjugates with triazole or amide as the link spacer in the bay position have now opened a window to regulate the supramolecular chirality by the groups substituted in the bay position of the perylenebisimide backbones. While planning synthetic schemes for triazolyl glycoconjugates, triazole(s) formation in the reaction sequence should be introduced as late as possible, because it exhibits a high degree of orthogonality with both functional groups and chemical conditions. Moreover, in the synthesis of multiple triazolyl groups in one molecule, the selectivity of the reaction toward terminal alkynes and temporary protection of alkynes with different labile protecting groups, such as a silyl group, play important roles in the subsequent synthesis of different triazole moieties.9 Likewise, the azide may be veiled as a primary amino group which can be easily and selectively converted to the corresponding azide through the well-established diazo transfer reaction. Such properties of the triazole coupling may hold a lot of promise for the sequential one-pot reaction and also for the generation of diverse libraries consisting of complex multipletriazole subunits. Through the above-described examples dealing with click-inspired 1,3-dipolar cycloaddition of azides and alkynes in an intermolecular fashion, it is obvious to conclude that the click protocol is broadly applied for the synthesis of a diverse range of triazolyl glycoconjugates with ample applications. Another class of very interesting carbohydrate-based molecules which includes the macrocyclic glycoconjugates with a triazole moiety as the spacer, obtained either by “intramolecular click” or in alternative intermolecular way, is covered in the next section of this review.

Scheme 34. Multiple Clicking of Polyfunctionalized Adamantane with Sugar Azides

Scheme 35. Click-Inspired Synthesis of Triazole Nucleoside 105

4. CARBOHYDRATE-BASED MACROCYCLES USING TRIAZOLE AS THE SPACER Carbohydrate-derived macrocyclic compounds are of growing interest due to the existence of several stereoisomers, which allows the design and development of a wide range of macrocycles.52,53,254 The multifunctionality of carbohydrates not only provides the possibility of linkage through the different positions of the sugar ring to enlarge the structural diversity, but also allows a modulation of the physicochemical properties (such as solubility, hydrophilic/lipophilic balance, biodisponibility, etc.). The presence of a furanoid or pyranoid cycle imposes geometric constraints, which is highly desirable for the design of conformationally restricted molecular platforms.52,254,255 Additionally, the chiral nature of carbohydrates allows the preparation of chiral cavities, which can be useful in several fields, including host−guest chemistry, chiral recognition, and also asymmetric catalysis. Finally, the synthesis of carbohydrate-derived macrocycles using sugar building blocks such as sugar amino acids (sugars containing both an amino and a carboxylic acid group)

Lindhorst and co-workers explored the synthesis of mono-, di-, and trivalent azobenzene glycoconjugates using click chemistry. The authors evaluated their photochromic properties and nicely demonstrated that azobenzene glycoconjugates 106 and 107 can be switched between two isomeric states (E- and Z-geometry) to change the spatial orientation of the glycoconjugate ligands (Scheme 36). Interestingly, the multivalency effect was noticed in photoisomerization, and the protocol would be applicable for the fabrication of a photoswitchable multivalent glycoassembly for bioevaluation.252 Utilizing amide or triazole as the linker would be an interesting option to address the link-spacer-controlled supramolecular chirality. In this regard, very recently, Wang et al. developed a 3108


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Scheme 36. Azobenzene Glycoconjugates 106 and 107 and Their Photochromic Properties Switched between Two Isomeric States252

Figure 12. Amide vs triazole linker as a possible option for the link-spacer-controlled supramolecular chirality.253

offers the possibility to access a variety of compounds in a

Huisgen’s azide−alkyne cycloaddition reaction has been widely applied for the construction of carbohydrate-containing triazole-fused polycycles,256,257 glycomacrocyles,52,53,258 and also

modular way.255 3109


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Scheme 37. Click-Inspired Synthesis of C-2- and C-3-Symmetric Sugar-Conaining Macrocyles266

cyclodextrin mimetics259,260 because of the appealing chemical behavior of the triazole skeleton. The potential of triazoles to direct the amide linkage, their chemical stability, and their contribution in numerous noncovalant interactions, including hydrogen bonding, dipole−dipole interactions, and π-stacking interactions, eventually lead to applications of the macrocyclic framework not only in powerful pharmacophores but also in drug carrier systems,261,262 molecular reactors, artificial receptors,263 and supramolecular chemistry.264,265 Gin et al. successfully utilized a series of mannosyl-based scaffolds comprised of a suitably substituted anomeric azide and a 4-propargyl ether at the two terminals in mono-, di-, and trisaccharides 109−111 to achieve the desired C-2- and C-3symmetric well-defined macrocycles containing carbohydrates (Scheme 37).266,267 Thus, the starting glycoconjugates having both azide and alkyne functionalities (109−111) on treatment with CuI in the presence of the organic base 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) undergo a cyclo-oligomerization reaction and afford high to excellent yields of the desired C-2- and C-3-symmetric carbohydrate-containing macrocycles 112−114. The macrocycles 112b and 113b are

known to bind with 2,4-hexadiyne-1,6-diol, even though with a small association constant, but not to the aromatic systems. Most likely, for these developed molecules to enter into the cavity, the openings of the cavities must not be too small, which was also supported by computational studies.266 The authors extended the synthesis of oligosaccharide macrocycles based on trisachharide 111. Thus, compound 111 on treatment with CuI and DBU in anhydrous toluene at 50 °C resulted in the formation of cyclodimer 114a (in 80% yield) along with a cyclotrimer (15% yield). Hydrogenolysis of macrocycle 114a and subsequent dialysis to remove the excess salts afforded macrocycle 114b, which has some different structural features as compared with β-CD. Compound 114b originated from mannose containing six sugar units and a twotriazole skeleton, whereas β-CD resulted from seven glucose units. The structure of 114b is presumably less rigid than that of β-CD, since the hydrogen bonding involving the hydroxyl group of the adjacent unit in compound 114b is prohibited by the C-2 stereochemistry of the pyranose sugars. Despite these structural dissimilarities with β-CD, macrocycles 114a and 114b act as hosts to 8-anilino-1-naphthalenesulfonate (ANS), where these 3110


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Scheme 38. Cu(I)-Catalyzed Cyclo-Oligomerization of Azido Alkyne-Functionalized Furanosides268

results blue shift a little; however, a remarkable enhancement in the fluorescence intensity is observed in an aqueous solution of ANS.267 Cyclic oligomerization of the furanose ring was also accomplished by the Cu(I)-catalyzed click protocol, which afforded macrocyclic products of various ring sizes. Various azido alkyne-functionalized furanosides possessing ester, amine, and amide moieties (115a−d) were prepared and subjected to clickinspired cycloaddition to give the desired macrocycles 116a−d comprising both a triazole unit and a carbohydrate residue (Scheme 38).268 Cyclic-peptide-containing macrocycles have been well utilized to generate the assembly of oriented nanotubes.269 By considering the polarity and hydrogen bond ability in the triazole residue, these skeletons are known to be an appropriate mimic of the amide bond. Two different regioisomeric triazoles (117 and 118) surrounded by the cyclic constitution were designed and attained separately through clicking the alkyne and azide functionality of elaborated precursors having cis-βfuranoid-based carbohydrates and β-alanine residues (Figure 13).270,271 As a consequence of the structural variation in packing and self-assembly of the resulting regioisomeric macrocycles 117

Figure 13. Regioselective peptidomimetic macrocycles self-possessed of β-alanines and cis-β-furanoid residues.

and 118, different polarities of the nanotubes resulted, mainly because of their different orientations of the functional groups. These peptidomimetic macrocycles may be used as useful model systems in favor of artificial ion channels, which are further supported by the recent work by the groups of Abell272 and James.273 3111


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cyclic frame. Through the available reports, it is obvious that CuAAC presents a great occasion for the cyclo-oligomerization of glycosides containing an azido alkyne functionality that leads to a high yield of the targeted macrocycles. However, their synthesis is always challenging because bifunctionalized precursors can cyclo-oligomerize and polymerize in several ways. Thus, purification of the desired intermolecular cyclization product is difficult and often results in a poor yield of the products. Synthesis of triazole-fused polycycles via intramolecular cyclization using the click reaction is also tedious because it leads to a sterically more congested 1,4-disubstitued 1,2,3-triazole, which is not the favored product. However, Huisgen’s cyclization may sometimes provide a good yield of the cyclized product due to congestion in the molecule, which would result exclusively in the highly favored 1,5-disubstituted products 121a−o (Figure 14).278 With the aid of the metal-free thermal cycloaddition approach, we recently demonstrated the highly facile synthesis of a structurally varied rare and novel series of C- and O-glycosyl bicyclic ring systems, e.g., sugar-derived morpholine-fused [5,1c]triazoles starting from 1-azido 2-alcohols via an in situ generated azido alkyne.279 Placing a click triazole in amino acid-containing glycohybrid macrocycles presents a tunable flexibility to the resulting scaffold to accomplish variable conformations that are promising chemical receptors. Therefore, considering the significance of the scaffold, amino acids, and carbohydrates, Nilsson et al. explored the click protocol and synthesized a novel and attractive macromolecule, which nowadays is considered a sterically controlled bifunctional skeleton with wide applications.277 The authors prepared methyl 2-amino-6-azido-3,4-di-O-benzoyl-2,6dideoxy-β-D-glucopyranoside and coupled it separately with two individual N-propiolyl dipeptides, such as propiolyl-Tyr-Tyr-OH (122a) and propiolyl-Arg(Mtr)-Tyr-OH (122b), to obtain macrocycle precursor 123. After optimization of the various cyclization methods for azido alkyne-based glycohybrid 123, reaction under catalysis of CuI in the presence of DIPEA in CH3CN was found to be the best one. Thus, the cyclodimerization of azido alkyne 123 using CuI/DIPEA in CH3CN under inert conditions afforded a high yield of C-2-symmetric macrocycle 124 containing two triazole units (Scheme 40).277 Nillson and co-workers further extended their work and developed a modular approach to fluorescent macrocycles.280 The suitably functionalized glutamic acid derivatives 126a and 126b were easily obtained through classical protecting group manipulation and amide bond formation procedures. Amine 126a was first coupled to the sugar amino acid (SAA) 125 using 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) and N-hydroxybenzotriazole (HOBt)281 followed by Fmoc deprotection and then a second coupling with acid 126b using DIC/ HOBt and afforded compound 127 containing an alkyne functionality. Macrocyclization of glycohybrid 127 with diazide 126c in the presence of CuI and DIPEA in acetonitrile under high dilution (0.22 mM) gave a 22% yield of the desired macrocycle 128 after 3 days at 45 °C (Scheme 41). Intramolecular olefin metathesis is an exceedingly reliable ringclosing method which has been successfully utilized to generate a large number of macrocyclic ring systems under mild conditions. Dorner and Westermann utilized a novel route via a clickcombined ring-closing metathesis approach and developed a library of an interesting class of macrocycles (130a−d) from the corresponding 6-azido glycosides 129a−d and 1,7-octadiyne. The authors employed several azido alkynes for the consecutive

A similar Cu-catalyzed click protocol has been recently employed for the development of carbohydrate-containing macrocycles of interesting properties, most notably the ability for metal complexation and the probability to deal with stereochemical aspects.274−276 The dimerization of 2-propynylor 3-butynylacetylated 6-azido-6-deoxyglycosides separately via a Scheme 39. Cu(I)-Catalyzed Cyclodimerization of Azido Alkyne-Functionalized Pyranosides277

thermally induced or MW-induced Click reaction afforded a high yield of the corresponding macrocyclic ring containing carbohydrate and triazole moieties.276 Copper-catalyzed, thermally assisted or microwave-assisted cyclodimerization of D-gluco-, D-galacto-, or D-manno-derived azido alkynes 119a−e having an alkyne functionality at the 2- or 3-position of the sugar led to formation of a macrocyclic ring holding two carbohydrate residues linked through two triazole rings (120a−e) (Scheme 39).277 The lower yield of dimeric glycosides (14−54%) was observed by the click reaction of bifunctionalized precursors, and a significant amount of higher oligomeric byproducts was obtained. The formation of product depends on the concerned sugar unit, its anomeric configuration, and also the size of the ring formed. The property of the host−guest interaction in these macrocycles depends on the size of the cavity, which can be finely tuned by varying the sugar residues and their number in the 3112


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Figure 14. Metal-free thermal 1,3-dipolar cycloaddition leads exclusively to 1,5-substituted triazole-fused polycycles.

Scheme 40. Synthesis of Macrocyclic Carbohydrate/Amino Acid Hybrids via CuAAC Reaction277

Scheme 41. A Modular Approach to Fluorescent Macrocycles280

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Scheme 42. Dimerization via a Combined ClickRCM Route for Macrocycle Synthesis282

To achieve more complex and symmetric sucrose-based chiral receptors, the Jarosz group further extended the work with dialkyne linkers where sucrose-derived precursor 149 was prepared and subjected to a sequence of reactions. Catecholand lutidine-derived dialkyne linkers upon click reaction with two molecules of azide 149 gave C-2-symmetric derivatives 150 and 151, respectively. In the subsequent step, the terminal free hydroxyl group of each of 150 and 151 was activated by mesylation to deliver compounds 152 and 153, respectively. Finally, the macrocyclization was attempted through substitution of mesyl moieties by ethylenediamine. Unfortunately, under standard conditions, this reaction proceeded only with dimesylate 152, giving a 5% yield, whereas 153 did not react at all. To bring about the cyclization of dimesylates 152 and 153, the authors investigated the reaction in the presence of templates (metal cations, aromatic compounds, and hydrogen bond donors and acceptors) which could assist the reaction by preorganizing the starting materials. Finally, (R)-(−)-2-phenylglycine methyl ester hydrochloride was established as an effective template that facilitated the cyclization, giving a 25% yield of the products 154 and 155 (Scheme 45).285 The Plantier-Royon group reported macrocycles derived from galacturonic acid, an oxidized form of D-galactose. The tactic involved the preparation of furanoside from D-galacturonic acid, which on further acetylation, BF3·OEt2-mediated glycosylation with propargyl alcohol, and deprotection afforded 156 in overall good yield. The trans-acylation of 156 with azido amine 157 furnished azido alkyne 158. The authors found that the outcome of the CuAAC was highly dependent on the reaction conditions. The reaction accomplished with CuI/DIPEA in water furnished cyclodimer 160 as the exclusive product, while the monomeric macrocycle 159 was obtained with use of CuSO4/NaAsc (Scheme 46).286 The authors cited that the click reaction between 156 and 157 before amidation failed to give the macrocyclic compound 159. The complexation properties of the resulting sugar-containing macrocycle 159 for Cu(II) cations showed that the cryptates were formed in a 1:1 metal:ligand ratio, indicated by electron

transformations, CuAAC using the CuSO4/NaAsc system followed by Grubbs I-mediated ring-closure metathesis (RCM), to obtain a high yield of inseparable sugar-containing macrocycles, where the E/Z-geometrical isomers were successfully separated through the reduction of the olefin under mild reaction conditions (Scheme 42).282 Likewise, click chemistry could be uniformly useful for intramolecular cycloaddition to afford an interesting class of triazole-fused bicyclic systems, including triazolophanes. The Dondoni group presented a synthetic strategy for accessing cyclodextrin-like C-n-symmetric macromolecules containing two, four, and six C-glucopyranoside residues. With the use of a sequential click reaction between azide- and alkyne-functionalized sugars, first bifunctionalized linear oligomers were generated, and then their intramolecular cyclization via CuAAC delivered triazole-linked macrocyclic C-n-symmetric structures 135, 136, 139, and 142 of varying cavity sizes (Scheme 43).283 Lewandowski and Jarosz284 explored the click reaction to access macrocycles derived from sucrose. Azide- and alkynebifunctionalized macrocyclic precursor 143 of sucrose was easily obtained from 1′,2,3,3′,4,4′-hexa-O-benzylsucrose in simple steps, and then its submission to Cu(I)-catalyzed click reaction conditions delivered both intramolecular and intermolecular cyclization products depending upon the concentration of the catalyst source and the corresponding starting material. Under a lower concentration of the Cu(I) source as well as azido alkyne, product 144 of intramolecular click was found to be the favored one. However, unexpectedly, 1,5-substituted 1,2,3-triazole 145 was also formed along with the mechanistically favored 1,4triazole regioisomer 144. It was assumed that teh unfavored 1,5regioisomer is also formed because of steric repulsion created in the small cavity of the 1,4-substituted triazolyl macrocycle. Thus, to confirm this assumption, an elongated azido acetylene analogue, 147, was designed and subjected to click reaction conditions. As per expectation, enlargement of the cavity size led to a release of strain, and thus, the reaction furnished the 1,4substituted macrocycle 148 exclusively (Scheme 44). 3114


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Scheme 43. Synthesis of C-n-Symmetric Triazole-Linked Cycloglucopyranosides

incorporating a sugar furanoside ring and aryl group was utilized to construct a triazolophane including strained monomeric 12membered triazole 162. Likewise, azido alkynes comprising the peptidic tethers on Cu(I) -catalyzed intramolecular clicking

paramagnetic resonance (EPR), UV/vis spectroscopy, and mass spectrometry analysis.286 Intramolecular click-inspired cycloaddition of an azide−alkyne scaffold connected together with a constrained tether system 3115


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click-inspired synthesis of cyclic pseudo-oligosaccharide macrocycles of promising chemotherapeutic potential. Thus, cyclooligomerization of an azido alkyne derived from D-galactose under Cu catalysis led to the formation of a cyclic pseudooligosaccharide in high yield. Subsequently, the resulting macrocycles were further investigated for enzymatic sialylation by Trypanosoma cruzi trans-sialidase, to obtain their possible inhibitor.291 Galactose-based bifunctional azido alkynes 170 and 171 holding an azido functionality at the anomeric position, i.e., C-1, or at C-6 and a 6-O- or 1-O-propargyl ether as an alkyne functionality for click purposes were developed first. Then the microwave-assisted click reaction using CuSO4/Cu turnings in anhydrous DMF successfully afforded the corresponding macrocycles in high yield. The concentration of the solution of bifunctional galactose precursors affected the cyclo-oligomerization results. Such oligomerization in dilute solution afforded cyclic dimers and trimers as the sole products. Using a similar reaction carried out in a concentrated solution, the corresponding cyclic tetramers as well as pentamers were also isolated in very low yields. The cyclo-oligomerization dimer and trimer products serve as templates for enzymatic sialylation with TcTS in the presence of a suitable sialic acid donor such as MUNANA and afford the desired sialosides. The resulting promising products 172−175 may be prospectively useful for biomolecular recognition studies (Scheme 50).291 In another approach, Chen et al. synthesized various sizes of macrocyclic oligosaccharides using a chemoenzymatic method wherein azido-containing sialic acid 177 was prepared from glycosyl azide 176 via aldolase-mediated conversion. Compound 177 was further activated in situ as the cytidine 5′-monophosphate (CMP) derivative 178, which on enzymatic reaction with acceptor 179, containing a galactose at the nonreducing end and a propargyl group at the reducing end, afforded trisaccharide 180. Intramolecular CuAAC−macrocyclization (180, 1 mM) furnished macrocycle 181 in 91% yield.292 Furthermore, the method was extended to the development of several interesting, but challenging, sialic acid-containing macrocyclic systems (181−183) in an efficient manner (Scheme 51). Likewise, a similar click-mediated cycloaddition of acyclic azide−alkyne octasaccharide 184 successfully resulted in the formation of well-defined 76-membered complex macrocyclic skeleton 185 (Scheme 52). These carbohydrate macrocycles were characterized by NMR, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and high-resolution MS (HRMS) data. The developed sialic acidcontaining macrocycles have high water solubility and are identified to interact with hydrophobic small molecules in a sizedependent mode. These sialic acid-containing macrocyles would probably be very interesting systems for the host−guest investigation in biological systems, which is unfortunately still not well documented in the literature. Synthetic macrocycles using the CuAAC click reaction of azides/alkynes have been designed and prepared for a wide range of biological (as glycolipids analogues, bioactive cyclopeptide mimetics, protein ligands, enzyme inhibitors/substrates, quadruplex DNA binders), chemical (for chiral recognition, as catalysts for asymmetric synthesis), and supramolecular or analytical (as synthetic receptors for ions and organic compounds) applications or as biomaterials. These studies open the way for designing new antibiotics with improved activity in resistant strains, or new chemotherapeutic drugs against multiresistant carcinoma, although the biological activity of most synthetic macrocycles has not been tested. Generation of

Scheme 44. Synthesis of Sucrose-Derived Macrocycles

afforded monomeric triazolophane-based cyclic systems of higher sizes. Thus, peptide-linked azido alkyne 163 obtained from the corresponding azidofuranose in the presence of CuSO4/NaAsc in aqueous t-BuOH underwent intramolecular click reaction and produced macrocycle 164 in 31% yield. However, the same reaction when performed in THF under the catalysis of CuI and DIPEA led to the formation of macrocycle 164 in 20% yield only. Furthermore, several azido alkynes including a furanoside-appended peptide on Cu(I)-catalyzed cycloaddition reaction gave furanoside-fused triazolophanes as part of the 12−17-membered ring in good yields (Scheme 47).287 A cyclophane-based macrocycle incorporating a carbohydrate is considered to be of great interest as it has wide applications in bioorganic and supramolecular chemistry.288 A short and brilliant synthesis of the glycotriazolophane macrocycle has been reported by Murphy et al. by utilizing a sugar amino acid derivative as a building block. Routine acid−amine coupling of compound 165 with p-xylene-1,4-diamine followed by de-Oacetylation using NaOMe in MeOH gave the sugar-based bisazide 166 in 37% overall yield. Azide−alkyne cycloaddition of bisazide 166 with p-bis(propargyloxy)benzene using CuSO4/ NaAsc in CH3CN/H2O gave the macrocycle 167 in 56% yield (Scheme 48).289 However, the poor solubility of the developed macrocycle prohibited its further examination in the molecular recognition phenomenon in an aqueous system. Sen et al. reported the synthesis of triazole-fused polycyclic glycosides 169 using cuprous oxide nanoparticles in an aqueous medium under aerobic conditions involving Sonogashira intramolecular 1,3-dipolar cycloaddition of azido alkynes (for example, compound 168) and aryl halides in 72−90% yield (Scheme 49). The authors utilized Cu2O as a reusable heterogeneous catalyst and applied it in three consecutive reactions. The reactions under sonication conditions to disperse the catalyst and increase its surface area make the protocol more feasible.290 In addition to the routine Cu-catalyzed intramolecular cycloaddiion, Field and co-workers presented a very interesting 3116


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Scheme 45. Amino Acid-Templated Macrocyclization To Access Sucrose-Derived Macrocycles 154 and 155

Ser-Glu dipeptide O-glycoside hybrids 186 consisting of a β-turn as a nonrepetitive structural motif. The authors envisioned an efficient bonding of 187 to lectin or the carbohydrate recognition domain (CRD) of human E-selectin (Scheme 53).296 Apart from this, significant efforts have been made in the utilization of the Cu(I)-catalyzed azide−alkyne cycloaddition reaction in combination with a chemoenzymatic peptide linking strategy for the synthesis of macrocyclic as well as large linear glycopeptides. Rutjes and co-workers contributed toward this end, and discovered that the synthesis of glycopeptides can readily be carried out by using the steps of enzymatic peptide coupling after CuAAC reaction (188 and 189) or reverting the sequence of the two strategies (191 and 192). The authors found that both the strategies were very compatible with each other, and a preference for amide bond formation should be given over the click reaction for ease of preparation of glycopeptides.297,298 The combination of NCL with the CuAAC reaction has enabled access to numerous triazole-based neoglycopeptides consisting of peptide chains bearing 20 amino acids (Scheme 54).299 The 1,2,3-triazole ring formation using click chemistry was found to be compatible with an NCL strategy as further supported by the work of Macmillan and Blanc, where the

new organic or organometallic catalysts from supramolecular interactions with carbohydrate-based macrocycles remains to be explored. Because of the rich availability of natural carbohydrates with well-defined configurations and their easy transformation/ functionalization, there is still plenty of room to design and synthesize carbohydrate-derived macrocyclic compounds as catalysts for asymmetrical synthesis or for various applications in biological, analytical, and material sciences.

5. GLYCOPEPTIDES AND PROTEIN CONJUGATES The stitching of peptides/proteins to sugars via Cu(I)-catalyzed click reaction293,294 appears interesting as the resulting glycopeptides and conjugated proteins by virtue of the triazole units become resistant to hydrolysis within the biological system. Click chemistry has emerged as an efficient ligation strategy that allows the preparation of numerous peptidotriazoles via CuAAC reaction of sugar-based azides/alkynes240 with their counterpart azides/alkynes functionalized at the peptides.241 Scolastico et al. reported their work on the synthesis of pseudopeptide conjugates using click chemistry.295 Similarly, the design and development of β-lactam-based glycoconjugates 187 was carried out using azide−alkyne cycloaddition to mimic lectin antagonist 3117


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Scheme 46. Synthesis of Galacturonic Acid-Derived Macrocycles Using Click Chemistry286

Scheme 47. Synthesis of Monomeric Triazolophanes from Furanoside-Tethered Azido Alkynes

authors employed a chemoselective nucleophilic displacement of alkyl bromides with side chain cysteinethiols. The investigation demonstrates that the order of the thioether and triazole ring formation was not crucial in the development of the designed neoglycopeptides.300 The macrocyclization of linear nonribosomal peptides and polyketides followed by their modification via linking with carbohydrate residues has emerged as an interesting strategy for improvement of the water solubilities and biological activities of such natural products. Walsh and Lin reported a chemoenzymatic method for the synthesis of cyclic peptide antibiotics modified with sugar residues. The authors prepared cyclic decapeptide tyrocidine (Tyc) analogues incorporated with three propargylglycines at the 3−8 positions (194) followed by a subsequent CuAAC reaction with 21 azido sugars, leading to the formation of glycopeptides 195 (Scheme 55). The authors also evaluated the developed glycopeptides in antibacterial and hemolytic assays, wherein a better therapeutic index in

comparison to that of naturally occurring tyrocidine was noticed.301 The click ligation strategy has also been widely exploited for enhancing the chemotherapeutic index of many well-known drugs. Tyc, being capable of penetrating the bacterial cell membranes, is known to have an adverse effect on human red blood cells (RBCs); hence, sugar-modified Tyc derivatives 196 and 197 were synthesized and evaluated for antibacterial activities. At a concentration of 3.0 μM, the compounds displayed activities similar to that of native Tyc (Figure 15). Many naturally occurring antibiotics contain carbohydrate macrocycles or glycosylated cyclic peptides.302 Thus, a library of mimics of these macrocycles and glycosylated cyclic peptides has been synthesized using a fusion of ring-closing metathesis (RCM) and Cu-catalyzed click chemistry.282 Vancomycin, a naturally occurring antibiotic, was modified via chemoenzymatic tools by Thorson et al. using flexible glycosyl transferases to obtained vancomycin analogue 198. The chemoselective ligation of 198 using CuAAC reaction furnished a library of related 3118


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Scheme 48. Click-Inspired Synthesis of Glycotriazolophane Macrocycle 167

groups on the periphery, on alkylation with hexynoic acid gave a compound having four alkyne groups on the periphery (203), which was then reacted with the tetrapeptide GSTA motif containing the TN-antigen at the threonine and serine residues bearing N-terminal azide 204 under click conditions using CuSO4/NaAsc in t-BuOH/H2O (1:1) to afford a tetraclicked dendrimer containing four glycosylated GSTA motifs joined via triazole linkages (205) (Scheme 58).304 The synthetic strategy of glycopeptide dendrimers has now emerged as a fast and efficient manner for biological assay of library members. The cyclopeptide-based heteroglycocluster has become of great importance in recent years due to its potential to evaluate the influence of heterogeneity in the carbohydrate−protein interaction. Renaudet and co-workers reported the synthesis of tetravalent glycopeptides based on the click reaction between tetraazido glycopeptides 206 and propargyl glycosides 207 using a Cu micropowder catalyst in the t-BuOH/NH4OAc system (Scheme 59).305 The resulting tetravalent glycoclusters 208, containing triazole linkages, were tested for inhibition with concanavalin A (ConA) and Ulex europaeus agglutinin-1 (UEA1), but these glycoclusters showed weaker inhibition relative to their oxime analogues. This protocol may offer 16- or 64-valent fucosylated glycodendrimers with the aid of well-known “click” as well as oxime ligation methodology. The molecules could be useful for the enzyme-linked lectin assay.305 The glycosylation of peptides comprising cysteine via click chemistry resulted in a series of glycopeptides.306 In a similar pattern, MW-assisted click glycoconjugation between propargylated α-GalNAc and multi-azido-functionalized peptides furnished a “Tn-antigen mimic”. Azidoalanine-containing peptides 209a and 209b, obtained by incorporating azidoalanine into the

Scheme 49. Synthesis of Triazole-Fused Polycyclic Glycosides in an Aqueous Medium

compounds 199 (Scheme 56).303 Mimics of the vancomycin antibiotics via click chemistry reveal that a carboxylic acid derivative was found to be twice as effective as vancomycin against antibiotic-resistant strains. The triazole-linked glycosidic amino acid 200 (FmocN L- TGA(Ac)4-OH) was achieved from click reaction of a sugar azide and Fmoc-protected L-propargylglycine followed by hydrolysis. Loading of trityl resin, followed by a sequence of reactions, such as synthesis of the pentapeptide, cleavage, cyclization, and deprotection of the cyclic arginine−glycine− aspartate peptide, afforded cyclic glycosyl peptide c(RGDy-NTGA) (202) (Scheme 57). Studies on the biodistribution of the 125I-labeled derivative of c(RGDy-NTGA) in mice with tumors expressing αvβ3 showed that c(RGDy-NTGA) selectively targets αvβ3 integrin with a high tumor to blood ratio. The results with c(RGDy-NTGA) bearing a triazole moiety linkage were found far better than those with the amide-linked glycosylated cRGD peptides, indicating the suitability of the triazole moiety in glycosylated peptide synthesis.207 Payne et al.304 established the rapid synthesis of MUC1 glycopeptide dendrimers using click chemistry. Thus, polyamidoamine, possessing an ethylenediamine core and four amino 3119


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Scheme 50. Click-Inspired Cyclo-Oligomerization of Azido Alkyne Precursors 170 and 171 and Their Subsequent Sialylation Lead to Cyclic Pseudo-Oligosaccharides 172−175291

linking a lipopeptide with 1−4 tumor-associated MUC1 glycopeptide antigens by reacting azido spacer groups with alkyne spacers to solve the common problem. This click conjugation is efficient, particularly if lipopeptide is one of the click reactants. For example, the clicking of multivalent dialkynefunctionalized lipopeptide 218 with the deprotected azidofunctionalized glycopeptides 219 under CuAAC conditions incubated at 40 °C overnight affords the complex multivalent glycopeptide antigens 220a−d in 50−65% yields (Scheme 62). For the complete conjugation, the glycopeptide was used in excess (4-fold), and the conjugation was also performed in deoxygenated water (since both the glycopeptides and lipopeptides are water-soluble). The developed protocol was highly efficient at generating strong immune responses counter to the glycopeptide−antigen structures.309 Though the CuAAC reaction appears appealing for straightforward access to many unnatural glycopeptides and derivatives of pharmacological importance, it is far behind in progression to clinical drugs being used today, because a number of metabolic pathways and safety concerns for triazole derivatives are still unexplored.

peptide backbone using standard solid support conditions, on click reaction with a glycosylalkyne in the presence of CuSO4/ NaAsc under MW exposure in the presence of H2O/t-BuOH (1:1) for 10 min afford almost quantitative yields of glycopeptides 210a and 210b. The product was deacetylated using NaOMe in alcohol at pH 11.3 to afford AFGP derivatives 211a and 211b in excellent yield and with high purity (Scheme 60). The authors demonstrated the click variant of antifreeze glycopeptides as a potent platform for preparation of numerous neoglycopeptides, although biological activities still need to be established.307 The authors extended the protocol for preparation of multivalent neoglycoconjugates of MUC1. GlcNAc-aligned neoglycoclusters featuring an azido functionality were first reacted by treatment of the GlcNAc core affixed with propargyl groups (212) with azido sugars under click conditions, and then the tosyl group was replaced by azido by treatment with NaN3 under reflux for 5 h to afford triazole-linked tetrasaccharides having an azido functionality (213a, 214a, and 215a). Furthermore, removal of the acetate group using NaOMe in methanol resulted in the corresponding azide-functionalized GlcNAc-centered neoglycotetrasaccharides 213b, 214b, and 215b followed by a second click with propargylglycine containing the MUC1 peptide (216) under standard click conditions to afford the designed multivalent neoglycoconjugates of MUC1 (217) in good yield (Scheme 61).308 The chemistries of glycopeptide and lipopeptide conjugation, in general, are not always compatible due to several practical problems. Kunz et al. utilized the high-yielding click protocol for

6. GLYCOCLUSTERS AND GLYCODENDRIMERS The multivalent display of carbohydrates has been considered an imperative principle of molecular recognition involved in biological systems, where a number of tailor-made ligands for natural protein receptors are well documented.310−312 Molecular assemblies, especially glycoclusters having a number of sugar residues, nowadays receive great consideration, predominantly 3120


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Scheme 51. Chemoenzymatic Synthesis of Complex Sialic Acid-Containing Macrocycles292

corresponding glycocluster 222a (Figure 17), which has an outstanding cluster effect and displays even 400 times more inhibitory activity against lectin RCA120 in comparison to the lactose analogue.318 Moreover, similar a effect was noticed; for example, glycocluster 222b, obtained through clicking or a clustered amino acid-derived alkyne with clickable azide 2azidoethyl β-D-galactopyranosyl-(1−4)-β-D-glucopyranoside under standard click conditions, displayed a significant inhibitory activity against galectin-1 (Kd = 3.2 μM).325 Click chemistry can afford carbohydrate-appended curdlans by a reaction between 6-azido-6-deoxycurdlan (derived from curdlan by treatment with triphenylphosphine, DMF, and lithium chloride and then carbon tetrabromide followed by reaction with sodium azide) and carbohydrate-derived alkynes. These carbohydrate-linked curdlans can afford stable macromolecular complexes consistent with one polycytosine strand and two polysaccharide strands which show strong and specific affinity toward lectins, and thus, they can be utilized as a new family of glycoclusters (Scheme 63).326 A very efficient strategy was applied for the straightforward synthesis of sugar-cored multimannosides by utilizing four different synthetic steps. The first step includes a PPh3/CBr4mediated regioselective azidation of different monosaccharides (such as D-glucose, D-maltose, and D-maltotriose cores), followed by consecutive acetylation to afford the required template

via embracing click-inspired conjugation. Such molecules were well utilized for the investigation of the important carbohydrate− lectin interaction and also for several protein recognition events involved in biological systems. These triazole-containing glycoclusters have several great properties, including a biomedically valid nucleotide,313 drug delivery,314−316 and well-known inhibition of galectin,313 lectin,317 and a number of glycosidases.318 To obtain an appropriate glycocluster having the above-mentioned properties, several terminal alkynes, including O-propargylated glycosides, C-glycosides, etc., have been productively clicked with polyazido carbohydrates as well as nonsugars such as calix[4]arene,249 amino acids,313 cyclodextrins,319 resorsin[4]arene,320 fullerene,321,322 and many other interesting cores under click-inspired conditions. Likewise, sugar-based azides were also clicked to a polyalkyne core and afforded a high yield of the corresponding N-glycosylated triazoles.323 Du and co-workers presented a convergent synthetic route for an easy access of C-3-symmetric (1−6)-N-acetyl-β-Dglucosamine octadecasaccharide. A hexasaccharide-based clickable azide on treatment with 1,3,4-tri-O-porpagylated benzene under standard click conditions afforded a high yield of the corresponding glycocluster 221 (Figure 16).324 A glycosylalkyne, for example, methyl 2,3,4,6-tetra-O-propargyl-β-D-galactopyranoside, on clicking with lactose azide under standard click conditions affords a high yield of the 3121


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Scheme 52. Chemoenzymatic Approach for Complex Macrocycles with Sialosides292

Scheme 54. Compatibility of Enzymatic Peptide Coupling and CuAAC Tool for Preparation of Glycopeptides299

co-workers to construct a polyazide-derivatized scaffold of multivalent glycoclusters for setting up 1-thio-β-D-galactoside moieties having an alkyne functionality and azides containing oligosaccharide scaffolds.327 The click reaction between Sgalactoside alkynes 225 bearing an oligo(ethylene glycol) linker of different lengths, with mono-, di-, tri-, and tetraazidecontaining oligosaccharides 226a−d, in the presence of CuSO4/NaAsc as the catalytic system using DMF/H2O as the solvent at rt for 10−16 h led to the formation of a very interesting class of glycoclusters (227a−d) containing one to four residues of 1-thio-β-D-galactose (Scheme 64). Similar click reactions under MW condition afford the desired glycocluster 227 in a shorter reaction time. Uhrig et al. reported the synthesis of hydrolytically stable glycoclusters bearing thiodigalactoside analogues (TDG), obtained from 6-S-acetyl-α-D-glucosyl bromide by treating it with the isothiouronium salt of 2,3,4,6-tetra-O-acetyl-β-Dgalactose via a thioglycosylation procedure, as recognition elements of β-galactoside-binding lectins.327 The thiodigalactoside analogue 228, obtained by propargylation of the corresponding disaccharide, on click coupling to azido sugars 229a and 229b under microwave irradiation conditions afforded good yields of the corresponding glycoclusters 230a and 230a, respectively (Scheme 65). Acetate group removal from glycocluster 231a using triethylamine in methanol/water under mild conditions gave an almost quantitative yield of the glycocluster with a free hydroxyl group (231b). These multivalent ligands were found to be resistant to enzymatic hydrolysis by E. coli β-galactosidase. Isothermal titration calorimetry was used to investigate the binding affinities of these ligands toward peanut agglutinin and human galectin-3. The investigations confirm that the monovalent ligand exhibited a comparatively higher binding affinity in comparison to the thiodigalactoside. Docking studies carried out with a model ligand on both the β-galactoside-binding lectins demonstrated additional interactions between the lectin amino acid residues

Scheme 53. Click-Inspired Synthesis of β-Lactam-Based Glycohybrids 187 as Lectin Antagonists296

(second step). Subsequent clicking with mannosylalkynes under standard click reaction conditions as the key step followed by deacetylation as the last step resulted in the formation of multivalent mannoside-based glycoclusters (for example, 224a and 224b, Figure 18) exhibiting a remarkable cluster effect.327 Regarding optimization of lectin and galectin inhibitors, the multivalency outcome is broadly examined, but modest attention was paid to the glycosidase activities. Toward this end, to seek out an effective inhibitor against β-galactosidase of Escherichia coli, the click-inspired protocol was explored by Kovensky and 3122


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Scheme 55. Macrocyclization and Modification of the Antibiotic Tyrocidine via CuAAC for Improvement of Solubility and Activity301

Figure 15. Antibacterial glycopeptides with enhanced chemotherapeutic index.

glycoclusters, for example, 232 and 233 (Figure 19). These glyclusters were recognized for their high chemotherapeutic values as putative inhibitors of lectin- or galectin-mediated processes. Several lectin systems are involved in the glycoside cluster effects for affinity enhancement in carbohydrate−protein interactions.328 Since such interactions are involved in cellular recognition processes, this interesting approach could find wide applications in medicinal chemistry.

with a clicked generated triazole ring, thus suggesting an encouraging consequence of this residue on the biological activity. Because of the adequate stability of S-linked glycosides under a hydrolytic environment and also their specific enzymatic affinity, an alkyne-armed oligoethyl-linked thiogalactoside could be a very suitable choice as a linker and thus was selected to click with the appropriate glycosyl azides to afford the targeted 3123


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Scheme 56. Library of Vancomycin Variants Designed by 1,3-Dipolar Cycloaddition of the Depicted Enzymes303

achieved via conjugation of α-CD/decane pseudorotaxanes by the Cu(I)-catalyzed click protocol.335 Compain et al. reported a click-inspired convergent strategy to access high-valency iminosugar clusters under standard copper catalysis under mild reaction conditions.336 To achieve maximum efficiency in this strategy, the authors used two successive click reactions; i.e., CuAAC was first used in the synthesis of trivalent dendrons via coupling of trialkynyl cores with azido iminosugars, while the second click allowed the grafting of azide-armed trivalent building blocks onto polyalkyne scaffolds. The pentaerythritol was used as a precursor for the synthesis of tripropargyl ether 239,337 which on reaction with 2chloroethyl ether furnished compound 240 as a starting substance for the first CuAAC (click). The microwave-assisted CuAAC reaction of tripropargyl ether 240 and azido iminosugar 241 furnished trivalent dendron 242,338 which on further treatment with sodium azide afforded 242 in quantitative yield. The authors utilized a simple clickable scaffold, for example, alkyne-functionalized tetrapropargyl ether 244, obtained in one step from pentaerythritol by porpargylation under standard conditions.339 MW-induced clicking of terminal alkyne 244 and dendron 243 under the catalysis of CuSO4/NaAsc in DMF/H2O (4:1) at 80 °C led to the desired dodecavalent iminosugar 245a in 56% yield. Subsequently, O-deacetylation of dendrimer 245a reacting in the presence of Amberlite IRA-400 (OH−) anionexchange resin afforded the expected cluster 245b in almost quantitative yield (Scheme 68). Once the synthesis of cluster 245b was accomplished, the authors applied the same synthetic procedure and coupled heptakis(2,3-di-O-methyl-6-O-propargyl)cyclomaltoheptaose (246)340 with azide 243 using click reaction conditions under microwave irradiation to furnish 21-valent iminosugar 247a in appreciable yield (Scheme 69). Preliminary biological investigation of both the developed multivalent iminosugars 245b and 247b provides an interesting and encouraging result, and the

There are many other macrocyclic platforms such as porphyrins,329,330 cyclic peptoids,331 cyclopeptides,332 etc. that are well utilized to construct the glycoclusters with a well-defined and precise geometry using click chemistry (Scheme 66). The cyclopeptide-based oligomannose-containing heteroglycocluster 235 was developed from the corresponding alkyne 234 using “click chemistry”. Accordingly, the cyclodecapeptide-templated oligomannose cluster was assembled by clicking the tetrakis(propargylamide) derivative 234 with an azide-armed tetrasaccharide using CuSO4/NaAsc in the t-BuOH/H2O system. This glycocluster displayed considerably high affinity binding to the HIV-neutralizing antibody 2G12, a well-accepted mimic of highmannose N-glycans.333 Consequently, multivalency mechanisms known to enhance carbohydrate recognitition are not limited to lectins only, but could also stimulate the carbohydrate-directed antibodies. Besides the triazolyl link formation within the cyclodextrin core, click chemistry also affords an exocyclic triazolyl linked to cyclodextrin, and these click-modified cyclodextrins have shown enormous potential in biomedical applications.334 Furthermore, a similar chemistry was extended for accessing β-CD core glycodendrimers, for example, 237a−e and 238a−e, by clicking the β-CD-derived azides 236a,b with different clickable dendrons such as an alkyne containing a secondary amine with Boc protection (Scheme 67).319 Both protecting groups (for example, N-Boc and O-Ac) from dendrimers 237a−e were successfully removed under standard reaction conditions and afforded the corresponding dendrimers 238a−e in good yields. Interestingly, these water-soluble dendrimers have shown competency for encapsulation of pDNA cyclodextrin and have potential applications in delivery systems, especially for nucleotides. Sugar-appended oligorotaxanes with a triazole moiety outside the CD core along with adjustable threading ratios can be 3124


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Scheme 57. Synthesis of Triazole-Linked c(RGDy-NTGA) Peptide from Glycosidic Amino Acid207

250,342 and the hexaadduct containing 12 terminal alkyne units thus obtained underwent clicking with glycosyl azide 249 under standard click conditions (Scheme 70). Fullerene iminosugar 252 and its monovalent analogue 248 were tested against several glycosidases. The multivalent and monovalent iminosugars displayed similar inhibition constants (Ki) for amyloglucosidase and bovine liver β-glucosidase, while a 9-fold decrease in affinity against sweet almond β-glucosidase was reported for the multivalent iminosugar compared to that of the monovalent iminosugar. Interestingly, up to 2150-fold enhancement in the binding was recorded for most of the scrutinized glycosidases. The multivalent dendrimer 252 was recognized as a promising inhibitor of green coffee α-galactosidase, while its monomeric analogue in the D-gluco series was totally inactive.341 Zhang et al. reported the click-inspired synthesis of cyclodextrin-based mannose and fucose clusters including glycoclusters and star glycopolymers (253 and 254, Figure 20) from azide-functionalized CD reacting with the respective sugar alkyne through combination of Cu-catalyzed click chemistry and copper-mediated living radical polymerization (Scheme 71).343 Without the need for any further protection steps and column chromatography for purification, this protocol is very useful. Surface plasmon resonance (SPR) analysis confirms that the developed cyclodextrin-based mannose star glycopolymer 254 displayed a high binding affinity for the human transmembrane lectin and performed as a promising inhibitor to prevent the binding of HIV envelope protein gp120 to DCSIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) at nanomolar concentrations. The authors disclose that the star glycopolymers with sufficient sugar units, for example, cyclodextrin-based mannose star glycopolymer 254, could work as competent inhibitors for the binding of gp120 with the carbohydrate recognition domains (CRDs) of DCSIGN. Interestingly, a glycopolymer having a number of sugar units displayed a high loading capacity of hydrophobic anticancer and anti-HIV drugs. These results encouraged the search for their wide applications in the development of lead molecules to treat HIV infection as well as in smart drug delivery. Nakamura et al. developed an efficient synthetic route toward the synthesis of 1,2,3-triazole-linked C-5-symmetric fullerene− carbohydrate conjugate 257.344 The building block pentaalkynylfullerene 255 was obtained from pentakis(4-sulfanylphenyl)fullerene, over which azide-functionalized glycosides 256 were assembled by the use of the click reaction (Scheme 72). In the case of nonpolar azides, this reaction was carried out with the catalyst CuBr/DIPEA in a toluene and DMSO system, which afforded quantitative yields of the product. The polar functionalities, such as carboxylic acids and unprotected alcohols containing complex sugars, also resulted in excellent yields of products under various conditions. Since it is not possible to purify the fullerene conjugates from their byproducts (produced by incomplete coupling), the success of the click reaction prompted development of complex glycoconjugates.344 Glycodendrimers, an exceedingly branched monodisperse system containing a number of sugar residues, nowadays have received considerably great interest due to their outstanding applicability in different fields such as pharmaceutics, nanotechnology, and catalysis, and most notably as drug delivery carriers,345,346 as well their diverse applications in biomedical science.347−350 Although a lot of high-yielding synthetic protocols have been well utilized to afford a wide variety of glycodendrimers, just after the invention of “click chemistry”, this extremely simplistic and regioselective protocol was greatly

dendrimers were further explored for their α-mannosidase inhibitory activity. The 21-valent cluster 247b showed the best inhibition, with a Ki value of 19 ± 3 nm. Likewise, 12-valent cluster 245b was also established to be a competitive inhibitor of jack bean α-mannosidase; however, its inhibitory potency was noticed to be inferior by 1 order of magnitude (Ki = 260 ± 30 nm).336 Compain et al. used the CuAAC reaction to evaluate the extent of effectiveness of multivalency on glycosidase inhibition using a fullerene scaffold decorated with an N-alkylated residue at N-1deoxynojirimycin at the periphery.341 Apart from inhibition of glycosidases, the authors anticipated that such compounds may be crucial for the assessment of the influence of multivalency on inhibition selectivity over several glycosidases. The debenzylation of O-benzylated iminosugar 248 gave iminosugar 249, which on subsequent treatment with different alkynes in the presence of CuSO4·5H2O/NaAsc furnished the desired glycodendrimers. A monomeric analogue obtained by clicking of 1-pentyne and azide 249 under click conditions was used as the monovalent model in the inhibition assay. The fullerene iminosugar ball 252 was developed in overall 83% yield via tetra-n-butylammonium fluoride (TBAF)-mediated in situ desilylation of compound 3125


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Scheme 58. Click-Inspired Synthesis of MUC1 Glycopeptide Dendrimers304

Scheme 59. Click-Inspired Synthesis of Tetravalent Glycopeptides Using Cu Micropowder305

explored to develop the desired glycodendrimers comprised of several simple saccharides, iminosugars, sialic acids, etc. using both the convergent and divergent approaches. Conventionally, due to the oxidative coupling known to proceed during the azide−alkyne clicking step, it is recommended to load clickable azide over the dendrimer partner rather than the terminal alkyne.351 Unprotected sugar moieties functionalized with azides/alkynes may be coupled together to generate doubly substituted dendrimers under mild reaction conditions with great ease. In addition to these, the high selectivity, excellent reaction yield, requirement of a minimum loading of copper catalyst,

coupling in aqueous solution, and moreover the well-known compatibility with carbohydrate make this click protocol very useful in glycodendrimer synthesis. Thus, the click approach was well utilized by the Riguera group to generate an interesting glycodendrimer, which is known to bind to lectin, by clicking of several glycosylalkynes with an azido-functionalized PEG-block copolymer under click reaction conditions.352 Furthermore, the authors report that the use of the CuAAC protocol coupled with ultrafilration could afford an extraordinarily rapid access of the targeted compound with wide applications.353 Likewise, Astruc and co-workers adopted an analogous protocol and successfully 3126


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Scheme 60. Synthesis of Neoglycopeptides Using an Azide-Functionalized Peptide Backbone307

dendrimers by utilizing high-yielding click chemistry as the key step (Figure 23).357 Likewise, the authors extended a similar click-inspired route to afford an additional variety of glycodendrimer. The sulfurated benzene core attached with clickable tris(hydroxymethyl)aminomethane (Tris)-derived alkynes on click conjugation with an organic azide, including α-mannopyranoside azide, resulted in the formation of a well-defined benzene core glycodendrimer.358 The developed dendrimers are unquestionably interesting, although no biological or material or catalytic activities were reported. In continuation, glycodendrimers with different cores, such as β-CD-based dendrimers as promising activators in cell adhesion and stimulation of monocyte or macrophage cell lines,359 multivalent presentation of mannose on hyperbranched polyglycerol, including their interaction with lectin,360 multivalent water-soluble organic nanoparticles via “surface clicking” of alkynylated surfactant micelles with sugar azides,361 and mannose-pendant conjugated polymers with veteran fluorescence self-quenching induced by ConA,362,363 were successfully developed by means of the well-established copper-catalyzed azide−alkyne cycloaddition reaction under mild conditions. Similarly, a series of multivalent neoglycoconjugates having two different sugar moieties with different anomeric and architectural configurations, different grafting patterns, and variable spacer length have been achieved by click-based strategies. Evaluation of the binding properties of these neoglycoconjugates toward ConA revealed that the substitution pattern and distance among the concerned sugars are the most significant parameters which influence the binding.364 The incorporation of specific ligands targeting the surface of a gallic acid−triethylene glycol dendrimer has been considered as a very capable tool in diagnosis and drug delivery systems. The versatility of such dendrimeric systems, the consequence of peripheral substitution on their uptake, and intracellular trafficking in living cells were recently further investigated. To

developed a series of very interesting glycopolymers containing 27, 81, and 243 residues of xylopyranoside sugar at the periphery of the dendrimer, for example, the giant glycopolymer 258 depicted in Figure 21.354 Likewise, the Sharpless group reported an extremely attractive diblock irregular glycodendrimer (259) which possesses dual functions of recognition and detection. With the aid of the convenient click protocol utilizing CuAAC as a key step of synthesis, a polyalkynylated dendritic scaffold containing a coumarin-based fluorophore was successfully clicked with a mannose-derived azide under standard click conditions to afford a high yield of glycodendrimer 259 (Figure 22).355 The reported glycodendrimer is known to cooperate with an appropriate receptor due to such modification at one end and, on the other hand, also facilitate detection of the concerned interaction, which is mainly due to the attachment of an appropriate core at the other end of glycodendrimer 259. Conclusively, compound 259 was acknowledged as extremely well-organized and to possess potent inhibitory activity of hemagglutination which was 240 times greater than that of the corresponding monomeric monosccharide unit. The functional groups present at the chain ends solely play a significant role in deciding the properties of the resulting macromolecule. This is obvious that if a sugar derivative with free hydroxyl groups is situated at the chain end of a glycodendrimer, it can formulate the availability for multivalent interactions. In addition, the extent of interaction in general is known to depend on the valency of the sugar; however, the reverse is not essentially always true mainly due to the scaffold flexibility, for example, PPIbased as well as PMAM-based dendrimers.356 Therefore, the click-inspired highly expedient protocol has been well utilized to obtain interesting, novel, and more stiff dendrimers useful to understand the topological effect on ligand interactions. In this regard, Roy et al. prepared a series of G(0) dendrimers 260 containing a rigid hexaphenylbenzene core with lactosylated and mannosylated residues at the chain ends of the periphery of the 3127


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Scheme 61. Click-Inspired Synthesis of Multivalent Neoglycoconjugates of MUC1308

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Scheme 62. Click-Inspired Conjugation of Two Glycopeptides with a Lipopeptide309

Figure 16. Structure of C-3-symmetric (1−6)-N-acetyl-β-D-glucosamine octadecasaccharide 221.324

Figure 17. Structures of click-inspired glycoclusters 221a and 222b as lectin inhibitors.

this end, biologically relevant ligands of different physicochemical properties have been selected to functionalize the surface of a dendrimer and also a PEG5000-dendritic block copolymer of [G3]-N3 (261). Due to the high degree of multivalency on the 27 peripheral azides, the core structure provides efficient conjugation as per the interest in the effective interaction with cell surfaces. Thus, the initial functionalization of [G3]-N3 (261a) with the alkynated fluorescein isothiocyanate (FITC) derivative 262a using the standard click reaction affords a high yield of the selective [G3]-FITC-N3 dendrimer (263a). Similar decoration of the remaining 26 azides with biologically relevant ligands, for example, glycosylalkyne 262b, affords the target glycodendrimer [G3]-FITC-Lac (264a) in an overall 77% yield (Scheme 73).365

The authors evaluated the consequence of peripheral groups on the cell uptake and also the intracellular trafficking of the gallic acid−triethylene glycol dendrimer. The modular architecture of the dendrimer systems may emerge as promising nanotools in biomedicine.365 Porphyrin derivatives have found application in cancer treatment, particularly in photodynamic therapy (PDT), which is known for more selective rather than traditional chemotherapy. Briefly, PDT requires three elements: a photosensitizer (e.g., porphyrins), light, and oxygen. The photosensitizer, upon exposure to a particular wavelength of light, generates lethal singlet oxygen that kills the tumor cell. 366,367 In the glycoconjugated porphyrin derivatives, the external glycosylated portion allows not only an increase in the water solubility, but 3129


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Scheme 63. Synthesis of Click-Derived CarbohydrateAppended Curdlans 223326

Scheme 64. Click-Inspired Synthesis of Multivalent Glycoclusters Containing 1−4 Residues of 1-Thio-β-Dgalactose (227a−d)

high yields (Scheme 74).369 Deacetylation of glycocluster 268 by treating it with ammonia in aqueous methanol under mild conditions afforded water-soluble glycoporphyrin dendrimer 269 in quantitative yield. Both the developed glycoclusters 268 and 269 were evaluated and function as monovalent probes as ligands of two different lectins, including ECA (agglutinin) from the legume plant Erythrina cristagalli and also recombinant human galectin-1. This class of molecules possess the promising chemotherapeutic potential useful for photodynamic therapy. The click protocol provides an ideal strategy to couple a porphyrin and carbohydrate together with triazole as a linker for new architectures of porphyrin glycoconjugates for different applications, including as water-soluble catalysts, photobactericidal cotton fabric material, liquid crystals, and therapeutics for photodynamic therapy (PDT).369−373 After the first contribution to click chemistry in a porphyrin system reported by Collman et al. in 2006,374 the methodology was extensively utilized for the synthesis of simple conjugates to the higher order porphyrincontaining dendrimers.369,375−378 The biological significance of glycoconjugated porphyrins in photodynamic therapy has been extensively studied, and that prompted us to develop porphyrin glycodendrimers. Utilizing the click-inspired convergent methodology, we recently developed a series of porphyrin-cored dendrimers (271−273) containing 8, 12, 16, and 24 β-Dglucopyranose residues at the periphery. Various first- and second-generation azide-functionalized dendrimeric wedges (270a−c) were obtained from simple starting materials through a series of facile reaction sequences and then coupled with the tetraalkyne-functionalized porphyrin core 267 (Scheme 75).379 The structure of the developed dendrimers was established by spectroscopic studies, including 1H and 13C NMR, MALDITOF-MS, IR, and size exclusion chromatography (SEC) analysis. The absorption−emission behavior of glycodendrimers and its modulation under the influence of a dendritic environment has been investigated, which showed insignificant changes in the porphyrin core upon addition of dendrons.379 On the other

Figure 18. Structures of multivalent mannoside-based clusters.

also tumor cell specificity. Moreover, the construction of a specific spatial arrangement of such glycodendrimers may allow the study of carbohydrate−protein interactions. Very recently, Snyder et al. developed a library of carbohydrate−porphyrin conjugates (CPCs) utilizing Cucatalyzed click chemistry. The authors reported a straightforward synthesis of a series of glycosylated porphyrins (265a−d) by clicking zinc(II) 5,15-bis(p-ethynylbiphenylyl)- or zinc(II) 5,10,15,20-tetrakis(p-ethynylbiphenylyl)porphyrin with several per-O-acetylated glycosyl azides under click reaction conditions (Figure 24).368 Because of their water solubility and other properties, these molecules are potential therapeutics for photodynamic therapy (PDT). Likewise, the MW-induced click reaction between an azidofunctionalized lactoside, 266, and a tetraalkynylated porphyrin scaffold, 267, afforded lactosylated porphyrin glycocluster 268 in 3130


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Scheme 65. MW-Induced Click Synthesis of Thiodigalactoside-Based Glycoclusters

Figure 19. Chemical structures of glycoclusters 232a−c and 233a−c as β-galactosidase inhibitors.

verified their ample suitability for those channels. The functional nature of such scaffolds may lead to additional exploitation of this thought to interfere with, control, or program carbohydrate binding to biological receptors. By taking advantage of the inclusion competency of the multivalent display, receptortargeted molecular delivery can be achieved through guest− multivalent display−lectin ternary complex formation provided that the corresponding supramolecular progression reveals an appropriate equilibrium constant. Chemical tailoring may be further put forward to endorse the development of glycomicelles,

hand, biological assessment for photodynamic therapy of the developed porphyrin-cored glycodendrimers has still not been reported. Through these well-established examples, a straightforward conclusiom can be made that the multivalency may amplify and thus modulate the biological information encoded by carbohydrates, one of the most abundant sources of natural products. Taking full advantage of this opinion requires suitable supports capable of presenting the code signs to the reader partner in an appropriate approach. Many multivalent systems have largely 3131


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Scheme 66. Click-Inspired Synthesis of an Oligomannose Glyocluster with a Cyclopeptide Platform

Scheme 67. Click-Inspired Development of β-Cyclodextrin-Containing Clusters

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Scheme 68. Synthesis of 12-Valent Iminosugar Clusters336

films, vesicles, or nanoparticles for different purposes, including sensing, diagnosing, or transport phenomena.

polymerization to furnish 276 via the ATRP technique.380 Route II made use of a TMS-protected propargylated methacrylate monomer, for example, 274b, to deliver the target glycopolymer 277 by means of the ARTP approach. Furthermore, trimethylsilyl protection was removed under standard conditions to produce the required alkynes for click purposes over which carbohydrates were placed. At the end, retro-Diels−Alder reaction of maleimide afforded the preferred glycopolymer 276 under simple and easily adoptable reaction conditions. Therefore, the aforementioned approach allowed access of the glycopolymer library retaining indistinguishable macromolecular features via alteration of the clickable glycosyl azide employed for the polymerization process.380 Route III presented a one-pot method for the CuAAC reaction between propargyl methacrylate 274a and an azido sugar combined with radical polymerization to afford 278.381These methods are quite useful and may be performed in industry to produce an appealing string of glycopolymers comprised of distinct sugars. CCCTP-mediated polymerization is a notable method which gives rise to ω-end-functional polymers with desired characteristics, including high chain end fidelity and controlled molecular weight. Recently, with consecutive utilization of CCCTP, the click protocol has been manifested to acquire the desired glycopolymers with wide applications. Homopolymerization of an alkyne monomer, for example, compound 274b, was first achieved under CoBF-mediated catalysis in the presence of azobis(isobutyronitrile) followed by TMS removal in the succeeding step. The polymer thus obtained has an ω-terminal vinyl group that can be functionalized by employing basecatalyzed 1,4-conjugate addition (thiol addition, popularly

7. GLYCOPOLYMERS During the past couple of years, the stepped-up implementation of glycopolymers in assorted domains of science and the simplistic synthetic approaches have instigated a surge of interest in synthesizing well-defined and multifunctional glycopolymers. The significantly productive and very adoptable click protocol has granted a method to functionalize polymer chains accompanied by numerous glycosides, and hence, it has turned out to be a perfect vehicle for polymerization.19,380 It has been brought into widespread service in coalition with diverse controlled polymerization approaches, such as atom transfer radical polymerization (ATRP),381,382 reversible addition fragmentation chain transfer (RAFT),383,384 ring opening polymerization (ROP),385 and cobalt catalyzed chain transfer polymerization (CCCTP),386 etc., to embody sugars over precise end groups, thereby accessing the complex glycopolymer framework. The click reaction favors both prepolymerization and postpolymerization functionalization. However, the latter is more recommended in practice because of its convenience, lower possibilities of any unwanted interaction among bulky functional groups, and sensitive polymerization approach. Haddelton and co-workers investigated the use of CuAAC in the preparation of glycopolymers functionalized with maleimide at the terminal position using the ATRP polymerization technique (Scheme 76, routes I−III). Accordingly, route I consisted of the CuAAC reaction of alkyne precursor 274a with an azido sugar to afford monomer 275, which underwent 3133


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Scheme 69. Synthesis of 21-Valent Iminosugar Dendrimer Using Click Chemistry336

known as “thiol−ene click”). Thereupon, various glycosyl azides were permitted to click with alkynes 279a,b under click reaction conditions by using CuBr in the presence of triethylamine in DMSO at 60 °C and afforded an interesting series of glycopolymers 280 consisting of different sugars (Scheme 77).385 Another productive polymerization approach is RAFT, which establishes a suitable functionality at the α- and ω-positions of the polymers. In addition, from the functionality control aspect, the method is reliable because it holds a good command over the molecular weight as well as polydispersity. Assorted quantities of glycopolymers have been produced employing the RAFTmediated click-inspired procedure. A representative example includes the very interesting work of the Stenzel group where click-inspired mannose-based glycopolymer 282, known to be reluctant to hydrolysis, was achieved with appreciable ease. The authors developed an inimitable monomer, for example, mannosylated 4-vinyltriazole 281, through the highly facile click protocol and polymerized it in the presence of a RAFT agent, 3-[[(benzylsulfanyl)thiocarbonyl]sulfanyl]propionic acid, to fabricate glycopolymer 282 (Scheme 78).383 Glycopolymers possessing a fluorescent residue at the carbohydrate scaffold have turned out to be an appealing contender meant for investigating several biological events, including biosensing owing to their biocompatibility, carbohydrate−lectin interactions, etc. In another investigation, Stenzel and co-workers prepared block polymers of poly(diethylene glycol methyl ether methacrylate) (PDEGMA) with poly(2hydroxyethyl methacrylate) (PHEMA) and poly(polyethylene

glycol methyl ether monomethacrylate) (PPEGMA) employing the RAFT polymerization process. Simple propargylation using propargyl bromide under basic conditions was used for the functionalization of the polymer that on clicking with different sugar azides under click reaction conditions afforded a thermoresponsive glycopolymer having interesting biological activities, such as a potent ricin toxin inhibitor.386 Making use of the same tactics, a polyfluorene-based glycopolymer, 284, has been synthesized which displays significant fluorescence quenching when occupied by a Ca2+ ion, likely due to the copper(II) arbitrate aggregation. Thus, commencing with fluorine with a clickable propargylated arm on clicking with fully acetylated lactosyl azide under standard click reaction conditions resulted in the formation of the preferred monomer 283 with great ease. Subsequent Suzuki−Miyaura coupling of compound 283 followed by deacetylation in the presence of NaOMe in methanol as the standard conditions afforded an interesting glycopolymer, 284 (Scheme 79).387 Similarly, a carbazole-based glycoconjugate was synthesized by Chen and Han via combination of the CuAAC reaction and Suzuki coupling.388 Suitably protected and unprotected sugar moieties were grafted onto polymers featuring a narrow molecular weight distribution by the simple Cu(I)-catalyzed click protocol. Poly(methacrylate)s bearing a terminal alkyne functionality, on clicking with C-6 or an α- or β-anomeric sugar azide, afford a series of polymer-supported carbohydrate materials 285. Following a coclicking synthetic protocol, a number of galactoseand mannose-containing multidentate ligands were developed (Scheme 80).389 3134


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Scheme 70. Synthesis of a Fullerene Iminosugar-Based Dendrimer341

Figure 20. Structure of cyclodextrin-based mannose star glycopolymer 254.

of molecules is not amenable to the large-scale synthesis for their industrial commercialization to be of human use. Huang and co-workers devised a click-chemistry-based approach for the development of polyphosphazene glycopolymers, wherein alkyne-functionalized poly(dichlorophosphazene) was mounted with carbohydrate-based azides using CuAAC.391 With further continuation of a similar established protocol, Reineke and co-workers synthesized a diazo trehalose monomer which was subjected to a polymerization process by treating the azide monomer with diverse dialkyne− oligoamine units linked with a secondary amine with Boc protection. The authors explored the click reaction for polymerization purposes via clicking a bisazido disaccharide (287) with alkynes 288a−c under standard click conditions (CuSO4/NaAsc in aqueous alcohol) and furnished macromolecular structures 289a−c, which on subsequent deacetylation and Boc removal were successfully converted to wellorganized glycopolymers 290a−c in good yields (Scheme 81).392 The resulting water-soluble glycopolymers were acknowledged as impressive carriers of nucleic acids. Furthermore, a highly efficient, versatile, and modular click-chemistry-combined cascade strategy was successfully utilized for one-pot synthesis of sugar-based polyfunctional macromolecules.393 Nguyen et al. reported an attractive and very adoptable synthesis of a bivalent, ring-opening metathesis polymerization

Capicciotti and co-workers reported a solid-phase synthesis of triazolyl-AFGP (antifreeze glycoprotein) analogues using a convergent approach, where multiple carbohydrate-containing molecules were coupled to a resin-bound peptide of synthetic origin in a single step.390 Adopting the routine click reaction conditions in the presence of CuSO4/NaAsc under MW radiation in dry DMF and treating the sugar azide with the appropriate peptidylalkyne resulted in the formation of the desired AFGP analogues in reasonably acceptable yield (Figure 25). Some of the developed compounds (286a and 286b) were recognized as moderate inhibitors of ice recrystallization. Although the triazole is well-known as a structural mimetic of an amide, the presence of the amide bond in addition to the triazole in the AFGP analogue is essential for its potent ice recrystallization inhibition (IRI) activity. C-Linked antifreeze glycoprotein derivatives have been shown to have potent IRI activity. On the other hand, the tedious synthesis of such a class 3135


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Scheme 71. Synthesis of Cyclodextrin-Based Mannose Glycoclusters and Star Glycopolymers

(WGA) on the basis of a fluorescence change of tryptophan in WGA.397 Prior to the employment of click chemistry, the synthesis of sugar monomers was hindered mainly because of the requirement of a number of protection−deprotection steps in carbohydrate chemistry and also chemo- and/or stereoselectivity. The incorporation of the Cu-catalyzed click procedure allows sugar monomers to be prepared first with great ease by the introduction of a clickable azide or alkyne functionality. However, the complete removal of the used copper catalyst still remains a challenge for evaluation of the biological applications of click products. This reaction has been utilized to develop interesting and useful glycopolymers with different topologies and carbohydrate contents. It has also been demonstrated to be a facile route to glycomonomers as well as a promising class of monomers based on vinyltriazole.

(ROMP)-capable monomer. This monomer has the ability to be polymerized well under normal conditions of the polymerization reaction into the corresponding neoglycopolymer, which was found to be a mimetic of the surface glycans on the gp120 envelope spike of the HIV virus. This click-inspired strategy for the orthogonal attachment of both the terminal Man-α-(1− 2)Man disaccharide unit of the D1 arm of Man9GlcNAc2 of HIV gp120 and the terminal Man-α-(1−2) unit of its D2 arm to a bivalent scaffold was well utilized to produce the resultant polymerizable monomer 291 (Figure 26).394 The surface modification of the azido-AcDEX (AcDEX = acetylated dextran) nanoparticles with a suitably functionalized mannosylated alkyne was accomplished with the aid of the highly efficient ligand-assisted click reaction under mild reaction conditions. Azido-AcDEX particle 292 was first suspended in N-(2-hydroxyethyl)piperazine-N′-ethanesulfonic acid (HEPES) buffer (concentration 0.1 M, pH 8.0) and then reacted with an alkynylated mannoside, 293, in the presence of CuSO4/NaAsc and tris(benzimidazolylmethyl)amines (e.g., tripotassium 5,5′,5″-[2,2′,2″-nitrilotris(methylene)tris(1H-benzimidazole2,1-diyl)]tripentanoate hydrate, (BimC4A)3, 8a, a commanding ligand commonly used for click purposes) to afford a good yield of the designed Man-AcDEX particle 294. Reaction in the presence of Cu-stabilizing ligand 8a makes the protocol more significant with an incremental rise in the rate of click coupling (Scheme 82).395 Interestingly, this particulate system made of a dextran-based pH-sensitive material could be engineered to exhibit immunomodulatory properties as per the existing procedure.396 The authors nicely demonstrated that the mannose monosaccharidetargeted cellular uptake by dendritic cells (DCs) results in an improved major histocompatibility complex class I (MHC I) antigen in comparison to that of the nontargeted particles. Matsuoka et al. reported a convenient access to glycopolymers by using a styrene-modified glycomonomer prepared from (chloromethyl)styrene as a key starting material and N-acetyl-Dglucosamine as a model carbohydrate monomer. The methodology concerned one-step conversion of the styrene derivative to an azidostyrene, which on treatment with a propargyl-GlcNAc furnished a carbohydrate monomer (295) after deprotection in good yield (Scheme 83).397 The water-soluble GlcNAc monomer was polymerized with or without acrylamide to give the corresponding white powdery glycopolymers, which were evaluated for their interaction against wheatgerm agglutinin

8. CLICK-INSPIRED CHEMICALLY MODIFIED NUCLEOSIDES Suppression of gene expression by synthesizing antisense oligonucleotides via the introduction of chemically modified nucleosides has gained a lot of attention.398,399 The synthesis of functionalized oligonucleotide derivatives, particularly those with a chemically tailored phosphate backbone, to evade both the physical and biological restrictions of the normal phosphodiester linkage, is under way in drug discovery research.400 The triazole formed by the Cu-catalyzed azide−alkyne cycloaddition (CuAAC) reaction has been well utilized as a linker in place of the phosphodiester linkage.401,402 In this connection, Lucas et al. has developed a well-defined 1,4-disubstituted triazole-linked 3′−5′-thymidine dimer as well a pentamer through clicking of the corresponding azido and propargyl precursors under normal click reaction conditions.403 Isobe and co-workers extended the synthesis of a suitably 1,4-disubstituted triazole-linked 10-mer analogue of thymine DNA which has a melting temperature (Tm = 61.1 °C) much higher than that of the corresponding DNA d(T)10 (Tm = 20.0 °C).404 Very recently, Prasad et al. synthesized an interesting triazole-linked nonionic xylo nucleoside dimer (298) including TL-t-TxL, TL-t-ABzxL, and TL-t-CBzxL using the CuAAC reaction of azide 296 and alkyne 297 (Scheme 84).405 Nucleic acid conjugates have widespread applications in biomedicine, such as in diagnostics and also in therapy, especially for cancer treatment. Very recently, Micura et al. successfully developed the synthesis of RNA conjugates bearing a fluorescent 3136


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Scheme 72. Click-Derived C-5-Symmetric Glycoconjugated Fullerene344

tag.406 The click reaction between 2-O-(2-azidoethyl)-RNA 299 and the fluorescent rhodamine alkyne derivative F545 (300) in the presence of the widely utilized click catalytic system CuSO4/ NaAsc afforded the dye-labeled RNA 301 (Scheme 85). The investigation was focused on inverse click labeling patterns and functionalized RNA with an azido group, instead of the traditional alkyne group. This alternative approach allows an increase in the versatility and an expansion of the range of applications of Staundiger ligation.407 Concerning the extension of the siRNA modification strategy,408 the authors have nicely developed three RNA duplexes endowed with a fluorescent label, F545. The work reported has strengthened the literature and given great scope to further investigation of bioconjugation using a click variant.

Furthermore, Pujari et al. utilized the copper-catalyzed click chemistry for the creation of cross-linking in DNA strands by clicking both the individual two complementary strands of oligonucleotide derivatives 2′-O-propargylated 2-aminoadenosine 302 and propargylated timidine nucleoside 303 with a diazido compound.409 The cycloaddition was performed in a stepwise manner to avoid side reactions such as homo-DNA duplex formation, which is the common problem faced in similar reaction sequences. Excess bisazide (alkyne/azide, in a 1:15 ratio) in the presence of Cu wire in H2O/MeCN was used for the selective formation of the monofunctionalized azido derivative from alkyne 302. Then, a subsequent second click was performed between the resulting azido intermediate and propargylated timidine nucleoside 303 to afford the cross-linked strands 304 3137


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Figure 21. Structure of glycodendrimer 258 containing of 243 xylopyranoside residues at the periphery.354

(Scheme 86).409 The developed cross-linked DNA conjugates may have promising applications in cancer therapy. Yamada et al. reported an exceedingly well-organized synthetic strategy to prepare oligoribonucleotide−ligand conjugates by utilizing the Cu(I)-catalyzed click condition, where the glycoconjugated oligonucleotide product was revealed to be useful for high-throughput assay.410 The authors utilized the clicking protocol at the monomer level aforementioned for oligonucleotide synthesis, followed by solution-phase postsynthetic “click conjugation”, and then an analogous conjugation on an immobilized oligonucleotide scaffold having a propargylated

moiety. Azido-functionalized ligands bearing an interesting group, including a lipophilic long chain alkyl group, cholesterol, oligoamine, and carbohydrate, etc., were successfully utilized to investigate the effect of the physicochemical features of the incoming clickable azide group on click-inspired triazole conjugation to the alkyne−oligonucleotide scaffold in solution and on an immobilized solid support. The MW-induced clicking of azido-functionalized ligands to a completely protected alkyne−oligonucleotide solid support preceding deprotection has been found to be an efficient “click conjugation strategy” useful for site-specific, high-throughput oligonucleotide con3138


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Figure 22. Structure of irregular glycodendrimer 259 containing coumarin as a fluorophore and triazolylmannose as a sugar residue at the end.355

jugate synthesis (Scheme 87).410 The developed siRNA conjugates effectively silenced the expression of a luciferase gene in a firmly transformed HeLa cell line. The postsynthetic connection of an azido-containing porphyrin to oligonucleotides having a 2′-O-propargylated uridine as well as an adenosine was successfully achieved in good yields via click coupling under mild reaction conditions.411 CuSO4/NaAsc in DMSO/H2O at room temperature for 72 h was used for clicking, if the oligonucleotides (ONs) contained just one propargyl group; however, for the incorporation of multiple porphyrins into ONs, microwave irradiation for 20 min at 70 °C was utilized, which resulted in almost total conversion of the starting ONs to the desired dendrimer.412 Campidelli and co-workers extended a similar chemistry and developed a porphyrin−oligonucleotide hybrid containing four oligonucleotides around the porphyrin core (307) (Scheme 88). For the CuAAC coupling, a mixture of N-methylpyrrolidone/ H2O was used as the solvent and the reaction was performed by utilizing the CuI/DIPEA catalytic system at rt. The 14-mer complementary strand having a thiol group was first incubated with the oligonucleotide hybrid and then after being exposed to the gold nanoparticles was imaged using transmission electron microscopy (TEM).413 Recently, a very interesting protein-mediated CuAAC click reaction with a human copper-binding chaperone was reported for the development of functionalized oligonucleotides 309

(Scheme 89).414 Ultramild labeling conditions, including the use of an aerated solution, low [Cu], and no need for any additional reagents, make this protocol green and highly acceptable to use in biological systems. Furthermore, the products obtained were probes for high binding affinity, specificity, and also Ph sensitivity of fluorescence. In addition to the carbohydrate, some peptide and fluorophore derivatives were also reported to display a remarkable selectivity as well as a high binding affinity for nucleic acid (DNA/RNA) targets.414 In another investigation, Neef et al. reported that cells which were infected by means of herpes simplex virus-1 could be selectively labeled by way of the gemcitabine metabolite analogue dF-EdU (2′-deoxy-2′,2′-difluoro-5-ethynyluridine) and a fluorophore containing an azide group via click chemistry. The selectivity in labeling is because of the phosphorylation of dFEdU mediated through viral, not human, thymidine kinases. This finding established an attractive and novel advancement for pathogen-specific bioorthogonal chemical labeling.415 The click protocol has been efficiently applied in the chemical modification of nucleic acids for different purposes.22,49 Very recently, Cassinelli et al. reported the construction of an interesting interlocked catenane ring system consisting of 24 DNA single strands. The architecture was brilliantly assembled via click chemistry between the six helix tubes having a 3′-alkyne- and 5′azido-functionalized system through single-stranded tiles. The authors showed how intramolecular cyclization stabilizes these 3139


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Figure 23. Click-inspired hexaphenylbenzene-centered glycodendrimers 260a and 260b.

DNA nanotubes against enzymatic degradation as well as thermal degradation.416 In a multifaceted combinatorial approach, Morvan and coworkers nicely utilized the click-combined phosphoramide chemistry and successfully developed a series of carbohydratelabeled oligonucleotides (313a−c) with wide applications. This chemistry was carried out over a solid support under very adoptable reaction conditions. The clickable alkyne 311 on the solid support, which contains a phosphodiester backbone, on MW-induced click coupling independently with different galactosyl azides, including compounds 312a and 312b, followed by routine deacetylation using an NH4OH solution under standard mild reaction condtions afforded the targeted carbohydrate-labeled oligonucleotides 313a−c (Scheme 90).417 A great variety of multivalent modified glycomolecules of sachharide-labeled oligonucleotides with a diverse arrangement

of carbohydrates could be achieved and have wide applications in chemical biology. Using a similar approach, the authors nicely established labeling of oligonucleotides by means of glycoclusters generated as part of two suitably substituted sugars, leading to mannose- or galactose-centered oligonucleotides, some at the 5′- or 3′-end or between the DNA chains. A frequent synthetic method includes straightforward click coupling to set up 1-O-propargyl-α-Dmannopyranoside on a solid support scaffold under standard click conditions with resin-bound compound 314, affording a high yield of mannose-conjugated derivative 315. Compound 315 having four free hydroxyl groups on subsequent reaction with the pentyn-4-yl of 6-bromohexyl phosphoramidites 316 afforded the required oligonucleotide 317, which has an elongated oligonucleotide chain containing an alkyne group suitable for click purposes. A second click coupling under normal 3140


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Scheme 73. Synthesis of [G3]-FITC-Lac and PEG-[G3]-FITC-Lac Glycodendrimers365

Figure 24. Glycosylated porphyrins 265a−d developed by click chemistry.

click conditions afforded the glycocluster 318, which was well

To obtain an ideal novel biological tool for pharmaceutical use, nucleic acids and their oligomers have frequently been proven to have a great advantage in recent years. For oligonucleotides, chemical modification can be used to moderate certain challenging features intrinsic in their native structure, for

utilized to produce an attractive series of targeted glycoclusterlabeled oligonucleotides 319 vital for the 3′-end labeling of the concerned oligonucleotide (Scheme 91).418 3141


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Scheme 74. Synthesis of Lactosylated Porphyrin Dendrimers

Effectively, the triazole ring results in an ideal linker in bioconjugation, as (a) it presents a good water solubility, thus allowing in vivo administration, (b) it is analogous to an amide function for its electronic properties, but is resistant to hydrolysis, (c) it is sufficiently stable in biological systems, and finally (iv) it is a rigid linker, which allows internal interaction between the two linked moieties to be avoided.420−422 Most commonly used bioconjugation methods, for example, isothiocyanate−amine, thiol−maleimide, and amine−carboxylic acid couplings, etc., are not used for in vivo labeling due to competing nucleophiles on nucleic acids, proteins, and other biopolymers.423−425 Labeling of biomolecules in biological systems, using well-known condensation reactions between carbonyl compounds (aldehydes or ketones) and hydrazides or aminoxy or related compounds, is not reasonable at the optimum pH of 5.0−6.0, as such linkages are reversible.426 The outstanding reaction profile of the Cu(I)-catalyzed clicked ligation of clickable azides and terminal alkynes has seen high success in bioconjugation chemistry for chemical ligation of two or more biomolecules by means of chemoselective reactions which are known to be orthogonal toward biological species. Only very few other reactions, for example, the native ligations427,428 derived from the intein process in ecology and the well-known Staudinger ligation, present suitable properties comparable to those of the CuAAC reaction.429

example, the polyanionic backbone and their susceptibility to nuclease-mediated cleavage. Furthermore, it is also used to append novel functionalities on the nucleic acid molecule for other downstream biomedical applications. The Cu(I)-catalyzed click technique certainly provides a flexible medium through which nucleic acids can be directly modified with great ease. Whether the goal is the creation of novel biopolymers, bioconjugated superstructures, polymerized chain reaction (PCR) templates, or gene-silencing or antiviral agents, the possibilities presented by a well-accepted modular click-based strategy are endless, particularly when considering the number of amendable sites present on natural nucleosides.

9. “CARBO-CLICK” IN BIOCONJUGATION AND LABELING Bioconjugation, a process of coupling a biomolecular building block (e.g., antibodies, nucleic acids, receptor binding proteins, and carbohydrates) with a xenobiotic (e.g., drugs and fluorescent tags), is a widely useful protocol in pharmaceutical sciences for several purposes, including drug delivery systems, therapy, and diagnostics. This is an interesting and useful method for understanding physiological and physiopathological functions, and in studying endogenous targets, enzymatic activity, and molecular recognition.419 The option to combine bionconjugation with click chemistry has emerged as a versatile tool with a wide range of applications. 3142


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Scheme 75. Development of Glycoconjugated Porphyrin Dendrimers379

Bertozzi et al. employed a click-inspired bioconjugation protocol intended for the detection of fucosylated glycoproteins of great biological significance. The protocol commenced with labeling related to the metabolic process on the surface of glycoproteins present in human T-lymphoma jurkat cells, which was completed through a fucosylated azide by means of the salvage reporter protocol and could be successfully analyzed in the subsequent step. Click-inspired chemistry was then implemented with the clickable azide-based lysates 321a−c

(obtained from the corresponding fucose-based azides 320a−c) with biotin-based alkyne 322 using a modified catalytic system comprised of CuSO4 as the standard Cu(II) source, TCEP as the reducing agent, and a well-known rate-accelerating triazole-based ligand, for example, BTTES, as the key step and afforded the desired triazole-labeled glycoproteins 323 under very adoptable mild reaction conditions (Scheme 92).430 The triazole-labeled glycoprotein was linked with an α-biotinylated antibody horseradish peroxidase (HRP) conjugate. The authors success3143


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Scheme 76. ARTP-Associated Click-Inspired Synthesis of a Glycopolymer380,381

Scheme 77. Combined CCCTP−Click Protocol Leading to the Formation of Glycopolymers 280a−c385

Scheme 78. Click-Inspired Synthesis of Glycopolymer 282 in the Presence of RAFT Agent383

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Scheme 79. Click-Inspired Polymerization Leading to a Fluorescent Backbone via Suzuki Coupling387

Scheme 80. Synthesis of Neoglycopolymer 285 via the “Combined Click−Living Radical Polymerization Approach” 389

Figure 25. Triazole-containing AFGP analogues 286.

workers explored the click protocol for analogous detection of fucose-based glycoproteins isolated from Bacteroidales. For this purpose, the bacteria were reacted with fucose-based alkyne 324, and then on routine metabolization through Bacteroidales successfully included in fucosylated glycoproteins present on the cell surface. The resulting alkyne-linked glycoprotein 325 was then clicked with a biotinylated azide using a Cu(I) source in the presence of another rate-accelerating triazole-based ligand, for example, BTTAA (2-[4-{(bis[(1-tert-butyl-1H-1,2,3-triazol-4yl)methyl]amino)methyl}-1H-1,2,3-triazol-1-yl]acetic acid), as the key step followed by cell lysis and a related bioprocess to

fully labeled fucosylated glycoproteins in human cells through click-inspired conjugation with azide 320c. Similar investigation with the other two azides (320a and 320b) confirmed that they were inactive, possibly because of the unnatural substrate tolerances of the enzymes. Bertozzi’s click-inspired bioconjugation protocol utilizing a 6-azidofucose-based monosaccharide has obvious wide applications in chemical biology, including for profiling protein fucosylation in biological systems. Members of the bacteroidales order may nicely adorn the fucose-containing cell-surface glycoproteins of promising use in chemical biology. In another investigation, Webler and co3145


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Scheme 81. Polymerization under Click Conditions392

Scheme 82. (BimC4A)3-Assisted Click Stirred Synthesis of the Mannosylated AcDEX Particle395

Figure 26. Structure of Man9GlcNAc2 and the terminal Man-α-(1−2) unit to form a bivalent scaffold with a polymerizable monomer.394

successfully afford the target triazole-labeled glycoproteins 326 and 327 under mild reaction conditions (Scheme 93).431 The protocol is highly sensitive as well as specific, can be significantly used to detect fucose-containing glycoproteins, and has promising applications in advanced glycoproteomic investigations. Both of the related glycoproteins are known to be involved in several cell−cell recognition processes, and the fucosylated one can be explored as a promising marker of tissue. Finn’s group demonstrated a click-inspired protocol for the chemoselective attachment of several important molecules to cowpea mosaic virus. Using standard N-hydroxysuccinimide (NHS) ester chemistry, the viral capsids were labeled with sugar azides, and subsequent clicking with a dye-derived chromophoric dialkyne (328) in the presence of CuSO4 and NaAsc under mild conditions furnished dye−alkyne derivatives 329. The authors realized the bioconjugation of the click partners giving the glycosylated virus 330 work efficiently under optimized conditions of a Cu(I) source (1 mM), including [Cu(CH3CN)4]OTf, [Cu(CH3CN)4]PF6, or CuBr, in the presence of rate-accelerating ligand 8 (3.0 equiv) as the key step (Scheme 94).432,433 However, the reaction was air sensitive and required an inert atmosphere for efficient CuAAC. A series of clickable oligomannose analogues (333a−c) were utilized as potential building blocks for the synthesis of virus

glycoconjugates, for example, a sugar immunogen to target HIV1. A two-step strategy was employed to generate the desired virus glycoconjugates 334a−c, first to acylate the surface amino groups using excess alkynyl N-hydroxysuccinimide ester 331 and then click with azides 333a−c under standard click conditions (Scheme 95).434 The click step was significantly enhanced by using ligand 8. Interestingly, the Qβ glycoconjugates with oligomannose clusters were shown to bind the antibody 2G12 with high affinity. The executed click-inspired protocol can be considered as valuable for the development of an interesting sugar-based vaccine component for HIV.434 Likewise, a similar chemistry was successfully implemented to demonstrate a very weak tumor-associated carbohydrate antigen 3146


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Scheme 86. Synthesis of Cross-Linked DNA Strands 304409

Scheme 83. Synthesis of Glycopolymers from a StyreneModified Glycomonomer397

Scheme 84. Click-Inspired Synthesis of a Chemically Modified Nucleoside

A fluorogenic probe triggered by bio-orthogonal chemical reactions has been successfully used for biomolecular imaging. However, during such a process, it is still tough to find a suitable probe for the identification of a structure to go through a dramatic fluorescence enhancement. In recent years, a number of reports have maintained that the click protocol is nicely used for fluorescence labeling in cellular systems. Sawa et al. commenced a similar click-inspired protocol using structurally related glycans bearing clickable azide groups.435 A fucose-based triazole as the fluorescent probe (340) was developed from a nonfluorescent precursor, for example, alkyne 338a, by clicking it with sugar azide 339b under click reaction conditions (Scheme 97).435 The authors successfully demonstrated the incorporation of the fucose-based azide into glycoproteins via the fucose salvage

(TACA) on bacteriophage Qβ viruslike particles 337a,b which elicit responses to the carbohydrate (Scheme 96). Glycan microarray analysis was used to confirm the selectivity of developed antibodies with Tn antigens, where developed IgG antibodies were found to react with the native Tn antigens on human leukemia cells. This brilliant investigation is preferred for the development of sugar-based anticancer vaccines by using viruslike particles as a potent antigen delivery system.84

Scheme 85. Synthesis of RNA Conjugate 301 via CuAAC Chemistry407

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into cell surface glycoproteins 345 (Scheme 98).436,437 The experiment was then repeated, but without the washing step, wherein the strong fluorescence signal of this azide dye resulted a a high background under no-wash conditions.438 The target identification of pharmacologically active molecules principally relies on affinity chromatography, activity-based probes, or photoaffinity labeling.439 The Click-to-kill concept was recently demonstrated by Perrin et al., where the synthesis of a cytotoxic amanitin analogue for biorthogonal conjugation was achieved using click chemistry. The developed amanitin analogue with a pendant propargylamide was shown to be as cytotoxic as the natural α-amanitin. The synthetic toxin was conjugated to peptides known to target the toxin to cells and reporters for fluorescent studies.440 Ballell and co-workers reported a multivalent photoaffinity probe for visualization of galectin-3 in biological protein mixtures. The method entailed the synthesis of lactose-derived azide 346, which was clicked with 3,5-bis(propargyloxy)benzoic acid using the standard catalytic system CuSO4/NaAsc under microwave heating conditions for 20 min and afforded triazole in 84% yield. The resulting triazole-containing acid on subsequent amide coupling using propargylamine in the presence of BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and DIPEA followed by deacetylation under standard reaction conditions afforded a high yield of divalent probe 347. The alkyne 347 was exploited to label galectin-3 and attached dye−azide 348 to the labeled protein via the propargylamide using a second click using CuSO4/TCEP under mild reaction conditions (Scheme 99).441 The authors reported the remarkable ability of the probe for the selective visualization of galectin-3 in protein mixtures even in cell lysates. Likewise, the authors extended the protocol and developed a Lac-based probe which could be useful for understanding the carbohydrate-binding protein interactions of galectin-1. The ethylene glycol linkers were used for imparting water-solubilizing properties, and introduction of an azide function at the terminus was used to achieve chemoselective click ligation with alkynes. The labeled proteins 351 were visualized in-gel by “clicking-on” a rhodamine moiety afterward (Scheme 100). The methodology was advantageous in terms of versatility and simplicity.442 A similar chemistry was implemented for the noninvasive imaging of fucosylated glycans in a zebrafish model, where the authors found the protocol to be promising for rapid in vivo imaging of biomolecules.86 Furthermore, the click protocol used for the conjugation of clickable azido glycan 352 with alkyne probes, for example, 353a−c, including rhodamine- as well as biotin-based alkynes, under standard click ligation conditions using CuSO4/NaAsc in the presence of the ligand THPTA (5c) afforded a high yield of the corresponding triazole 354 (Scheme 101).443 Through this investigation, the authors established the labeling of cell-surface glycans on mammalian cells in culture without a loss of cell viability. Likewise, Soriano et al. reported the use of the ligand BTTES (6) for biocompatible click chemistry between alkyne 355 and biotin azide, or alternatively the click chemistry between the azide 357 and a biotin alkyne to afford respectively compounds 356 and 358 (Scheme 102).85 This protocol has wide applications, especially in the detection of glycoconjugates present on the surface of live cells. In addition, mucin-related glycoproteins were successfully detected through the chemical reporter technique and also the in-gel fluorescence scanning method.444,445 Bertozzi et al. demonstrated that the metabolic cross-talk between the GalNAz

Scheme 87. Cu-Catalyzed Clicking of a GalNAc-Based Azide with Porpargylated Oligonucleotide 306410

pathway. Fluorescence microscopy was used to visualize the intracellular localization of glycoconjugate 341. This clicktriggered fluorogenic labeling protocol was adequately sensitive and also selective to visualize fucosylated glycoproteins in cells. By considering the benefit of the practical relationship between EHOMO of a pendant aryl substituent and the fluorescence quantum yield, the Bertozzi group identified a potential fluorogenic azidofluorescein analogue, (4azidonaphthyl)fluorescein (344), to label proteins having a clickable alkyne (343) and also the glycoproteins on cells with an exceptional selectivity. The authors carried out the metabolic labeling of Chinese hamster ovary cells at a 50 μM concentration for 3 days and established 342 as a biological imaging reagent.436,437 Bovine serum albumin (BSA) was functionalized with peracetylated N-(4-pentynoyl)mannosamine to determine the selectivity of 342 to label alkyne-tagged proteins. These cells converted mannosylated alkyne Ac4ManNAl to the corresponding alkynylsialic acid, which was then clicked with (4azidonaphthyl)fluorescein (344) using CuSO4/NaAsc and TBTA as standard click conditions, and sucessffully incorporated 3148


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Scheme 88. Synthesis of Porphyrin−Oligonucleotide Hybrid 308413

GlcNAz and is tagged on an azido sugar on its native substrates, which can be easily detected through click-inspired labeling using an appropriate probe.446 Furthermore, Jiang et al. reported a fast protocol for labeling glycans on the cell surface, especially an alkynylated protein in crude cell lysates, using click-accelerating ligands, for example, BTTPS (3-[4-({bis[(1-tert-butyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)-1H-1,2,3-triazol-1-yl]propyl hydrogen sulfate) and BTTP (3-[4-({bis[(1-tert-butyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)-1H-1,2,3-triazol-1-yl]propanol), in combination with a clickable picolyl azide derivative. This methodology demonstrated 5-fold-increased sensitivity compared to that with a nonchelating azide with Western-blot-based detection. The authors achieved 20−38-fold greater efficiency in click-inspired conjugation in living systems with nondetectable toxicity when an electron-donating picolyl azide was used. Furthermore, this azide in combination with BTTPS was used to detect the click-triggered cell-surface glycans using flow cytometry (Scheme 103). In live mammalian cells, about 30− 45 min was required for a monosaccharide building block, 359, to be metabolized and incorporated into cell-surface glycoconju-

Scheme 89. Protein-Mediated Click Reaction with a Human Cu-Binding Chaperone for the Synthesis of Functionalized Oligonucleotides414

salvage and O-GlcNAcylation pathways may be used for the identification of O-GlcNAcylated proteins. At the first step, N(azidoacetyl)galactosamine is metabolized and then epimerized to UDP-N-(azidoacetyl)glucosamine (UDP = uridine diphosphate). Subsequently, O-GlcNAc transferase accepts UDP3149


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Scheme 90. Solid-Supported Click-Inspired Protocol Valuable for Designing Multiple Labeled Oligonucleotides417

gates. The glycans were detected as early as the two-cell stage. This was the first report where such labeled glycans 361 were detected, for example, in zebrafish embryos, in an animal model using bioorthogonal click chemistry.447 The excellent credibility, regioselectivity, and bioorthogonal property of the click reaction make it an important strategy for probing and perturbation of biosystems. Since this technique allows real-time detection in vivo, it is a valuable tool for elucidation of the spatial and temporal aspects of biomolecular functions. A creative approach toward the development of innovative and smart strategies should be employed for exploration of the click reaction in this field to enhance its potency.448 The advancement of technological facilities related to this field is also required for harnessing the click methodology more effectively. Various chemical and enzymatic changes that occur to derivatized probes after they enter the cell are other drawbacks related to the use of bioorthogonal labeling, which

should be controlled precisely to take full advantage of click chemistry in bioconjugation and labeling.

10. CARBOHYDRATE MICROARRAYS AND SELF-ASSEMBLED MONOLAYERS Carbohydrate microarrays, which are framed by immobilization of thousands of glycans over a solid surface with high density and in a well-ordered manner, have attained much consideration as a highly potent and provident means to study the functional behavior of many glycans and glycan-binding proteins simultaneously.449,450 Development of advanced analytical methods, such as quartz crystal microbalance (QCM)453,454 and surface plasmon resonance (SPR),451,452 which do not require labeling, as well as surface-based real-time techniques, has significantly supported the exploration of carbohydrate microarrays in the field of biology and biomedics to assist in the discovery of novel diagnostic tools and therapeutics. The Cu(I)3150


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Scheme 91. Click-Inspired Synthesis of Oligonucleotide-Conjugated Mannose-Centered Glycodendrimer418

catalyzed click reaction has emerged as the most appropriate and convenient approach for attachment of azide- or alkynefunctionalized glycoconjugates onto various alkyne/azide counterpart grafted solid surfaces in a multivalent manner. The credit for introducing the azide−alkyne click reaction in the development of carbohydrate microarrays goes to Wong et al., who employed this facile reaction for synthesis and in situ immobilization of saccharides onto the solid surface of a microtiter plate.455 They developed an alkyne-functionalized

polystyrene microtiter plate via noncovalent binding with terminal akynes, containing aliphatic chains of 14 carbon atoms. This alkyne-functionalized plate was clicked with 11 different sugar azides through CuAAC in methanol solvent at room temperature, and finally their extent of derivatization by fucosyl and/or sialyl entities was studied by evaluating them against various potential lectin inhibitors. Furthermore, enzynmatic fucosylation of a microtiter-plate-attached N3151


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Scheme 92. Bertozzi’s Click-Inspired Bioconjugation Using a Fucose-Based Azide for the Detection of Fucose-Containing Glycoproteins430

Scheme 93. Click-Inspired Parallel Bioconjugation Using Fucose-Based Alkyne 325431

acetylglucosamine entity afforded sialyl Lewis X, which showed IC50 values consistent with previous studies in solvent.455 Soon after, Wong et al. modified the strategy to facilitate a recyclable and much stronger covalently linked array which can be characterized by standard analytical methods such as the NMR technique and mass spectometry.456 The modified strategy avoided use of long lipid chains and included a disulfide bond as an easily cleavable site. Alkyne-functionalized solid surface 364 can be afforded either by reaction of linker 362 with an Nhydroxysuccinimide-coated microtiter plate or by reaction of linker 363 (derived from 362) with an amine-functionalized microtiter plate. CuI-catalyzed click reaction of sugar azides with the developed alkyne-tethered microtiter plate 364 successfully assembled microarrays 365. Reduction of the disulfide bond of 365 afforded easy-to-characterize thiol 366 (Scheme 104). This

approach was favorably utilized in interaction studies of HIV antibody 2G12.456 Chaikof and co-workers developed carbohydrate microarrays by Cu(I)-catalyzed clicking of an alkyne-functionalized α,ωpoly(ethylene glycol) linker grafted onto an N-(ε-maleimidocaproyl)-derivatized glass plate with lactose azide.457 Later on, Cai et al. introduced an innovative approach by tethering carbohydrate moieties onto a nonoxidized silicon surface.458 Grafting of trimethylgermanyl (TMG)-protected terminal alkynes 368 onto a hydrogen-terminated Si platform (367) through photohydrosilylation afforded TMG-protected akynefunctionalized Si substrate 369. Cu(I)-assisted facile deprotection of 369 in an aqueous medium produced 370, which on clicking with oligo(ethylene glycol)-linked azido sugars 371a,b afforded microarrays 372 capable of binding proteins (Scheme 3152


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Scheme 94. Chemoselective Attachment of a Glycoconjugate to Cowpea Mosaic Virus432,433

Scheme 95. Click-Inspired Synthesis of Virus Glycoconjugates 334 and 336434

105). The deprotection and CuAAC, both being Cu(I)catalyzed, can be combined in a single step.458 Oligo(ethylene glycol) groups present on unreacted alkynes passify them, which hinders nonspecific binding of proteins on the monolayer assembly. The physiochemical aspects of carbohydrate arrays can be easily modulated when they are immobilized on a polymer surface, which is helpful in carbohydrate−lectin studies. Ramstrom and co-workers reported the photoinduced assembly of perfluorophenyl azides 373 on the various polymer-coated gold surfaces. Consecutive amide coupling reactions on this

assembly afforded an alkyne-grafted solid surface (374). Clicking of these alkyne-grafted monolayers with different azido sugars in the presence of a Cu catalyst resulted in carbohydrate-embedded microarray 375 (Scheme 106).459 Ravoo et al. adapted a novel microcontact printing technique for generation of glycol micrroarrays by Cu(I)-catalyzed clicking of carbohydrate-derived alkynes with azide-functionalized monolayers.460 In a similar way, Norberg et al. presented photoclick immobilization of carbohydrates through functionalization of specific polymeric surfaces with alkynes and subsequent clicking with sugar azides, including 2-azidoethyl3153


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Scheme 96. Extended Synthesis of Qβ Conjugates 33784

Scheme 97. “Click-Inspired” Fluorescent Labeling of Cellular Glycans435

Scheme 98. Fluorogenic Azido Fluorescein for Labeling Alkyne-Functionalized Glycoproteins on Cells438

assembly of alkylsilanes with a terminal alkyne functionality was grown on a silicon, glass, or quartz substrate, which was attached with carbohydrate moieties having an azide functionality using the click reaction.461 This facile self-assembly technique was also employed by Zhang et al. for grafting a disulfide linker (376) with a long alkyl chain and a terminal alkyne functionality on a gold plate.451 Subsequent click reaction of alkyne-functionalized gold plate 377 with different sugar azides comprised of triethylene

functionalized (R)-D-mannopyranoside. Evaluations of the protein recognition properties allow for real-time analysis of the association/dissociation effects of unlabeled proteins of the carbohydrate-presenting surfaces, making the protocol a versatile and potential method for other applications.454 Miura et al. explored the advantageous method of selfassembly to afford carbohydrate-immobilized substrates with higher protein−carbohydrate interaction. A well-arranged self3154


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Scheme 99. CuAAC for the Selective Labeling of Galectin-3 in Cell Lysates441

substrate 379 with a D-mannopyranoside-derivatized azide. Later on, the phosphoramidite linker 381 was introduced, which on oligonucleotide elongation, labeling, and ammonia treatment led to the formation of Cy3-oligonucleotide 382 (Cy3 = cyanine 3). This linker, containing mannose with four alkyne functionalities, on clicking with fucosylated azide 383 afforded a fucosylated glycocluster in appreciable yield. Incorporation of nonpolar residues in the course of the consecutive clickings resulted in decreased solubility. To overcome this solubility problem, the authors performed hydrolysis of the fucosylated glycocluster by treating it with aqueous ammonia to obtain the fucosylated glycocluster 384 (Scheme 108).462 Evaluation of the binding assays of developed fucomimetics for PA-IIL was done using a carbohydrate microarray. The most effective binding was shown by the antenna-like fucomimetics and mannose-centered fucomimetics 384 bearing four fucosyl residues. The authors evaluated the significance of the core moieties with linker arms in different crown-like sugar-centered fucosylated glycoclusters and found that the mannose core was more suitable than glucose and galactose cores.462 Gerland et al. further explored this strategy by developing 25 multivalent galactosylated clusters at the nanoscale with different structural and topological properties. The evaluation of the binding assays of these glycoclusters with LecA (lectin A) again established the mannose moiety as the most promising and preferred core over glucose and galactose moieties.463 In an interesting click-inspired investigation on oligonucleotide pentofuranose-centered as well as mannitol-centered glycoclusters, Ligeour et al. demonstrated that the topology and nature of the linker can be considered as the predominant factors to attain a high affinity rather than valency.464 We can conclusively say that click chemistry has become a robust immobilization strategy for the fabrication of surface-

Scheme 100. Click-Inspired Rhodamine-Based Chemical Probe442

glycol spacers, followed by clicking of the unreacted alkyne terminals with triethylene glycol azide, resulted in carbohydratefabricated self-assembled monolayers 378 (Scheme 107). The amide bond present in the SAM makes it more stable and rigid, whereas the triethylene glycol units hinder nonspecific adsorption. These properties establish these SAMs as potent nonlabeled sensors for SPR and QCM.451 Pseudomonas aeruginosa (PA), because of the emergence of resistant strains, causes chronic respiratory infection. The fucosebinding protein PA-IIL is supposed to recognize/adhere to the host cell and be involved in formation of a biofilm; thus, it can be a prospective therapeutic target. Keeping this view in mind, Gerland et al. developed a series of 16 fucosylated glycoclusters of different arrangement patterns via a combined application of click chemistry and DNA solid-phase synthesis.462 The authors first developed the solid-supported mannose platform 380 by MW-assisted click reaction of the propargyl-functionalized solid 3155


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Scheme 101. Labeling of Mammalian Cell-Surface Glycans443

Scheme 102. Click-Inspired Detection of Glycoconjugates Present on the Surface of Live Cells

linker, and many times being a part of the conjugated fluorophore and contributing to the reporter. Chemosensors incorporated with carbohydrates are especially important due to the availability of numerous hydroxyl groups along with oxygen atoms which can form a suitable binding site for cations.470 Click chemistry being used as a linking strategy for incorporation of sugar molecules in the design and development of fluorescent chemosensors is a fast-growing technique for cation detection. However, only a handful of fluorescent chemosensors structured with sugars for selective cation detection are known in the literature.29 On the basis of the domino effect of a carbohydrate-based dipyrromethane system as a fluorescent probe for Cu2+/Cd2+ ions,471 using fluorogenic dual click chemistry, we have recently reported carbohydrate-based fluorescent sensors 385a and 385b capable of detecting Cu2+ ions with high selectively via fluorescence quenching.472The glycosyl sensors 385a and 385b were prepared from cheap and readily available D-glucose (Scheme 109), wherein the isopropylidene-protected form of D-glucose was reacted with

based carbohydrate arrays and monolayers facilitating highthroughput lectin−carbohydrate investigations for the identification of lectin proteins of particular relevance in pathology.

11. “CARBO-CLICK” IN SENSING AND DETECTION OF ANALYTES Chemical sensing may be simply considered as a measurable change signaled by interaction of an analyte with a receptor.465−468 Generally, the chemosensors have the ability to control the emission spectra upon fluorophore binding or reaction with an analyte. Some of these chemosensors exploit the conformational changes or redox potential for sensing. Click chemistry has emerged as a powerful tool for designing a wide range of chemosensors for detecting analytes, for example, sensing of cations and anions.469Apart from the benign chemical conditions, synthetic simplicity, and modular character of the click-based approach, the resulting 1,2,3-triazoles may contribute to a variety of roles, i.e., binding of analytes, often serving as a 3156


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Scheme 103. Kinetics of Sialic Acid Biosynthesis in Mammalian Cell Lines447

Scheme 104. Oligosaccharide Microarrays Covalently Attached to a Solid Surface by a Cleavable Linker456

the dibromo derivative of p- and m-xylene followed by selective 5,6-O-isopropylidene removal, subsequent NaIO4 oxidation, and finally NaBH4 reduction in the same pot to furnish the corresponding alcohols 386a and 386b.471The dihydroxyl arms of both compounds 386a and 386b were propargylated and then, in the final step, clicked separately with fluorescent-deactivated 3-

azidocoumarin, delivering their respective bis(triazolyl) probes 385a and 385b, which differed in the relative positions of the triazolocoumarin arms attached through the phenylene ring. Detection limits of 6.99 and 7.30 μM were measured for chemosensors 384a and 385b, respectively. Computational 3157


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Scheme 105. Tethering of Sugar Moieties on a Silicon Platform Using CuAAC458

Scheme 106. Click-Assisted Carbohydrate Decoration over a Polymer-Coated Gold Surface459

calculations (DFT) were performed to explain the analogous

Several chemosensors were designed using click chemistry tools for the detection of some important analytes.473,474 The fluorescent chemosensors 388 and 389 consisting of D-ribose

optical behavior of 385a and 385b toward Cu2+.472 3158


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Scheme 107. Grafting of Sugar Moieties on Gold-Substrate SAMs via Click Reaction451

Scheme 108. Synthesis of a Crown-like Tetrafucosylated Glycocluster with a Mannose Core (384)462

unusual distortion between the two pyrene units on binding Hg2+ at the coordination center of the sensor.473−475 Despite cyclodextrins being a widely explored scaffold in host−guest chemistry, little is known about click-based cyclodextrin sensors.475 Liu et al. reported a fluorescent Cd2+ sensor

linked to a pyrenyl residue via triazole units were developed for the detection of trace levels of the highly toxic Hg2+ ion (Figure 27).473−475 The authors observed an efficient fluorescence quenching on addition of the Hg2+ ion to developed sensing systems. Computational calculations (DFT) demonstrated an 3159


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Scheme 109. Synthesis of a D-Glucose-Derived Chemosensor for Cu2+ Ions472

Figure 28. Structure of a β-cyclodextrin core fluorescent Cd2+ sensor with an attachment of 8-hydroxyquinoline (390) and pyridine-2′yltriazole fluororophores bound to Zn2+ (391).

Figure 27. Chemosensors appended with D-ribose on pyrenyl residues via click chemistry.

fluorescence observed in 392. Additionally, the fluorescence response was enhanced further on adding adamantanecarboxylic acid as a guest on the cyclodextrin scaffold; i.e., sensor 393 exhibited a cooperative binding of Cd2+ and Zn2+ with the carboxylate group present as a guest moiety (Scheme 110).476 Xie’s group functionalized cyclodextrin with pyridin-2yltriazole as a fluorophore to afford a sensing system, 394, that demonstrated a strong selectivity for Zn2+ ions.478 Similarly, the functionalization of β-cyclodextrin with a benzothiadiazoyltriazole fluorophore furnished 395, which selectively quenched the fluorescence response in the presence of Ni2+ at physiological pH (Figure 29).479 Moreover, a reasonable selectivity was observed for Ni2+ over other ions, and Cu2+, Co2+, and Hg2+ ions to some extent. Fujimoto et al. exploited the concept of the host−guest relationship using a cyclodextrin scaffold, and developed a

(390) consisting of 8-hydroxyquinoline-functionalized β-cyclodextrin via CuAAC (Figure 28).476The authors noticed a significant enhancement in the fluorescence of 8-hydroxyquinoline at physiological conditions due to binding of Cd2+. The developed chemosensor exhibited reasonable selectivity for Cd2+, while fluorescence quenching was observed with Cu2+ and Fe3+ ions and also with Ag+, Hg2+, and Pb2+ ions to some extent. In another investigation, Souchon et al. incorporated pyridin-2′-yltriazole fluororophores into β-cyclodextrin to provide a similar sensing phenomenon.477 The pyridinyltriazole group is recognized as an important core for sensing as phenyland (hydroxymethyl)triazole models of similar analogues 391 do not show any fluorescence emission.477 The sensor 390 detected Cd2+ by virtue of binding to the nitrogen of quinoline and triazole residues, causing an enhanced 3160


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Scheme 110. Binding Modes for Cd2+on Cyclodextrin-Based Sensing Systems476

Figure 29. β-CD-derived pyridin-2-yltriazole sensing system 394 and benzothiadiazoyltriazole chemosensors 395.

sensing system which was incorporated with β-cyclodextrin, DNA, and pyrene moieties for allocation of binding, dimeriza-

physiological pH,482 while the sensor 397 featuring a single anthracene unit caused enhancement of the fluorescence of the Cu2+ ion (Figure 30).483 In recent years, several sensing systems appended with carbohydrates have been developed using CuAAC, wherein the triazole rings have taken part in the recognition event specifically for metal ions, i.e., Ag+, Cu2+, and Ni2+ (Figure 31). Chen et al. reported the click-chemistry-inspired synthesis of chemosensor 398 consisting of bis(triazolocoumarin)s fastened over monosaccharides. The authors prepared 398 by microwave-assisted dual click reaction of silylated sugars with azidocoumarin.484 The sensor 398 showed a quenching effect in the presence of Ag+ ions in water. An anthraquinone-based sensor, 399, featuring Dglucose residues on either ring via triazole linkages was synthesized to detect Cu2+ ions owing to the quenching behavior. With differential pulse voltammetry (DPV), the authors observed a variation of the electrochemical behavior of 399 when Cu2+ was present in traces.485 Similarly, sensors 400 and 401 featuring α-ketoesters attached to sugar residues at the 2,6- or 3,4-positions were developed for selective detection of Ni2+ (Figure 31).486 Very recently, glycolipid crown ethers 402 and 403 were synthesized in good yields by clicking via the CuAAC reaction of diazide-tethered ethylene glycols with dialkynes generated from lauryl glycoside (Figure 32). Computational studies established

Figure 30. Carbohydrate-based aza crown ether fluorescent sensor.

tion, and signaling properties, while a triazole unit served as a passive connecting unit between the reporter and the binding site. The authors used these sensing systems for detection of unsaturated fatty acids that demonstrated a host−guest complex binding stoichiometry of 2:1.480 Furthermore, on placing an adamantane-1-carboxylic acid in the system, the binding stoichiometry was altered to 1:1.481 Hsieh and co-workers prepared bis(triazole) sensors 396 and 397 by CuAAC reaction of azidoanthracene with aza sugar-based alkynes. Compound 396 selectively quenched the fluorescence of Cu2+ and Hg2+ at 3161


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Figure 31. Bis(triazole)-linked carbohydrate-based chemosensors 398−401.

sensing systems. A brief account of carbohydrate-based chemosensors includes those containing a triazole linker not just as a structural unit but also with a crucial role in the recognition event for cations. By combining this technique with the use of carbonbased nanomaterials and metallic particles and nanostructuring of polymeric films, a further enhancement of their properties could be achieved.

12. “CARBO-CLICK” IN LIPID FUNCTIONALIZATION Lipids, generally described as small hydrophobic or amphiphilic molecules, are building blocks which play a key role in biological systems by contributing to many functions such as energy storage, signaling, transport of material, and acting as a structural component of the cell membrane.489,490 These properties of lipids make them useful agents not only for drug delivery, gene transport, and imaging,491,492 but also for the development of systems mimicking membrane environments.493 The importance of lipids has driven scientists toward the study of lipid functions and harnessing their valuable properties. For this purpose, CuAAC has been proven as a helpful means for understanding and mimicking lipid functions.494,595 The wide spectrum of applications associated with controlled functionalization of intact membrane assemblies has generated a deep interest in this field. Carbohydrate-based labeling reagents are successfully tagged with lipids via click chemistry for functionalizing the membrane surface. Schuber et al. tagged mannose moieties on the surface of preformulated liposomes by CuAAC between α-thiomannose azide 406 and an alkyne grafted on a glycerolipid backbone via a tetraethylene glycol spacer (407).496 An improved copper chelation strategy along with water-soluble ligand bathophenanthroline was employed instead of traditional CuAAC conditions for a better yield and to maintain the membrane integrity. Target proteins were found successfully bound to the resulting mannose-tagged liposomes by agglutination of the lectin concanavalin A. Sun and co-workers

Figure 32. Structures of glycolipid crown ether analogues of cationbinding activity.487

that the nitrogen and oxygen atoms in these macrocycles may serve as potential sites for binding of cations.487 Xu et al. reported numerous fluorescent glycosyl derivatives containing azido groups and reported their basic photophysical properties and applications.488 The authors utilized the azido sugar 404 for the synthesis of fluorescent triazolylglycosyl conjugates via click chemistry for potential applications in different biological investigations (Scheme 111).488The fluorescent glycoconjugates N-[3-cyano-1-[2,6-dichloro-4(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazol-5-yl]-1-(2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2deoxy-β-D-glucopyranosyl)-1H-1,2,3-triazole-4-methanamine (405a), and two other related glycoconjugates 405b and 405c were utilized efficiently to depict the path for translocation of sugar pesticides in plants. The authors noticed very prominent fluorescence under a confocal laser scanning microscopy (CLSM) study of the root tip meristem that evidenced their accumulation in the root tip meristem. Thus, the 1,4-disubstituted triazole has been increasingly used in recent years as a connecting unit for bringing the sugar residues to a suitable platform for the development of chemical 3162


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Scheme 111. Synthesis of Fluorescent Glycohybrid Molecules 405a−c488

Figure 33. Carbohydrate-based labeling reagents and the corresponding tagged lipids.496

used lactose-based azide 408 for tagging cholesterol liposomes containing 5 mol % lipid 409 (Figure 33). Mild reaction conditions, a high yield, and the fact that it is unaffected by a broad range of functional groups are the key features which have led click chemistry toward the development of valuable glycolipid analogues. Solaiman et al. have reported an interesting synthesis of multiple dimer lipid 412 via reaction of azido triglycerol analogue 411 with alkynyl glycolipid 410 (Scheme 112).497 An advancement to the synthesis of glycolipid analogues resulted in some complex analogues with highly useful properties. A protected alkyne-grafted analogue of monophosphoryl lipid A, a significant glycolipid which plays an important role in endotoxicity by toll-like receptor 4 activation, was developed by Guo et al. This clickable derivative 413 was used to develop modified analogues to be used as immunostimulants to counter sepsis. Clicking with azide 414, alkynegrafted glycolipid analogue 413 afforded conjugate 415 with great convenience in spite of the hindrance created by the complex structure of the glycolipid analogue (Scheme 113).498

Involvement of biologically active lipids in the noncovalent protein−lipid binding interaction is a pronounced role of lipids in the living world.499,500 Protein function and localization are generally regulated by these binding interactions. Proteins, which are capable of binding and modifying lipids, can be effectively identified and characterized by development of appropriate probe-based strategies.501 The modification of the lipid structure is involved in the development of a lipid activity probe for enforcing covalent labeling of target proteins; also a secondary moiety is introduced for labeling and manipulating tagged proteins. Because of the bioorthogonal nature of the click reaction, clickable functional groups, i.e., azides and alkynes, are potent tags for postderivatization of labeled proteins. Many lipid activity probes based on multiple click chemistry have been developed so far using these strategies. Phosphatidylinositol polyphosphate lipids interestingly bind and activate a number of proteins. Moreover, the interactions between phosphatidylinositol polyphosphates and proteins are generally aberrant in many diseases.502 In this series, Best et al. developed an activity probe corresponding to the headgroup of phosphatidylinositol 3,4,5triphosphate which was, on gel fluorescence scanning, found 3163


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Scheme 112. Synthesis of Dimer Lipid Analogue 412497

scanning calorimetry (DSC) was successfully employed to understand the concentration-dependent membrane perturbation, solubilization, and thermotropic phase transition progression of 1,2-dipalmitoylglycero-3-phosphocholine multilamellar vesicles (MLVs) induced by glycoconjugate 420, which obviously exemplify the appreciable competency of the GTHCC in perturbing the lipid bilayer membrane organization.509 Using a combined multicomponent click approach, convenient development of glycolipids can be achieved with a carbohydrate/triazole/lipid hybrid architecture. In a recent report, Labrada et al. utilized the Ugi four-component reaction to achieve double lipidic scaffolds with clickable azide or akyne functionalities.510 The scaffolds with an azide functionality (421) were conjugated with mono- and trisaccharide alkynes 422 by clicking in the presence of Cu(Ac)2 and sodium ascorbate in THF/H2O (Scheme 116) to afford triazole-based neoglycolipids 423 (Figure 36).510 In a similar way double lipidic scaffolds bearing an alkyne functionality (424) were clicked with sugar azides 425a−d to afford neoglycolipids 426a−h (Scheme 117, Figure 37). This method is highly efficient and straightforward and provides an easy and versatile protocol toward the synthesis of neoglycolipids having remarkable structural similarity with naturally occurring glycosphingolipids as well as with complex anticancer glycolipids of synthetic origin. The authors presented important information regarding the cis/trans isomerization of the tertiary amide bond using dynamic NMR experiments. Because of its ease of implementation, versatility, wide substrate scope, and other benefits, this protocol may offer a new outlook for the development of glycolipids with prospective relevance in medicinal chemistry. These examples evidently explain the use of bioorthogonality of the click reaction for the development of several valuable glycolipids consisting of simple to complex architectures. These glycolipids have a significant impact on the study of lipids for functionalizing the membrane surface and characterization of proteins in tumor cells. The biomedical advantages of these clickderived glycolipids have motivated scientists to harness this field

effective in labeling of the Pleckstrin homology (PH) domain of Akt (protein kinase B).503,504 The lipid activity probe 416 was screened for characterization of target proteins in cancer cell extracts. Probe 416 positively bound the target proteins, which was exploited for labeling and identification of 265 protein targets, including 44 known phosphatidylinositol 3,4,5-triphosphate proteins as well as a number of novel target proteins (Figure 34). In addition to these, some other carbohydrate-clickable derivatives have been developed so far for future applications as linkers for spacer molecules and lipid rafts (Scheme 114). The use of an oligosaccharide as a spacer can be a useful option to supplement the common spacers oligo(ethylene glycol) spacers. Oligosaccharide-derived linkers such as 418 can be harnessed as glycolipid−fluorophore or glycolipid−protein conjugates with variable linker lengths (tri-, penta-, and heptasaccharide moieties) to be used as probes.505 The click protocol is well-known to facilitate a homogeneous coupling of unprotected sugars (hydrophilic end) and paraffin components (hydrophobic end). The combination of low molecular weight alcohols as an inert medium with click coupling of the surfactant domains evades mainly hydrophobic contaminations of the surfactant; consequently, the click-mediated triazole interestingly links the two surfactant domains, and thus offers easy access to pure surfactants.506 Very recently, a solvent-free mechanochemical strategy was used to develop carbohydrate-anchored triazole-linked lipids 419. These analogues were interestingly found to self-assemble in solvents in different patterns (i.e., size and shape) based on the sugar linked to the lipid. Also the self-assembly of these analogues was found to be dependent on the structure of the lipid, the temperature, and the solvent (Scheme 115).507 Recently, Rao and Mishra developed a nontoxic glucose− triazole-hydrogenated cardanol conjugate (GTHCC), 420, using azide−alkyne cycloaddition (Figure 35).508 The authors extended their investigation to the interactions of the developed cardanol glycoconjugate 420 with a lipid membrane. A technique based on a fluorescence molecular probe and differential 3164


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Scheme 113. Synthesis and Functionalization of an Alkyne-Grafted Analogue of Monophosphoryl Lipid A498

Figure 34. Activity-based characterization of proteins by lipid probe 416.503,504 3165


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Scheme 114. Development of a Clickable Spacer505

Figure 35. Glucose−triazole-hydrogenated cardanol conjugate.508

from 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, to afford the desired N1-benzotriazole-linked glycoconjugates in high yields under mild reaction conditions (Scheme 119).519 Williams and co-workers evaluated the glycosyl donor ability of anomeric N1-benzotriazoles, 1,4-disubstituted triazolyl glycoconjugates, and also 1,4,5-trisubstituted triazoles in a variety of glycosidation reactions.513 The 1,4,5-trisubstituted glycosyltriazoles containing two electron-withdrawing groups on reaction with a suitable acceptor using a promoter successfully afforded the desired glycosidation product, while the 1,4-disubstituted glycosyltriazoles under similar reaction conditions were considered to be unreactive (Scheme 120). Glycosidation of various triazoles (e.g., compounds 431, 434a, and 434b) with different acceptors such as alcohols, thiols, (TMS)Cl, and (TMS)N3 in the presence of a suitable promoter under an inert atmosphere affords a high yield of the corresponding Oglycosides, S-glycosides, glycosyl chlorides, and glycosyl azides.513 The glycosyl-N1-benzotriazoles on treatment with thiocresol in the presence of a catalytic amount of the promoter SnCl4 were shown to be unreactive, while introducing electronwithdrawing groups into the donor, for example, tetrafluorobenzotriazole derivative 431, under similar reactin conditions successfully resulted in a high yield of the desired S-glycoside. The glycosidation results are depicted in Table 2.

with more effort and interest. Some recently developed glycolipids are on the way to show their potency as linkers for spacer molecules and lipid rafts. This invention points toward a promising future of carbohydrate click chemistry in lipid studies.

13. APPLICATION IN THE GLYCOSYLATION REACTION 13.1. Intermolecular Glycosylation

The continuous interest in carbohydrate-based molecules in drug discovery and development has led to the development of a simple and easy glycosidation methodology to accomplish the required regio- and/or stereoselectivity in the glycosidation product. Although a number of glycoside bond formation methodologies are known,198,511,512 regio- and stereocontrol is not always achieved. Several glycosyl donors, such as trichloroacetimidates, halides (e.g., iodide, chloride, bromide), phosphites, sulfide, sulfones, etc., were invented and investigated in different glycosylation reactions. In addition to these glycosyl donors, Williams et al. recently employed glycosyltriazoles, obtained from their corresponding anomeric sugar azides by clicking with terminal alkynes, to obtain the desired stereoselectivity in the glycosidation product.513 The cycloaddition reaction of sugar azides with a benzyne intermediate, prepared in situ from a suitable anthranilic acid derivative, delivers the glycosylated N1-benzotriazoles and related triazoles in appreciable yield (Scheme 118).513 Interestingly, similar efforts using azide and benzyme under click conditions could generate a wide range of benzotriazolecontaining molecules with diverse applications.514 Alternatively, this skeleton was constructed starting from o-haloanilines via diazotization and amine coupling followed by intramolecular Narylation using CuI/Cs2CO3.515 Considering the advantages of benzotriazole as a leaving group, proton activator, and anion generator and in other synthetic applications, we successfully utilized these molecules for the development of pharmacologically active skeletons via cleavage of the benzotriazole ring.516−518 Likewise, Yadav et al. reported a fluoride-triggered clicking of different sugar azides with benzyne, generated in situ

13.2. Intramolecular Glycosylation

The intramolecular glycosylation reaction, considered as one of the commanding ways to attain high selectivity, has been categorized into three main classes: (i) leaving-group-based, (ii) functional-substituent-based, and (iii) rigid-spacer-based intramolecular aglycon delivery (IAD).520 Various spacers, including malonyl, succinyl, glutaryl, or a peptide, and their combinations with rigid spacers such as phthaloyl, isophthaloyl, and o- or mxylene residues have been well investigated in the rigid-spacerbased IAD. In many cases the glycosylation results are successful and encouraging for further extension of the investigation.521 Therefore, to attain superior anomeric selectivity and a high reaction yield, Schmidt and co-workers recently investigated triazole as a rigid spacer in intramolecular glycosylation.522 The triazolylmethyl moiety in combination with the well-known oand m-xylylene moieties was effectively utilized as a comparatively rigid spacer system in intramolecular glycosylation reactions. The strategy was commenced with phenyl 3,4,6-triO-benzyl-2-O-propargyl-1-thio-D-glucopyranoside (438), which was first connected with O-[2-or 3-(azidomethyl)benzyl]protected acceptors (for example, 439, 443, 447, 451, 455,

Scheme 115. Mechanochemically Developed Carbohydrate-Anchored Triazole-Linked Lipids507

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Scheme 116. Synthesis of Glycolipids (423a−j) from Lipid Azides (421)510

Figure 36. Structures of triazole-based glycolipids developed according to Scheme 116.510

Scheme 117. Synthesis of Glycolipids 426a−h from Lipid Alkynes 424510

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Figure 37. Structures of triazole-based glycolipids 426a−h developed according to Scheme 117.510

Scheme 118. Thermally Induced Azide−Alkyne Cycloaddition Leading to the Triazolyl Glycoconjugates 427−434513

458, 462, 466, 470, and 474) under click conditions followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated p-methoxybenzyl (PMB) group removal from the resulting disaccharides to obtain the desired donor−acceptor-linked triazolyl disaccharides 441, 445, 449, 453, 456, 460, 464, 468, 472, and 475. These donor−acceptor-linked disaccharides could be subjected to intramolecular aglycon delivery (IAD) under standard conditions to afford triazole-containing macrocycles.

Finally, removal of the triazole spacer may lead to the generation of the desired glycosylation products 442, 446, 450, 454, 457, 461, 465, 469, 473, and 476 presumably in good yield and with high anomeric stereoselectivity (Scheme 121). To this end, glycosylalkyne 438β was first clicked with O-[2(azidomethyl)benzyl]-protected acceptors 439 using CuI/ DIPEA in CH2Cl2 to obtain disaccharide 440, which was then treated with DDQ in H2O/THF for 2 h at 0 °C to obtain donor− 3168


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and 474 under click conditions followed by removal of the accepting hydroxy groups (except for compounds 456 and 475; both already have a free hydroxyl group) to generate the desired donor−acceptor-linked triazole-containing disaccharides 441, 445, 447, 453, 460, 464, 468, and 473, which finally on IAD using NIS/(TMS)OTf in anhydrous CH2Cl2 under an inert atmosphere for 2−3 h furnished the targeted disaccharide moieties containing macrocycles, respectively 442β, 446α,β, 450α, 454α,β, 457α,β, 461α,β, 465α,β, 467α,β, 473α,β, and 476α. In many cases, good glycosylation results were achieved. Although the anomeric selectivity is dependent on various factors, the deciding one seems to be the ring size as evident from the results (Table 3). The intermolecular glycosylation reaction with a disaccharide having a free hydroxyl group obtained from alkyne 438α by a similar set of reactions also led to the same result. Thus, we can conclude that the diastereofacial control in the intramolecular glycosylation is almost independent of the configuration of the glycosyl donor (438α or 438β). The glycosylation reactions carried out even at room temperature generate exclusively the βanomer. Unfortunately, an attempt to remove the spacer was not very successful in the first investigation. To overcome the problem associated with the approach presented in Scheme 121, Schmidt et al. further extended the investigation utilizing the o-azidobenzyl group to create a regioselective triazole skeleton as a rigid spacer.523 The O-linked ortho-substituted arylazido containing an accepting hydroxy group on click with alkyne results in the preferred linkage between the donor and acceptor via triazole as a rigid spacer (step 1). The restricted conformational mobility and also the favorable direct interaction between the phenyl and triazolyl moieties results in a lower conformational mobility than that of the 2-(azidomethyl)benzyl group. The glycosidation step as part of the formation of a 14-membered ring could favor IAD (step 2) and also the convenient removal of the triazole spacer from the resulting macrocycle at the end of the final reaction sequence (step 3, Scheme 122). Possible anchimeric assistance in IAD can be rationalized. The involvement of the N-3 atom of triazole in the stabilization of the anomeric carbenium ion as part of a six-membered ring may occur from either side, i.e., the α- and/or the β-side. However, the 2-O-linked (1-phenyl-triazol-4-yl)methyl group exerts almost no anchimeric assistance in the glycosidation reactions. Conclusively, the electron-donating tendency of the triazolyl skeleton ends up to be a relatively small one (Scheme 123). The click reaction between the 2-O-propargylated glycosyl donor and the O-(2-azidobenzyl) acceptor containing a vicinal hydroxy group followed by IAD resulted in β-(1−3)- and α-(1− 2)-coupled disaccharides as a component of 14-membered macrocycles. Likewise, azide 478a combined with glycosyl donor 477 using the click reaction afforded donor−spacer−acceptor 479, which on NIS/TfOH-prompted IAD afforded a high yield of β-(1−3)-linked disaccharide 480. A similar reaction sequence starting from compound 478b afforded surprisingly a different glycosidation result, mainly the α-(1−2)-linked product 483, despite the formation of 14-membered macrocycles (Scheme 124).523 Interestingly, triazole as a rigid spacer was readily cleaved under Birch reduction conditions. Thus, the treatment of triazolyl macrocycle disaccharides 480 and 483 with Na/liquid NH3 at −75 °C followed by acetate protection using Ac2O resulted in the formation of stereochemically pure disaccharides 481 and 484 in good yields (Scheme 125).

Scheme 119. Click-Inspired Synthesis of 1,4-Disubstituted Glycosyltriazoles519

Scheme 120. Different Glycosyltriazoles Used as Donors in Various Glycosidation Reactions

Table 2. Glycosyltriazoles as Donors in Various Glycosidation Reactions513

a

Under an inert atmosphere. bAnomeric selectivity was determined by H NMR of the crude product. cIsolated yield by column chromatography. 1

acceptor-linked triazole-containing disaccharides 441. Both the synthetic steps are high-yielding and easy to perform. NIodosuccinimide (NIS)/(TMS)OTf-promoted glycosylation reaction of compound 441 in anhydrous CH2Cl2 for 2 h under inert conditions led to the formation of targeted macrocycle 442β (58% yield, >98% β-selectivity) as part of a 15-membered ring. The glycosylation yield with compound 441 using NIS/ (TMS)OTf indicated absolute β-selectivity and was found to be concentration-dependent as 1.1 equiv of NIS affords a low yield of macrocycle disaccharide 442 compared to 2 equiv of NIS. Likewise, clicking of 438β with O-[3-(azidomethyl)benzyl]protected acceptors 443 followed by a similar set of reactions, such as PMB removal followed by IAD, afforded disaccharide macrocycle 446. The β-selectivity dropped to a 3:1 β/α ratio, probably due to the 16-membered macrocyclic ring formation.522 The reaction was investigated with various systems, for example, 438β conjugated with O-[2-(azidomethyl)benzyl]protected acceptors 439, 443, 447, 451, 455, 458, 462, 466, 470, 3169


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Scheme 121. Intramolecular Glycosidation through Click-Generated Triazole as a Rigid Spacer522

489a,b in the presence of ionic liquids in combination with microwave dielectric heating in excellent yields.525 The authors also experimented with the reaction of 486 with sugar acetylene where a lack of product was observed on partial coupling; hence, the authors concluded that with the formation of the first triazole ring further reaction occurs readily due to the involvement of Cu(I)−triazolide−ethynyl complexes in the reaction course. Likewise, Bew et al. reported the CuAAC reaction was used to generate calix[4]arene O-glycosides526 featuring carbohydrate residues anchored at the upper rim of the calixarene platform via triazole rings (Scheme 129). Imberty and co-workers prepared different clusters of Ogalactosylated calix[4]arene having vital conformations using click chemistry.527 Field et al. extended the same click strategy and developed a series of trypanocidally active lactose-based glycoclusters presented on calix[4]arene cores.528 The cone conformation clusters dipropargyl (494a and 494b), tripropargyl (494c), and tetrapropargyl (494d) tert-butylcalix[4]arenes were reacted with 8-azido-3,6-dioxaoctyl galactopyranoside (495) in the presence of CuI/DIPEA under MW irradiation, followed by deacetylation under standard conditions (triethylamine in aqueous methanol) to obtain glycoclusters 496a−d in good to excellent yields (Scheme 130).529 Similarly, the galactosyl calixarenes 497 and 498 with different conformations were synthesized via CuAAC (Figure 38). The binding affinity of such compounds to the P. aeruginosa lectin PA-IL was determined using isothermal titration calorimetry, and comparisons were made using a monovalent ligand, 500 (Figure 39). In titration experiments the trivalent glycocluster 496c as well as the tetravalent ones 496d, 497, and 498 demonstrated an enriched binding up to 200-fold larger compared to that of 500, while the bisgalactose clusters 496a and 496b could not bind to PA-IL. Thus, the authors established that the tetragalactosyl cluster 497 with a 1,3-alternate conformation matched suitably with the PA-IL tetramer topology. In a modeling study of cluster 497, two oppositely directed galactose residues were found to be associated with the binding sites of one PA-IL tetramer, while the remaining two were readily available for another PA-IL tetramer.

The successful cleavage of the triazole spacer may be useful for further strengthening the rigid-spacer-mediated intramolecular glycosylation strategy. Although other combinations between Dgluco-, D-manno-, and D-galactopyranoses and their functional analogues are reasonably limited, the described spacer-linked IAD protocol for the desired anomeric selectivities could be useful as a consistent building block for the oligosaccharide syntheses with wide applications.

14. DEVELOPMENT OF CALIXARENE GLYCOSIDES AND GLYCOCLUSTERS 14.1. Triazole-Linked Calix[4]arene C-Glycosides

The calixarene scaffold fastened to glycoclusters has become significant for understanding carbohydrate−protein interactions in a variety of viral and bacterial infections.250,524 Sufficient stability of the triazole linker under a variety of reaction conditions, and its ability to form hydrogen-bonding and dipolar interactions, has enabled the anchoring of a conformationally rigidified tetrapropoxycalixarene scaffold. Dondoni and Marra reported the use of Cu(I)-catalyzed azide−alkyne cycloaddition as a formidable tool for anchoring calix[4]arene scaffolds with carbohydrates.249 Thus, coupling of gluco derivative 485 with the bis(azidopropyl)calix[4]arene 486b furnished C-glycoclusters 487a in quantitative yield. Further transesterification of 487a afforded the calix sugar 487b (Scheme 126). Likewise, glycosylalkynes 485a and 485b on treatment with tetrakis(azidopropyl)calix[4]arene 488 in the presence of CuI/ DIPEA at room temperature afforded a good yield of the corresponding C-glycoclusters 489 suitable for bioassays (Scheme 127). In the second approach, a calix[4]arene functionalized with an ethynyl group was coupled with azido sugars, for example, galactosylmethyl azides 103a and 103b and underwent CuIcatalyzed cycloaddition with tetraethynylcalix[4]arene 490, giving tetravalent glycoclusters 491a and 491b in excellent yields (Scheme 128).249 Both compounds 491b and 489b differ in terms of the position of the carbohydrate unit and the calix[4]arene fragments. The Dondoni group also reported the CuAAC of the galacto analogue of the tetraglucosylcalixarenes 3170


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Table 3. Click Reaction of Glycosyl Azide with Alkyne 438β Followed by IAD

a

Azide:alkyne = 1.1:1, CuI/DIPEA at rt. bIsolated yield by column chromatography (SiO2). cIAD conditions: NIS/(TMS)OTf, anhydrous CH2Cl2 under an inert atmosphere for 2−3 h. dAnomeric selectivity was determined by 1H NMR of the crude IAD product.

lower rim using CuSO4·5H2O/NaAsc and t-BuOH/DCM in the presence of water.530 In preliminary studies, the authors

Likewise, Chinta and Rao synthesized calix[4]arene conjugates appended with galactosyl as well as lactosyl residues at the 3171


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Scheme 122. Alternate Click-Mediated Spacer Generation for Intramolecular Glycosylation523

Scheme 123. Possible Anchimeric Assistance in IAD523,a

a

(HIA) inhibition. The porphyrin and calixarene scaffolds having 1,3-alternate topologies displayed a slight preference in binding. The binding studies of these glycoclusters to galectin-1 were carried out using the surface plasmon resonance (SPR) technique and HIA inhibition, wherein porphyrin and calixarene scaffolds having cone conformations exhibited strong selectivity.531 Glyconanoparticles are nanoparticles capped with carbohydrate lipids or peptides and are generally employed in targeted drug delivery, vaccines, and antiadhesive technology. The globular and polyvalent configuration of carbohydrates in such nanopraticles can result in multivalent interactions, and hence may be significant in reimbursement of the low affinity of carbohydrates for their protein receptors.532−535 de la Fuentes and Penades prepared glyconanoparticles via coating of metal and metal oxide nanopraticles with oligosaccharides, and presented a biomimetic model of cell-surface carbohydrates.536 Since the immobilization of glycosides directly on TiO2 nanoparticle surface presents a hurdle, Dondoni and Marra prepared triazole-linked calix[4]arene O-glycosides starting from specially functionalized (azido and carboxyl) calix[4]arene scaffolds,537 followed by their immobilization on TiO2 nanoparticles by virtue of carboxylate groups binding tightly to the TiO2 surface.538,539 For example, calix[4]arene 509 was reacted with TiO2 in acetone at room temperature to afford calixarenecoated TiO2 nanoparticle 510. The CuAAC of calixarene-coated TiO2 nanoparticle 510 with O-propargylated sialoside 511 furnished the target glyconanoparticle 512 (Scheme 134). The authors used the IR technique for monitoring the azide−alkyne click reaction, while analytical calculations regarding the loading of glycocluster per gram of TiO 2 was determined by thermogravimetric analysis (TGA). The biological importance of these hybrid materials lies in the fact that the clustering unit 5-N-acetylneuraminic acid (Neu5Ac) itself exists as a complex glycan on cell-membrane-associated mucins and glycoproteins, and plays a crucial role in a wide range of molecular recognition processes.540

LG = leaving group, Pr = promoter, and R = protecting group.

evaluated the conjugates 502−504 for their interaction with a plant-derived lectin, i.e., jacalin, using fluorescence spectroscopy, wherein the developed clusters exhibited almost the same fluorescence quenching (Scheme 131). The conformational changes arising throughout the interaction of 502, 503, and 504 with jacalin were monitored by circular dichroism (CD). The authors observed a significant change in the ellipticity of 504as the protein ellipticity remained unaffected in 502 and 503.530 Vidal et al. synthesized diversified porphyrin- and calix[4]arene-based lactosylated glycoclusters via CuAAC. The authors took an alkylated porphyrin derivative along with three topological conformers of calix[4]arenes and performed their click reaction with azido lactoside in the presence of microwave irradiation (Schemes 132 and 133). 531 The developed glycoclusters were evaluated for their binding affinity with ECA (isolated from legume plants, i.e., E. cristagalli) and galectin-1. In binding studies of glycoclusters to ECA, the IC50 values were determined by enzyme-linked lectin assays (ELLAs), while micromolar concentrations were fixed by hemagglutination 3172


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Scheme 124. Glycosylation through IAD with the Donor Triazole as a Rigid Spacer−Acceptor-Linked System523

Scheme 125. Schmidt’s Protocol for the Successful Removal of the Triazole Spacer under Birch Conditions523

14.2. Triazole-Linked C-Glycocluster−Oligonucleotide Hybrids

515 and 516 was accomplished using a DNA-based microarray methodology.542 In these studies, the hybrids 515 and 516 displayed no affinity for binding to PA-IL, despite having good affinity for binding to RCA 120. In immobilized glycoconjugates, the lowest lactose concentration essential for exclusion of 50% of RCA 120 was considered as IC50. The results were compared with those of mono- and trivalent galactosides. The glycoconjugates 515 and 516 (Figure 41) exhibited a poor cluster effect as the observed affinity could not exceed that of the monovalent conjugate.542

Moni et al. prepared numerous multivalent complex sugar− nucleotide hybrids 515 and 516 using calix[4]arene C-glycosides 513 and 514 as precursors, wherein the lower rim of the calix[4]arene scaffold was functionalized with azido tethers (Figure 40).541 The authors synthesized these multivalent structuresto access their binding affinity toward PA-IL and Ricinus communis agglutinin (RCA 120) (Figure 41). The assembly of the multivalent complex sugar−nucleotide hybrids 3173


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Scheme 126. Synthesis of Triazole-Tethered Calix[4]arene CGlycosides by the Dondoni Group

Scheme 128. Click-Inspired Synthesis of Tetravalent Calix[4]arene Glycoclusters525

Scheme 127. Click-Inspired Synthesis of Triazolyl Calix[4]arene C-Glycosides causes severe nephropathy and leads to organ failure.545,546 Likewise, the influenza A viruses known to cause human flu epidemics exhibit hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins547 to recognize Neu5Ac in the host cell; however, they work differently during infection and diffusion of the virus. The adhesion of the virus is mediated by HA, whereas NA is liable for release of sialic acid residues from the termini of glycoconjugate receptors, and thus spread the viral infection. Therefore, Neu5Ac-decorated calix[4]arene is capable of binding strongly to HA or NA compared to natural ligands and would have potential activity against influenza A viruses. The propargyl thiosialoside 518 was the key reagent in this approach and underwent a CuAAC reaction with azido calix[4]arene scaffolds.548 The Cu(I)-catalyzed reaction of calix[4]arene tetraazide 498 with propargyl thiosialoside 518 (slight excess) followed by deacetylation furnished a tetravalent calix[4]arenebased S-sialoside cluster, 519a, containing a flexible Npropyltriazole tether. Likewise, calix[4]arene S-sialoside 519b featuring a cone topology (Schemes 135 and 136) and calix[4]arene S-glycoside 521 were prepared via the CuAAC click reaction (Scheme 136). Dondoni and co-workers further considered the synthesis of sialylated calix[4]arene clusters featuring sialyl residues decorated at the upper as well as lower rim for binding to two distinct viral particles simultaneously or a couple of HA trimers situated on a sole virion. Thus, octavalent sialo cluster 523a displaying a total of eight sialyl residues at the upper and lower rims of calix[4]arene was prepared by reaction of 518 with the octaazide 522 using CuI as a catalyst in the presence of i-Pr2EtN. The high yield of isolated compound 523a (in 72% yield) indicated an efficient CuAAC reaction, and the compound after deprotection afforded an octavalent sialo cluster, 523b, in pure form (Scheme 137).549 In a hemagglutination inhibition (HI) assay, the calix[4]arene S-sialosides 519a, 519b, 521b, and 523b significantly inactivated BKV. However, all the developed multivalent sialosides were less active compared to 524 (Figure 42), a monovalent analogue having a similar aglycon structure for comparison. Additionally, the clusters 519a, 521b, and 523b significantly inhibited the hemagglutination induced by influenza A virus, 519b displayed

Hence, the authors established that the spatial arrangement has a very definite role to play in realization of multivalence. 14.3. Triazole-Linked Calix[4]arene S-Sialosides

The anomeric carbon−sulfur bond is generally resistant to a variety of chemical and enzymatic conditions, which is an important structural feature of such compounds. Among the complex family of sialosides, N-acetylneuraminic acid (Neu5Ac) is generally used as a common carbohydrate component for synthesis of these compounds. Dondoni and co-workers reported the synthesis of calix[4]arene-based sialyl clusters to understand the recognition events during virus infections. The clusters decorated with Neu5Ac are supposed to interfere in sugar−protein recognition, and hence are significant against polyomavirus, also known as BK virus (BKV),543,544 which 3174


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Scheme 129. Click-Inspired Synthesis of Bis-O-glycosylated Calix[4]arenes by the Bew Group526

Scheme 130. Click-Inspired Synthesis of Lower Rim Triazolyl Calix[4] arene Glycoclusters

functions on either rim when treated with an azido sugar

no HI activity up to 50 mM concentration, and sialoside 524 demonstrated a poor inhibitory effect. Thus, the authors concluded that a moderate glycoside cluster effect must be operative to cause an increase in the activity compared to that of monovalent 524. Likewise, sialoside 523b exhibited HI activity close to those of 519a and 521b.

followed by reaction with glucosyl thiol furnished calix[4]arene S-glycoside 527a having a unique combination of thiol−ene coupling and click chemistry (Scheme 138). It has been well-established that “click chemistry” due to its

14.4. Assembly via Thiol−Ene Coupling

high efficiency, specificity, and biocompatibility is greatly utilized

Dondoni and Marra efficiently used “thiol−ene coupling” 550,551 in addition to click chemistry for the preparation of diversified calix[4]arene S-glycosides552,553 featuring thiol and triazole fragments on either rim of the calix[4]arene platform. Hence, calix[4]arene scaffold 525 appended with alkene and alkyne

in the chemical modification of calixarenes for different applications. Several calixarene-based triazoles are well documented as chemosensors because of their three major characteristics, chromogenicity, fluorescence, and wettability.554,555 3175


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15. DEVELOPMENT OF GRAPHENE NANOSHEETS “Click chemistry” has been greatly utilized to obtain an assembly of covalently linked nanocrystals and nanotubes of diverse applications in different fields of science.556 Likewise, the coppercatalyzed azide−alkyne cycloaddition reaction has been applied for developing glyconanomaterials, such as, glyconanotubes and glyconanoparticles of various applications in the medicinal field.557−560 Namvari and Namazi successfully functionalized graphene oxide (GO) with monosaccharides as well as disaccharides on the basal plane and edges using CuAAC clicking of terminal alkynes with azides to fabricate water-soluble graphene nanosheets.561 The methodology involved the treatment of GO 528 with NaN3 to add an azide functionality on the plane that underwent click reaction with a sugar alkyne derived from different monosaccharides (e.g., glucose, mannose, and galactose) and a disaccharide (such as maltose) to afford saccharide-grafted graphenes 530 (Scheme 139). In another approach, the authors successfully connected 1,3-diazidopropan2-ol via acid−alcohol coupling onto the edges of graphene oxide 528, which in the next step was clicked with a peracetateprotected glucose alkyne to afford compound 532 (Scheme 140). The highlighted feauture of this methodology is that both sugar-grafted graphene oxide sheets were reduced by sodium ascorbate during click coupling. The authors found that the content of functionalization of graphene oxide on the plane was significantly higher than that on the edges, which was evidenced by scanning electron microsocpy (SEM) and TGA. The

Figure 38. Tetra-O-glycosylated calix[4]arenes in 1,3-alternate (497) or partial cone (498) topology.

Figure 39. Chemical structures of monovalent ligands 499 and 500.

Scheme 131. Click-Inspired Synthesis of Triazolyl Calix[4]arene Conjugates 502−504530

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Scheme 132. Click-Inspired Synthesis of Glycoclusters for Inhibition of Galectin-1531

developed glycoside-grafted graphene nanosheets (GNSs) were effortlessly dispersed in aqueous media and were also found to be stable for about 15 days.

The poor basicity of 1,2,3-triazoles provides them a tendency to remain nonprotonated at physiological pH. Studies reveal that the nonprotonated sp2-hybridized nitrogen atoms of the triazoles may work like a partial positively charged anomeric carbon in the glucosidase-catalyzed reaction and may behave as specific glycosidase inhibitors. From the inspiration of natural antidiabetic drug acarbose, Perion et al. developed a library of saccharidyltriazoles using click chemistry, where the developed triazoles appreciably inhibited the α-glycosidase enzyme.568 Basu and co-workers synthesized 1β-D-glucosyl-4-phenyltriazole (533) and 1-β-D-galactosyl-4phenyltriazole (534) (Figure 43) using the click reaction. These molecules are recognized as modified β-glucosidase enzyme inhibitors. The inhibitory activities of these molecules were investigated by a percentage assay against three different βglycosidase enzymes, E. coli galactosidase (ECG), sweet almond glucosidase (SAG), and bovine liver galactosidase (BLG). In comparison to DNJGal and DNJ gluco, galactose derivative 533 displayed reasonable inhibition of ECG. Glucosyltriazole derivative 534 was found to be an improved inhibitor of BLG compared to the analogue 533. None of the derivatives displayed significant inhibition of SAG.569 Later, Field and co-workers expanded the utilization of the click reaction to developing a series of 21 α-D- and β-Dglycosyltriazoles in pyranose form, which were assessed for their inhibition activities of GH1 (sweet almond β-glucosidase) and GH13 (yeast α-glucosidase). The developed compounds were found as a series of glucosidase inhibitors effective in the 100 μM range and interacted with the active site of the enzyme differently. Such inhibitors originated by treating sugar anomeric azides and alkynes having various functionalities under the CuSO4/NaAsc catalytic system in heating conditions at 70 °C using the microwave or conventional method, which afforded click products 536a−542a/536b−542b in excellent yield (Scheme 141).570 Additionally, β-D-glucopyranosyl azide was treated with diverse alkynes via changing the catalytic system using CuSO4/Cu turnings at room temperature, which afforded compounds 543−548 in good yield. They also investigated the difference in the rate of reaction of two anomers with diverse alkynes and concluded that the β-anomer reacted faster (10−45 min) than the α-anomer (45−120 min) for complete consumption of the reagents.570 The change was correlated with the anomeric effect where anomeric azides displayed dipole

16. TRIAZOLYL GLYCOCONJUGATES AS ENZYME INHIBITORS As the estimated pool of drug candidates is 1062−1063 discrete molecules, it is not always useful to make a special effort to introduce a desired substituent in a particular position of the scaffold; however, the click technique can be useful for the synthesis of a wide range of modular building blocks for organic synthesis in both small- and large-scale applications. This approach derived from the observation that Nature can instead be considered as a role model for us; however, there is always an excitation and indeed a great challenge for the synthetic chemist to synthesize those molecules that Nature forgot to synthesize. Neither azides nor their click product “triazoles” are Nature’s creations. In recent years, the click reaction has been found to be an important tool for the lead optimization of drug molecules as effective therapeutic agents.11,13 Carbohydrates are involved in numerous metabolic processes, including antimicrobial defense, cell−cell interaction, cell migration, etc., which makes them potential candidates for drug design.562 However, some of the associated properties, such as moderate pharmacological activities, a compact range of receptivity, and a tedious synthetic approach, draw a margin over their emergence as drug candidates. However, click-inspired coupling of carbohydratebased azides and desirable alkynes with attached protecting groups is highly compatible because of the inert nature of the triazole ring regarding processes involving protection/deprotection and glycosylation, which establishes this method as a powerful technique to access sugar mimetics.563,564 Numerous triazolyl glycoconjugates were designed and developed, where many of them showed promising biological activities. This section focuses on the impact of triazolyl glycoconjugates in drug discovery and development. 16.1. Glycosidase Inhibition Activities

Various glycosidic bonds are constructed and broken during numerous physiological and pathological processes which can be synchronized by synthesizing new inhibitors of glycosidases and glycosyl transferases that act as sole catalysts in these processes. Hence, these inhibitors may work as potent therapeutic agents to treat diseases such as diabetes,565 viral infections,566 or cancer.567 3177


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Scheme 133. Click-Inspired Synthesis of Glycoclusters for Binding Studies with Galectin-1531

angiogenesis therapy and synthesis of improved inhibitors compared to 1-DNJ 553 and aryltriazole 552, Zhou et al. developed a few glycohybrid molecules which preferred two separate pathways to angiogenesis inhibition. They subjected Nalkylated 1-DNJ to the click reaction, resulting in iminosugarbased molecules with bifunctionality, 554a−c (Figure 45). Compound 554c showed better α-glycosidase activity (IC50 = 1.15 μM) than DNJ (IC50 = 1.67 μM) and displayed improved inhibition of BAEC (bovine aortic endothelial cell) multiplication (IC50 = 0.105 mM) compared to 552 (IC50 = 0.347 mM).573 Just a simple change in a molecule sometimes causes a remarkable improvement in the biological activities. Replace-

character; this phenomenon was further confirmed through data provided by X-ray crystallography. By exploring the Cu-catalyzed click reaction, Diot et al. studied the effect of multivalency on glycosidase affinity and selectivity by synthesizing multivalent imino sugars via treating the azido derivative of glycosidase inhibitor 1-DNJ with oligoethylene containing alkynes to give multivalent imino sugars 549−551 (Figure 44). These analogues were investigated for different glycosidase inhibitory activities, where some of them exhibited promising biological activity profiles.571 The significant inhibitory activity of DNJ-based glycopolypeptides against α-mannosidase was rather encouraging, and further extension of the work was demanded.572 For the purpose of 3178


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Scheme 134. Synthesis of Glyconanoparticle 512 from Calixarene-Coated TiO2 Nanoparticle 510

with alkynyl glycosides with unsaturation or coumarins bearing propargyl groups to afford biologically relevant glycohybrids 555−558 (Figure 46). These developed molecules were examined for their glycogen phosphorylase, α-glucosidase, and glucose-6-phosphatase inhibitory activities; a few of the representative triazole-based glyco derivatives (555−558) showed promising inhibitory activities.575 Exploring the same protocol, Ferreira et al. developed a library of 1,4-disubstituted 1,2,3-triazole derivatives (559−562) which were obtained on coupling of diverse sugar azides and alkynes (Scheme 142).576 The biological activities of the developed compounds have been investigated against glucosidase inhibitory activity using maltase (MAL12, obtained from yeast) as a representative enzyme. One of them, the coupled product of methyl 2,3-O-isopropylidene-β-D-ribofuranoside and 4-(1-cyclohexenyl)-1,2,3-triazole, was found to have manifold greater inhibitory potential than acarbose (the standard drug). A binding mode consistent with a mechanism involving transition-statemimicking was revealed on the basis of docking studies on a homology model based upon MAL12. However, the true potential of these triazolyl conjugates was corroborated by their ability to reduce the postprandial blood glucose level in rats.

Figure 40. Calix[4]arene C-glycosides functionalized with azido groups at the lower rim.

ment of the ring oxygen in a monosaccharide (e.g., D-glucose) by a N-atom constitutes an interesting class of compounds, known as iminosugars, that possess α-glucosidase inhibitory activities. Click-inspired incorporation of the triazole skeleton coupled with such iminosugars results in promising enzyme inhibitory activities useful in the drug development against diabetes.571−573 Recently, we have presented a fast and facile preparation of bicyclic iminosugars via ionic liquid [NMM]+[HSO4]−-prompted conjugate addition and Mitsunobu reaction.574 Utilizing the click reaction, a library of 1,2,3-1H-triazole glycoconjugates having several glycosyl units or a chromenone substituent have been reported. Glycosyl azides were treated

16.2. Glycogen Phosphorylase Inhibitor

Glycogen phosphorylase acts as a functioning enzyme for the control of hyperglycemia in type 2 diabetes. Xie et al. also used the click approach to design oleanolic acid glycoconjugates which were assessed for glycogen phosphorylase inhibitory activity; among various compounds, compound 563 showed remarkable inhibitory activity (IC50 = 1.14 μM.)577Molecular docking studies reveal the feasible binding modes of compound 563. 3179


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Figure 41. Multivalent glycocluster−oligonucleotide hybrids.

Scheme 135. Synthesis of Triazolyl Calix[4]arene S-Sialosides 519 via Click Chemistry

Scheme 136. Click-Inspired Calix[4]arene S-Sialosides 521 Decorated at the Lower Rim548

The click approach was further expanded to design pentacyclic triterpene heteroconjugates with the C-28 carboxylic acid propargyl esters of maslinic, oleanolic, and ursolic acid triterpenes and acetylated D-glucose-based azide or amine derivatives, where compound 564 showed moderate inhibition against rabbit muscle glycogen phosphorylase a (RMGPa) (IC50 = 26 μM).578 A simple glycoconjugate, 4-phenyl-N-(β-Dglucopyranosyl)-1H-1,2,3-triazole-1-acetamide (565), devel-

oped by Loganathan and co-workers, is considered as a potential inhibitor of glycogen phosphorylase with Ki = 17.9 μM.579 Furthermore, a simple modification leading to compound 566 showed good inhibitory activity against glycogen phosphorylase (IC50 = 13.6 μM).580 Very recently, Goyard et al. reported glycogen phosphorylase inhibitors bearing a traizole ring in conjugation with a glucose sugar via click-inspired triazole formation. Cycloaddition of Boc-propargylamine with peracetylated glucosyl azide followed by deacetylation afforded tert-butyl {[1-(β-D-glucopyranosyl)-1,2,3-triazol-4-yl]methyl}carbamate 3180


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Scheme 137. Click-Inspired Calix[4]arene S-Sialosides Decorated at the Upper and Lower Rims549

The microwave-assisted click reaction produced triazolyl glyconconjugates bearing phenylalanine and tyrosine aryl Cglycosides (Scheme 145). The successive bioassay for PTP1B activity for these glyconconjugates suggests that molecules containing carboxylic acid and benzyl moieties were the most potential PTP1B inhibitors (IC50 = 5.6 μM for 580 and IC50 = 5.5 μM for 581).584 A class of mono- and bisphenylalaninyl and -tyrosinyl glucosides were recognized as PTP1B inhibitors by the Chen group.585 Glucosyl scaffolds incorporated with one or two phenylalanine or tyrosine substituents on the 2,3-, 2,6-, 3,4-, 4,6-, and 6-positions were synthesized in excellent yields under MWassisted click chemistry. Among these synthesized compounds, 4,6-disubstituted tyrosinyl glucoside was found to have maximum PTP1B inhibitory activity as revealed by successive bioassays. Several bis(triazolyl) glycosyl acids and esters were developed, among which compounds 582 (Ki = 14.4 μM) and 583 (Ki = 8.7 μM) exhibited maximum activity against PTP1B (Figure 48). Furthermore, the glycoconjugate 583 was found to be efficacious against TCPTP (IC50 = 31.0 ± 9.6 μM).585 In another attempt, O-propargylated sugars 585 and 586 were clicked with manifold-substituted azides 584 to synthesize triazolyl α-ketocarboxylic acid-derivatized glycoconjugates (Scheme 146). Among these, glycosyl carboxylic acid derivatives 589 and 590 were discerned as potent PTP1B inhibitors for manifold selectivity relative to a group of homologous PTPs (IC50 = 3.2 μM for 589a, IC50 = 11.1 μM for 590a, and IC50 = 5.6 μM for 590b).586 A class of 1-O-triazole-linked threoninyl, serinyl, tyrosinyl, and phenylalaninyl sugars were developed using microwave-facilitated Cu(I)-catalyzed azide−alkyne 1,3-dipolar cycloaddition carried out by Yang and co-workers (Scheme 147).587 These triazolyl glycopepetides were recognized as potential inhibitors of PTP1B and CDC25B with selectivity over various phosphatases. For instance, compound 594 (with IC50 = 5.1 μM) was found to have selectivity and act as a potent inhibitor of PTP1B over other PTPs that were tested.587 A series of dimeric benzoylated and benzylated β-CD-glucosyl and β-CD-galactosyl 1,4-dimethoxy-substituted benzenes and naphthalenes were designed by the Xie group using the click approach. These compounds were subjected to ceric ammonium nitrate (CAN) oxidation, leading to the synthesis of the corresponding quinone derivatives. The in vitro studies revealed that dimeric benzoylated glycosyl dimethoxybenzenes and benzoquinones 595−596 were excellent inhibitors of PTP1B (IC50 = 0.62−0.88 μM), although gluco and galacto derivatives were also reported to have similar results.588 Similarly, Obenzylated glycosyl molecules were recognized to have protein tyrosine phosphatase (PTP) 1B inhibitory activity and were also found to be several-fold selective over other homologous PTP inhibitors. The inhibition activity against a group of homologous PTPs and PTP1B was further remarkably exhibited by triazolelinked glycosyl dimers of 597 and 598 with IC50 values of 1.5 ± 0.1 and 5.2 ± 0.3 μM, respectively. (Figure 49).589

Figure 42. Structure of sialoside ligand 524.

(567).581 Moderate inhibitions of glycogen phosphorylase enzyme were shown by compound 567 (IC50 = 620 lM), along with its amido derivative 568 (IC50 = 650 lM) (Figure 47). 16.3. PTP1B Inhibitory Activities

Protein tyrosine phosphatases (PTPs) act as significant therapeutic targets for treatment of various human diseases. Xie and co-workers used amino acids with an alkynyl substituent (569) and various sugar azides (570) for synthesis of PTP inhibitors via click chemistry. Galactosyl-, glucosyl-, and mannosyltriazoles derivatized over threonine and serine amino acids were designed as depicted in Scheme 143, in which glycohybrids 571 and 572 were acknowledged as effective PTP1B inhibitors in a selective manner against a group of homologous PTPs (IC50 = 5.9 ± 0.4 μM for 571 and IC50 = 7.1 ± 1.0 μM for 572).582 A family of benzyl 6-triazolo(hydroxy)benzoic glucosides were reported as PTP1B inhibitors by Tang and co-workers (Scheme 144).583 A new class of PTP1B inhibitors were also recognized in the form of glycoconjugates supported by (hydroxy)benzoic derivatives (575a, IC50 = 8.7 ± 1.4 μM; 575b, IC50 = 6.7 ± 0.5 μM), sugars, and alkyl chains. These glycoconjugates were found to be remarkably selective over LAR (leukocyte antigen-related tyrosine phosphatase), TCPTP (T-cell PTP), SHP-1 (PTP-1 having SH-2), and SHP-2.

16.4. Carbonic Anhydrase Inhibitor

Carbohydrates have undermined the propensity to pass across the plasma membranes. Further studies reveal that carbonic anhydrases (CAs), particularly isozymes CA IX and CA XII bound to the membrane, support a system that regulates the pH, which in turn permits tumor cells that proliferate and survive to induce hypoxia. Also, carbonic anhydrases IX and XII are potential targets for the advancement of new cancer therapies 3181


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Scheme 138. Calix[4]arene S-Glycosides via Combination of Thiol−Ene Coupling and CuAAC Click Chemistry553

Scheme 139. Click-Inspired Functionalized Graphene Oxide561

In this regard, Wilkinson and co-workers designed a series of glycoconjugate benzenesulfonamides by using the click approach under which sugar moieties are linked to high-affinity aromatic sulfonamides. The developed compounds 599−602 (Figure 50) were assessed for their capability to inhibit human carbonic anhydrase (CA) isozymes. In fact, compound 601 showed promising activity and selectivity against CA IX associated with cancer cells.592,593

involving hypoxia. Hence, the inhibitors of CAs can act as potential anticancer agents; in this regard, it has been found that the sugar tail provides a valuable tool for generation of CA isozyme-selective compounds because the stereochemical diversity in the carbohydrate part of the developed molecules provides the active sites in CA topological studies to give various potential and selective hCA IX inhibitors.590,591 To date, there are limited numbers of molecules which have been identified in animal model systems and CA-pertinent cells. 3182


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Scheme 140. Click-Inspired Manufacture of Water-Soluble Graphene Nanosheets561

and thereby facilitates viral adhesion to the target cell.597,598 On the other hand, neuraminidase splits these virus-attached sialic acid residues from cellular glycoproteins and glycolipids and therefore allows virus entry into the cells.599 In 1969, 2,3dehydroneuraminic acid (DANA, 605), a transition-state analogue of sialic acid, was recognized as an inhibitor of neuraminidases,600 and during the 1990s, sialic acid-modified highly potent and selective neuraminidase inhibitors zanamivir, commonly known as Relenza,601 606, and oseltamivir, commonly known as Tamiflu,602 607, were identified and approved as drugs (Figure 52). However, rapid exposure of resistant influenza virus groups due to modification of these surface glycoproteins necessitates development of new vaccines. Therefore, over the past few years several groups have modified these sialic acid mimetics to formulate better inhibitors which can effectively bind to enzyme active sites and thus treat influenza by arresting the synthesis of neuraminidases in a direct manner. 16.5.1. Zanamivir-Based Neuraminidase Inhibitors. The strategy to couple molecular structures with discrete properties representing the combined properties of the parent entities has emerged in recent years. Exploiting similar aspects, zanamivir analogues were synthesized by Jiang and co-workers that counter avian influenza (H5N1) in an efficacious manner603 as it is active against the neuraminidase enzyme. The cleavage of sialic acid residues from the glycolipid and glycoprotein portions is the determining step for influenza virus replication. This step is solely triggered by neuraminidases,. These neuraminidase inhibitors act directly by restricting neuraminidase enzyme synthesis. A zanamivir library was developed with C-4-triazolyl substituents (609 and 610) utilizing click chemistry starting from a common precursor, 608 (Scheme 148). The developed zanamivir analogues were subsequently screened, where

Figure 43. Glycosyltriazole analogues as potential glycosidase inhibitors.

Morris et al. developed a library of carbohydrate-based small molecules (Figure 51) and evaluated them for CA inhibitory activity that mimics that against CA IX (protective part) under an acidic tumor-inducing microenvironment.594 Some of the developed molecules inhibit CA IX and XII with nanomolar Ki values of 5.3−11.2 nM. Particularly, compounds 603a and 603b act as CA IX-induced survival blockers and are developed as cancer cell-selective inhibitors under in vivo conditions. A notable structure−activity relationship (SAR) concerning isozyme selectivity for cancer-related CAs was found for compound 603a and a trisubstituted galactose derivative, 604b, having a short hydroxyl-containing group at the fifth position of the triazole ring.594 Furthermore, it is riveting to note that by employing the ruthenium-catalyzed click reaction (RuAAC) a family of 1,5disubstituted 1,2,3-triazolylbenzenesulfonamide glycoconjugates were synthesized with properties similar to those of a number of CA inhibitors and found to block CA IX activity. 16.5. Neuraminidase Inhibitors: Antiviral Activities

All kinds of influenza viruses are defined by their two unique surface glycoproteins, hemagglutinin and a neuraminidase.596 The hemagglutinin recognizes the sialic acid moiety of the host 3183


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Scheme 141. Click-Inspired Synthesis of α- and β-D-Glucopyranosyltriazoles570

Azide 611 and an alkyne along with an aldehyde were clicked via the CuAAC reaction and gave a mixture of triazolyl aldehyde with carbohydrate-containing units and the corresponding acetal in a 5:2 ratio, which further underwent reductive amination with lysine protected by an amino functionality, resulting in sialoside 614. 16.5.2. DANA-Based Neuraminidase Inhibitors. DANA, another transition-state analogue of the sialidase enzyme, has been modified by several groups to obtain potent inhibitors for neuraminidases.607,608 Zou et al. designed a library of DANAbased inhibitors for the mammalian NEU3 enzyme by modifying it at the C-9 and N-5-Ac positions using the click reaction.609 The molecular docking studies of DANA in the NEU3 active site provided evidence that a large hydrophobic part adjoined to the C-9 position is present in sialic acid. Therefore, to comprehend the topological binding site of the NEU3 enzyme, a variety of substituents were appended over the C-9 and N-5-Ac positions of DANA with the anticipation of effective interaction with the hydrophobic pocket of the enzyme. Starting from Neu5Ac following a number of steps, N-5-(azidoacetyl)- and 9-azido-9deoxy-DANA derivatives were prepared and subsequently clicked with different alkyne-functionalized substituents. Evaluation of enzymatic inhibition showed markedly improved activity in the case of C-9-triazolyl substitution (6) with hydrophobic substituents such as phenyl (617a) (20 ± 10 μM), hexyl (617b) (23 ± 4 μM), and phenoxymethyl (617e) (45 ± 3 μM), whereas N-5-acetyltriazole derivatives exhibited significantly reduced activity as compared to DANA (Table 4). Additionally, it has

compound 610 significantly exhibited activity against avian influenza virus (AIV) (IC50 = 6.4 μM) in comparison to zanamivir (IC50 = 2.8 μM).604 Also, in search of promising neuraminidase inhibitors, multivalent constructs of zanamivir have been prepared by attempting Cu-catalyzed click cycloaddition between C-4- and C7-azido analogues of zanamivir and various alkyne-functionalized multivalent cores.605 The CuAAC reaction was very well utilized by Linhardt and co-workers to develop a class of sialic acid derivatives with 1,2,3triazolyl linkages by clicking methyl [5-acetamido-3,5-dideoxy-2azido-D-glycero-α-D-galactonon-2-ulopyranosid]onate (611) with various terminal alkyne functionalities. The developed triazolyl sialic acid analogues underwent screening for neuraminidase inhibitory activity using various techniques to develop a different family of neuraminidase inhibitors to cure influenza.606 5-Clicking 611 with dec-1-yne resulted in acetamido-3,5-dideoxy-2-(4-octyl-1H-1,2,3-triazol-1-yl)-D-glycero-α-D-galactonon-2-ulopyranosidic acid (613), which has been acknowledged as a highly functional conjugate (IC50 = 28 μM, comparable to that of Neu5Ac2en). In the same way, 615, a mimic of disaccharides (IC50 = 17 μM), and dendrimer 616 (IC50 = 20 μM) were also scrutinized. (Scheme 149).606 Sialic acid derivatives with aldehyde functionalities are helpful for conjugating the surface of a protein by employing reductive amination. This strategy can be visualized in a KLH-carrier protein that governs antibody production. 3184


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Figure 44. Synthesis of multivalent imino sugars via the copper(I)-catalyzed click reaction.

Among them, two frontier molecules, 619 and 620 (Figure 53), were identified as potential Vibrio cholerae neuraminidase (VCNA)- and human neuraminidase-2 (hNeu2)-selective inhibitors, by subjecting them to successive screenings: one screeing was performed when the reaction mixture was crude, and the second screening was performed over the isolated compounds. Copper ions in the 1 M concentration range deactivated hNeu2 in the click reaction during the first screening, and this effect was further countered by adding a small excess of EDTA, which results in a decline of the rate of activation. The aglycon substituent appreciably enhanced the binding properties of the sialoside unit (619, K1 = 61 μM; 620, K1 = 216) in both a potent and selective manner. 16.5.3. Cholera Toxin Inhibitors. Cholera toxin (CT), a member of the family of bacterial toxins, exerts its toxic effect upon binding with the target receptor GM1 ganglioside present at the host surface cells. Cheshev et al. designed a library of nonhydrolyzable functional mimetics of oGM1 gangliosides by connecting the two pharmacophoric moieties galactose and sialic acid using the click reaction (Scheme 150).610 In relation to a single pharmacological sugar moiety, addition of the carbohydrate moieties in developed CT molecules enhanced the affinity by 1- or 2-fold.

Figure 45. Angiogenesis antagonists of 1-deoxynojiromycin analogues (552−554).

been concluded from the studies that insertion of the triazole moiety also contributed toward the enhanced inhibition potency of the DANA derivatives. Click-inspired synthesis of a library of 2-(difluoromethyl)phenyl sialoside with emphasis on the aglycon moiety was performed by using a terminal alkyne and an azide framework.605 3185


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Figure 46. Click-inspired triazolyl glycoconjugates 555−558 as inhibitors of glycosidase enzymes.

sites.613 Therefore, designed scaffolds that bind strongly with these sites would effectively block the sialic acid transfer event and, in principle, would be good inhibitors. In the sequence of developing dynamic inhibitors for the T. cruzi trans-sialidase (TcTS) enzyme, the click reaction was explored by Carvalho and co-workers for developing a smallscale family of 1,4-disubstituted galactosyltriazole derivatives that were found to inhibit the TcTS enzyme.614 This enzyme plays a crucial role in the invasion and recognition events related to host cells and permits the parasite to escape from the immunogenic responses. A series of 46 disubstituted triazoles (632c,d− 654c,d) with definite regioselectivity were obtained from clicking galactose-based azides at either the C-6 (630) or the C-1 (631) position and a group of 23 terminal alkynes under microwave conditions. The synthesized sugar-based triazoles were tested for inhibitory activity against TcTS and were found to be inhibitors of the enzyme in a range of 0.5−1.0 mM in a moderate to weak manner. Among them, compound 636d displayed significant 37% inhibitory activity, but in vitro evaluation of the same library for trypanocidal activity against trypomastigote forms of Y strain T. cruzi (benznidazole as a control) confirmed compound 647c as the most efficacious inhibitor with optimum activity (Scheme 151).614 Likewise, the same group explored the investigation and designed a library of 1,2,3-triazolyl sialyl mimetic neoglycoconjugates by clicking azide-containing sugars (galactopyranose and glucopyranose) and the amino acid threonine with alkynefunctionalized sialic acid and galactose precursors.615 The TcTS inhibitory activities of compounds 655−659 (Figure 54) were tested at 1.0−0.5 mM concentrations and compared with that of DANA, which showed higher inhibitory activity than compounds 655 and 656 but not compounds 657−659, whereas assessment of the trypanocidal antiparasite activity verified compound 656 as the most powerful inhibitor with IC50 in the 260 μM range. Therefore, the results provided evidence of the necessity of sialic acid and a galactosyl unit in the development of more effective inhibitors for Chagas disease. Campo et al. derived triazole-linked linear oligomers and macrocycles via clicking oligomerization of azido alkynefunctionalized galactose. The developed compounds exhibited inhibition against T. cruzi macrophage invasion.616

Scheme 142. Synthesis of Triazolyl Glycoconjugates as αGlucosidase Inhibitors

16.5.4. Trypanosoma cruzi trans-Sialidase (TcTS) Inhibitory Activities. The parasite Trypanosoma cruzi molds an enzyme, popularly known as trans-sialidase, involved in the parasite−host interaction, which is the key phenomenon involved in the cell invasion system and related infections, has emerged as a budding therapeutic target for Chagas disease.611 Utilizing the wide scope of the click approach, various inhibitors of the T. cruzi trans-sialidase (TcTS) enzyme based on sialic acid modification have been targeted. TcTS essentially modifies the carbohydrate coat of the parasite cell surface by catalyzing the transfer of sialic acid from host cells to the terminal βgalactopyranosides in the mucin coverage of the parasite cell surface, which in turn is an obligatory adaptation for the parasite to escape from the human immune response.612 The crystal structure of the TcTS enzyme depicts the presence of two distinct sialic acid (acceptor) and galactose (donor) related active 3186


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Figure 47. Triazolyl glycoconjugates 563−568 as glycogen phosphorylase inhibitors.

They found that enhanced binding affinity cardinally depends upon the charge interaction.617The binding affinity and specificity are two key factors for the molecule to be appropriately active, and it is inferred that increasing hydrophilicity has a positive impact on the binding affinity but may affect the specificity negatively. The methodology involved the CuAAC reaction of N-acetylated azidoneuraminic acid derivative 662 with alkynes 660 and 661 to afford click products 663 and 664, which on further deprotection with aqueous trifluoroacetic acid (TFA) furnished compounds 665 and 666 (Scheme 152). These molecules were assessed against α-(2,3)-sialyltransferase Cst-06 and Cst-I of Campylobacter jejuni bound fusion protein along with maltose. The triazole-linked compounds 665 and 666 mimic the phosphodiester bond with sialic acid having an αanomeric configuration and exhibit less than 50% inhibitory

Scheme 143. Synthesis of Triazolyl Glycoconjugates as Potential PTP1B Inhibitors

16.5.5. Sialyltransferase Inhibitors. The strategy of targeting variations in molecular systems and their potential to inhibit bacterial sialyltransferase was implemented by Zou et al.

Scheme 144. Triazolyl Glycoconjugates as Potential Protein Tyrosine Phosphatase Inhibitors

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Scheme 145. Carboxylic Acid and Aromatic Moieties Bearing Glycosyltriazole as PTP1B Inhibitors

Scheme 147. Glycosyltriazoles as Selective Potential PTP1B Inhibitors587

Figure 48. Synthesis of triazole-bearing glycoconjugates as potential PTP1B inhibitors.

activity (500 μM). The Ki for 666 was 160 μM, which is 2 times lower than the Km of CMP-Neu5Ac (400 μM).617 Nishimura and co-workers designed sugar nucleotides that were synthesized artificially and acknowledged as the first potent inhibitors with high specificity for the α-2,3-(N)-sialyltransferase (α-2,3-ST; IC50 = 8.2 μM) rat recombinant (Figure 55).618 Compound 667 was recognized as a positive substrate for the α2,6-(N)-sialyltransferase (α-2,6-ST; Km = 125 μM) rat

recombinant. This versatile strategy was further confirmed by recognition of 668 and 669 for human recombinant α-1,6fucosyltransferase VIII (R1,6-FucT; Ki = 13.8 μM) and α-1,3fucosyltransferase V (α-1,3-FucT; Ki = 293 nM)618 Likewise,

Scheme 146. Glycosyl α-Ketocarboxylic Acid-Linked Triazoles as PTP1B Inhibitors586

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Figure 49. Developed triazolyl glycoconjugates as potential PTP1B inhibitors.

matic kinetic screening exposing compound 670 as the most efficacious competitive human OGlcNAcase (Ki = 185.6 μM) inhibitor.619 16.6. Anticancer Activities

Cancer is one of the most common global concerns affecting a wide range of people. Several epipodophyllotoxin-derived anticancer agents, including vinblastine, paclitaxel, vincristine, camptothecin derivatives, etoposide, irinotecan, and topotecan, are clinically proven drugs used on a global level.215 Augmenting cancer cases have obligated synthetic chemists to develop effective anticancer agents targeting both prevention and cure. It is a well-known fact that cancer cells have abundant oligosaccharide antigens on their surface, which provides them potential to act as markers for both active and passive forms of cancer. Also, the carbohydrate analogues exhibit antigenic properties to arouse an antitumor response in the immune system, by conjugating them with other biomolecules.

Figure 50. Structures of glycoconjugate membrane impairment carbonic anhydrase inhibitors.

similar chemistry was explored to construct therapeutic agents of O-GlcNAcase. Furthermore, the Wang group reported enzy-

Figure 51. Carbonic anhydrase inhibitors synthesized by the click approach.594 3189


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Figure 52. Structures of approved neuraminidase inhibitors.

Scheme 148. Development of Zanamivir Analogues Employing Cu-Catalyzed Click Reaction

Scheme 149. Click-Inspired Synthesis of a Triazolylsialic Acid Library of Nuraminidase Inhibitors606

tives.620 Per-O-acetylated glycosyl azide derivatives treated with the propargyl ester of GA following the principles of the click

The Parida group employed the click strategy to design a class of glycosyltriazole-linked 18β-glycyrrhetinic acid (GA) deriva3190


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Table 4. Neuraminidase Inhibition Activity of the Developed Glycosyltriazoles

a

Alkynes used. bDerivatives of DANA. cIC50 (M) values of the developed glycoconjugates examined for neuraminidase inhibition activity.

evaluated for their cytotoxic activity against several cancer cell lines with/without MDR (multidrug resistance) phenotypic character and nontumor BJ fibroblasts and MRC-5 under in vitro conditions. The conjugated systems were found to have increased activity. Octyl esters at the ortho position of the aromatic residue of the azido and glycosylated units displayed IC50 = 93.2 μM for 674 and 23.8 μM for 675 for CEM lymphoblasts. Compound 675 was more active as compared with the deacetylated derivative. Similarly, compounds 676 and 677 having octyl esters in the meta and para positions were reported as the most potent ones and displayed a significant decrease of the IC50 values.621 Blagg et al. explored the click reaction emphasizing amides in natural products to develop triazole-containing novobiocin analogues.622 The developed compounds were evaluated for antiproliferative effects against cell lines of breast cancers, i.e., SKBr-3 and MCF-7, and the results resembled those of analogues having amide units. Furthermore, Western blot analysis of Hsp90-dependent client protein degradation supported the idea of a common mechanism for Hsp90 inhibition in both structural systems. Compounds 678 (IC50 = 13.16 ± 3.85 μM against MCF-7 and IC50 = 21.22 ± 5.99 μM against SKBr-3) and 679 (IC50 value of 18.33 ± 4.67 μM against MCF-7 and IC50 = 8.17 ± 0.11 μM against SKBr-3) (Figure 57) displayed maximum potency in inhibition against SKBr-3 and MCF-7 in the designed series.622 Chang et al. developed a series of cyclopamine glycoconjugates, where triazole 680 (IC50 value of 33 μM) showed greater activity against lung cancer cells compared to cyclopamine.623 Freitas and co-workers developed a series of 12 8hydroxyquinoline triazolyl glycoconjugates by clicking 8-O-

Figure 53. Sialosides as effective inhibitors of VCNA and hNeu2.

approach afforded glycosyl-derivatized triazoles of 18β-glycyrrhetinic acid (Figure 56). De-O-acetylated triazolyl molecules containing free hydroxyl substituents in the carbohydrate part were assessed for their anticancer properties against cervical cancer cells (HeLa) in humans and normal kidney epithelial (NKE) cells. Compounds 671 and 672 showed promising anticancer activities for HeLa cells, exhibiting IC50 values of 13.76 ± 5.30 and 21.50 ± 2.24 μM, respectively.620 Hradilova and co-workers performed a similar click chemistry and developed conjugates from terminal-alkyne-containing ortho, meta-, and para-substituted and D-mannose-based azido benzoates (Scheme 153).621 The developed molecules were 3191


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Scheme 150. Synthesis of Bidentate Cholera Toxin Ligands Using Click Chemistry610

functionality to afford a desirable anticancer vaccine (Figure 59).627 Interestingly, a nanoparticle-based two-step scheme designed to target tumor cells in vivo utilizing the click-inspired metabolic glycoengineering concept has been reported recently. In the first step, intravenous incorporation of nanoparticles (glycol chitosan) produces an azide functionality on the tumor tissue. In the second step, intravenous injection for clicking results in the enhancement of the ability of nanoparticle-based drugs to target tumor cells. The enhanced tumor-targeting ability may result in significant enhancement of the cancer therapeutic value.628

alkylated quinolines with sugar azides and evaluated them against in vitro arresting proliferation of various types of cancer cells.624 Compound 681 exhibited potential antiproliferative and enhanced selective actions in targeting cancer cells of the ovaries (OVCAR-03, GI50 less than 0.25 mg mL−1); it exhibited greater activity than the drug doxorubicin taken as a reference (OVCAR03, GI50 = 1/4 × 0.43 mg mL−1).624 Anjos and co-workers designed a sugar triazole-linked 1,2,4oxadiazole series, 682, via clicking acetylated D-glucosederivatized azide and propynyl 3-(3-aryl-1,2,4-oxadiazol-5-yl)propionic acid esters (Figure 58). Two compounds of the series showed some cell-growth inhibitory activity against NCI-H292 and HEp-2 strains in lung carcinoma and larynx carcinoma, respectively.625 Formation of microtubules made up of tubulin proteins is a fascinating target to arrest cell division and achieve apoptosis by disturbing the dynamic equilibrium of the microtubular network. Among the known microtubule-stabilizing antitubulin agents, discodermolide or epothilones and paclitaxel are common agents. Keeping paclitaxel as a base entity, Manach and co-workers synthesized a class of paclitaxel mimics, 683, by stereoselective β-glycosylation of L-glucurono-γlactone, which in turn were subjected to the click reaction with azido aromatic structures. The developed members inhibited tubulin depolymerization in a remarkable manner and displayed cytotoxic activities.626 The Danishefsky group reported the synthesis of a relevant anticancer vaccine employing the click reaction, where keyhole limpet hemocyanin (KLH) polypeptide carriers were fabricated with oligosaccharide antigens by utilizing triazole moiety 684. Employing CuAAC, the glycosyl mimetics of sugars that reside over cancer cells were synthesized and incorporated over the carrier protein, which can possibly act as antigens for triggering antibodies. Tumor-related azido glycopeptides 684a−c were clicked with KLH carrier proteins armed with an alkyne

16.7. Insecticidal Activity

Yang et al. reported an interesting approach by coupling the parent compound with a sugar unit to convert nonmobile insecticides into mobile ones in phloem tissue.629 The authors found that coupling a non-phloem-mobile insecticide with a glucose group permits it to be converted into a phloem-mobile insecticide, and consequently glycosyltriazole 687 (GTF) was synthesized utilizing the click approach between sugar azide and N-acetylene 685 in the presence of either CuSO4/NaAsc or CuI/ DIPEA (Scheme 154).629 GTF was found to be mobile in sieve tubes on the basis of the phloem mobility test performed in seedlings of Ricinus communis., but as it was found that the insecticidal activity of GTF is lower than that of fipronil, the effectivity of GTF depends upon the extent through which it dissociates the parent molecule in the living system. A degradation test performed in adult castor bean plants reveals that GTF is converted into fipronil. This indicates that GTF despite its lower insecticidal activity but ability to reconvert into fipronil, the active insecticidal counterpart in the plant, can be used as an efficacious insecticidal compound. 3192


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Scheme 151. Click-Inspired Synthesis of Galactose-Based TcTs Inhibitors614

16.8. Antifungal and Antibacterial Activity

and resulted in biological activity of the prepared glycoconjugates, proving that the utilized method was facile for the synthesis of antifungal agents.630 The Zhang research group proposed a feasible method for the derivatization of neomycin B (689) through modification of the fifth position of the parent molecule.631Many developed compounds are found to be more potent antibacterial agents than neomycin as revealed by structure−activity relationship studies against aminoglycoside-resistant bacterial strains facilitated by enzymes that modify the aminoglycoside structure. Also, some of the developed compounds displayed remarkable antibacterial activity for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).631 Likewise, Reddy and co-workers synthesized various carbohydrate-based 1,2,3-triazoles bridging tetrahydrofuran. All developed molecules were investigated for different biological assays such as antimicrobial, antibacterial, and antifungal activities, and two of them (691 and 690) displayed quality

In a few decades, extensive utilization of immunosuppressant drugs and catheters and prolonged use of broad-spectrum antibiotics in diseases such as cancer and AIDS will be responsible for tremendous enhancement in the frequency of critical fungal and bacterial infections. Most of the antifungal and antibacterial medicines available in the market are toxic with respect to living systems and are even prone to emerging resistant strains. Therefore, such urgent requirements turn modern research toward the development of biological-system-friendly and effective antimicrobial agents. Most probably, 1,2,3-triazoles will be of considerable interest for this purpose. In this regard, incorporation of alkyne/azide groups on unprotected sugars has been carried out using simple glycosylation processes of alkynyl alcoholic moieties and azidebearing alcohols in a single step followed by copper(I)-catalyzed click reaction between the alkyne/azide counterparts. These processes created triazole-possessing glycosyl derivatives 688 3193


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Figure 54. Structures of glycoconjugates with TcTS inhibitory activity.615

Scheme 152. Click-Inspired Synthesis of Sialosides as Inhibitors of Sialyltransferase617

results with an MIC value of 25 μg/mL for 691 as an antimicrobial agent and an MIC value of 12.5 μg/mL for 690.632 6-Triazolo-6-deoxyeugenol glucoside 692 was found to have antibacterial properties against Gram-negative bacteria Salmonella typhimurium with an IC50 value of 49.73 μM and low toxicity (CC50 = 157.83 μM), clearly revealed by in vitro cytotoxicity evaluation on mouse spleen cells.633 Compound 693b, from a library of trideoxy sugars, is recognized as a highly active molecule displaying an MIC value of 0.78 mg/mL for S. aureus

and Klebsiella pneumoniae and an MIC value of 3.12 mg/mL for methicillin- and vancomycin-resistant S. aureus. Interestingly, compound 693a exhibited excellent antifungal activity, presenting an MIC value of 0.39 mg/mL for Trichophyton mentagrophytes.634 A urinary tract infection, also known as a bladder infection, originates through uropathogenic E. coli and is responsible for a critical health issue. Thus, considering this issue, a series of multimeric heptyl mannoside-based glycoconjugates, obtained by a high-yielding azide−alkyne click protocol, were 3194


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Figure 55. Chemical structures of triazlolyl glycoconjugates as sialyl transferase inhibitors.

disease highly contributes to increasing mortality rates. To date DOTS (directly observed treatment, short course) serves as the treatment for tuberculosis and involves a six month course of drugs (rifampin, isoniazid, pyraminazide, and ethambutol in some cases). However, the severe side effects, toxic nature of the drugs, and emerging resistant microbial strains necessitate the synthesis of advanced drugs that can act as more effective antituberculosis agents.636 Interestingly, the click approach was extended to adjoining an adamantyl group in compound 695, leading to promising activity against strains of bacteria and fungi. The bioinformatics study suggests that the involvement of bacteria−protein cocrystals may prompt penicillin-binding protein-2 as the maximum acceptable therapeutic target for triazolyl glycoconjugates. However, the known bactericidal potential of an adamantyl urea against M. tuberculosis with an interesting mode of action such as the abolition of the translocation of mycolic acids from the cytoplasm compelled the evaluation of the adamantane-based triazolyl glycoconjugates for the search for potency against M. tuberculosis.637 Likewise, the Tripathi research group developed a library of 1,4-disubstituted triazolyl glycoconjugates inspired by the click reaction via treatment of 5-azido-5-deoxyxylo-, -ribo-, and -arabinofuranoses with diverse terminal-alkyne-functionalized molecules. These synthesized compounds were examined for M. tuberculosis H37Rv, and the triazolyl glycoconjugate 696 (Figure 61) displayed mild activities in vitro, showing an MIC value of 12.5 μg/mL.638 Click-inspired reaction of an azide group attached on the surface of cellulose nanocrystals and the cationic porphyrin

Figure 56. Glycosyltriazoles of 18β-glycyrrhetinic acid as anticancer agents.620

screened for their adhesion inhibition of piliated E. coli to human bladder cells, where a tetravalent multimer (694) displayed inhibitory concentrations 6000- and 64-fold lower than those of the corresponding mannose and heptyl α-D-mannoside.635 The chemical structures of antifungal and antibacterial triazolyl glycoconjugates are depicted in Figure 60. 16.9. Antitubercular Activities

Mycobacterium tuberculosis bacteria are solely responsible for tuberculosis, which is a giant dilemma of global concern as this

Scheme 153. Synthesis of Glycosyltriazoles as Anticancer Agents621

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Figure 57. Chemical structures of anticancer agents constructed via triazole linkages.624

decamer derivatives. Biological assay of the developed oligomers confirmed the varying inhibitory tendencies for mycobacterial α(1,6)-mannosyltransferases. Among various analogues, hexamannoside and octamannoside exhibited the highest activity (IC50 = 0.14−0.22 mM) (Figure 63).640 Polakova et al. reported triazole-containing 1,6-oligomannosides 700 of varying chain lengths interconnected by 1,2,3triazole linkers using the “click” reaction (Scheme 155) and screened them for their activity in a mycobacterial mannosyltransferase (ManT) assay.642 Hexamannoside and octamannoside from the developed molecules displaying IC50 = 0.14−0.22 mM demonstrated maximum inhibition against mycobacterial α(1,6)-mannosyltransferases. The novel conjugates synthesized were very similar in structure to that of the confirmed substrate for ManT, wherein 1,2,3-triazole linkers were used to adjoin each mannose unit instead of glycosidic linkages; however, the glycosidic linkage between the hydrophobic aglycons installed at the first carbon remained unaltered. The screening of modified analogues with mycobacterial ManT provided products elongated by one or two sugar units with an R-(1−6) linkage. Therefore, the results suggested that the designed disaccharide and trisaccharide substrates were well recognized by the ManT enzyme, although the efficiency of the shifting is slightly reduced due to replacement of the glycosidic linkages with triazoles. From the results, it has been concluded that an efficient mannosyl acceptor for Man T should have a properly altered spatial orientation and relative distance in terms of the number of entities between sugar moieties. The enzyme needs a free primary hydroxyl substituent and a hydrophobic aglycon, which are present in the developed compounds. In addition to this, the variations in comparison to a single glycosidic linkage were also well tolerated in a comparatively broader range.642 In the same direction, the group further modified their work and developed mycobacterial mannosyltransferase (ManT) inhibitors 701−705 containing 2−3 mannopyranoside entities which are linked through a triazole ring in place of a glycosidic linkage via clicking the alkyne and azide functionalities on the mannose units, where only one glycosidic linkage among the nonglycan part and starting mannose unit remained unchanged. The synthetic analogues 701−705 (Figure 64) were examined for ManT activity of the mycobacterial membranes in the in vitro

Figure 58. Triazolyl glycoconjugates as anticancer agents.

alkyne was utilized for the modification of nanocrystals, which were considered as useful for quick, proficient, and economic sterilization of a reasonable bacterial range. The porphyrin− cellulose nanocrystals 697 (Figure 62) displayed outstanding efficiency toward the inactivation carried out photodynamically in Mycobacterium smegmatis and S. aureus and mild activity against E. coli.639 The mycobacterial α-(1,6)-mannosyltransferase enzyme has a cardinal role in the cell wall biosynthesis in M. tuberculosis; hence, modification in such molecules which inhibit this enzyme efficiently will be very effective to prevent tuberculosis. Dondoni et al. designed novel (1,6)-oligomannose analogues containing triazole units via exploring the click reaction. Ethynyl α-Cmannoside coupled with alkyl 6-azido-α-C-mannopyranoside under 1,3-dipolar cycloaddition reaction afforded triazolo oligoside 698 in good yield.640 The covalent bridging between two carbohydrate moieties or a carbohydrate moiety and a noncarbohydrate moiety through triazole ring formation is a dependable strategy with respect to drug development.55 Dondoni et al. have designed a novel class of (1,6)-oligomannose derivatives with triazole linkages. The group achieved (1,6)ligation between α-D-mannose units utilizing the well-developed alkyne−azide click reaction of ethynyl α-C-mannoside and alkyl 6-azido-α-C-mannoside to afford linear oligomers in significant yield.641 Using the same approach, they obtained various triazolebridged mannose-based 1,6-oligomers, including hexamer and 3196


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Figure 59. Glycoconjugated carrier protein (KLH): precursors for anticancer vaccines.627

presence of the 701 and 705 derivatives in the reaction system. These derivatives having free hydroxyl groups at the C-6 carbons act as acceptors for ManT.643 Conte et al. on the contrary investigated the inhibition effect of the developed triazole-based oligomannosides against ManT by octyl (1→6)-α-D-mannodisaccharide, which behaves as an acceptor, and by M. smegmatis membranes, which act as a source of the enzyme, while both of the hexameric and octameric analogues were found to be highly efficient oligomers displaying approximately 95% inhibitiory activity (at a 1 mM concentration).640

Scheme 154. Glycosyltriazoles with Potential Insecticidal Activity629

16.10. Antileishmanial Activity

Leishmaniasis is a parasitic disease prevailing mostly in povertystricken societies, caused by more than 20 species of protozoans which belong to the kinetoplastida family. The disease is spread by more than 30 species of phlebbotomine female sand flies that act as a vector for this epidemic and clinically diverse disease.644 Hence, in this perspective, Tiwari et al. prepared a diversified library of triazolyl-O-benzylquercetin glycoconjugates via CuAAC.645 The methodology involved the generation of diverse O-benzylquercetin alkynes by selective protection followed by propargylation of quercetin, a well-known polyphenol significant against a wide range of clinical conditions.646 The click reaction of the developed O-benzylquercetin as the alkyne part (706− 708) with deoxy azido sugars 705 furnished triazolyl-Obenzylquercetins 709−711 regioselectively (Scheme 156).645 The promastigote and amastigote developmental stages of Leishmania donovani were used for screening the antileishmanial activities of the developed glycoconjugates 709−711, with the

assay.643 The inhibitory effect of the compounds was determined by the thin-layer chromatography (TLC) analysis of full range radioactive lipids containing [14C]Man from GDP-[14C]Man. The formation of labeled phosphatidylinositol mannosides/ poly(prenylphosphoryl) mannoses was not affected by the 3197


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Figure 60. Antifungal and antibacterial triazolyl glycoconjugates.

Figure 62. Porphyrin attached on the surface of cellulose nanocrystals 697 displayed inhibition of M. smegmatis and S. aureus.639

Figure 61. Triazolyl glycoconjugates as antitubercular agents. Figure 63. Structure of 1,6-α-D-oligomannosides developed via click chemistry.

analogue 709 having a single triazole bridge at the C-5 position exhibiting potential inhibition compared to the bis(triazolyl) glycocojugates 711 and C-3′-linked triazolyl glycoconjugates 710. Out of all of the developed quercetin glycans, two of them (709a and 709b) displayed remarkable activity in in vitro conditions against the promastigote developmental stage and intramacrophase amastigote stage of L. donovani.645

(Scheme 157).649 The developed triazoles were tested for HIV-1 protease and HIV-1 reverse transcriptase inhibition and showed 52−60% and 94−99% inhibitory tendencies, respectively, at 50 μM.649 These analogues may represent a lead optimization for the further development of more active inhibitors. The dual action on both the targets represents a very interesting strategy in the antiviral therapy. In fact, the onset of drug-resistant viral variants, which often occur during the therapy, involves the simultaneous administration of both HIV1 RT and PR inhibitors, and the use of multiple ligands or “portmanteau inhibitors” could facilitate patient compliance.

16.11. HIV-1 Inhibitors

HIV-1 reverse transcriptase (RT) is a member of the polymerase enzyme family and is required for the conversion of retroviral RNA into DNA, and is therefore essential for viral replication.647 HIV-1 protease (PR) is an aspartic protease, and it takes part in the formation of all the structural viral proteins: matrix, capsid, and nucleocapsid.648 Therefore, these enzymes represent two interesting therapeutic targets for HIV infection, which accounts for more about 2.0 million deaths every year. An effort to develop new chemical entities (NCE) against this deadly disease is emerging as a big challenge for medicinal chemists. Olomola et al. developed a series of dual HIV-1 protease and reverse transcriptase inhibitors 714 by clicking the substituted coumarins 712 (a well-known HIV-1 protease inhibitor) with the HIV-1 reverse transcriptase inhibitor azidothymidine (AZT, 713)

16.12. Antiproliferative Activity

Recently, Thorson et al. prepared a series of perillyl alcohol (POH) neoglycosides, and evaluated their antiproliferative activity against cell lines of A549 and PC3.650 The authors observed that the carbohydrate moiety can induce the antiproliferation process and inhibition of the phosphorylation step of the ribosomal protein (S6). This carbohydrate-dependent 3198


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Scheme 155. 1,2,3-Triazole-Bridged Octyl (1,6)-α-D-Oligomannosides, Acceptors for Mycobacterial Mannosyltransferase642

Figure 64. Glycoconjugates against ManT activity.

Scheme 156. Synthesis of Antileishmanial Triazolyl-O-benzylquercetin Glycoconjugates645

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Scheme 159. Click-Inspired Synthesis of Triazolyl α-GalCer Derivatives

Scheme 157. Key Steps for the Synthesis of Dual Inhibitors 714 for HIV-1 PR/HIV-1 RT649

and they were identified as genuine ligands for activating receptors of the NKT cells.652 step was considered the most probable mechanism of action. The synthesized neoglycosides were evaluated for their affinity toward the Cu-catalyzed click reaction and the latent effect of the triazolyl glycan part for POH biological activity. Glucoside 715 was clicked with azidohydroxypropane, which afforded parallel 6′-triazole perillyl glucoside 716 in 82% yield (Scheme 158).650

Scheme 160. Click-Inspired Synthesis of Glycopeptide Hybrid Lactam Mimetics654

16.13. Potent Agonistic Antigen for T-Cell Receptors

Lee and co-workers developed a library of triazolyl α-GalCer derivatives (719a−f), in which azide is substituted instead of amide in the lipid and designed 718. Thus, the developed azido derivative 718 was clicked with diverse terminal-alkynecontaining long aliphatic chains while the chain lengths varied in an incremental manner (Scheme 159).651 Because α-GalCer is a highly potential agonistic antigen of the T-cell receptor categorized under natural killer cells (NKT cells), it was used in immunization studies. The authors observed an enhancement in the IL-4 vs IFN-γ biasedness of cytokines after the conversion of α-GalCer’s amide by the triazole ring. Also, the elongation of the lipid part affected the stimulation effect wherein the developed triazole derivatives confirmed an equivalent stimulatory effect on cytokine production for α-GalCer, and showed a stronger Th2 cytokine response. Because IL-4 is an important cytokine to manage autoimmune problems such as type-1 diabetes, and multiple sclerosis, the developed triazole derivative may be crucial for the treatment of these diseases.651 Likewise, Slamova et al. developed β-2-acetamido-2-deoxygluco-GlcNAc-triazole derivatives using the MW-assisted click reaction. Talaromyces flavus CCF 2686 β-N-acetylhexosaminidase acted as a hydrolyzing agent for the synthesized derivatives,

16.14. Lectin Binding Activity

Lectins are proteins which specifically bind to carbohydrate structures (mono- and oligosaccharides) and play an important role in biological processes such as cell recognition events.563,564,653 Palomo and co-workers designed hybrids of glycopeptide lactam mimetics (722 and 723) that bind lectins using the click reaction between β-1-azido-L-fucose (721) and αacetamido-α-propargyl-β-lactam (720).654 The binding of the developed hybrids to Ulex europaeus lectin-1 (UEL-1) occurred after a “bent to extended” change in conformation around the triazolylmethylene moiety in 722, which rotates in a partial manner (Scheme 160); this was further confirmed by NMR and molecular dynamics (MD) studies. Compound 723 was found to bind well with lectin. The demonstration that these molecules can behave as true glycomimetics of flexible shape was assessed by a collaborated NMR and docking technique, introducing a model lectin that binds fucose, i.e., UEL-1, as a receptor.

Scheme 158. Synthesis of a Triazolyl Glycoconjugate with Antiproliferative Activity650

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Figure 65. Triazolyl glycoconjugates with galectin (S-lectin) inhibitory activity.

Scheme 161. Modification of E-Selectin Antagonists Using the Click Reaction

chemists have developed new glycosyl derivatives. Considering this view, Giguere et al. synthesized triazolyl clusters with monoor multivalency based on galactose and lactose sugars using the click reaction. These clusters were found to have improved binding ability with special emphasis on inhibiting Gal-1. A maximum inhibiton pattern was observed for galactoside triazole clusters 725, which displayed inhibiton with a value of 1250 μM, while trivalent lactosyl cluster 724 showed an affinity value of 20 μM for galectin proteins (Figure 65).234 Similarly, Tejler and co-workers developed some glycosyl clusters via regioselective clicking of acetylene derivatives of diverse amino acids with azidoethyl β-D-galactopyranosyl-(1→ 4)-β-D-glucopyranoside. Of all of them, the cluster 726 exhibited a lower activity (Kd = 3.2 μM) and was detected as a potential inhibitor of the Gal-1 protein (Figure 65).313 16.14.2. Selectin (C-Type Lectin) Binding Activity. Selectins are a different class of lectin proteins known as Ctype lectins and are expressed in the vascular endothelium and in circulating leukocytes. They participate outstandingly in the quick response to inflammation via controlling trafficking and homing of leucocytes at the inflammation site. Therefore, the

Furthermore, it was revealed that interactions exist between mimetic 723 and UEL-I.654 On the basis of the structural homology of their carbohydrate recognition domain (CRD) and amino acid sequence, animal lectins are found in various families identified as S-, C-, L-, I-, M-, P-, and R-types.655,656 This section focuses on the synthesis of Stype galectins and C-type selectins utilizing Cu-catalyzed click chemistry. 16.14.1. Galectin (S-Lectin) Inhibitory Activity. Galectins are proteins which bind cytosolic β-D-galactoside and are capable of changing their conformation in progressive, separation phases under a diverse range of biological processes. Gal-3, a type of galectin, is responsible for the origination of colon cancer and resulting malignant growths and progressive brain tumors and is a cardinal part of the innate immune system. The literature reveals that regulation of the apoptosis process is governed by Gal-3 and Gal-1 proteins, while Gal-1 stabilizes the HIV virus on the host cell surface and assists with HIV-1 infection.655 Naturally occurring glycans show insignificant affinity for the galectin proteins. Therefore, to diminish the harmful effect of these proteins and to enhance the affinity of glycans, synthetic 3201


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Scheme 162. In Situ Investigation of the Fucosyltransferase VI Inhibitor via Preparation of 1,2,3-Triazole on a Microtiter Plate659

Figure 66. Click-inspired synthesis of carbohydrate arrays on a microtiter plate.

design and development of selectin inhibitors can be considered a potential way to treat inflammation. Presently, three selectin proteins are acknowledged, E-selectin, L-selectin, and P-selectin, known to be responsible for expression in endothelial cells activated by cytokine, all leucocytes and active platelets, and endothelial cells, respectively. Cell adhesion molecules are generally involved in protection of the body from interaction of pathogens. The process begins with blood leucocyte−selectin ligand interaction. Such inflammatory responses if continued for a long duration can lead to fever, atherosclerosis, rheumatoid arthritis, etc., but developing new inhibitors to block the interaction of selectin via its antagonists can serve as an inspiring approach for treatment of inflammatory

diseases. Ernst and co-workers synthesized a series of such antagonists related to the sLeX structure utilizing the click method. Here, they replaced Neu5Ac with S-isoserine (Scheme 161).657 Of several developed sLeX-based triazole derivatives via the click reaction of seven separate alkynes, nonsubstituted triazole 728 and azide 727 exhibited improved interactions for Eselectin.657 Several alkynes, including acetylene (C2H2) were used in this investigation. Salts of metal-like calcium carbide and sodium hydroxide were also utilized for triazole synthesis via copper acetylide formation.658 The method is promising, although little is known to date; thus, further extension is required in carbohydrate chemistry. 3202


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Scheme 163. Synthesis of Alkyne/Azide-Functionalized C-Sialoside Monomers and Their Click Reaction662

16.15. Fucosyltransferase Inhibitors

fucosylation/sialylation against potential inhibitors of lectin proteins (Figure 66).455 Carbohydrates residing on the terminal glycan chains of the mammalian cell surface are targets of many receptors which play a crucial role in numerous biological events. Structurally diverse sialic acid molecules as terminal substituents participate in many physiological and pathological cell recognition events of cells with bacteria and viruses.660,661 Therefore, understanding the molecular basis of sialic acid−receptor interactions serves to drive the design of variously modified and multivalent sialosides in the search for potent chemotherapeutic agents and diagnostic tools. Papin et al. employed the Cu(I)-catalyzed click reaction in designing spatially well-defined C-sialoside clusters comprised of diverse cores that could interact differently with various biological targets depending upon their valency and geometrical arrangement.662 Different oligovalent C-sialosides were synthesized by adapting two highly efficient synthetic strategies, including samarium-catalyzed Reformatsky coupling and Cu(I)-catalyzed click reaction. Various alkyne- or azide-functionalized polyvalent cores were clicked with sialic acid residues comprised of complementary functionality. The two possible pathways have been demonstrated for the ready access of azideand alkyne-containing sialic acid residues from their anomeric

The fucosyltransferase enzyme plays a key role in the biological origination of sLeX (sialyl Lewis X) and sLeA (sialyl Lewis A), which are present in cell-surface glycolipids and glycoproteins. This enzyme acts as a key entity in cell recognition events, including malignant cancers, fertilization and embryo development, lymphocyte trafficking, immunity, etc. It is involved in the catalysis of glycosylation of sialyl Lewis X and sialyl Lewis A by prompting L-fucose transfer from guanosine diphosphate β-Lfucose to a particular hydroxyl moiety of sialyl N-acetyllactosamine to recognize the inhibitory compounds for this enzyme. Wong and co-workers developed a series of 85 guanosine diphosphate β-L-fucose triazoles via exploration of the click reaction over a microtiter plate. GDP was the common skeleton, but variations were instigated in the hydrophobic part and chain of the linkers. One of the developed molecules, 731, displayed potential inhibitory activity specifically for the Fuc-T VI enzyme (IC50 value of 0.15 μM) (Scheme 162).659 Furthermore, the work was continued, and the authors prepared carbohydrate microarrays using the click reaction via grafting of the developed sugar azides 732a−k on alkynefunctionalized long aliphatic chains present on a microtiter plate. After that, these conjugates were investigated for degree of 3203


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Scheme 164. Synthesis of Biologically Active Mannose-Centered Tetragalactose Clusters663

Figure 67. 1,2,3-Triazole-based glycodendrimers with a benzene carboxamide core.664

16.16. Other Biologically Active Triazolyl Glycoconjugates

acetates. Reductive samariation of anomeric acetate 733 with the symmetrical cyclic ketone piperidin-4-one and subsequent azide functionalization resulted in sialosides 736a,b. In a similar way, the reductive samariation of alkyne-functionalized piperidin-4one afforded a good yield of alkyne-functionalized sialosides 735. The structure of one of the oligovalent C-sialosides, 737, is depicted in Scheme 163.662

Recently, Ligeour et al. reported the synthesis of three selected mannose-centered galactoclusters (740−742) using the coppercatalyzed click reaction. After introduction of an alkyne functionality on four hydroxyl substituents present at the remaining carbons of the pyranose structure, they employed these alkynes (738a,b) under the click reaction with galactose3204


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Scheme 165. Synthesis of AuNP Derivatives 745, Functionalized with β-CD (745a) and Lactose (745b) and Both Simultaneously (745c)667

“Herlich magic bullet concept”. DDSs take advantage of the use of macromolecules, including polymers, dendrimers, hydrogels, micelles, polymeric nanoparticles (NPs), and liposomes, to improve the ADMET (absorption, distribution, metabolism, elimination, and toxicity) properties of drugs and to identify targeted therapies, which is demonstrated by rapid advances of click chemistry.665,666 Vargas-Berenguel et al. reported the clickinspired synthesis of three interesting gold nanoparticles (AuNPs) (745), functionalized with β-CD, lactose, or both βCD and lactose.667 As drug nanocarriers, AuNPs protect drugs from degradation or inactivation in biological conditions. The inner cavities with lipophilic structures and outer surfaces with hydrophilic structures in β-CD cyclic oligosaccharides are able to interact with diverse guest molecules to form inclusion complexes with no covalent nature, gifted with increased water solubility. Clicking of azide with propargyl β-D-lactoside or monopropargyl-β-CD in the presence of (EtO)3P·CuI followed by treatment with aqueous KOH afforded the bis[alkyltetra(ethylene glycol)] disulfides 744. Then the AuNPs were functionalized with 744 to obtain the desired AuNP derivatives 745a−c (Scheme 165).667 The loading capability of these nanoparticles for the anticancer drug methotrexate (MTX) was evaluated. It was noticed that retention of MTX is greater in AuNPs 745a,c, incorporating βCD substituents. The results indicate that the complexation is mainly because of the drug encapsulation in the β-CD hydrophobic cavity but not in the linkers only. Lactose with its β-D-galactoside moiety interacts with human lectin galectin-3 (Gal-3), which is a protein that binds carbohydrate and then is overexpressed on the cancer cell surface and is involved in tumor progression and metastasis. However, lactose cannot work as efficiently as cyclodextrins (i.e., drugs) for the CD cavities in the bifunctionalized AuNPs bearing both β-CD and Lac. The presence of a triazole ring as a linker between AuNPs and β-CD or Lac is utilized to maximize the number of active carbohydrates and CD moieties by minimizing the steric hindrance. The authors highlighted the potential of hybrid AuNPs 745a−c as

based azides 739a,b to afford three different galactoclusters (Scheme 164).663 These galactoclusters were developed in solution in significant amounts without the DNA sequence. These developed clusters were further evaluated for their binding toward LecA through different bioanalytical techniques, hemagglutination inhibition assay (HIA), enzyme-linked lectin assay (ELLA), surface plasmon resonance (SPR), isothermal calorimetry (ITC), and DNA-dependent glycoarrays, and two of them showed high affinity. This result confirmed the advantages of the aromatic part of the galactoclusters for LecA binding with Kd values below 200 nM found for 740 and 741. After that, two glycoclusters were examined for inhibition activity for biofilms and displayed remarkable binding toward LecA with Kd values of 157 and 194 nM from isothermal titration calorimetry. Also, these clusters displayed 40% inhibition toward biofilm formation at 10 μM concentration.663 From the studies of dendrimers regarding their synthesis, structure, and applications, it is a well-known fact that the presence of triazoles as branching moieties and six-membered pyranose sugars at the peripheral positions generally improves the anti-inflammatory activity of such macromolecules. Because of the enhanced activity against inflammation, higher generation dendrimer synthesis is preferable over lower generation dendrimer synthesis. Rajakumar et al. synthesized glycodendrimers using teh alkyne−azide click reaction (for example, dendrimer 743, Figure 67) having 12 and 18 α-D-glycopyranosides at the peripheral positions, and triazole as a branching unit. The developed dendrimer 743 exhibited remarkable activity against the anti-inflammatory assay.664 In addition to the extensive application of triazolyl glycoconjugates, obtained through click chemistry, as a wide range of enzyme inhibitors and also NCEs in drug discovery and development, these sugar-based molecules were utilized in the drug delivery systems, as evidenced by suitable examples described in this section. The development of drug delivery systems (DDSs) aimed at a controlled distribution of drugs selectively targeting an organ or a tissue is focused on the 3205


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Another radiotracer, 3′-deoxy-3′-[ 18 F]fluorothymidene ([ F]FLT, 746b), is also useful for tumor detection and is recognized as a great diagnostic tool (Figure 68). SPECT and PET are eminent molecular imaging techniques which are sensitive to even a very minute amount of radioactive tracer.672 PET is considered to be more sensitive and gives better spatial resolution and quantification. On the other hand, SPECT is comparatively less expensive and is a more practical approach toward nuclear medicine for regular diagnostic use. Both of the techniques are used widely for characterization and measurement of the biological properties at the cellular and molecular levels.673 The azide−alkyne click reaction is an appropreate reaction and is far better than the conventional methodologies for the development of carbohydrate-based imaging probes for several reasons, such as higher decay-corrected radiochemical yield, higher specific activity, and shorter synthesis time. Synthesis of radiotracers must be rapid and selective and should preserve functional groups on the bioactive molecule. These requirements are satisfactorily fulfilled by the click reaction of azides and alkynes. The azide and alkyne groups are inert to the other functional groups of carbohydrates, proteins, peptides, and nucleic acids. Moreover, the resulting triazole ring is stable under physiological conditions.7,674,675 Following this strategy, Kim and co-workers applied the click reaction to afford short-lived positron emitter (18F, t1/2 = 109.8 min) 18F-labeled triazole-linked glycoconjugates.676,677 The protocol was extended for radiolabeling and patented.678 Radiolabeled 4-[(2-[18F]fluoroethyl)-1-(β-D-glucopyranosyl)]1H-1,2,3-triazole (747) was developed as a substitute for the effective and most employed PET radiotracer 2-[ 18 F]fluorodeoxyglucose ([18F]FDG) (Scheme 166). The in vivo behavior of peptides, including their stability and blood clearance, can be enhanced by their glycosylation.679 Considering this, Maschauer and Prante designed and evaluated different sugar-based α- and β-anomeric azides as labeling building blocks for the glycosylation of potential radiotracers via a click-chemistry-based two-pot three-step reaction.680 3,4,6-TriO-acetyl-2-O-[(trifluoromethyl)sulfonyl]-β-D-mannopyranosyl azide (748) was found to be the most suitable precursor for 18F radiolabeling in this regard. The 18F-labled azide building block 749, when used for labeling of Fmoc-L-propargylglycine, showed 76% and 60% radiochemical yields (RCYs) for peracetylated and unprotected building blocks, respectively. Prante et al. extended this work and came forward with labeling of different peptide moieties for PET by 18F-labeled azide 749 using the click reaction (Scheme 167). In a short reaction time of 1 h and 15 min, moderate RCYs (17−20%) and 55−210 GBq/μmol specific activities (ASs) were obtained for labeling of RGD or neurotensin derivatives with L-propargylglycine with this method.681 The in vivo analysis of the [18F]FGlc-RGD peptide with U87MG-bearing mice revealed better blood clearance as well as better stability in αvβ3-integrin-expressing tumors due to attachment of a glycosyl moiety in the labeled RGD. Also, an appreciable value (0.49% ID/g, 60 min pi) of specific tumor uptake was shown by [18F]FGlc-RGD (Scheme 167).681 Later, Fischer et al. employed the same strategy to afford 18Flabeled glycoconjugates of folic acid.682 [18F]Fluorodeoxyglucosyl folate 753 was developed by clicking a folate alkyne derivative with 2-deoxy-2-[18F]fluoroglucopyranosyl azide in high RCY (25% dc) and good AS (90 GBq/μmol) (Scheme 168). Again an increase in the hydrophilicity of the radiotracer was noticed due to attachment of the glucose moiety. Specific and high uptake for FR-positive tumors (10.03 ± 1.12% ID/g, 60 min pi) and kidneys

potent delivery systems with respect to site specificity for anticancer agents.667 From the above-described examples dealing with the scope of the Cu(I)-mediated 1,3-dipolar cycloaddition reaction in carbohydrate chemistry with wide applications in the area of drug discovery and development, it is obvious to conclude that the “carbo-click” has enormous potential in lead optimization.10,11,13,668,669 The protocol provides diverse carbohydrate conjugates as potential chemotherapeutic agents. Carbohydrates presented inside or on the cell surface are an ingredient in a major class of biomolecules and manage various pathological and physiological actions. Therefore, the facts compel us to identify the best function of the adaptable click methodology in glycoscience or in designing the highly active and selective pharmacologically important triazolyl scaffolds, which have potential pharmaceutical applications. Furthermore, “click chemistry” was well examplified for diagnostic purposes. The search for novel diagnostic systems to diagnose pathologies aimed to increase the early understanding of diseases is challenging in the medical sciences. Bioorthogonal click reactions make it easy to diagnose several diseases, and have particularly found potential applications in positron emission tomography (PET). Functional processes are shown in three-dimensional aspects by positron emission tomography, in our body, and this method has diverse applications in diagnostics, including oncology, cardiology, and neuroimaging. In this method, emitted γ-rays are detected by a positron-emitting radionuclide to be incorporated into a molecule of pharmacological importance.

18

17. 18F-LABELING IN “CARBO-CLICK” Radiolabeling has emerged as an effective means to assess novel molecular therapies and cures noninvasively. The direct observation of many biological and biochemical courses is essential for understanding the complex organization and interactive behavior of molecular components of living cells. In this regard, radiolabeled biomarkers are made out of biologically active molecules by combining them with suitable radioisotopes for an in vivo assessment of target-specific pharmacodynamics of the prospective drug. In the past few decades, with the discovery of new biological targets, the demand for novel and potent methodologies, capable of effectively grafting radioisotopic nuclei of appropriate decay characteristics on a pharmaceutically

Figure 68. Successful radiotracers [18F]FDG (746a) and [18F]FLT (746b).

significant molecule, has increased. Carbohydrates, being important metabolic molecules, are taken by tumor cells more actively.670 Thus, for several decades radiolabeled carbohydrate derivatives have been successfully employed as imaging probes with single photon emission computed tomography (SPECT) and positron emission tomography (PET). Among the few radiotracers available in clinics, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG, 746a), the foremost approved carbohydrate-derived radiotracer, is still extensively used in PET imaging.671 3206


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Scheme 166. Two Alternative Pathways To Afford Radiolabeled 4-[(2-[18F]Fluoroethyl)-1-(β-D-glucopyranosyl)]-1H-1,2,3triazole

Scheme 167. 18F-Glycosylation of Mannopyranosyl Azide 748 with 749 and Subsequent Clicking with Peptide Moieties681

Scheme 168. 18F-Glycosylation of a Folate Derivative

(42.94 ± 2.04% ID/g, 60 min pi) was shown by in vivo studies of 753 using KB tumor-bearing mice. The G-protein-coupled neurotensin receptor 1 (NTS1)683,684 is a very significant molecular target for imaging purposes because of its specific abundance as well as overexpressed behavior in many tumors and negligible expression in undiseased tissues, which makes it specific for the treatment of cancer.685,686 Considering its importance in cancer therapy, many efforts have been employed so far to develop diagnostic radioligands for detection of NTS1-positive tumors as well as agents for its radiotherapy. Prante et al. synthesized a diarylpyrazole glycoconjugate, 759, using MW-assisted palladium-catalyzed aminocarbonylation and click-based ligation of a terminal alkyne

with 2-deoxy-2-[18F]fluoroglucosyl azide.687 The methodology commenced with 6-chloro-1-hexyne, which underwent deprotonation using n-BuLi and subsequent treatment with triisopropylsilyl chloride [(TIPS)Cl] to afford the protected alkyne 754. Further reaction of alkyne 754 with N,N′dimethylpropane-1,3-diamine furnished a protected diaminoalkyne, 755, which was transformed to the amide 757a via Pdcatalyzed aminocarbonylation of the aryl bromide 756 under microwave irradiation.688 Removal of the protecting groups using TBAF afforded free alkyne 757b, which was employed as a precursor for the radiosynthesis of 758 by Cu-catalyzed click reaction with 2-deoxy-2-fluoroglucosyl azide (749) (Scheme 169). The labeled glycoconjugate 758 exhibited outstanding 3207


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Scheme 169. Synthesis of Diarylpyrazole Glycoconjugate 758687

selectivity and affinity toward the potent NTS1 antagonist SR142948A-derived NTS1-overexpressing tumors. The in vivo studies of the very first nonpeptide tracer 785, using NTS1expressing tumor-bearing mice, showed good results for PET imaging of prostate, mammary, and pancreatic carcinoma.687 Prante et al. further extended the methodology and developed 18 F-fluoroglycosylation of alkyne-bearing RGD peptides via click chemistry to target the integrin receptor. The authors implemented this protocol in search of an 18F-labeled RGD glycopeptide with favorable biokinetics and developed a series of RGD glycopeptides having 6-fluoroglycosyl residues derived from different monosaccharide and disaccharide units for this purpose. The promising CuAAC-based methodology gave the glucosyl ([19F]6Glc-RGD, 759b), galactosyl ([19F]Gal-RGD, 759c), maltosyl ([19F]Mlt-RGD, 759d), and cellobiosyl ([19F]Cel-RGD, 759e) conjugated peptides in appreciable yields. The developed RGD glycopeptides 759b−e showed high affinity for αvβ3-positive (11−55 nM), αvβ5-positive (6− 14 nM), and αvβ3-positive (90−395 nM) U87MG cells (Figure 69).689 Interestingly, using the click-reaction-based one-pot protocol, another series of labeled RGD peptide triazolyl glycoconjugates was developed with high RCYs (up to 81%) via clicking 18Flabeled glycosyl azides with the alkyne-grafted cyclic RGD peptide in 15−20 min at 60 °C. The methodology used a much lower amount of the peptide precursor. The in vivo studies of the developed glycopeptides with U87MG tumor-bearing nude mice relative to the 2-[18F]fluoroglucosyl analogue revealed that [18F]6Glc-RGD (760b) and [18F]Mlt-RGD (760d) showed lower liver and kidney uptake by PET, whereas [18F]2Glc-RGD (760a) showed specific tumor uptake (Figure 69).689

Figure 69. Labeled RGD peptides targeting the integrin receptor synthesized via click chemistry.689

Vala and co-workers came forward with a new approach for direct derivatization of peptides,18F-labeled (2-azidoethyl)-63208


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Scheme 170. Labeled Glutathione Derivative Synthesis through Clicking

Scheme 171. Labeled Thymidine Derivative Synthesis through Clicking

Scheme 173. Synthetic Protocol for Labeled Triazolylglucose Reported by Chi et al.695

fluoroglucoside 763 in five steps from glucoside 761. Azide 763 was clicked with S-propargylated glutathione 764, using Cu(Ac)2/NaAsc in water at 60 °C, to afford labeled glutathione derivative 765 with 63% radiochemical yield (Scheme 170).690 Labeled thymidine derivative 767 was synthesized from uridine derivative 766 by clicking it against 2-[18F]fluoroethyl azide, catalyzed by CuI and ascorbic acid at 80 °C in an aqueous solvent (Scheme 171). The product was afforded with 75% radiochemical yield.691,692 The significant stability of this thymidine derivative in human plasma and considerable uptake in A431 tumors suggested in vivo metabolism and its future as a helpful tracer for tumor cell proliferation. In a very interesting study, thymidine-derived azide was clicked with a dialkylsilylated alkyne to develop new silylated thymidine derivative 768, which was further fluorinated with K[18F]F−K222 to afford compound 769. A similar chemistry was

implemented for another series of 3′-silylated thymidine precursors, which were developed by conjugation of dialkylsilylated azides and thymidine-derived alkynes. This strategy can be considered as a reliable alternative to the actual [18F]FLT radiotracer (Scheme 172).693,694 Chi et al. synthesized labeled triazolylglucose 771 via click reaction of labeled acetylinic derivative 770 with acetylated or free azidoglucose using CuSO4/NaAsc in the t-BuOH/H2O solvent system (Scheme 173).695 The account of carbohydrate-based radiolabeled probes defines their extraordinary contribution in the field of biomedical

Scheme 172. Synthesis of 18F-Labeled Silylated Thymidine Derivative 769

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Mo metallic centers) makes triazolyl carbohydrate derivatives useful as scaffolds to develop valuable chelating ligands with technetium(I) tricarbonyl and rhenium(I) tricarbonyl cores. There are two types of synthetic strategies to afford carbohydrate-based chelating ligands. First is a “regular click ligand” in which a sugar-derived azide is clicked with an alkyne prochelator, resulting in a tridentate ligand system (Scheme 174).51 The other way gives an “inverse click ligand” which can be afforded by clicking a sugar-derived alkyne against an azide prochelator. Mindt and co-workers applied the “regular click strategy” to develop triazole chelator 773 via Cu(I)-catalyzed clicking of a Dglucose-derived azide with L-propargylglycine (772). Subsequently, the addition of [99mTcCO3]+ to the reaction mass using a one-pot synthetic protocol afforded 99mTc−tricarbonyl complex 774 (Scheme 175).696 Likewise, Fernández et al. have prepared a stable 99mTc(CO)3−glucose−histidine complex derivative, functionalized at the C-2 position using the Mindt click-to-chelate protocol under one-pot conditions (Scheme 176). The complex 775 was found over 90% radiochemically pure with hydrophilic nature and a low binding tendency toward plasma proteins. Biodistribution studies showed low blood and liver uptake, moderate tumor uptake, rapid urinary excretion, and good retention in C57BL/6 mice bearing induced Lewis murine lung carcinoma. Rapid clearance from the muscle promoting high tumor/muscle ratios was found favorable.698 The “click-to-chelate” strategy was successfully applied to develop hypoxia imaging agents. These imaging agents are significant radiotracers for the evaluation of the oxygenation status of a tumor, which is essential for assessment of the success of radiation therapy.699 A similar protocol was extended for investigating the efficacy of bi- and tridentate click chelators toward 99mTc−tricarbonyl labeling of 5-nitroimidazoles.700 Besides the one-pot click-to-chelation approach, complexation with metals, including radionuclei, without the involvement of the triazole N has also been investigated by a few researchers, and the results are encouraging for diverse applications. The synthesis of metal−carbohydrate conjugates is an appealing area for clinical diagnosis and cellular imaging.701,702 In this context, Gouin et al. developed a series of functionalized pyridine−tetraacetic acid ligands to glucoside and maltoside scaffolds. An alkyne-grafted potent lanthanide chelate, which satisfied the structural aspects for development of magnetic resonance imaging contrast agents, was coupled with glycosyl azide using click chemistry to graft the bifunctional ligand. A bifunctional chelate, 776, was clicked with azido-functionalized carbohydrate cores to afford ligands 777 (Scheme 177).703 Likewise, Mukhopadhyay and co-workers synthesized sugarbased triazolyl compounds using the “click” methodology and exploited the developed molecules in different carbohydrate− lectin binding studies through fluoresence analysis (Figure 71). The authors found that mannose-containing compounds 781b and 781d gave a positive response with ConA. Furthermore, the former one demonstrated binding affinity for any carbohydratefunctionalized oligothiophene and ConA interaction by the use of an ITC experiment.704,705 Gouin et al. developed a practical pathway to group Tcchelating agents and Rh complexes with a carbohydrate scaffold via click chemistry. In their study, glucopyranosyl azide was clicked with alkyne-branched chelating agent 782, promoted by CuSO4/NaAsc in a tert-butyl alcohol−water system. Under normal conditions, derivative 783 was afforded along with its Cu

imaging by SPECT as well as by PET. Click chemistry has added a very interesting and valuable chapter in it by proving itself as a magnificent tool for rapid and selective development of new carbohydrate-derived probes for 18F-radiolabeling. Also the shorter reaction time, high radiochemical yield, and high specific activity are the key features related to the click reaction which make it superior to other labeling methodologies. A large number of click-derived carbohydrate-based imaging probes have been found useful in tumor detection, and the field is being explored for the development of new and more efficient probes for use in medical science.

18. CARBOHYDRATE CLICK-TO-CHELATION The click-to-chelate strategy is nowadays recognized as an immensely effective protocol for the radiolabeling of medicinally and radiopharmaceutically interesting molecules, particularly with technetium and rhenium tricarbonyl cores.51 Due to the shorter reaction time, higher specific activity, and higher decay-

Figure 70. Mindt’s “click-to-chelate approach” for the radiolabeling of medicinally relevant molecules.696

corrected radiochemical yield, click chemistry has emerged as an effectively promising method for the chelating technique. The Cu-catalyzed click approach synthesizes and conjugates the tridentate chelating system simultaneously for formation of stable radiometal complexes. Development of numerous novel radiotracers with promising potential for translation into the clinic could be achieved by the click-to-chelate strategy. Using this powerful tool, Mindt et al. successfully developed tridentate 1,2,3-triazole metal chelator derivatives of pharmaceutically important biomolecules (such as bombesin, thymidine, and phospholipids) in a single step with significant yields (Figure 70).696 Due to the increased consumption of carbohydrates in tumor tissues, this class of molecules is considered as a significant tool in metabolic assessment of tumors.697 Furthermore, electronic and structural similarity of 1,4-disubstituted 1,2,3-triazoles with 1,4disubstituted imidazoles of N-derivatized histidines (which have extremely good chelating properties, especially with Re, Tc, and 3210


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Scheme 174. “Regular Click” and “Inverse Click” Strategies To Afford Carbohydrate-Based Chelating Ligands

Scheme 175. One-Pot Synthetic Procedure for Radiolabeled Conjugates696

Scheme 176. Regular Click Ligand Functionalized at the C-2 Position of Glucose Using the Click-to-Chelate Protocol698

with fac-[99mTc(CO)3(H2O)3]+, and to afford Re complexes, a prechelated Re(CO)3 was used for clicking. Biodistribution studies in undiseased male Wistar rats revealed that 99m Tc(CO)3

complex, which was analyzed by ESI-MS, whereas under microwave irradiation derivative 783 was formed in pure form (Scheme 178).706 99mTc complexes were obtained by mixing 783 3211


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Scheme 177. Synthetic Procedure for Development of Potent Pyridine−Tetraacetic Acid Glycoconjugate Ligands and Their Lanthanide(III) Complexes703

Figure 71. Triazolyl glycoconjugates in different carbohydrate−lectin binding studies through fluoresence analysis.704,705

complexes 784a and 784b displayed in vitro stability against histidine exchange reactions, rapid blood clearance and a high in

vivo stability in the form of long-term retention in spleen and stomach. Moreover, this study also proposed an interesting 3212


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Scheme 178. Tethering of Tc-Chelating Agents and Rh Complexes onto a Sugar Scaffold706

Scheme 179. Synthesis of Carbohydrate-Based Dendrimer−Ru Chelates707

DTTA-hexyne (DTTA = diethylenetriaminetetraacetic acid) dendron 788 followed by deprotection, hydrolysis, and titration with GdCl3 (Scheme 180). The reaction afforded seven paramagnetic arms containing β-cyclodextrin click cluster 791, with each arm furnished with two water exchange sites.708 The remarkably high relaxivity profile (43.4 mM−1 s−1 at 9.4 T) at high magnetic field as well as enhanced contrast on a human MRI scanner are fascinating features associated with this discrete contrast agent. Besides this, the envelope of fascinating and helpful properties of β-cyclodextrin, including hydrophobicity,

feasible path for directly tethering a prechelated Re(CO)3 by click chemistry. Seeberger and co-workers have put forward a synthetic route for carbohydrate-based dendrimer−Ru chelates. Amide-based glycodendron 786, bearing a focal azide group, was clicked with an alkyne functional core, 785, in the presence of CuSO4 and NaAsc in THF/water to build Ru(II)-centered glycodendrimer 787 (Scheme 179).707 A novel macromolecular magnetic resonance imaging (MRI) contrast agent has been developed by Bryson and co-workers by clicking acetylated perazido-β-cyclodextrin with protected 3213


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Scheme 180. Synthesis of a Paramagnetic β-Cyclodextrin Click Cluster708

makes it an extraordinarily potent host scaffold functionalized with biological receptor-specific targeting moieties. A different series of chelates containing two triazole moieties was developed by Cu(I)-catalyzed clicking of N,N′-diprop-2ynylphthalamide/N,N′-diprop-2-ynylisophthalamide/pyridine2,6-dicarboxylic acid bisprop-2-ynylamide with azides of β-Dglucopyranoside and α-D-mannopyranoside. Complexation of these ligands with ZnCl2 in acetone/methanol shows that the chelation with Zn takes place at N-3 of the triazole moieties and the CO group of the amide.709 Therefore, we may conclude that the “click-to-chelate” strategy has simplified the synthesis of glycoconjugate chelates in which 1,4-disubstituted triazole plays an important role as a

metal-chelating system. Efficient labeling of these chelates with organometallic cores of Tc/Re/Mo results in in-vivo- and invitro-stable complexes. Also due to the increased consumption of the carbohydrate moiety by tumor tissues, these glycoconjugate chelates have enormous applications in metabolic evaluation of tumors. This elegant strategy to develop metal-labeled glycoconjugates for diagnosis purposes has given a number of chelates having vast biomedical importance and is being explored for development of structurally diverse chelate systems suitable for complexation with other metals. 3214


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19. CARBOHYDRATE CLICK-TO-CATALYSIS

room temperature for Michael addition of ketones to nitrostyrenes. Here, the triazole linkage between the sugar moiety and pyrrolidine ring provides an additional structural feature for high catalytic activity and enantioselectivity (Scheme 182).718 In addition to organocatalysts, the peculiar structural features of the carbohydrate moiety have also been used in the development of a variety of ligands.719,720 These chiral ligands in the form of their transition-metal complexes have helped in catalyzing the transformation of a prochiral substrate by shaping the space around the reaction center in a dissymmetric way. A high level of reactivity and selectivity has been achieved by catalysis through these carbohydrate-based ligand complexes. The click-to-chelation strategy not only is useful for radiolabeling but also has emerged as an efficient and environmentally benign protocol for development of Pd ligands for catalysis purposes. Khiar et al. have developed carbohydrate-based bidentate and polydentate ligands from 4,6-benzylidene-2-deoxy-2-amino-βglucopyranosyl azide (795) by clicking it with different alkynes (Scheme 183).721 Ligands 797, 798, and 799 showed high activity in the form of 100% product yield for allylic alkylation of 1,3-diphenylpropenyl acetate with dimethyl malonate. Among the three ligands, ligand 797 produced the highest S:R ratio (80:20) at 25 °C in CH2Cl2, which could be further enhanced up to 90:10 at 0 °C in CH3CN. On the other hand, ligands 798 and 799 afforded the racemic form of the allylated product (Scheme 184).721 Ligand 797 coordinates through the enantioselective P−N site and affords good enantioselectivity, but in the case of polydentate ligands 798 and 799, the metal possibly binds through the nonenantioselective P−N site, which affords a racemic product (Figure 72).721 Zhang et al. reported the synthesis of a β-cyclodextrin-based ligand for coordination with palladium.722 The β-CD-derived azide on conjugation with 2-ethynylpyridine via Cu(I)-catalyzed click reaction gives triazole-functionalized β-CD 800, which on stirring with Pd(OAc)2 in toluene gives the Pd complex 801. This complex showed very high catalytic acivity for Suzuki− Miyaura coupling reactions in neat water (Scheme 185).722 Recently, Shen et al. synthesized D-glucosamine-derived 2pyridyl-1,2,3-triazole ligand 802 by clicking D-glucosamine azide with 2-ethynylpyridine. The complex of this ligand with Pd (complex 803) efficiently catalyzed solvent-free Heck crosscoupling between different aryl halides and olefins. The catalyst can be easily recovered from the reaction mixture for reuse. The catalyst was successfully utilized for the synthesis of marketed antitumor drug Axitinib (Scheme 186).723 Thus, “click-to-

In the past few decades, organocatalysts have been proven as valuable tools for catalysis of various synthetically useful transformations and incorporation of enantioselectivity. Despite the increasing utility of organocatalysts in the world of synthetic chemistry, the potent basic substrates for generation of organocatalysts are still very few in number. In this regard, the carbohydrate moiety, due to its ready availability, several stereogenic centers, high functionality, and other fascinating structural features, provides a promising scaffold for development of enantioselective catalysts. The efforts of chemists have successfully brought forward some very interesting carbohyScheme 181. Synthesis of Michael Addition Catalyst 794 via Click Reaction718

drate-derived molecules that can efficiently catalyze different organic reactions, and this number has been increasing manifold day by day.710−713 Being functionally diverse, environmentally benign, and of low toxicity, carbohydrate-derived organocatalysts are also preferably used in drug discovery processes.714,715 The carbohydrate-linked pyrrolidine ring has been efficiently used as an organocatalyst for Michael addition.716,717 In this series Wang et al. designed and developed a sugar-based pyrrolidine catalyst for Michael addition of various nitroolefins to ketones. They introduced a chiral pyrrolidine moiety to the sugar scaffold via Cu-catalyzed click reaction of an L-prolinederived azide, 792, with an α-D-glucose-derived alkyne. CuI was used as the clicking catalyst along with DIPEA in a mixed solvent system of chloroform/ethanol/water (9:1:1) (Scheme 181).718 A 10 mol % concentration of catalyst 794 in neat conditions gave up to 98% yields, with high diastereoselectivities (syn:anti = 94:6 to 99:1) and high enantioselectivities (91% to >99%) at

Scheme 182. Michael Addition Catalyzed by Sugar-Based Organocatalyst 794718

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Scheme 183. Synthesis of Ligands 797, 798, and 799721

Scheme 184. Allylic Alkylation of 1,3-Diphenylpropenyl Acetate with Dimethyl Malonate Catalyzed by Pd Using Ligands 797− 799721

sulfonium ions.725,726 In addition to these moieties, the chiral pool of carbohydrates has also been harnessed to produce potent ILs.727,728 The very first example of a 1,2,3-triazolium ionic liquid (806) has been recently developed by Jha and Jain by Cu(I)catalyzed click reaction of a glycosylalkyne with a glycosyl azide followed by quaternization with methyl iodide (Scheme 187).729 Screening of this series of glucose−triazolium ILs for Cu(I)catalyzed amination of aryl halides with aqueous ammonia suggested that grouping of the glucose moiety with a triazolium core makes these molecules potent ligands in which free hydroxyl groups of the glucose moiety facilitate the stabilization of the Cu(I) species during the reaction course and cause this moiety to assist in the catalytic process of the amination reaction (Scheme 187).729 Likewise, syntheses of D-xylose-based ionic liquids have also been achieved recently. β-Propargyl xyloside 807 on clicking with an azide (phenyl or hexyl) followed by deprotection and methylation affords ionic liquid 808 (Scheme 188).730 Although the developed ionic liquids were not applied for practical purposes by the authors, by considering their hydrophilicity and other properties, these ILs can be used as unconventional solvents or chiral agents for synthesis or catalysis in an aqueous medium under mild conditions. However, the ecotoxicity and biodegrability of these ILs must be determined prior to their application.

chelation-to-catalysis” has been proven to be an efficient tool for the development of a series of new promising catalysts. Resin-supported organocatalysts have an advantage of insolubility and high recyclability. Pericas et al. reported polystyrene (PS)-supported organocatalysts developed via click chemistry. In the first example, catalytically active L-proline was anchored to Merrifield resin with a triazole linkage for catalyzing the asymmetric aldol reaction in water,724 whereas, in the second example, a Merrifield resin-derived alkyne was clicked against (S)-2-(azidomethyl)pyrrolidine for catalyzing enantioselective Michael addition in water (Figure 73).141 The high catalytic activity and enantioselectivity of these catalysts may be attributed to the hydrophobic nature of the polystyrene backbone and hydrophilic nature of the triazole−proline/pyrrolidine system. Although, there has been no example of resin-supported carbohydrate-based organocatalysts reported so far, these catalysts (804a, 804b, and 804c) can be considered as a ray of hope for the development of a carbohydrate variation of such catalysts. In the past few years, chiral ionic liquids (ILs) have been shown to be promising and green solvent catalysts for asymmetric synthesis. Many naturally occurring chiral moieties, such as (−)-menthol, (S)-nicotine, (−)-ephedrine, and amino acids, have been used as potential precursors for the development of chiral ILs with pyridinium, ammonium, imidazolium, and 3216


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Figure 72. Coordination sites of ligands 797, 798, and 799.721

Scheme 185. (a) Synthesis of Pd Complex Catalyst 801 and (b) Application of Catalyst 801 in Suzuki−Miyara Coupling722

Scheme 186. (a) Synthesis of Pd Complex Catalyst 803 and (b) Efficient Use of Catalyst 803 in the Synthesis of the Antitumor Drug Axitinib723

812 (Scheme 189).731 These NPs were stabilized (DSNPs) by the zeroth-generation dendrimer and encapsulated (DENPs) by the first-generation glycodendrimer. Characterization of the AuDSNPs and Au-DENPs was ascertained using UV−vis spectroscopy and high-resolution transmission electron microscopy, where Au-DSNPs show an average diameter of 7.2 nm, whereas Au-DENPs were found to have an average diameter of 4.0 nm. Au-DSNPs 812 considerably catalyzed the reduction of 4-

Very recently, Rajkumar and co-workers developed goldnanoparticle-decorated glycodendrimers using click chemistry. The designed gold nanoparticles (NPs) were developed in appreciable yield by stabilization or encapsulation of the triazolyl glycodendrimers. Phenolic dendron 810b, obtained by clicking 1,3-bis(azidomethyl)phenol (809) with propargyloxyacetylated glucose, on propargylation followed by a second CuAAC reaction with azide 811 afforded glycodendrimer Au-DSNPs 3217


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20. CONCLUSION AND FUTURE PERSPECTIVE Cu(I)-catalyzed 1,3-dipolar cycloaddition of an organic azide and a terminal alkyne (CuAAC or click chemistry) is a remarkably proven protocol for a facile access of simple to complex molecular structures comprising a 1,4-disubstituted triazole skeleton with great efficacy and exceptionally high regioselectivity. This 1,3-dipolar cycloaddition was discovered more than a century ago in 1893 by A. Michael,732 and Wittig and Krebs later reported an efficient procedure for the generation of 1,2,3triazole using a cycloalkyne and azidobenzene.733 However, the azide−alkyne cycloaddition reaction was thoroughly studied in the 1960s by R. Huisgen,1−4 and the regioselectivity in triazole formation with the aid of Cu catalysis (Cu click) gained extensive application in different areas of science just after the Meldal− Sharpless discovery in 2002.6,7 This “click protocol” has achieved huge significance in different fields such as chemical biology, polymer science, protein chemistry, material science, surface chemistry, supramolecular chemistry, microarrays, macrocyclization, sensing and detection of analytes, dendrimer and cluster synthesis, catalysis, lead optimization as enzyme inhibitors, radiolabeling, and many more. Because of the comparative inertness of the triazole heterocyclic ring and also the compatibility of click chemistry with carbohydrates toward a sequence of protection and deprotection steps, CuAAC is nowadays considered a well-established and successfully implemented protocol to obtain the desired multivalent carbohydrate-based molecules with wide applications. The amazing efficacy of this reaction has been nicely explored for a variety of carbohydrate as well as oligonucleotide modifications. In addition, click-inspired synthesis is well recognized to deliver several multivalent neoglycoconjugates, including glycopolymers, glycopeptides, glycodendrimers, glycoclusters, glycomacrocyles, macromolecules, and glycoarrays. Click chemistry, a very proficient methodology, is not different from the rule of nature as hundreds of efficient synthetic protocols also bear few limitations. Indeed, before the Meldal− Sharpless CuAAC invention, several 1,4-disubstituted triazoles obtained through other synthetic protocols were well documented in the literature.11,734,735 However, just after the “click discovery”, this chemistry found exponential importance in the literature, even more than any of the reactions investigated during past 10 years.65 Despite that, along with the 1,4disubstituted triazoles as the sole product, the click reaction sometimes creates byproducts such as oxidative coupling of copper(I) acetylides to afford a bis(triazolyl) compound in tiny quantities, resulting in a drop of the reaction yield even after the complete consumption of the starting materials. Bis(triazole) can be achieved as a sole product utilizing an inorganic base and air. In the presence of stoichiometric amounts of copper(I) halides, the azide−alkyne coupling is known to favor the 5-halogenated 1,2,3-triazoles. Particularly, a dimeric 5,5′-bis(triazole) was obtained as the sole reaction product when similar clicking was carried out in an excess of CuCl and 4-(dimethylamino)pyridine (DMAP).736 Excess alkyne used in azide−alkyne cycloaddition results in triazole−alkyne oxidative coupling, which leads to 2alkylated trisubstituted triazoles.737 Also, electrophiles present in the reaction medium may demetallize the Cu−triazole intermediate, which can afford undesired scaffolds.738,739 Likewise, sulfonyl azide−alkyne clicking in an aqueous medium afforded N-sulfonylated amides; however, suitable catalysis could give the expected result.98,99,740 By changing the reaction conditions, click protocol affords an efficient synthesis of the

Figure 73. PS-supported organocatalysts: an inspiration for polymersupported carbohydrate-based organocatalysts.

Scheme 187. Preparation of Glucose-Linked 1,2,3-Triazolium Ionic Liquid 806 and Its Use in the Amination of Aryl Halides729

Scheme 188. Syntheses of D-Xylose-Based Ionic Liquids730

nitrophenol to 4-aminophenol with NaBH4 in aqueous conditions. The catalytic activity was studied using UV−vis spectroscopy (Scheme 189).731 These representative examples reveal that “click chemistry” has evolved as an advantageous tool for harnessing the chiralityinducing property of carbohydrates in the field of catalysis. The easy approach toward carbohydrate-based azides and alkynes as well as mild and environmentally benign reaction conditions makes the click protocol an easy and efficient way to produce a variety of carbohydrate-based ligands, organocatalysts, and ionic liquid catalysts. These catalysts have enormous applicability in synthetic chemistry for development of new facile routes and green techniques. Besides this, their utility in the synthesis of medicinally important compounds makes them more valuable. The click-to-catalysis technique is being enriched day by day with ongoing research, and new dimensions such as solid-phase catalysis and the click-to-unclick strategy are waiting to be explored in this field. 3218


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Scheme 189. Synthesis of Glycodendrimer Au−DSNPs 812 Useful for the Reduction of 4-Nitrophenol in Aqueous Conditions731

expected triazoles.741 Bertrand et al. utilized α-carbamatesubstituted alkynes for the CuAAC, where surplus product was obtained via generation of an intermediate carbenium ion at the α-position with subsequent loss of carbamate.742 Ynamides such as N-alkyne-substituted imidazolinones, when subjected to clicking with azides under normal click conditions, afforded decomposed products,743−745 but careful addition of an alkyne using a syringe pump and anhydrous conditions gave high yields of the expected triazoles.722 Despite these limitations, this chemistry has enormous potential in different fields of science. As evident from the literature, every day 2−3 publications emerge dealing with “click chemistry”, which reveals its utility and scope in solving the challenging problems of drug discovery and development, click-to-chelation, and chemical biology and catalysis in chiral synthesis. Reactions of an alkyne with acyl azide under normal conditions are sometimes very complicated. Therefore, in addition to the known Cu catalysts, there is a need to discover even more suitable catalysts that can afford the required regioselective product under mild conditions by using scaffolds other than a simple azide or alkyne. The exploration of a multicomponent approach for click chemistry is also required as this can add new dimensions in this field. Few triazoles have been well utilized to catalyze some reactions under mild conditions. When we move

toward the application of carbo-click in catalysis, unfortunately, carbohydrate-based triazoles have not gained much attention and only a few have been explored in asymmetric synthesis. The recently developed “click-to-unclick strategy” 746,747 can be useful for the characterization of polymer-supported triazolyl glycoconjugates, which can open new paths for further developments in solid-supported catalysis by carbo-click. This review nicely demonstrated that the mechanically facilitated cycloreversions can assist in the development of novel bioconjugation as well as other useful chemical ligation methods. Furthermore, the ruthenium-catalyzed click reaction (RuAAC), which generates regioselectively 1,5-disubstituted triazole, has been little investigated and requires more exploration in different fields of science. This review is hopefully useful and may compel researchers to utilize click chemistry and its variants in diverse branches of scientific and industrial research. At last, we conclude that the Cu-catalyzed click reaction has enriched the world of carbohydrate chemistry by developing various fantastic glycoconjugates having a wide spectrum of applications ranging from medicinal chemistry to material science and from chemical biology to catalysis. 3219


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AUTHOR INFORMATION

medals, such as the Dr. D. S. Bhakuni Award, Indian Chemical Society (2004), the Young Investigator Prize (2004), the Most Cited Paper Award (in 2006 from Elsevier and in 2015 from Bentham Science), the Dr. Arvind Kumar Memorial Award, Indian Council of Chemists (2010), the Uttar Pradesh (UP) Council of Science & Technology (CST) Young Scientist Award (2010), the Prof. R. C. Shah Memorial Award, The Indian Science Congress Association (2011), the Dr. Ghanshyam Srivastava Memorial Award, Indian Chemical Society (2012), the 1st Tatva Scientist of the Year-2014, International Academy of Physical Sciences, the Young Scientist Award-2012, Chemical Research Society of India (CRSI), the 1st Dr. H. C. Srivastava Memorial Award, ACCTI (2012), the Professor A. S. R. Anjaneyulu 60th Birthday Commemoration Award-2014, Prof. N. Roy Award for Excellence in Synthetic Carbohydrate Chemistry-2015, etc. In addition, he was invited to participate in NOST-2014 (National Organic Symposium Trust).

Corresponding Authors

*E-mail: [email protected]. Phone: +91-542-6702466. Fax: +91-542-236817. *E-mail: [email protected]. Phone: 530-754-6037. Fax: 530752-8995. Present Address §

B.B.M.: Center of Innovative and Applied Bioprocessing, Mohali-160071, Punjab, India. Notes

The authors declare no competing financial interest. Biographies

Vinod K. Tiwari, born in Bihar, India, in 1976, has been an Assistant Professor of Organic Chemistry at Banaras Hindu University (BHU) since 2005. After obtaining his M.Sc. (1998) from BHU, he worked on the development of carbohydrate-based molecules of chemotherapeutic potential at the Central Drug Research Institute, Lucknow, India (with Dr. R. P. Tripathi as his mentor), starting in 2000 and obtained his Ph.D. degree from Jawaharlal Nehru University, New Delhi, in 2004. He was offered a Lecturership at Bundelkhand University, Jhansi, India (2004− 2005), before starting his independent research career at BHU (2005 to present). He worked on the chemoenzymatic synthesis of complex carbohydrate-containing molecules as a Postdoctoral Fellow (with Prof. Xi Chen as his mentor) at the University of CaliforniaDavis, United States (2007), and subsequently on the novel intramolecular glycosidic bond formation methodology as a Visiting Scientist (with Prof. Richard R. Schmidt as his mentor) at Universität Konstanz, Germany. He has had interest in the benzotriazole methodology since 2005 through his postdoctoral research with Prof. Alan R. Katritzky at the University of Florida, United States. His present research interest focuses on different aspects of carbohydrate chemistry and organic synthesis. He has supervised eight Ph.D. students and completed three major research projects (Department of Science & Technology (DST), University Grants Commission (UGC), and Council of Scientific & Industrial Research (CSIR)). He has delivered numerous invited lectures at different institutes in India and abroad (over 70) and serves on the editorial board of several journals, including Trends in Carbohydrate Research, the International Journal of Carbohydrate Chemistry, and Biochemical Compounds. He edited the popular book Opportunity, Challenge and Scope of Natural Products in Medicinal Chemistry and recently assisted with editing the ARKIVOC issue in honor of Prof. Richard R. Schmidt. He serves as a Joint Secretary for the Association of Carbohydrate Chemists & Technologists, India (ACCTI) (2014 to present). Dr. Tiwari has significantly contributed over 100 peerreviewed publications (h-index = 26), including several patents and invited book chapters. He has received many prestigious awards and

Bhuwan B. Mishra was born in Uttar Pradesh, India, in 1977. He started his doctoral research at the Department of Chemistry, Centre of Advanced Study, Banaras Hindu University, Varanasi, India, in 2005, and obtained his Ph.D. degree in 2009 under the supervision of Prof. Vyasji Tripathi. He then worked as a Council of Scientific & Industrial Research (CSIR) Research Associate with Dr. V. K. Tiwari. He recently joined the Center of Innovative and Applied Bioprocessing (CIAB), Mohali, India, as a Scientist-C to start his independent research career. He has significantly contributed toward the isolation and characterization of natural products and the development of novel synthetic methodologies for numerous heterocyclics and carbohydrate derivatives of great medicinal value. He has published over 37 papers, including original articles and book chapters in national and international journals and books. He has received several prestigious awards, namely, the Young Scientist Award (2010−2011) from the Council of Science & Technology (CST), Uttar Pradesh, India, and the Fast Track Young Scientist Project (2013) from the Department of Science & Technology (DST), New Delhi, India.

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Institution, Varanasi, India. After completing the qualifying exams, including the Common Entrance Test (CET) (2012), Graduate Aptitude Test in Engineering (GATE) (2013), and National Eligibility Test-Lectureship (NET-LS) (in 2013), he joined the Department of Chemistry at Banaras Hindu University (Varanasi, India) for his Ph.D. degree under the guidance of Dr. V. K. Tiwari. His doctoral research is focused on the development of a novel synthetic methodology through benzotriazole ring cleavage.

Kunj B. Mishra was born in 1986 in Bhabhua, Bihar, India. He completed his B.Sc. (2006) and M.Sc. (organic chemistry, 2008) degrees from Dr. B. R. Ambedkar University, Agra, India. He passed the CSIR-UGC NET (Council of Scientific & Industrial ResearchUniversity Grants Commission National Eligibility Test) qualifying exam in 2011 and joined the Ph.D. program at the Department of Chemistry, Banaras Hindu University (Varanasi, India), under the guidance of Dr. V. K. Tiwari on a project entitled “Cu-Catalysed Click Reaction in Carbohydrate Chemistry”. He was awarded the Young Scientist Award (YSA) by the United Group of Institutions, Allahabod, India (in 2014), and Best Poster Award-2014 at the 6th NIPER (RBL)CDRI (National Institute of Pharmaceutical Education and Research (Raebareli)-Central Drug Research Institute) symposium. He has contributed about 10 publications in national and international journals and recently submitted his Ph.D. thesis.

Xi Chen is a Professor in the Department of Chemistry at the University of CaliforniaDavis, United States. She received her B.S. degree in chemistry from Xiamen University, China, in 1994 and her Ph.D. degree in biological/organic chemistry from Wayne State University, United States, in 2000. She worked at Neose Biotechnologies, Inc. for 21/2 years before joining the faculty of the Department of Chemistry at the University of CaliforniaDavis in August 2003. Her group strives to understand carbohydrate-related biological processes in the areas of cancer, inflammation, immunology, and viral and bacterial infection. The current research focuses are (1) developing chemoenzymatic approaches for synthesizing structurally defined complex oligosaccharides and glycoconjugates, (2) studying carbohydrate−protein/cell interactions and exploring the functions of carbohydrates as potential prebiotics and antimicrobials, (3) collaborative crystal structure and mutagenesis studies of glycosyltransferases and other carbohydrate biosynthetic enzymes, and (4) designing and synthesizing sialidase inhibitors. Prof. Chen has contributed more than 140 peer-reviewed publications and over 20 patents. Prof. Chen is an Associate Editor of Carbohydrate Research and serves on the editorial board of Trends in Carbohydrate Research.

Nidhi Mishra was born in Allahabad, Uttar Pradesh, India, in 1984. She obtained her B.Sc. (2005) and M.Sc. (organic chemistry as specialization, 2007) degrees in chemistry from the University of Allahabad, Allahabad, India. She worked as a synthetic chemist on a drug discovery project related to the development of heterocyclic skeletons of pharmaceutical interest at Chembiotek Research International (a contract research organization, Kolkata, India) from 2007 to 2010. After obtaining a Junior Research Fellowship from the CSIR-UGC NET (Council of Scientific & Industrial Research-University Grants Commission National Eligibility Test) in 2014, she joined the Department of Chemistry at Banaras Hindu University for her Ph.D. degree under the guidance of Dr. V. K. Tiwari. Her topic of interest is sugar-based organocatalysis, and presently, she is working on the development of carbohydrate-based organocatalysts using click chemistry and their application in stereoselective synthesis.

ACKNOWLEDGMENTS V.K.T. thanks Banaras Hindu University (BHU), the Department of Science & Technology (DST), the University Grants Commission (UGC), and the Council of Scientific & Industrial Research (CSIR) (Grant No. 02(0173)/13/EMR-II) for funding, and Dr. Divya Kushwaha for initiating research on click-chemistry-inspired porphyrin glycodendrimer synthesis during her Ph.D. study. We gratefully acknowledge Dr. Rama P. Tripathi, Central Drug Research Institute, Lucknow, India, and Em. Prof. Richard R. Schmidt, Universität Konstanz, Germany, for their constructive sugessions and encouragement. ABBREVIATIONS Ac acetyl ANS 8-anilino-1-naphthalenesulfonate AIBN azobis(isobutyronitrile) ATRP atom transfer radical polymerization AuNP gold nanoparticle

Anoop S. Singh was born in Varanasi, Uttar Pradesh, India, in 1986. He obtained his B.Sc. (2008) and M.Sc. degrees in chemistry (specializing in organic chemistry, 2010) from the Udai Pratap Autonomus 3221


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AZT

azidothymidine 2-[4-({bis[(1-tert-butyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)-1H-1,2,3-triazol-1-yl]ethyl sulfate BTTES Bn benzyl BSA bovine serum albumin Bz benzoyl CAs carbonic anhydrases CCCTP cobalt-catalyzed chain transfer polymerization CuAAC Cu(I)-catalyzed alkyne−azide cycloaddition β-CD β-cyclodextrin DBU diazabicyclo[5,40]undec-7-ene DDSs drug delivery systems DFT density functional theory DIC N,N′-diisopropylcarbodiimide DIPEA N,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DNJ deoxynojirimycin ECG Escherichia coli galactosidase EMC N-(ε-maleimidocaproyl) Gal-3 galectin-3 GalNAz N-(azidoacetyl)galactosamine GDP-fucose guanosine diphosphate β-D-fucose GlcNAz N-(azidoacetyl)glucosamine Glu glucose ICP-MS inductively coupled plasma mass spectrometry KLH keyhole limpet hemocyanin Lac lactose MHC index minimal hemolytic concentration index MIC minimal inhibitory concentration MUNANA 2′-(4-methylumbelliferyl)-α- D -N-acetylneuraminic acid MW microwave NaAsc sodium ascorbate NCLs native chemical ligations Neu5Ac N-acetylneuraminic acid NS N-hydroxysuccinimide PDT photodynamic therapy PEG polyethylene glycol PET positron emission tomography PMAM poly(amidoamine) PPI poly(propyleneimine) PTP protein tyrosine phosphatase QCM quartz crystal microbalance RAFT reversible addition−fragmentation chain transfer RCY radiochemical yield ROP ring-opening polymerization RuAAC Ru-catalyzed azide−alkyne cycloaddition SAG sweet almond glucosidase SAMs self-assembled monolayers siRNA short interfering RNA SPR surface plasmon resonance TBTA tris[(benzyltriazolyl)methyl]amine TCEP tris(2 carboxyethyl)phosphine TcTS Trypanosoma cruzi trans-sialidase THPTA tris{[(3-hydroxypropyl)triazolyl]methyl}amine TTTA tris{{4-[(trimethylsilyl)methyl]-1,2,3-triazolyl}methyl}amine US ultrasound

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Cu-Catalyzed Click Reaction in Carbohydrate Chemistry - Chemical

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