Quest for Novel Chemical Entities through Incorporation of Silicon in

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Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds Remya Ramesh, and D. Srinivasa Reddy J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.7b00718 • Publication Date (Web): 17 Oct 2017 Downloaded from http://pubs.acs.org on October 17, 2017

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Journal of Medicinal Chemistry

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds Remya Ramesh, a,b and D. Srinivasa Reddy a,b * a CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India b Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 025, India E-mail: [email protected]

Abstract In order to optimize a lead molecule for further development, bioisosteric replacements are generally adopted as one of the strategies. Silicon appears to be the right choice as a carbon isostere because of the similarity in chemical properties. Silicon can be strategically introduced in a molecule to modulate its drug like properties, providing medicinal chemists with an unconventional strategy for replacing a carbon atom. Silicon can also be introduced to replace other heteroatoms, and can act as a surrogate of functional groups such as olefin and amide as well. The present perspective focuses on the opportunities that silicon incorporation offers in drug discovery, with an emphasis on case studies where introduction of silicon has created a benefit over its carbon analog. We have tried to highlight all the recent developments in the field and briefly discuss the challenges associated with them.

1. About silicon Silicon is an element (atomic no. 14) that belongs to the third row of the periodic table, positioned just below carbon. It is the second most abundant element in

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the earth’s crust, the first being oxygen. Although, both carbon and silicon exhibit a valency of four and form tetrahedral compounds, there are certain differences in their properties. Unlike silicon, carbon is the element of life displaying a very rich and unique chemistry, with a branch of organic chemistry entirely dedicated to carbon compounds. The ability of carbon to form diverse compounds is due to its unique property of self-linking (catenation). Silicon does not form stable π bonds and Si-Si σ bond (230 kJmol-1) is weaker than the Si-O bond (368 kJmol-1).1,2 Owing to the higher stability of Si-O bond, silicon occurs in nature as silicates and silica.

2. Silicon as bioisostere of carbon Bioisosteres are groups with similar physicochemical properties, and display similar biological activity in a broad sense. Bioisosteric replacements are commonly practised in medicinal chemistry, to modulate the properties of a molecule and for creating intellectual property (IP) space.

3-5

Due to the similarity of silicon to carbon,

over the years there has been growing interest in biological evaluation of organosilanes over the years. Silicon can be considered a bioisostere of carbon and offers an innovative avenue in drug discovery.6-13 The substitution of carbon with silicon in biologically active compounds is also known as the “silicon switch”. The effect of silicon substitution has also been explored in agrochemicals14,15 and odorants as well. The relationship between structure and odor with respect to silicon substitution is well studied.16-18 Tacke

19-25

and Wannagat26 are considered to

be pioneers in this field.

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3. Silicon in medicinal chemistry The similarity between carbon and silicon makes silicon an ideal choice as a carbon bioisostere in drug discovery. Unlike elements such as tin, silicon does not have any inherent toxicity.7,27 The introduction of silicon also provides freedom to operate as most patents do not cover silicon as part of their claims. Some of the differences between carbon and silicon can be efficiently utilized in drug design and lead optimization. Such differences include: Larger carbon-silicon bond length: The bond length of C-C is 1.54 Å and that of C-Si is 1.87 Å i.e. C-Si bond is almost 20% longer than a C-C bond.1 This can lead to changes in shape and conformation of the molecule and can also alter the way in which the molecule interacts with a receptor. Increase in lipophilicity: Silicon analogs are more lipophilic than their carbon counterparts.28 Therefore substitution of carbon by silicon can lead to improved cell penetration and can ultimately result in an improvement in potency. The increase in lipophilicity can also be beneficial in the design of drugs targeting bacteria or the central nervous system.29 In some cases, it can also be detrimental, due to liabilities such as poor solubility and metabolic clearance. Therefore, one needs to balance the concept, depending on the drug target and its location in the body. Difference in bonding preferences: Silicon prefers higher coordination numbers when compared to carbon.1,2 Silanediol does not undergo dehydration to form silanone whereas geminal diols are not stable in the case of carbon. Thus, silicon offers a novel chemical space and provides access to compounds



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for which corresponding carbon analogs are not available. This has been exploited in designing transition state mimics. Silicon can also extend its coordination number to six, which is useful in the formation of coordination complexes. Higher electropositivity of silicon: Silicon is more electropositive than carbon which leads to a difference in bond polarity. According to the Pauling scale, silicon has an electronegativity of 1.74, whereas carbon has a value of 2.50. This can cause subtle differences in the behaviour of silanols and carbinols.8 The utility of organosilanes in drug discovery has been reviewed in the past, as well.6-13 In 2013, a very useful perspective on medicinal applications of organosilicon compounds by Franz and Wilson was published in this journal and attracted the attention of many research groups.8 We are writing this perspective considering the importance and interest in the medicinal chemistry fraternity. A recent review by Hashimoto13 and book chapters by Tacke,12a and Sieburth12b are also worth mentioning here. Selected examples from literature are discussed in this perspective, highlighting the potential of silicon in medicinal chemistry. The focus is on case studies where the introduction of silicon has created a benefit over its analog.

4. Modification of metabolic pathways Any drug, after reaching the body, undergoes enzyme-catalyzed biochemical modification called metabolism.30 During this process, administered drugs get converted to more polar compounds and are excreted from the body. Due to the difference in bonding properties, silicon analogs can have a different metabolic fate compared to the parent carbon compound. The change in chemical reactivity could be


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utilized in drug design to alter problematic metabolic pathways. This was nicely illustrated by Tacke and co-workers in the case of antipsychotic drug haloperidol (1). 31-34

Haloperidol causes a neurotoxic side effect that is attributed to its metabolite,

pyridinium compound 3 (figure 1). Compound 3 is structurally similar to 1-methyl-4phenylpyridinium (MMP+) that kills dopamine producing neurons of the brain and can induce Parkinson disease.35-38

Figure 1. Metabolism of haloperidol The corresponding silicon analog (4) follows a different metabolic pathway devoid of the dehydrated compound 5 and the toxic pyridinium metabolite.32,39 Ndealkylation and hydroxylative ring opening were found to be the major pathways leading to metabolites 6 − 8 (figure 2). The inherent stability of the Si-O bond and the instability of the Si=C makes the molecule to adopt this alternate pathway.



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Figure 2. Silahaloperidol and major metabolites Similar carbon/silicon switching was also done in another related compound, trifluperidol (9) and analogous results were obtained (figure 3).32,40 In the case of silicon analog (10), hydroxylation of the piperidine ring leading to opening of the ring was found to be the major metabolic pathway. Reports indicate that there is significant difference in conformational behavior of the silicon analog. Due to increased C-Si bond length, silapiperidine chair form is more flattened compared to the piperidine chair conformer.31

Figure 3. Trifluperidol and its silicon analog Tacke and co-workers incorporated silicon in loperamide (11), a commonly prescribed anti-diarrheal drug.41 The structure of loperamide is similar to haloperidol, although they act on completely different targets. Compounds 11 and 12 showed


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similar potency for the µ1 opioid receptor and had similar physicochemical properties.

Figure 4. Metabolism of loperamide and its silicon analog The metabolic pathways of both compounds (11 and 12) were found to have marked differences (figure 4). The major metabolites 13, 14 and 15 of loperamide were stable in circulation. Similar metabolites 16 and 17 were observed in the case of the silicon analog, but the analog of 15 was not detected. Instead, another metabolite 18 resulting from the α-oxidation and ring opening was found. The silanediol 18 showed high clearance and was rapidly eliminated from the circulation thus reducing the burden of metabolites.41 These reports show that silicon incorporation in drugs can lead to alternate metabolic pathways which can be advantageous.



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5. Novel chemical space provided by silicon 5.1. Silanols as transition state mimics Proteases are enzymes that hydrolyze the amide bond of peptides and are involved in various physiological reactions. Inhibition of specific proteases has been found to be useful in controlling several diseases and hence proteases have become an interesting pharmaceutical target.42 Proteases stabilize the tetrahedral diol formed by the addition of water and this diol then collapses to individual peptides. Any compound that can mimic the enzyme-substrate interactions present in the tetrahedral intermediate, and does not undergo hydrolysis, could inhibit the enzyme (see structures 19 − 22).43

Figure 5. Design of protease inhibitors mimicking the transition state In fact, Sieburth pioneered the use of stable silanediol of the general formula 22 to mimic the gem diol transition state involved in protease hydrolysis.43-51 Silicon favors sp3 hybridization over sp2 and hence geminal silanediols are stable and do not undergo elimination to form the silanone (Si=O). Silanediol has gained attraction in medicinal chemistry as a bioisostere of carbonyl hydrate and some of the inhibitors


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known in the literature are shown in figure 6 (compounds 23 – 26).43,46,47,50 The increased hydrogen bonding ability of silanols is an advantage which allows the silanediols to interact efficiently with the active site of enzyme. Simple silanediols undergo polymerization, but sterically hindered diols are found to be stable. Silanediol 26 is inferior to the carbinol 27, which had potency similar to the marketed drug indinavir (28). This decreased activity may be due to the larger size of silicon.49

Figure 6. Silanediols as protease inhibitors Olsen and co-workers synthesized analogs of vorinostat (29), a histone deacetylase (HDAC) inhibitor and studied their biological activities.52 Most of the HDAC’s require Zn2+ as a cofactor and are called Zn2+ dependent histone deacetylases. Silanediol 31 was synthesized owing to its ability to coordinate zinc with affinity similar to that of hydroxamic acids. The activities of all the compounds were tested against 11 HDAC isoforms (activity against two isoforms shown in figure



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7). The trifluoromethyl compound 30 and silanediol 31 showed moderate activities and may be considered as promising leads.

Figure 7. Silanediol analog of vorinostat The biological activity of silanediols prompted organic chemists to develop efficient synthetic routes to access them.53 Studies were also carried out to understand the mechanism of inhibition as this knowledge is essential for taking the compounds forward.54 Since protease inhibitors represent an important class of therapeutic agents, silanediols have great potential and further research in this area can lead to more potent and selective inhibitors. Pietschnig and co-workers extended the concept of silanediols to silanetriols, in order to mimic the transition state of ester hydrolysis.55 Silanetriols with bulky substituents (32−34) were synthesized so as to prevent self-polymerization and were evaluated for their inhibition of the enzyme acetylcholinesterase (AChE). Compound 33 showed the highest inhibition rate and the IC50 was found to be 121 µM. This compound showed reversible inhibition of the enzyme which is a prerequisite for therapeutic agents. Although it is debatable, many researchers believe that irreversible inhibitors can lead to damage of the enzyme.56 Hence, reversible silanetriol inhibitors may find use in developing future therapeutic agents.


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Figure 8. Silanetriols as AChE inhibitors 5.2. Silicon containing complexes Silicon can exhibit coordination numbers higher than 4 due to the presence of empty 3d orbitals. The silicon complex Pc-4 (36), built on the framework of phthalocyanine (35), went to clinical trials for use in photodynamic therapy (PDT).5759

In PDT, the photosensitizer, when excited by light of particular wavelength,

interacts with molecular oxygen and generates reactive oxygen species.60-63 This reactive oxygen species (ROS) then kills the cells in the illuminated area by inducing apoptosis. The photosensitizer is cleared from healthy tissues more rapidly, which leads to their accumulation in tumour cells.62 The photophysical properties of phthalocyanines can be modified by varying the ring substituents, axial ligands, and the central metal atom. The silicon phthalocyanine 36 has the right balance between lipophilicity and hydrophilicity. After cellular uptake, Pc-4 accumulates in the mitochondria

and

causes

photocytotoxicity.

Recently,

another

modified

phthalocyanine Pc-227 (37) was reported which upon photolysis gives 36 (figure 9).64



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Figure 9. Silicon phthalocyanines Meggers and co-workers reported the biological activity of hydrolytically stable silicon containing octahedral polypyridyl complexes 38 − 41 (figure 10).65 Studies showed that the complexes 40 and 41 intercalate between the DNA base pairs. DNA intercalators have a variety of therapeutic applications mainly in the area of cancer therapy.66 A follow-up of this work, led to the synthesis of several hexacoordinate silicon complexes and NMR spectroscopy studies proved that they bind to G-quadruplex DNA.67 Because of non-toxicity and natural abundance, use of silicon is advantageous over the commonly used transition metals in designing complexes with pharmaceutical applications.


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Figure 10. Hypervalent silicon complexes as DNA intercalators Silatranes (42; Y= O) are compounds having pentavalent silicon with a transannular dative bond between N and Si.68,

69

Some of the compounds from this

class are reported to have interesting biological activities (antibacterial, antifungal, anticancer, antiviral, anti-inflammatory etc.).70-74 Kurup and co-workers reported that 1-ethoxysilatrane (43) inhibits cholesterol biosynthesis and rats treated with the compound showed a decrease in serum cholesterol.73,74 OC2H5 O

R Y Y

Si N

Y

Y = O; Silatrane Y = N; Azasilatrane Y = C; Carbasilatrane Y = S; Thiasilatrane

42

O

Si N 43

Figure 11. Silatranes


O


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6. Increase in lipophilicity by introduction of silicon 6.1. Silicon incorporation to increase brain penetration The endothelial cells of the brain capillaries have tight junctions which is called blood brain barrier (BBB). This barrier selectively allows the passage of certain molecules to the brain and prevents others, making drug delivery to the brain a tough task.75,76 It is known that small lipophilic molecules diffuse through this barrier. The incorporation of silicon into a molecule increases its lipophilicity, which can increase the BBB penetration of a drug. Reddy and co-workers designed and synthesized silicon analogs of oxazolidinone antibiotics and evaluated their biological activity (figure 12).77 Linezolid is the first marketed oxazolidinone drug and is used as an antibiotic. The thiomorpholine Sutezolid is in clinical trials for treating tuberculosis. Several compounds were synthesized with silicon replacing the O/S atom of the ring. The brain pharmacokinetics of the most active compounds (44 − 46) revealed that silicon incorporation caused significant increase in brain to plasma ratio. Among them, the compound 46 had 29-fold higher brain/plasma ratio with respect to Linezolid. This increase in CNS exposures is due to the increase in lipophilicity of the compounds which is also evident from the cLogP values.


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Figure 12. Silicon incorporation in linezolid 6.2. Silicon analogs of campothecin The increase in lipophilicity due to silicon incorporation was utilized in the synthesis of stable campothecin analogs. Campothecin (47) is an anticancer natural product that inhibits the enzyme DNA topoisomerase I. The δ-lactone moiety of campothecin is susceptible to hydrolysis in vivo. The lactone form (47), which can distribute into the cell, is considered to be the active form. The carboxylate of 47 binds strongly to human serum albumin which causes an increase in the rate of lactone hydrolysis so as to maintain the equilibrium.78



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O

N

N

OH

N O HO

O OH

N

O

H HO

O

O

campothecin (carboxylate form)

campothecin (47)

Si Si

Si HO N

O

N O

karenitecin (48a)

O

N

O

N

N

N HO

HO

O

O HO

O

HO O

DB-67 (48b)

O

DB-91 (48c)

Figure 13. Silicon analogs of campothecin An increase in lipophilicity leads to increased partitioning into red blood cells resulting in less hydrolysis of the lactone. Several silicon analogs were synthesized and two of them, karenitecin (48a) and DB-67(48b) were evaluated in human clinical trials for cancer.78-85 Another closely related compound, DB-91 (48c) penetrates the blood brain barrier and hence was tested for cancers of the central nervous system.85

7. Drug design utilizing the electropositivity of silicon 7.1. N+/ Si exchange Zifrosilone/MDL 73,745 (50) is a silicon compound that went to clinical trials for treating Alzheimer’s disease.86-88 It was proposed that Alzheimer’s patients have a deficiency of the neurotransmitter acetylcholine and so medications that help to increase the concentration of acetylcholine would be beneficial.89 The enzyme acetylcholineesterase (AChE) catalyzes the hydrolysis of acetylcholine and hence inhibitors of this enzyme were tested for Alzheimer’s disease. Trifluoromethyl


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ketones such as 49 were reported to inhibit AChE.90,91 An ammonium/silicon switching in 49 resulted in lipophilic compound 50, which also showed AChE inhibition (figure 14). The greater electropositivity of silicon creates an ionic charge that interacts with the cation binding site of the target enzyme. This drug design strategy (to create a positive center in a neutral molecule) can be used in medicinal chemistry as an alternate option.

Figure 14. N+/ Si exchange in zifrosilone Tacke and co-workers applied the concept of N+/Si exchange in the muscarinic M2 receptor modulators (figure 15).92,93 W84 (51) inhibits the dissociation of [3H]NMS, an orthosteric radiolabeled ligand of the receptor. The silicon analog 52 was also found to be an allosteric modulator of the receptor, but it exhibited positive allosteric modulation (enhances binding of [3H]NMS to receptor). Here silicon switching has transformed the molecule from allosteric inhibitor to allosteric activator. However, it was found that the neutral compound (2-fold exchange) was inactive.



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Figure 15. Silicon analog of W84 7.2. Hydrogen bonding capability of silanols The hydrogen bonding ability and acidity of silanols is higher compared to corresponding carbinols, due to π bonding between p orbitals of oxygen and empty 3d orbitals of silicon.94 This property can be useful in pharmacophores where hydrogen bonding interactions are important. Baney and co-workers showed that silicon incorporation increased the antibacterial activity in a series of hydroxyl compounds 53 – 56 (figure 16).95

Figure 16. Alcohols and their corresponding silanols; X= C/Si Compound

Minimum Lethal Concentration (MLC in %, g/g) E. coli

S. aureus

P. aeruginosa

E. faecalis

53a

13.54

10.61

9.79

13.33

53b

2.36

2.48

2.36

3.15

54a

5.09

4.17

3.96

5.67

54b

1.04

0.80

0.87

1.14

55a

5.23

4.37

3.67

5.63

55b

1.23

1.04

1.00

1.32

56a

0.96

0.78

0.71

0.93

56b

0.27

0.26

0.35

0.42

Table 1. Antibacterial activity of compounds 53 − 56


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This increase in activity (see table 1) is probably due to increase in hydrogen bonding ability as well as lipophilicity. The authors also proved that the hydrogen bonding ability of silanols is almost twice of that of the corresponding alcohols with the help of IR spectroscopy. Another example where an increase in potency of silanols was reported is discussed in a later section (figure 22). Fujii and co-workers investigated the biological activity of a silanol analog (58) of known nuclear receptor modulator 57.96 The corresponding carbon analog 59 was synthesized for comparison purpose. The perfluoroalcohol groups have higher acidity than the corresponding hydrocarbon alcohols due to the presence of trifluoromethyl groups. The octanol-water partition coefficient of all the three compounds 57 − 59 was determined experimentally. It was found that the silanol 58 had an intermediate lipophilicity between that of 57 and 59. Compound 57 showed significant activity towards multiple nuclear receptors LXRα and β, FXR, PXR and RORγ, whereas alcohol 59 was not active. Silanol 58 exhibited activity towards PXR and RORγ comparable to that of the parent compound 57, whereas it was inactive towards LXRα and β. From molecular docking studies, it was ascertained that the hydroxyl group is not involved in any hydrogen bonding interaction with RORγ receptor. In the case of LXRα, LXRβ and PXR, the hydroxyl group interacts with His407 of the receptor protein. This indicates that both hydrogen bonding ability and lipophilicity has a major role to play in the activity of these compounds. From the biological activity results, it was suggested that the silanol group could be considered as an isostere of perfluoroalcohol group.



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Figure 17. Silanol as an isostere of perfluoroalcohol group

8. Taking advantage of the increased bond length of silicon 8.1. Silicon as an isostere of olefinic double bond Combretastatin A-4, a natural product, displays potent anti-cancer activity by inhibiting tubulin polymerization. The compound has a cis-olefin that tends to isomerize in solution and hence there have been attempts to replace this olefin with any stable isostere.97 Nakamura et al. assumed that because of the larger C-Si bond length, a silicon linker can be used as a bioisostere of olefin (figure 18). Computational calculations showed that the distance between the benzene rings is almost the same in combretastatin A-4 (3 Å) and the silicon analog 60 (3.03 Å). In carbon analog 61, this distance was found to be 2.47 Å. Docking studies suggested that the newly designed silicon compound 60 and combretastatin A-4 occupied the colchine-binding site of tubulin. Several silicon analogs were synthesized and evaluated using in vitro assays for anti-cancer activity (human breast cancer cell line). The natural product showed an IC50 of 0.004 µM and the newly designed silicon analog (60) also showed activity (IC50 0.043 µM), but lesser than the natural product. One of the silicon analogs (62) showed an IC50 of 0.007 µM similar to the natural product, whereas the corresponding carbon analog 63 (IC50 0.075µM) was less active. The stability of the compounds in solution was also analyzed which showed that


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compounds 60, 62 and 63 were stable. It was observed that the concentration of combretastatin decreased to nearly 85% under similar conditions.98

Figure 18. Silicon analogs of combretastatin A-4 The same concept was extended to aliphatic cis olefins and found to be successful.99 The cis-olefin present in PPAR-α agonist oleoylethanolamide (64) was substituted with a silyl linker and the biological activity of analogs 65 – 68 were evaluated. The diethyl derivative 66 showed moderate activity, but was less than that of compound 64. The substituents on silicon and the chain length influenced the activity of the compounds. The fatty acid chain occupies the hydrophobic pocket of the receptor and docking studies indicate that silyl group improves this hydrophobic interaction.

Figure 19. Silicon linker as olefin isostere



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8.2. Silicon as amide surrogate Fujii and co-workers replaced the amide functionality in retinoic acid receptor inverse agonists belonging to the phenanthridinone class (69 and 74) with a silyl group and studied their biological activity.100,101 Docking studies showed that the amide is not involved in hydrogen bonding with the receptor and the binding site is hydrophobic.102 The analogs 70 − 73 showed similar IC50 for the inhibition of RORγ as that of parent compound 69. The activities of 71 (IC50 = 4.2 µM) and 73 (IC50 = 4.4µM) were slightly better than that of compound 69 (IC50 = 4.7µM). However, the inhibition of 75 (IC50 = 18 µM) was found to be 2-fold less compared to the carbon compound 74 (IC50 = 37 µM). Thus, in these examples taking advantage of silicon’s increased bond length to replace a olefin/ amide led to an increase in activity.

Figure 20. Silicon analogs of phenanthridinone derivatives

9. Silicon incorporation to improve the potency Lipophilic silicon analogs display better cell penetration compared to their carbon analogs and can lead to increase in potency in certain drugs. Other properties such as polarization of the bond, increased bond length, conformational changes etc. can also cause an increase in potency.


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Kagechika and co-workers substituted silicon in place of carbon in 4substituted phenols and evaluated their estrogenic activity.103 Out of all tested compounds (76 − 83), the triethyl silicon derivative 81 showed the highest potency. Silicon substitution caused an increase in activity for all the compounds in the series (figure 21). Docking studies showed that the trialkyl group at p position lies in a hydrophobic pocket of the estrogen receptor, suggesting that the improvement in activity may be due to the increase in lipophilicity caused by silicon substitution.

Figure 21. Estrogenic activity of phenols Tacke studied the effect of C/Si bioisosterism in muscarinic antagonists (84 – 89, figure 22).104 As mentioned, muscarinic acetylcholine receptors are activated by the neurotransmitter acetylcholine and antagonists of this receptor are useful in treating Parkinson’s disease.



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Figure 22. Silicon switch in muscarinic antagonists (X = C or Si) Silanols showed increased binding affinities for all the four receptor subtypes (M1 − M4) compared to the corresponding carbinols. The highest improvement in potency was found for the pair 88 (table 2). Compound

Si/C affinity ratio

pair

M1

M2

M3

M4

84

1.6

2.0

2.0

1.6

85

1.3

2.0

-

1.3

86

10.0

5.0

7.9

16

87

2.5

1.6

3.2

3.2

88

40

50

32

40

89

6.3

13

10

6.3

Table 2. Binding affinity ratios of silicon to carbon analogs


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DeGrado and co-workers reported organosilyl amine inhibitors of M2 protein of influenza A virus.105 It is known that lipophilicity can improve the potency of M2 inhibitors because the protein has a hydrophobic binding pocket. The spirane amines 90 − 93 were synthesized and the activities against A/M2-V27A were evaluated (figure 23). Silicon analogs 91 and 93 showed an increase in potency compared to their carbon counterparts 90 and 92. The authors suggest that this is probably due to the lipophilicity as well as larger ring size which provide a better binding of the molecule with the receptor protein.

Figure 23. Antiviral activity of silaspirane amines Tacke and co-workers studied the effect of carbon to silicon switch in the retinoid agonist SR11237 (94).106 Since silicon substitution causes an enlargement in ring size, the indane derivatives 95 and 98 were also made for the sake of comparison. Due to higher C-Si bond length, the ring size of 94 and 98 are expected to be same. The potencies of 94 and 97 were found to be similar with the silicon analog 97 exhibiting a slightly higher activity. However, in the cases of indanes the sila analog 98 was found to be almost 10-fold more potent compared to its corresponding carbon compound 95. Similar enhancement in activity (almost 10-fold) was also observed in the case of another retinoid agonist, tamibarotene (99 vs 96) and AM580 (4-[(5,6,7,8Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid).107



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Figure 24. Silicon switching in retinoids Lee and co-workers investigated the anti-allergic activity of silicon substituted oxadiazoles. The silicon containing compound 100 was found to be more potent than the corresponding carbon derivative 101 using RBL-2H3 in vitro model. Compound 100 suppressed the mast cell degranulation in antigen sensitized cells in a dose dependant manner. The compound also effectively reduced anaphylaxis in an in vivo mouse model with an activity comparable to that of anti-histamine drug diphenylhydramine.108

Figure 25. 1,3,4-oxadiazoles with anti-allergic activity Smith and co-workers reported the synthesis and biological activity studies of sila analogs of quinoline/ferroquine derivatives and their metal complexes.109,110 Further extension of this work led to the identification of thiosemicarbazone complexes (103, 104) with antiplasmodial activity.111 IC50 values against the chloroquine sensitive P. falciparum strain NF54 are shown in figure 26. Silicon analog 102b was found to be highly potent compared to the carbon compound 102a.


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However, in the case of metal complexes, the activities of carbon and silicon analogs (103a vs 103b; 104a vs 104b) were found to be comparable.

Figure 26. Antiplasmodial activity of thiosemicarbazone complexes Reddy and co-workers studied the effect of silicon substitution in morpholine antifungals. Fenpropidin (105) and fenpropimorph (106) are marketed fungicides whereas amorolfine (107) is applied topically for nail infections. Several compounds were synthesized and the sila analog 108 came out as the lead of the series with better MFC (minimum fungicidal concentration) than the parent compounds (105 − 107) against various human pathogenic fungi (table 3). The silicon analog 109 also showed good activity.112

Figure 27. Silicon switching in morpholine antifungals



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Compound

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Minimum fungicidal concentration (MFC in µg/mL) C. albicans

C. neoformans

C. glabrata

C. tropicalis

A. niger

105

0.5

32.0

16.0

> 256

> 256

106

4.0

64.0

128.0

> 256

> 256

107

8.0

64.0

32.0

> 256

> 256

108

0.5

2.0

2.0

64.0

256

109

8.0

4.0

8.0

64.0

64.0

Table 3. Antifungal activity of compounds 105 – 109 Reddy group repurposed the rimonabant scaffold for tuberculosis and studied the effect of silicon substitution on their potency. Rimonabant is an inverse agonist of the cannabinoid receptor CB1 and was marketed for treating obesity. A systematic study of rimonabant analogs (110 − 113) revealed that silicon substitution led to a dramatic improvement in anti-TB potency of this series (110 vs 112, 113). Two compounds 110 (MIC 0.031 µg/mL) and 111 (MIC 0.39 µg/mL) were identified as leads. This increase in potency may be due to the higher cell wall penetration of lipophilic silicon compounds.113


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Si O N N

N NH

SAR optimization

NH

N N

Cl

Cl

N

Si

N

N N Cl

Cl

Cl Rimonabant CB1 receptor blocker for treating obesity MIC: 25 g/mL (Mtb, H37Rv)

Cl 110 MIC: 0.031 g/mL (Mtb, H37Rv) % plasma stability (human): 100 % metabolic stability in HLM: 20.3

N

Cl

N

N

Si

N Cl

N

Cl 111 MIC: 0.39 g/mL (Mtb, H37Rv) % plasma stability (human): 100 % metabolic stability in HLM: 93.1

N

N

N

N

Cl

N

Cl

Cl

Cl

110 MIC: 0.031 g/mL

112 MIC: 25 g/mL

113 MIC: 1.56 g/mL

Figure 28. Rimonabant analogs towards tuberculosis Padron and co-workers studied the effect of TBS group (a protecting group commonly used in organic chemistry) on the cytotoxic activity of substituted tetrahydropyrans.114 The cLogP of the TBS protected alcohols were found to be higher compared to free alcohols as well as other protecting groups. The growth inhibitory activities of the compounds were checked in two cancerous cell lines, HL60 and MCF7 (figure 29). The derivatives having TBS group at 3rd position showed anti-cancer activity (115 vs 114/ 116/ 117; 119 vs 118; 121 vs 120). This observed activity by the introduction of TBS group may be due to better cell penetration of the lipophilic TBS compounds.



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Figure 29. Cytotoxic effects of tetrahydropyran derivatives (NA = not active) Along similar lines, Trindade and co-workers studied the role of TBS group in the antitumor activity of a series of 5-hydroxymethyl furfural derivatives (122 − 125).115 Compounds 124 and 125 were the most potent from this series (figure 30). Wang and co-workers reported that a 5’silyl group is essential for the antiviral activity of triazolyl thymidine analogs (see compounds 126 and 127).116 The improved activity of sila ethers compared to their hydrophilic derivatives was reported by other groups as well.117-119 These results indicate that the TBS group can be employed to increase cellular uptake of compounds. However, TBS groups are expected to be labile under gastric (acidic pH) conditions and the decrease in aqueous solubility is a concern.


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Figure 30. TBS groups to enhance potency Since silyl ethers can be cleaved to hydroxyl groups in vivo, they can be used in designing prodrugs.28,120 Peterson and co-workers reported the anti-proliferative activity of ureidoadenosine derivatives such as compound 128.121,122 It was known that hydroxyl derivative 129 binds to the ATP binding site of the kinase BMPR1b. Dysregulation of BMP (bone morphogenetic protein) signalling is associated with various pathological conditions such as cancer. Hence, it was suggested that the activity of silyl derivatives may be due to inhibition of BMPR1b by 129 and compound 128 may be a prodrug. Hydroxyl derivative 129 did not show any antiproliferative activity indicating that lipophilic TBS group is necessary to enhance cell



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penetration. Cleavage of the silyl group in cytoplasm gives the active compound 129, which in turn inhibits the BMP signalling cascade.

Figure 31. Silyl derivative 128 is a prodrug

10. Silicon substitution to modulate pharmacological selectivity In certain compounds, silicon substitution leads to a change in receptor selectivity. In the case of compound 52 (discussed in section 7.1), silyl substitution transformed the molecule from allosteric inhibitor to allosteric activator. Hashimoto and co-workers reported a change in receptor selectivity by silicon substitution in compounds 130 − 132.123 It was previously reported that some of the analogs of the known vitamin D receptor (VDR) agonist 130 (X = C) showed slight androgen receptor (AR) antagonistic activity.124,125 The silicon analogs showed decreased VDR agonistic activity compared to their parent compounds. However, they displayed better androgen receptor antagonistic activity compared to carbon compounds (figure 32).


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Figure 32. Change in receptor selectivity by silicon switching Tacke and co-workers synthesized silicon analogs of venlafaxine (133) which is a marketed antidepressant (in racemic form) belonging to serotonin-noradrenaline reuptake inhibitor class.126 Enhanced acidity of silanols 134 and 135 can be beneficial leading to an increased hydrogen bonding interaction with the receptor. However, it was found that silanols 134 and 135 displayed a different pharmacological profile. Electron density studies suggested that the difference in conformation and electron distribution of the silicon analog is responsible for this change of behaviour.127

Figure 33. Silicon analogs of venlafaxine Silicon analogs showed decreased serotonin reuptake inhibition (table 4). Interestingly sila analog 134 showed higher selectivity for the noradrenaline reuptake transporter. The pure enantiomers were prepared by diastereomeric resolution. The authors further postulated that selective noradrenaline reuptake inhibitors maybe



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useful in treating emesis (vomiting). Accordingly, (R)-134 was evaluated in animal models and showed anti-emetic activity at 5 mg/kg. 128 Compound

IC50 (µM) Serotonin

Noradrenaline

Dopamine

rac- 133

0.020

0.149

4.430

(R)-133

0.030

0.061

19.600

(S)-133

0.006

0.754

6.670

rac- 134

1.063

0.109

2.630

(R)- 134

3.168

0.251

5.270

(S)- 134

0.791

4.715

36.350

rac- 135

0.904

0.275

0.707

Table 4. Monoamine reuptake transporter inhibition of venlafaxine and analogs Compounds 136a - 139a were known to be highly selective σ1 ligands. The silicon substituted analogs 136b - 139b showed higher affinity for the σ1-receptor compared to the carbon compounds. At the same time, the affinity of the sila compounds for the σ2-receptor was found to be decreased. Hence, in this case silicon incorporation lead to an increase in receptor selectivity (σ1 over σ2). The compound 136b had a 221-fold selectivity for σ1 over σ2 receptor. Compound 139b had a 63-fold selectivity for σ1 receptor which is 21-fold higher compared to its carbon analog 139a.129


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Figure 34. Affinities of compounds 136 -139 for the σ-receptor Recently, Tacke group reported the synthesis of several silicon incorporated 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives of lead compound 140 (figure 35).130 They evaluated the in vitro biological activity using GPR81 and GPR109A, two novel and potential targets for the treatment of diabetes. Although silicon incorporation reduced potency against GPR81, it slightly improved the potency with GPR109A. This suggests that silicon analogs (141 and 142) can become dual activators by targeting both GPR81 and GPR109A simultaneously (table 5). This dual nature may find additional benefits in further pharmacological studies.

Figure 35. Towards dual activators of GPR81 and GPR109A Compound 140

logD (pH 7.4) 4.2

EC50 (GPR81) 0.24 µM


EC50 (GPR109A) 2.1 µM


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141

4.8

1.0 µM

1.2 µM

142

4.6

1.2 µM

1.3 µM

Table 5. In vitro biological activities of compounds 140 - 142

11. Silicon incorporation to improve the pharmacological properties Silicon incorporation can be used to enhance the drug like parameters of a lead molecule. Introduction of silicon in haloperidol (figure 2) resulted in an altered metabolic pathway that was devoid of the toxic pyridinium metabolite. Miller and coworkers reported biological activities of a sila analog of doramapimod (144) in which the t-butyl group was replaced with a trimethylsilyl moiety. Doramapimod (BIR-796, 143) is a p38 MAP kinase inhibitor, tested in humans for treating inflammatory disorders. Sila analog 144 showed slightly inferior in vitro activity against p38 MAP kinase compared to the parent compound 143. However, the human microsomal stability of the silicon derivative was higher than doramapimod. Both the compounds were tested for their in vivo efficacy in LPS induced TNF-α mice models and compound 144 with silicon incorporation showed better profile.131

Figure 36. Silicon substitution in p38 MAP kinase inhibitor

12. Silicon-containing amino acids 36 ACS Paragon Plus Environment

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Unnatural amino acids are used to probe the bioactive conformation of peptides and find applications in peptidomimetics.132,133 Amino acids with silicon incorporation have several attractive features that can be useful in drug discovery.134,135 But, only a few silicon amino acids are known and with limited structural variations.136-150 Cavelier group has made significant contributions in this area.136-149 Some of the known silicon containing amino acids are shown in figure 37 (145 – 148). Incorporation of a lipophilic silicon moiety can improve the cell penetration as well as stability of the peptide towards biodegradation. An elaborative review on silicon amino acids appeared recently in literature from the Cavelier group.135

Figure 37. Some of the known sila amino acids The synthesis of silaproline 147 (Sip) was first reported by Cavelier group.144 The cLogP value of Fmoc-silaproline was experimentally found to be 14 times greater than Fmoc-proline, which shows that it is more lipophilic than proline. The authors incorporated this proline surrogate in place of proline in the neurotensin analog. Neurotensin is a neuropeptide containing 13 amino acids and has analgesic and hypothermic effects. The natural neurotensin undergoes proteolytic decomposition near to the proline residue and hence is injected along with enzyme inhibitors. The neurotensin analog with silaproline was active even in the absence of protease inhibitors which indicates that silicon incorporation improved the stability of the peptide in vivo.145 In another report, the replacement of proline with silaproline on the 37 ACS Paragon Plus Environment


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hydrophobic face of a cell penetrating peptide led to a 20-fold enhancement in cellular uptake.146 Bristol-Myers Squibb has claimed silaproline containing compounds that modulate the activity of inhibitors of apoptosis (IAP). IAPs are proteins that regulate apoptosis and are reported to be overexpressed in cancer tissues.151 New analogs were tested for their inhibition of XIAP and compound 149 showed the highest potency.152

Figure 38. IAP modulator containing silaproline Silaproline was also incorporated in one of Merck’s lead compound MK-4882 (150), a hepatitis C virus (HCV) inhibitor. The Pro-Val dipeptide subunit is essential for the activity of compound 150. Several analogs were made by varying the central core and by manipulating the proline unit. Compounds 151 and 152 containing silicon and fluorine appeared to be promising candidates for further development. These compounds displayed good half-life (7.6 h and 6.7 h respectively; rat IV) and plasma exposure.153,154 Interestingly, silicon substitution led to an improvement in half-life of the compounds when compared to their carbon counterparts.


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Figure 39. HCV inhibitor containing silaproline Although not exactly relevant in this section, a recent report on antiviral compounds with silicon incorporation is worth mentioning. Wang’s group demonstrated the organosilicon compounds could be utilized towards antiviral agents, which targeting multidrug-resistant influenza A viruses. The antiviral activity and selectivity index were superior when compared to its counterpart made of carbon.155 The proline unit of captopril (153), an ACE inhibitor was replaced with silaproline and its biological activity was evaluated. However, silacaptopril (154) displayed a lower inhibition of ACE. This decrease in activity may be due to an increase in steric hindrance.141



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Figure 40. Captopril and its silicon analog The replacement of leucine with TMS-alanine (145, figure 37) in the neurotensin analog led to an increased affinity for the neurotensin receptor. The peptide containing TMS-alanine showed potent analgesic effects in animal models of pain.140 Tacke and co-workers studied the effect of silicon incorporation in decapeptide cetrorelix, a GnRH (gonadotrophin-releasing hormone) antagonist. The TMS-alanine containing peptide showed significant activity in vivo with increased duration of action.156 β-amino acids with silicon incorporation have also been reported in literature. Jennifer and co-workers published the synthesis of silicon containing cyclic β-amino acids of the general formula 155.157 Skrydstrup and co-workers synthesized β-amino acids 156 and 157 and incorporated them in antimicrobial peptide alamethicin. One of the sila peptides showed 20-fold increase in calcein release compared to alamethicin.158

Figure 41. Silyl β-amino acids


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Marutake et al. synthesized and evaluated the silicon analogs of pregabalin (figure 42).159, 160 Pregabalin is an analog of gamma-amino butyric acid (GABA), a neurotransmitter present in the central nervous system. It is used to treat epilepsy and neuropathic pain. The anti-allodynic activity of the compounds 158 and 159 were checked in spinal nerve ligation models. The activity of 159 was found to be comparable to that of pregabalin. Interestingly, both the silicon analogs 158 and 159 did not show any anti-convulsant activity of pregabalin. Pregabalin causes dizziness and had hypalgesic effects that was not observed in rats dosed with 158 and 159. These results suggest that silicon analogs 158 and 159 can be considered as pregabalin analogs with reduced CNS side effects.159

Figure 42. Silicon containing GABA analogs Further optimization of the series led to the development of compounds 160 and 161.160 In rotarod experiments, rats administered with pregabalin lost their balance showing CNS side effects. The silagaba compounds were found to be devoid of any CNS side effects in rotarod experiments. PK experiments showed that the distribution of pregabalin into brain is more when compared to the silicon analogs that may be a reason for its side effects. The silagaba compounds showed weak binding to α2-δ protein which is presumed to be the target of pregabalin. This indicates that sila compounds may be binding to some other proteins causing similar allodynic activity as pregabalin.



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Along these lines, Reddy and co-workers synthesized silicon incorporated amino acids (alpha, beta and gamma; 162 − 164) with unusual 5,5-trans fusion starting from allylsilanes (figure 43). The ease of formation of this skeleton was explained by the larger C-Si bond length as compared to a C-C bond. The synthesis of lipophilic and constrained silicon analog of GABA (164) is interesting because conformationally rigid GABA analogs are known for the treatment of several CNS disorders. The sila-GABA derivative is similar to the marketed anti-epileptic drug gabapentin and another clinical candidate atagabalin.161 It is interesting to note that 5,5-trans fusion of diquinane resembles the stereochemical orientation of methyl groups of atagabalin.

Figure 43. Silicon amino acids with 5,5-trans fusion

13. Organosilanes that entered clinical trials Although there are no marketed drugs containing silicon, some of the compounds have entered human clinical trials (figure 44). To the best of our knowledge, nine compounds have been tested in humans; the results of which indicate


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that silicon incorporation does not cause any toxicity concerns.7, 162 In fact, silabolin, a prodrug of the steroid nandrolone was available in Russia and used by athletes.28, 163

Figure 44. Organosilanes that entered human clinical trials

14. Challenges and way forward



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The benefits of introducing silicon in drug like scaffolds were discussed in detail in this perspective. However, this area is associated with certain challenges and drawbacks. One of the main challenges is to design efficient synthetic routes to access the target molecule containing silicon. The availability and cost of starting materials is a concern and the synthesis may involve uncommon reagents. Due to the inherent instability of certain bonds such as Si-H and Si-X, less structural variations are possible in organosilanes. Pharmaceutical companies may find this field less attractive because working on a scaffold not present in any marketed drug is riskier. Although, increased lipophilicity is advantageous for improving potency, it can hamper the druggable properties of the molecule such as aqueous solubility. Hence, the right balance between lipophilicity and hydrophilicity should be maintained while striving for more potent molecules. Although silicon offers potential avenues to medical chemists, the area remains underexplored. Advancement in synthetic methodologies which provide easy access to organosilicon compounds can attract more research groups to work on this interesting field.166-168 Recently, Arnold and co-workers reported the synthesis of organosilanes using heme proteins under physiological conditions.169 Prior to these findings, the synthesis of organosilanes using living organisms were not known. Although we have seen many stories with the concept of “silicon incorporation”, none of these has resulted in a marketed drug. All that is needed is one silicon-containing drug to make it to the market, to fuel interests in siliconincorporation, as seen with the “deuterium trick”. Once this is done, then more people from industry and academia can take up this concept seriously and use it in their lead optimization projects. The coming years will hopefully see a few candidates with


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silicon incorporation in clinical evaluation and possibly the identification of further opportunities (may be serendipitous!) with this interesting class of compounds.

Author Information *Corresponding author: Dr. D. Srinivasa Reddy; E mail ID: [email protected]

Notes The authors declare no competing financial interest.

Acknowledgements We thank our colleagues Vasudevan, Rahul, Seetharam, Gorakh, and Akshay for their contributions

to

silicon-based

medicinal

chemistry

from

the

group

and

discussions/suggestions while preparing this perspective. Thanks to Aubrie Harland, School of Pharmacy, University of North Carolina for proofreading the article. We are also thankful to the reviewers for their useful suggestions in revising the manuscript. We acknowledge funding from CSIR, New Delhi through XII Five Year Plan projects (ORIGIN: CSC0108; NICE-P: CSC0109; NCL-IGIB joint program: BSC0124) and BIRAC (Biotechnology Industry Research Assistance Council), DBT, New Delhi for the support through CRS Scheme (BT/CRS0046/CRS-02/12).

Abbreviations [3H]NMS, [3H]N-methylscopolamine; LXR, liver X receptor; FXR, farnesoid X receptor; ROR, retinoid-related orphan receptors; HL60, Human promyelocytic leukemia cell line; BMPR1b, bone morphogenetic protein receptor type-1B;



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Biographies Remya Ramesh completed her M.Sc. in Applied chemistry from Cochin University of Science and Technology, India, in 2011. She began her research career in CSIRNational Chemical Laboratory, Pune, India under the guidance of Dr. D. Srinivasa Reddy. Her doctoral research was mainly focused on the synthesis of sex pheromones and biologically active compounds containing silicon. Currently, she is working as a postdoctoral research associate with Prof. Jeffrey Aubé in the Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, USA. D. Srinivasa Reddy received his Ph.D. in 2000 from University of Hyderabad (Prof. Goverdhan Mehta) followed by postdoctoral work at the University of Chicago (Prof. Sergey Kozmin) and the University of Kansas (Prof. Jeffrey Aubé). During the subsequent 7 years in drug discovery pharma industry, he successfully led a couple of drug discovery programs, among which one of the molecules discovered by his team is currently in Phase-II clinical trials. His current research interests are total synthesis of biologically active natural products and medicinal chemistry with a special emphasis on silicon incorporation. He was recognized with many awards including the Shanti Swarup Bhatnagar (SSB) prize in chemical sciences, a prestigious recognition in India. Recently, he was appointed as an editor of Bioorganic & Medicinal Chemistry Letters.

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Quest for Novel Chemical Entities through Incorporation of Silicon in

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