Design, Synthesis, and Biological Activity of Unnatural Enediynes

Chem. Rev. 2007, 107, 2861−2890

2861

Design, Synthesis, and Biological Activity of Unnatural Enediynes and Related Analogues Equipped with pH-Dependent or Phototriggering Devices Moumita Kar and Amit Basak* Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India Received June 2, 2006

Contents 1. 2. 3. 4.

Summary Introduction Strategies for the Design of Enediynes Approaches for pH-Based Triggering 4.1. Category 1: Activation through Enediyne to Eneyne−Cumulene Conversion 4.2. Category 2: Activation through Acid- or Base-Catalyzed Ring Opening 4.3. Category 3: Activation through Salt Formation 4.4. Category 4: In Situ Generation of Enediynes through Allylic Rearrangement/β-Elimination 4.5. Category 5: Activation through Acid-Catalyzed Enol to Keto Tautomerism 4.6. Category 6: Base-Catalyzed Intramolecular Transannular Reaction in Macrocyclic Enediyne 5. Approaches to Photo-irradiation-Based Triggering 5.1. Category 1: Use of Enediynes Activated toward Photo-Bergman Cyclization 5.2. Category 2: Activation of Enediynes via Photo-induced Electron Transfer 5.3. Category 3: Photo-excitation of Enediyne Metal Complexes via Ligand-to-Metal or Metal-to-Ligand Charge Transfer 5.4. Category 4: Photo-activation of Locked or Acyclic Enediyne 5.5. Category 5: Activation of the Prodrug via Photolysis of Cyclopropenone/Diazoketone 5.6. Category 6: Activation via Photo-isomerization of Azobenzene-Based Enediynes and Sulfones 6. Concluding Remarks 7. Acknowledgement 8. References

2876 2876

actual clinical stage against certain types of tumors has generated an unprecedented flurry of research activities in the field of chemistry, biology, and medicine in search of new therapeutic agents. Various factors, such as ring strain, the proximity of carbon atoms undergoing covalent connectivity, etc., play important roles in controlling the process of diradical generation via cycloaromatization, and the lead from Mother Nature continues to be followed, as evidenced from the report of numerous synthetic mimics of the natural products. A major focus of research in this field involves the synthesis of designed enediynes to correlate their chemical and biological activity coupled with a novel triggering mechanism. Triggering of enediynes is necessary to activate them to generate the reactive form under appropriate conditions. Variations of pH and photo-irradiation are two important methods for triggering enediynes that are stable under ambient conditions. In this review, the synthesis and reactivity of endiynes and analogous molecules equipped with such triggering devices is discussed along with the analysis of the current level of biological activity achieved thus far.

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2. Introduction

2881

The first discovery of natural enediyne antibiotics1-11 in the late 1980s and the investigation on the fascinating mode of biochemical action12 of this class of natural products through the generation of benzenoid diradicals stimulated chemists to reinvestigate a fundamental chemical process of cycloaromatization discovered almost 3 decades ago.13-18 The process, now known as Bergman cyclization13-18 (BC), is primarily responsible for the antitumor activity of one set of naturally occurring enediynes, such as calicheamicins. A similar chemistry for the eneyne-cumulene and eneyneallene systems, explored in 1989 and known as Myers-Saito cyclization (MSC),19-22 is believed to be at the heart of antitumor activity of another group of naturally occurring enediynes, such as neocarzinostatin, inflicting oxidative DNA cleavage. Since the discovery of the mechanism of action of calicheamicin and neocarzinostatin, methods other than BC and MSC to generate diradicals have been developed.23 All of these are shown in Scheme 1. Apart from their DNAdamaging activity, these diradicals have recently been shown to rupture the protein structure via oxidative cleavage of the peptide bond.24 This proteolytic activity also explains the resistance mechanism employed in pathogenic bacteria against such toxic secondary metabolites,25 e.g., calicheamicin γi. While the acyclic enediynes undergo thermal cycloaromatization at elevated temperatures only (g200 °C), the natural enediynes cyclize spontaneously at physiological

2861 2861 2864 2865 2865 2867 2872 2874 2875 2875

2882 2884 2884 2887 2888 2888

1. Summary Oxidative DNA cleavage by the diradical species generated from enediyne or enyne-cumulene progenitor is believed to be at the heart of the biological activity of the naturally occurring enediyne antibiotics. These serve as a perfect example of a prodrug designed by Nature. The promotion of certain members of this class of natural products to the * To whom correspondence should be addressed. Telephone: 91-322277628. Fax: 91-3222-55303. E-mail: [email protected].

10.1021/cr068399i CCC: $65.00 © 2007 American Chemical Society Published on Web 06/23/2007

2862 Chemical Reviews, 2007, Vol. 107, No. 7

Kar and Basak Scheme 1. Methods of Generating Diradicals

Moumita Kar received her B.Sc. from Vidyasagar University in 2000 and completed her M.Sc. in pure chemistry (with an organic chemistry emphasis) in 2002, from Calcutta University, with a brilliant academic record. She then worked as a project fellow in Chembiotek Research International, Kolkata, for 1 year before joining the research group of Professor Amit Basak at the Indian Institute of Technology, Kharagpur, in 2004 for her doctoral study. Her research project covers the field of design, synthesis, and evaluation of chemical as well as DNA-cleaving activity of novel enediynes, with particular emphasis on the development of novel photo- and pH-mediated triggering devices for their activation. Ms. Kar is currently a Senior Research Fellow (CSIR, Government of India) and is a life member of the Chemical Research Society of India.

Amit Basak obtained his Ph.D. from Calcutta University under Professor S. K. Talapatra in 1982 and his D.Phil. in 1986 from Oxford University under Professor Sir Jack E. Baldwin. After his postdoctoral research with Professor Craig Townsend at the Johns Hopkins University, Baltimore, MD, he joined the Indian Institute of Technology, Kharagpur, in 1991 and is currently the Chairman of the Department of Chemistry. Professor Basak’s research interests involve the development of artificial DNAcleaving agents, in particular the enediynes, understanding the roles that various weak interactions, such as electrostatic, hydrogen bond, field effects, etc., play in controlling the kinetics of cycloaromatization processes. Asymmetric synthesis, turn mimetics, and biotransformations are other areas in which his group is currently researching. Professor Basak has been a visiting professor at the Johns Hopkins University and the University of Basque Country, San Sebastian, Spain. He is an Editorial Advisory Board member of Chemical Communications and the Canadian Journal of Pure and Applied Chemistry and is a Fellow of the Indian Academy of Sciences, Bangalore. He is a recipient of the CRSI medal for his research contribution, State Scholarship for higher study at Oxford, and University Gold medal.

temperature, and that is the inherent property of 9- or 10membered monocyclic enediynyl systems.26 Nature, however, has incorporated locking devices27 into these systems, which ensure the safe delivery of the molecule to the target before the enediyne functionality is activated toward diradical generation and hydrogen-atom abstraction from the sugarphosphate backbone of DNA, following an intriguing

biochemical-triggering mechanism.28 The chemistry of the triggering or activation process for the natural enediynes primarily involves a change of hybridization29 at a carbon center encompassing the enediyne moiety or an opening of the epoxide ring fused onto the enediyne in bi- or tricyclic fashion30 (shown in Schemes 2 and 3, respectively). This structural change is believed to lower the activation barrier for the cycloaromatization process either by bringing the terminal acetylenic carbon atoms (the c and d distance)31 closer or by easing the overall conformational restrictions.32 It is difficult to judge the effect of one factor independent of the other on the overall kinetics of BC, and quite often, both the c and d distance and strain factor act synergistically to drive the process of diradical generation at a physiologically relevant temperature. The prediction of the kinetics of

Unnatural Enediynes and Related Analogues Scheme 2. Mechanism of Biological Action of Calicheamicin

Scheme 3. Mechanism of Biological Action of Dynemicin

Chemical Reviews, 2007, Vol. 107, No. 7 2863

the stability of the designed enediynes. The target enediynes should have a half-life that enables full characterization of the molecule. The intrinsically reactive enediynes prepared thus far have half-lives ranging from ∼10 to 36 h at the biological temperature of 37 °C. The term “decent half-life” used in this review refers to the half-life within that range. There has also been significant progress in recent years in the area of the theoretical evaluation of various parameters, mentioned above, affecting the kinetics of Bergman and related cyclization reactions. Density functional theory (DFT)-based calculations [Becke-Lee-Yang-Parr (BLYP)] by Schreiner et al.33,34a and Yu et al.34b on monocyclic enediynes have shown that there is no predictive relationship between the alkyne carbon distance and the cyclization activation enthalpy. However, for similar monocyclic systems, a crude relationship does exist between the c and d distance and the kinetics of BC. Nicolaou’s empirically formulated critical range of 3.31-3.20 Å for spontaneous cyclization at room temperature was also revised and extended to 3.40-2.90 Å.33 These calculations were in agreement with the argument that ring-strain effects may become more important in strained systems. It may be mentioned that BC leading to the formation of a diradical is an endothermic process, which indicated a product-like TS for the reaction. Dimethyl substitution at both of the alkyne termini increases the endothermicity of the reaction by 12 kcal mol-1, thus supporting the assumption of a productlike TS for BC. The greater the endothermicity, the slower the kinetics of BC. Schreiner et al. have also shown that an alternate mode of cyclization, namely, C1-C5 covalent connection leading to a fulvene diradical (2.003), is much more endothermic than the corresponding C1-C6 connection (BC) and hence is unfavorable.35 Calculations based on electron localization functions (ELFs) and the catastrophe theory36 revealed that mechanical deformation of the C1-C2-C3 unit and repulsion between the two alkyne functionalities lead to an early formation of diradical character at C2 and C5 atoms. Covalent bonding occurs between C1 and C6 atoms when they are at a distance of 1.791 Å. σ aromaticity appears in the vicinity of the TS, whereas π aromaticity sets-in in the final stage of the reaction path when the ring is about to be formed. Another important point to note in BC is the orthogonal relationship of the diradical with the aromatic π system. This ruled out the influence of a mesomeric effect upon the stability of the radical and hence the cyclization rate. Recently, Alabugin et al.37 have shown how ortho substituents in benzannulated enediynes exert a significant influence on BC kinetics (the so-called ortho effect) (Scheme 4). They Scheme 4. Ortho Effect in BC (Alabugin)a

BC considering the c and d distance factor as proposed by Nicolaou et al.31 mainly relies on the ground-state configuration of the enediynes, and the rule (critical c and d distance for spontaneous BC ) 3.31-3.20 Å)31 applies well for simple monocyclic enediynes without much strain. The prediction based on the strain factor,32 on the other hand, relies on the energy difference between the transition state (TS) and ground state for the cycloaromatization process. The latter theory thus supports the consideration of the stereoelectronic factor for the design, synthesis, and study of the chemical and biological reactivity of synthetic mimics. In reality, both of the factors need to be considered while designing new enediynes as possible therapeutic agents. One other important point that is to be kept in mind is regarding

a Acceleration of the BC rate is observed for X ) OMe, NH +, NO , 3 2 and CF3.

have cleverly used an efficient way to control BC kinetics via the interaction of the in-plane acetylenic orbitals with spatially proximal ortho substituents. This interaction can be either destabilizing through steric or stabilizing through


Kar and Basak

Figure 1. (a) Single- and double-strand cuts in DNA. (b) Supercoiled plasmid DNA. (c) Relaxed plasmid DNA. (d) Gel electrophoresis pattern of various forms of plasmid DNA [form I, supercoiled; form II, nicked, single-stranded (ss) cleavage; form III, linear, doublestranded (ds) cleavage].

hydrogen-bonding/hyperconjugation/electron transfer. DFTbased calculations38 have shown that the ortho effect operates through the σ framework of the resulting neutral diradical intermediate. Apart from the warhead, which is the enediyne moiety present in the natural products, a recognition element is also incorporated in these molecules, which provides efficiency and selectivity against the nucleic acid. Thus, the carbohydrate portion of calicheamicin (2.016) and esperamicin, with an unusual hydroxylamino sugar unit, binds to the minor grove of DNA and places the enediyne warhead properly.39 Cellular nucleophiles then attack the trisulfide, forming a thiolate anion perfectly positioned to form dihydrothiophene via conjugate addition to the bridgehead double bond.29 This triggering mechanism initiated by the thiolate generation removes the conformational restrictions for BC by changing the hybridization state of the bridgehead carbon from sp2 to sp3 as well as by lowering the c and d distance (Scheme 2). In dynemicin (2.020), the dihydroxyanthraquinone acts both as a DNA recognition unit as well as a device for activating the enediyne. Triggering is initiated by the twoelectron reduction of the anthraquinone part to anthraquinol, which is followed by electron flow to generate a quinone methide with concomitant epoxide ring opening.39 The electrophilic quinone methide is most likely trapped by water to generate a cis-diol. This structural rearrangement leading to the opening of the epoxide eases the stereoelectronic restrictions for the generation of a DNA-cleaving diradical via BC (Scheme 3). For a general reader, it is pertinent to mention here that usually there may be two types of DNA cleavages, the singleand double-strand cuts. This is delineated in Figure 1a. The typical experiment that is usually carried out to check the DNA-cleaving activity is to use a supercoiled plasmid DNA. Single-strand cleavage means the breakage or nicking of only one of the two strands, which enables the DNA to relax. On the other hand, a linear form will result if cuts are produced on complimentary sites (or close to complimentary sites) of both of the strands. The mobilities of all three forms in a gel under electric field are different and hence can be easily identified. A typical picture of the three forms of DNA is shown along with the gel pattern (Figure 1). With regard to the efficiency of DNA-cleavage activity, most of the

synthetic enediynes show cleavage at micromolar concentrations, while calicheamicin is effective even at nanomolar concentrations (1 pg µL-1). Thus, in comparison to the natural enediynes, the cleavage efficiency of designed enediynes can only be termed as moderate.

3. Strategies for the Design of Enediynes The cycloaromatization reaction of enediyne and related systems has created never-ending opportunities for organic chemists in developing strategies to make artificial enediyne constructs. That is precisely the reason for an explosive growth in publication in this area of research. In the past 15 years or so, various enediyne models have been designed with the objective of enhancing their reactivity toward BC as well as lowering the toxicity under suitable triggering conditions. The basis of all of these designs can be classified into the following: (1) In the case of acyclic enediynes, conversion into a cyclic40/metallocyclic41/pseudocyclic42 network, which undergoes cycloaromatization (BC) at a lower temperature as compared to their progenitor, forms the basis of the design. Otherwise, isomerization to the more reactive eneyne-allene system,43 which spontaneously undergoes MSC, is an attractive alternative. (2) In the case of cyclic systems, the generation of reactive cyclic enediynes from precursors, which are made ambiently stable by incorporation of small, strained ring systems, is an attractive strategy. The activation process may involve the removal of strain via the opening of small rings under various conditions.44 Oxidative activation of stable cyclic enediynes45 or organometal-mediated activation offers alternate pathways.46 (3) For macrocyclic enediynes, conversion into systems of appropriate smaller size (e.g., 10-membered) that react under ambient conditions has been used for activation.47 All of these approaches are summarized in Scheme 5. This review will describe only those cases where the rate of BC is perturbed by changes in pH and upon photoirradiation. Both of these triggering methods are not only interesting but are important because this will allow one to develop target-specific chemotherapeutic agents. There is no precedence of these types of triggering of enediynes in Nature thus far; in that respect, the idea is quite novel, although Nature’s inspiration cannot be ruled out. Many interesting

Unnatural Enediynes and Related Analogues Scheme 5. Strategies for Designing Enediynesa


longer wavelength increases the penetrability. One major aim in enediyne research is to use molecules that can be activated by light of a higher wavelength.

4. Approaches for pH-Based Triggering An extensive survey of literature reveals that the various strategies adapted for pH-based triggering of enediynes can be classified into the following five categories (Scheme 6). Development of chemistry under each category is subsequently described. Scheme 6. Strategies for Designing Enediynes with pH-Based Triggering Devices

a (a) heat/ambient conditions;40 (b) metal ions;41 (c) hydrogen bond, charge transfer;42 (d) H+, OH-, RM, coenzyme;43 (e) nucleophile, light, OH-, reduction;44 (f) oxidation;45 (g) organometal-mediated activation;46 and (h) transannular reaction.47

results have been obtained using these approaches, which will be summarized here followed by some logical conclusions. It may be mentioned here that Zaleski et al.48 have recently written a review on pH-mediated triggering of enediynes, but that is limited to only metal complexes of enediynes. We aim to address all of the efforts made to generate pH- and light-mediated triggering devices. The question that naturally strikes our mind is what extra benefit does pH- or light-based triggering devices offer. The advantage of pH-based systems stems from the fact that tumor cells have acidic pH,49 which can even be lowered further by administering hyperglycaemic agents,50 while the normal cells remain unaffected. Thus, greater selectivity against tumor cells is expected with enediynes triggered by acidic pH. Although no apparent advantage seems to be there if the triggering happens under alkaline conditions (physiological pH), nonetheless, several enediyne prodrugs have been designed and subsequently synthesized.51 These could be activated under mild basic conditions to the corresponding cytotoxic drugs. Some of these have been shown to possess excellent IC50 values against a number of cancer cell lines. Many of these even showed selectivity against cancer cells, although the origin of selectivity is not very clear. It has been speculated that the cancer cells may contain specific tumor-associated factors, which may be activating these systems preferentially. Other possibilities include the difference in permeability of membranes for these compounds in various cell types and the differences in the ability of the cell machinery to repair the damage caused by these agents. In recent times, a light-mediated procedure, called the photodynamic therapy (PDT),52 has become important for selective killing of tumor cells that are quite localized and yet metastasized. The procedure combines a drug and a light of particular wavelength. The light used for PDT can come from a laser or other source. The laser light can be directed through an optic fiber to deliver light at the appropriate localized area. One important issue in PDT is the penetrability of the light through the tissue, and that is why PDT is less effective toward large tumors. The use of light of a

4.1. Category 1: Activation through Enediyne to Eneyne−Cumulene Conversion This is perhaps one of the widely exploited strategies in pH-based triggering. Toshima and co-workers,53 in their quest to develop new DNA-cleaving agents related to the neocarzinostatin chromophore, synthesized the cyclic sulfide 4.001. The latter on oxidation with mCPBA produced the allenic sulfone 4.002, which when treated with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), isomerized to the eneyne cumulene 4.003. The cumulene, being extremely reactive, underwent spontaneous MSC under ambient conditions to the diradical that was able to cause damage to doublestranded (ds) DNA (Scheme 7). In subsequent papers, Toshima et al.54-56 reported that the thia, oxa, or aza enediyne, represented by structures 4.006, 4.007, and 4.008, respectively, undergo MSC when subjected to weakly acidic or basic conditions. Under such pH values, the compound first isomerizes to the eneyne-allene and

2866 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 7. Activation of Cyclic Sulfones via Eneyne-Cumulene Conversion (Toshima)a

a

Kar and Basak Scheme 9. Activation through Eneyne-Allene via Decarboxylation (Shibuya)a

(a) mCPBA; (b) DBU; (c) O2, 1,4-CHD; and (d) 1,4-CHD.

Scheme 8. Activation through Eneyne-Allene Conversion (Toshima)

a

subsequently undergoes MSC (Scheme 8) to generate the toluene diradicals. The latter have been shown to cleave ds DNA. Shibuya et al.57-60 in a series of interesting papers exploited the approach depicted under this category. In their first publication,57 the group reported the synthesis of enediyne model compounds represented by 4.011, which produced the eneyne-allene 4.012 and ultimately generated toluene diradicals 4.013 via a reaction cascade triggered by hydrolysis of the malonyl ester group under basic conditions (Scheme 9). In another report,58 the eneyne-allene 4.018 was generated using the anchimeric assistance of a neighboring naphthoate ester moiety. The prodrug in this case is the 3° ether 4.016, which upon treatment with TFA in benzene at room temperature generated the eneyne-allene 4.018 via a nucleophilic attack from the napthoate moiety in a SN1′ manner. The process is assisted by the flow of electrons from the phenolic hydroxyl group. The allene 4.018 then smoothly undergoes MSC to the toluene diradical 4.019A. Abstraction of H from 1,4-cyclohexadiene produced the derivative 4.020, which underwent hydrolysis to the phenol 4.021 (Scheme 10). An alternate charge-separated resonance structure 4.019B abstracted H+ and OH- from water to produce the hydroxy phenol 4.023.

(a) KOH and (b) EtOH.

The polar character in the intermediate diradical species 4.019 lowers the DNA-damaging ability. Apart from alkylation of DNA bases, which leads to their cleavage, indiscriminate trapping by other nucleophiles may be lowering the cleavage efficiency. Moreover, the cation is highly stabilized by the adjoining aryl groups, which may also lower its alkylation potency. To suppress that aspect, enediyne models having electron-withdrawing groups were designed59 and subsequently synthesized by the same group. These molecules, represented by 4.024, upon treatment with TFA in the presence of 1,4-cyclohexadiene (1,4-CHD) in benzene or MeOH at 37 °C afforded the phenol 4.028 as the only isolable product, thus indicating that cycloaromatization proceeded via a diradical pathway as shown in Scheme 11. Shibuya’s group has also developed60 a pyridoxal-mediated cycloaromatization of an enediyne model system. Taking a cue from the fact that propargyl glycine acts as an irreversible inhibitor of pyridoxal phosphate-dependent enzymes by virtue of the isomerization into an allenic system after the imine formation, the group has designed an acyclic enediynyl amine 4.029. This, upon treatment with pyridoxal in the presence of a base (Et3N), underwent isomerization to the eneyneallene 4.032 after the imine formation. The allene then reacts via the MSC pathway at room temperature to generate the products 4.032 and 4.033 (Scheme 12). The use of acetic anhydride/pyridine followed by acid hydrolysis facilitated the isolation of the products from the crude reaction mixture. Kerwin’s group61 has recently prepared 4-aza-3-ene-1,6diyne systems represented by structure 4.034 and demonstrated that these compounds possess powerful pH-dependent DNA-cleavage activity with some degree of cytosine specificity. The probable mechanism involves isomerization to the aza eneyne-allene system, which undergoes aza MSC

Unnatural Enediynes and Related Analogues Scheme 10. Activation through Eneyne-Allene Conversion by an Intramolecular SN′ Reaction (Shibuya)a

Chemical Reviews, 2007, Vol. 107, No. 7 2867 Scheme 11. Activation through Eneyne-Allene Conversion by Lactonization (Shibuya)a

a

a

(a) TFA and (b) H2O.

to generate methyl pyridinium diradicals 4.036 (Scheme 13). The latter then cleaves the ds DNA, producing mainly singlestrand cuts at a concentration of 100 µM. Another possible mechanism of DNA cleavage involves the alkylation pathway through the intermediacy of 4.037 or through the formation of carbene intermediate 4.039 via the ylide 4.038.

4.2. Category 2: Activation through Acid- or Base-Catalyzed Ring Opening In this strategy, the designed molecules have one special structural feature in common and that is, in all of these cases, the cyclic unstable enediyne has been made stable by the fusion of a locking device, which is usually a small ring, such as an epoxide, a β-lactam, or even an isooxazoline ring. All of these molecules are equipped with pH-based triggering devices, which unlock them by opening the small ring. With the removal of strain, the molecules become active under ambient conditions.

(a) TFA and (b) H+ shift.

Inspired by the chemistry of the natural dynemicins, Nicolaou et al.62 first reported the synthesis of a series of analogues in which the flow of electrons to open the epoxide ring was blocked by the incorporation of protecting groups in potential donors. In one such design, the pivaloyl group was used to protect the free phenolic OH group to generate the enediyne 4.040. Base-promoted hydrolysis produced the free phenolic form 4.041, which is now capable of promoting the epoxide ring opening via the flow of electrons followed by BC as shown in Scheme 14. Similar to dynemicin, electrons can also flow from the ring nitrogen if its lone pair is free. On that basis, the enediyne 4.045 was synthesized by Nicolaou and coworkers.63 The interesting feature of this molecule is that the nucleophilic N atom is made non-nucleophilic by protection with a 2-(phenylsulphonyl) ethoxy carbonyl group. The group falls off upon treatment with mild bases, thus leading to the generation of free amine 4.046. The lone pair, being free, now flows toward the direction of epoxide, which then opens up. With the release of strain, the resulting compound 4.048 shows BC under ambient conditions (Scheme 15). All of these enediynes described above have DNA-cleaving activity at micromolar concentrations, resulting in the formation of both relaxed and linear forms. In the design of dynemicin analogues by Unno and coworkers,64 the sensitivity of epoxide rings under acidic conditions was exploited. Thus, several novel analogues designated by structure 4.050 were made, and their DNAcleaving potential under acidic conditions was evaluated. It was demonstrated that the size and electronic character of the substituents (R1 and R2) at the C9 position critically influenced the DNA-cleaving ability of the synthesized

2868 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 12. Activation through Pyridoxal-Mediated Eneyne-Allene Conversion (Shibuya)a

a

(a) Et3N and (b) (i) Ac2O, Py; (ii) HCl, H2O.

enediynes. The compounds represented by 4.050 were shown to undergo BC under acidic conditions (Scheme 16). A similar cascade of reactions involving ring opening and BC may operate in cancer cells because they are sufficiently acidic with pH less than 7.49 From previous discussions, it is amply clear that, among the various small ring systems, Nature has picked up the epoxide ring to lock the unstable enediynes, with the reason being the easy unlocking of these systems by opening of the strained epoxide ring by an acid-catalyzed process or opening because of an inward flow of electrons. Other small ring systems, such as cyclopropyl or cyclobutyl, have been neglected because of the difficulty in opening them in the biological environment. One other small ring that satisfies these conditions is certainly the β-lactam systems; it is biorecognizable,65 and its inherent strain has been exploited in almost all of the designs of β-lactam antibiotics.66 The advantage of using β-lactam as a molecular lock lies in the fact that, in addition to the strain that it imparts into an enediyne fused onto it, the ring can also be easily opened by the nucleophile (thiol),67 enzymes, such as transpeptidase68 or β-lactamase,69 or under basic conditions.70 The first use of β-lactam as a molecular lock was reported from our laboratory71 and is manifested in β-lactam-fused bispropargyl sulfones. Incidentally, the bispropargyl sulfones 4.054 were reported to be good DNA-cleaving agents (Nicolaou et al.).72 The mechanism involves isomerization to the allenic sulfones 4.055, which, being a good Michael acceptor, invites a DNA base to add in a conjugate fashion to generate a positive charge on the DNA base, ultimately resulting in a Maxam-

Kar and Basak Scheme 13. Activation Pathways of Aza Enediynes (Kerwin)

Gilbert-type cleavage73 (Scheme 17). An alternative mechanism, involving the formation of diradical 4.058 via GarattBraverman rearrangement,74 does not occur at least in the systems that Nicolaou et al.72 have studied. Subsequently, Kerwin reported75 the synthesis of crownether-based cyclic bispropargyl sulfone 4.060 to take advantage of the well-known metalloregulation of DNA binding. In the presence of alkaline aqueous buffer, the compound cleaved supercoiled DNA presumably via a Maxam-Gilbert type of alkylation pathway. This was concluded from the isolation of the enol ether 4.062 formed by methanol addition to bisallenic sulfone (Scheme 18).76 Dai et al.77 has reported the synthesis and DNA-cleaving activity of novel propargylic sulfones 4.063 under basic conditions. Expectedly, enhancement of potency was observed for compounds with DNA-intercalating moieties (Scheme 19). Although two definite pathways (Maxam-Gilbert or Garatt-Braverman) exist for showing DNA-cleavage activity by the bispropargyl sulfones, the critical step remains the propargyl-allene sulfone isomerization. In 1995, as already mentioned, we reported the use of a β-lactam moiety to arrest this isomerization process in a β-lactam-fused bispropargyl sulfone system 4.065. In a sense, the β-lactam ring acted as a molecular lock in stabilizing the bispropargyl sulfone even under basic conditions.71 On the contrary, catechol- or alizarin-based propargyl sulfones 4.068 and 4.071 readily isomerized to the allenic sulfones 4.069 and 4.072 under the same conditions (Scheme 20). Presumably, the β-lactam ring imposes some kind of stereoelectronic constraint, which disfavors the yne to allene isomerization. A few months after the publication of the propargyl sulfone work, Banfi and Guanti reported the first synthesis of β-lactam-fused enediynes 4.076 and 4.077.78-80 They have elegantly demonstrated that the β-lactam ring can act as a

Unnatural Enediynes and Related Analogues Scheme 14. Activation of Dynemicin Model Enediynes by Base-Mediated Deprotection of the Pivaloyl Group (Nicolaou)a

Chemical Reviews, 2007, Vol. 107, No. 7 2869 Scheme 16. Activation of Enediyne through Acid-Catalyzed Ring Opening of Epoxide (Unno)a

a

R1, H (OAc); R2, OAc (H). (a) p-TsOH‚H2O, THF-d8, 37 °C.

Scheme 17. Chemistry of Bispropargyl Sulfones (Nicolaou)a

a

(a) LiOH, H2O-EtOH, 25 °C.

Scheme 15. Activation of Dynemicin Model Enediyne via Base-Catalyzed β-Elimination (Nicolaou)

a

(a) (i) H2O and (ii) pH > 7.

Scheme 18. Chemistry of Crown-Ether-Based Bispropargyl Sulpone (Kerwin)a

locking device to stabilize the otherwise unstable 10membered enediyne system. Opening of the β-lactam ring unlocked the system, which enabled it to undergo BC. The authors have also developed a β-lactam-fused enediyne system 4.079 with a nucleophilic handle that under mildly alkaline conditions (pH 7.5) opens up the β-lactam ring,

a

(a) mCPBA, DCM; (b) NaOH, H2O, MeOH.

thereby activating the enediyne toward BC (Scheme 22). Thus, the azetidinyl enediynes (or lactenediynes, the name given by Banfi and Guanti) are indeed ideal candidates for evaluation as antitumor and antibiotic agents.

2870 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 19. Propargyl Sulfones with a DNA-Intercalating Moiety (Dai)

Scheme 20. Reactivity of β-Lactam-, Catechol-, and Anthraquinone-Based Bispropargyl Sulfones (Basak)a

a

(a) mCPBA, NaHCO3, DCM.

Kar and Basak Scheme 21. Nozaki Reaction Route to Azetidinyl Enediyne (Banfi and Guanti)a

a (a) Pd(PhCN) Cl , CuI, piperidine, THF; (b) (i) AgNO , KCN; (ii) I , 2 2 3 2 morpholine, benzene, rt; (iii) (COCl)2, DMSO, NEt3, CH2Cl2; and (c) CrCl2, NiCl2 (cat.), THF, rt; (iv) Ac2O, pyridine.

The fascinating development in this area continued with the report81 from our laboratory in the beginning of 1996 (a few months after Banfi’s work) on the synthesis of 1,4-fused azetidinyl enediynes 4.086. The 10-membered enediyne 4.086 was stable at room temperature, although the corresponding monocyclic counterpart 4.08982 spontaneously cyclized at room temperature with a decent half-life (36 h at 30 °C), again demonstrating the ability of the azetidinone ring to act as a molecular lock. Because of the importance of these enediynes, it is pertinent to briefly mention their synthesis in this review. In Banfi’s method,79 the key step is an intramolecular addition of acetylene to an aldehyde involving the Nozaki reaction80 (Scheme 21). From our laboratory, we have thus far published three methods for the synthesis of β-lactam-fused enediynes. Among the first two methods that were developed, one involved an intramolecular N-alkylation81 (Schemes 23 and 24), while the other involved an intramolecular carbene insertion83 (Scheme 25). Both of these methods suffer from the fact that the starting precursor is either a β-lactam or cyclic enediyne, both of which are sensitive systems. To bypass the problem associated with their sensitivity and instability, we have very recently reported a method where the two rings are formed in a single step by an intramolecular Kinugasa reaction as shown in Scheme 26.84 The methodology demonstrated the power of the Kinugasa reaction85 in making sensitive molecules, such as the ones described here. Under basic conditions (pH 8), the β-lactam-fused enediyne 4.094 showed single-strand cleavage of supercoiled plasmid DNA (pBR 322) at a concentration of 50 µM (Figure 2).86 No such cleavage was observed if the incubation was carried out under neutral conditions. It has been proposed that, under alkaline conditions, the β-lactam slowly hydrolyzes to produce the amine 4.094A, which is predominantly present in the protonated form (pKa of secondary amine is 10-11)87 and is the actual cleaving agent. Studies to prove this hypothesis have been described in section 4.3. The results

Unnatural Enediynes and Related Analogues Scheme 22. Triggering of Azetidinyl Enediyne by Intramolecular Nucleophilic Ring Opening (Banfi and Guanti)a

Chemical Reviews, 2007, Vol. 107, No. 7 2871 Scheme 23. Intramolecular N-Alkylation Route to Azetidinyl Enediyne (Basak)a

a

(a) X, Pd(PPh3)4, CuI, rt; (b) MsCl, Et3N; and (c) K2CO3, DMF.

Scheme 24. Synthesis and Reactivity of 10-Membered Azaenediyne (Basak)a

a

(a) (i) HF, CH3CN, H2O, 96%; (ii) MsCl, Et3N, CH2Cl2, -30 °C; (iii) NaN3, DMF, 60 °C, 87%; (iv) PPh3, THF, H2O, rt; (v) Boc-ON, Et3N; (vi) MeONa, MeOH, 0 °C, 85% and (b) TFA. a

clearly showed the potential of the β-lactam-fused enediyne 4.094 as a cytotoxic agent. It can possibly be used as a lead compound for future drug development. Recently, from our laboratory, the synthesis of isooxazolidine-fused enediynes has been reported.88 The main objective behind making these compounds was to study the effect of the 5-membered isooxazolidine ring on the BC kinetics. One advantage that these systems might offer is the possibility of the locking ability of the isooxazolidine ring and the reductive opening of the ring via N-O cleavage under acidic conditions for possible activation of the compounds.

(a) MsCl, Et3N, 0 °C and (b) K2CO3, DMF.

The isooxazolidine-fused enediynes 4.102 and 4.103 were synthesized by intramolecular cycloaddition of the alkene with the nitrone;89 both of the functionalities were crafted in the same molecule. The reactivity of the enediynes was studied by recording the onset temperatures during differential scanning calorimetry (DSC) measurements. It was found that both of the enediynes have similar onset temperatures, indicating only a marginal role of the stereochemistry at the bridgehead carbons. Attempted reductive ring opening by cleavage of the N-O bond under acidic conditions (Zn/HOAc) gave the product 4.104, which was however obtained in very low yield (5%) (Scheme 27). Anyway, the ring-opened enediyne 4.104, being 11-membered, was found to be stable under ambient conditions. An elaborate study of its reactivity toward BC could not be performed because of its low yield of formation, and hence, the role of the isooxazolidine ring upon the reactivity of the parent enediyne


Kar and Basak

Scheme 25. Carbene Insertion Route to Azetidnyl Enediyne (Basak)a

Figure 2. Interaction of supercoiled DNA (in tris-acetate buffer, pH 8.0) and enediyne 4.094 in aceotnitrile; incubation was continued upto 48 h and analyzed by agarose (0.7%) gel electrophoresis using ethidium bromide stain: Lane 1: DNA; Lane 2: DNA + enediyne 4.094 (50 µmol); Lane 3: DNA incubated for 48 h. Scheme 27. Isooxazolidine-Fused Enediynes (Basak)a

a (a) EtOCO(CH )COCl, Et N, CH Cl ; (b) K CO , PTSN ; and (c) 2 3 2 2 2 3 3 Rh2(OAc)4, CH2Cl2, rt.

Scheme 26. Kinugasa Reaction Route to Lactenenediynes (Basak)a

a (a) C H , reflux and (b) (i) Zn, HOAc; (ii) ArSO Cl, Et N, DCM, 6 6 2 3 0 °C.

locking ability of the isooxazolidine. Anyway, further exploration is necessary to come up with a firm conclusion.

4.3. Category 3: Activation through Salt Formation

a

(a) Et3N, CuI, CH3CN.

could not be established. However, the very high onset temperature for BC of the fused systems does indicate the

The rationale behind the activation upon protonation of an enediyne with a basic functionality near the enediyne moiety lies in the fact that the electron-withdrawing effect (-I or electron transfer) lowers the repulsion between the in-plane alkyne π orbitals (Koga-Morokuma hypothesis).90 Alternately, it can be said that protonated enediyne, by electron withdrawal, lowers the singlet-triplet gap and thus favors the triplet state. The triplet, being a better hydrogen abstractor, then produces the cleavage of DNA. The reactivity of the diradical in the singlet and triplet states was evaluated by computational analysis by Chen et al.91 These authors predicted slower hydrogen abstraction by a singlet diradical as compared to the triplet state. The prediction has been confirmed for the singlet didehydroanthracene diradical, for which the hydrogen-abstraction rate from 2-propanol was found to be reduced by 2-3 orders of magnitude relative to phenyl or 9-anthryl radicals. For a singlet ground-state biradical to show radical-like chemistry, e.g., hydrogen abstraction, it must add extra energy to scale up the singlettriplet gap. The singlet lies below the triplet because it is

Unnatural Enediynes and Related Analogues

stabilized and, accordingly, one has to pay back the stabilization energy to reach a TS where the two electrons in the nonbonded molecular orbitals (NBMOs) are uncoupled to reach the triplet state. One can also summarize that an increase in the electron density in the intervening σ bonds can increase the through-bond coupling and hence increase the singlet-triplet splitting. Conversely, decreased electron density will decrease the coupling and hence decrease the singlet-triplet gap. Thus, the in-plane lone pair of the nitrogen atom in the 2,5-didehydropyridine diradical lies antiperiplanar to the σ bonds coupling the NBMOs and therefore could donate electron density. However, when the nitrogen is protonated, the effect is reversed. This has been confirmed by ab initio computed singlet-triplet gaps, where the didehydropyridine with its lone pair shows a much larger singlet-triplet gap than when it is protonated.92 The protonated azaenediyne, being mostly in the triplet state, should be a better hydrogen-atom abstractor. The first strategy is reflected in the works from the research group of Alabugin et al.,93 as well as from our group. The former group has reported93 that BC rates in benzannulated enediynes 4.105 can be tuned by varying the electronic nature of the ortho substituents (Scheme 28). The

Chemical Reviews, 2007, Vol. 107, No. 7 2873 Scheme 29. Reactivity of Pyridine Diamine Based Enediyne and its Salts (Basak)

Scheme 28. Ortho Effect in Benzannulated Enediynes (Alabugin)

DNA at a pH of 7.8. Both the double-strand cut (linear form) as well as the nicked form could be seen using pBR 322 plasmid in micromolar concentrations (Figure 3). With most striking of them is the acceleratory effect on BC kinetics when an amino group at the ortho position is protonated 4.107 (ortho effects has been described in section 2). From our laboratory, such acceleration of the BC rate upon protonation has been reported in the case of 2,6-diamino pyridine-based enediynes 4.114.94 The latter was prepared by double N-alkylation of the bis-sulfonamide 4.112. Deprotection using PhSH under basic conditions (K2CO3)94 gave the free amine 4.114. Attempted dialkylation of diboc pyridine diamine failed to give us the target product. The reactivity of the enediyne and its salts 4.115A-4.115C with acids of various pKa values was studied by DSC,95 which indicated the lowering of the onset temperature for BC upon salt formation. Interestingly, the extent of lowering was shown to depend upon the degree of salt formation, which was monitored by 1H nuclear magnetic resonance (NMR) studies. The greater the degree of salt formation, higher the lowering of the onset temperature for BC. The synthesis of the enediyne and the perturbation of various onset temperatures are shown in Scheme 29. We have also reported that the free amine 4.091, which is an intermediate96 for the synthesis of β-lactam-fused enediyne 4.094 by the carbene insertion route, is able to cleave ds

Figure 3. Interaction of supercoiled plasmid DNA (pBR 322) (in Tris-acetate buffer at pH 8.0) and enediynes 4.091 in acetonitrile. Incubation was continued up to 24 h and analyzed by agarose (0.7%) gel electrophoresis using ethidium bromide stain. Lane 1, DNA; lane 2, DNA plus enediyne 4.091 (50 µmol).

Figure 4. Interaction of supercoiled plasmid DNA pBlueScript SK+ (in Tris-acetate buffer at pH 8.0) and enediyne 4.091 in acetonitrile. Incubation was continued up to 24 h and analyzed by agarose (0.7%) gel electrophoresis using ethidium bromide stain. Lane 1, DNA; lane 2, DNA plus enediyne 4.091 (50 µmol).


pBlueScript SK+ plasmid, only the nicked form could be seen at similar concentrations (Figure 4).97 The protonated form has been proposed to be the DNA-damaging agent because the positively charged nitrogen withdraws electrons from the in-plane π framework, thus lowering the barrier to BC. Through-bond or through-space perturbation of the singlet-triplet barrier in the diradical could also be responsible for such cleavage activity. This result lends support to our earlier explanation of the DNA-cleaving ability of the β-lactam-fused enediyne 4.094. It may be mentioned here that, very recently, we have demonstrated that the protonated amine 4.091 (in the form of tosylate salt) indeed undergoes BC at 30 °C with a half-life of ∼30 days (Scheme 30). The

Kar and Basak Scheme 31. Reactivity of Azaenediyne (Kerwin and Chen)

Scheme 30. Synthesis and Reactivity of Free Amine from 10-Membered Azaenediyne (Basak)a

a

(a) MsCl, Et3N, 0 °C; (b) K2CO3, DMF; and (c) PhSH, K2CO3, DMF.

reason for differential cuts shown for pBR322 is not known at present. However, the sequence specificity is certainly a possibility. The cyclization chemistry of C,N-dialkynyl imine 4.122 (azaenediyne) in which one of the ene carbons is replaced by nitrogen was first reported by Kerwin’s group.98 A year later, Chen and co-workers91 did computational and trapping studies on 2,5-didehydropyridine diradical 4.123. Both of the groups reported that the ultimate product of BC, which would be a pyridine derivative 4.127, could only be isolated if there was a small amount of picric acid. Computational studies have shown that the singlet diradical, which is stabilized by the pyridine N lone pair, is a poor hydrogenatom abstractor as compared to the triplet diradical, which is mainly the species generated from the protonated form of azaenediyne (Scheme 31).

4.4. Category 4: In Situ Generation of Enediynes through Allylic Rearrangement/β-Elimination The impetus for this type of design was derived from the chemistry of an artifact of the natural enediyne maduropeptin

chromophore.99 The artifact 4.129 was obtained during isolation of the parent enediyne using methanol. In the artifact, an intramolecular nucleophilic attack in an SN2′ fashion generates the reactive enediyne functionality 4.130, which then undergoes BC and shows DNA-damaging property (Scheme 32). This overall cascade of reactions represents an emerging strategy for the design of the enediyne prodrug. The first example of an attempted generation of an enediyne from its prodrug by this strategy came from the laboratory of Grierson et al.100 His group synthesized dihydro-1,2-oxazine 4.132 by a regioselective Diels-Alder reaction between a diene (a part of enediyne) 4.131 and a nitroso derivative. Subsequent N-O bond cleavage under reductive acidic conditions (Zn/HCl/CH2Cl2) produced the amine 4.133, which, contrary to expectation, failed to induce the SN2′ attack to generate the enediyne system 4.134 (Scheme 33). It was concluded that, in 4.129, the ring strain is most likely also a key factor in contributing to the artifact rearranging to maduropeptin. To avoid the formation of the strained aziridine ring system during allylic rearrangement, Dai et al.101 adopted an intermolecular strategy for enediyne generation from the prodrug. Dai’s group designed and synthesized the alcohol 4.135, which, upon treatment with nucleophiles, such as ethanol or water, in acidic medium, underwent a SN2′ reaction to generate the reactive enediyne system 4.137. This then underwent BC under ambient conditions, and the resulting diradical 4.138 was able to cleave ds DNA (Scheme 34) at millimolar concentrations, producing relaxed DNA. Most recently, Dai’s group102 has reported on the synthesis of a number of enediyne prodrugs possessing free hydroxymethyl groups on the exocyclic double bond. These compounds as represented by 4.145 at a pH of 8.5 inflict singlestrand cleavage in circular supercoiled DNA. A mechanism based on allylic rearrangement to form a putative epoxyenediyne 4.144 has been proposed. The silylated analogues 4.140 could also be activated by ultraviolet (UV) irradiation

Unnatural Enediynes and Related Analogues Scheme 32. Triggering of Maduropeptin Artifact (Zein and Schroeder)

Chemical Reviews, 2007, Vol. 107, No. 7 2875 Scheme 33. Attempted Triggering of a Maduropeptin Model Enediyne (Grierson)a

a Troc ) Trichloroethoxycarbonyl. (a) Et NIO , CH Cl , 0 °C and (b) 4 4 2 2 Zn, HCl, CH2Cl2, 0 °C.

Scheme 34. In Situ Generation of Enediyne by Allylic Rearrangement (Dai)a

via photochemical alkene isomerization followed by a similar epoxy enediyne formation. Cleavage of DNA may have taken place via both BC pathways, involving hydrogen abstraction by the diradical and alkylation of the DNA base followed by a Maxam-Gilbert-type reaction (Scheme 35). In another strategy, Takahashi et al.103 prepared the cyclic 1,5-diyne derivative 4.149 equipped with a good leaving group in one of the two propargylic carbons separating the alkynes. Treatment with a base-like DBU converted 4.150 via β-elimination to the 10-membered enediyne 4.151, which then smoothly underwent BC under ambient conditions (Scheme 36).

4.5. Category 5: Activation through Acid-Catalyzed Enol to Keto Tautomerism On the basis of the way of activation of calicheamicins and esperamicins via conjugate addition that converts bridgehead sp3 carbon into a sp2 carbon, Semmelhack and co-workers104 have designed an enediyne system 4.154 in which a double bond is present at the bridgehead in the form of an enol. Conversion of the enol into the keto form 4.155 under acidic conditions removes the bridgehead double bond and triggers the molecule toward undergoing BC. It is interesting to note that similar acid treatment of the enolic enediyne system 4.157 generated the ketone 4.158, which is, however, stable under ambient conditions (Scheme 37). The reason for this anomalous behavior (less reactivity) of the substituted ketone is likely to be steric in origin.

a

(a) CSA, EtOH.

4.6. Category 6: Base-Catalyzed Intramolecular Transannular Reaction in Macrocyclic Enediyne Keeping in view of the fact that macrocyclic enediynes of ring size 11 or more are stable at physiological temperature, it is possible to broaden the scope of designing the

2876 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 35. In Situ Generation of Enediyne in Silylated Analogues (Dai)a

Kar and Basak Scheme 36. In Situ Generation of Enediyne via β-Elimination (Takahashi)a

a

a

X ) OH, OAc, OCH2OMe.

possibilities of enediynes, if an intramolecular transannular reaction is conceived to reduce the ring size of a large macrocyclic system (Scheme 38). This in turn should enhance the rate of BC. If the ring-containing enediyne portion after the intramolecular reaction is of appropriate size (9 or 10), BC can occur under ambient conditions, provided that the other ring is not too small (3- or 4-membered). The transannular reaction may be possible if both nucleophilic and electrophilic centers are present in the non-enediynyl portion of the macrocycle. An amine as a nucleophile and a carbonyl functionality as an electrophilic center can jointly serve the purpose. Because of several advantages, nitrogen-containing cyclic enediynes have assumed significant importance in recent years as compared to the oxygen or sulfur analogues because of certain advantages in the former system. The key step in the synthesis of nitrogen-containing systems (10-membered or more) is the intramolecular N-alkylation of an acyclic substrate, which worked nicely to give the cyclic product in high yield.105 However, all efforts to extend the same methodology to prepare the 9-membered analogue 4.159 failed, and we could only isolate a dimeric macrocyclic enediyne 4.161 via initial intermolecular N-alkylation (Scheme 39).106 This change of reactivity was attributed to the stereoelectronic constraint imposed by the severely strained

(a) MsCl, Py and (b) DBU, THF.

9-membered enediynyl system. Recently, we have reported47 the synthesis of two macrocyclic-protected amino enediynes 4.162A and 4.163A. These have been successfully deprotected to the corresponding free amines 4.162 and 4.163, respectively, under basic conditions. The compound 4.163, which has the ability to form a 10-membered ring via an intramolecular nucleophilic attack was found to be unstable and thus underwent BC after the initial transannular reaction. For the other compound 4.162, such a reaction is unfavorable because that would involve the formation of a 9-membered ring (Scheme 40).

5. Approaches to Photo-irradiation-Based Triggering A thorough literature survey reveals that a wide variety of strategies have been adapted to photochemically activate enediynes (phototriggering). Some of these strategies involve BC induced by irradiation. Others use irradiation to bring about a structural change in the prodrug, which is then activated toward thermal BC. All of these strategies can be classified into the following categories (Scheme 41).

5.1. Category 1: Use of Enediynes Activated toward Photo-Bergman Cyclization Turro, Evanzahav, and Nicolaou107 were the first to show that enediynes also undergo cycloaromatization upon photoirradiation and to produce products similar to that obtained in a thermal BC. The process is now popularly known as Photo-Bergman cyclization (photo-BC). These authors reported the formation of naphthalene derivatives 5.002 when an isopropanol solution of n-propyl- or n-phenyl-substituted enediyne 5.001 was irradiated. However, in addition, products resulting from photoreduction of one of the alkynes are also formed (compounds 5.003 and 5.004) (Scheme 42). Unlike the thermal counterpart, photo-BC is not as versatile and the quantum yield as well as the actual isolated

Unnatural Enediynes and Related Analogues Scheme 37. Triggering via Acid-Catalyzed Enol-Keto Tautomerization (Semmelhack)a

Chemical Reviews, 2007, Vol. 107, No. 7 2877 Scheme 39. Attempted Synthesis of 9-Membered Enediyne (Basak)

Scheme 40. Reactivity of Macrocyclic Enediyne (Basak)a

a

(a) HCl (6 M), 0 °C, KCl-HCl at pH 2.0, 37 °C.

Scheme 38. Designing Macrocyclic Enediyne

yield of the cyclized product are usually low. However, certain enediynes can still show facile photo-BC, depending upon the nature of substituents at the alkyne termini or the electronic nature of the ring fused onto the enediyne. The use of different modes of energy transfer is another approach to improve the efficiency of photo-BC. In the past few years, several novel enediynes were synthesized that could be activated toward BC upon irradiation. All of these have been described in a chronological fashion. It may be mentioned that the photo-BC will be an efficient and symmetry-allowed process108 if the photochemical excitation involves the in-plane p orbitals, which is likely to be the case (vide Figure 5), because such excitation promotes

a

(a) K2CO3, PhSH, DMF.

an electron from the molecular orbital (MO) that is C1-C6antibonding to a MO, which is C1-C6-bonding. Thus, the excitation should increase the extent of C1-C6 bonding at a relatively early reaction stage. Unfortunately, the in-plane excitation requires much more energy than the excitation of the out-of-plane orbitals and is hence difficult to access experimentally. However, the efficiency of the photochemical BC can be increased by decreasing the energy gap between the in-plane frontier orbitals. This can be achieved by putting the enediyne framework in a cyclic cage, e.g., in a 10membered ring. Decreasing the C1-C6 distance destabilizes


Kar and Basak

Scheme 41. Strategies for Photo-activation of Enediynes

Figure 5. (a) Frontier in-plane orbitals involved in photo-BC. (b) Comparison of the antiaromatic region for the π-π* interaction pattern for photo-BC with the antiaromatic TS for the [2s + 2s] cycloaddition. (c) Effect of locking the enediyne moiety in a cycle on the energy gap between the frontier in-plane MOs.

Scheme 42. Photo-BC (Turro and Nicolaou)

the occupied MO in which the interaction between the end orbitals is antibonding and, at the same time, stabilizes the

empty MO, which has favorable interactions between the end orbitals. With a decrease in the energy gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), photo-BC is favored. Capitalizing on this variant of BC, Funk and Williams109 designed the pyrene-based enediyne 5.005, which was tethered to an aminoalkyl side chain to provide affinity for DNA (Scheme 43). This, upon irradiation in the presence of pBR 322 DNA, inflicted cleavage of the latter, resulting in its degradation, producing both forms II and III at micromolar concentrations. This is the first example of an enediyne-based DNA photocleaver. Hirama et al.110 have reported the photo-BC of several nonbenzenoid enediynes. It has been argued that photo-BC of these enediynes could play an important role in 1,4didehydrobenzene chemistry because it could be carried out at low temperature. This, in turn, will allow for the characterization of the intermediates. These authors reported the photo-BC of 1,2-diakynyl cyclopentene 5.008. Usually, the yield of cyclized product was low (∼3%), except for the dipropynyl derivative in which case the cyclized product was isolated in yields up to 71%. No photoreduction products were observed unlike in the case of the benzenoid counterpart. The 10-membered enediyne 5.010 upon similar irradiation with a low-pressure Hg lamp produced the cycloaromatized product along with the acyclic enediyne. The latter was generated via retro-BC (Scheme 44). It may be noted that such a retro-BC product was not isolated under the thermal conditions. Russell and his group111 have reported facile photo-BC of pyrimidine-based enediynes 5.013 in isopropanol solution to quinazoline (X ) H or OH) (Scheme 45). It is interesting to note that the corresponding ketone 5.015 failed to undergo photo-BC; however, it did give cyclization products only

Unnatural Enediynes and Related Analogues Scheme 43. Photo-activated Pyrene-Based Enediyne (Funk and Williams)

Chemical Reviews, 2007, Vol. 107, No. 7 2879 Scheme 45. Reactivity of Pyrimidine-Based Enediynes (Russell)

Scheme 46. Pathways for Protein Degradation by Enediynes (Jones)

Scheme 44. Photo-BC of Non-benzenoid Enediynes (Hirama)

under thermal conditions. This clearly demonstrated different activation parameters controlling the kinetics of BC under thermal and photochemical conditions. As already mentioned, apart from their DNA-cleaving property, the enediynes have been shown to possess protein-cleavage ability and, indeed, this is one of the mechanism via which microorganisms producing enediynes protect themselves through the sacrifice of a protein that is secreted by the organism itself. In recent years, Jones et al. in a series of papers112-115 elegantly showed the likely mechanism of protein cleavage and then went on to design and synthesize photo-activated enediynes and study their protein-cleaving ability. The mechanism of protein cleavage involved the formation of radical 5.018 at the captodatively stabilized R carbon, which then reacts with molecular oxygen to form the peroxo radical 5.020.112 This can undergo strand scission or cross-linking (Scheme 46). Jones’s group provided considerable support for the proposed mech-

anism by carrying out the cycloaromatization in the presence of labeled amino acids, such as dideuteriated glycine (A) (Scheme 47), when the deuterium got abstracted by the diradical to form compound 5.027. The isolation of the dimerization product 5.030 and the amide 5.031 together with the deuteriated aldehyde 5.032 could be explained on the basis of the formation of glycyl radical 5.028. Conjugates of photo-activated enediynes and amino acids or porphyrins or spiroalcohols were also synthesized by Jones’s group.113,114 These conjugated assemblies readily underwent photo-BC upon irradiation, thus making them potential agents for photodynamic therapy.116 In the year 2005, this group reported115 an elegant photo-activated enediyne 5.033 based on a pyrene mimic connected to various amino acids (Scheme 48). These molecules upon irradiation can cause degradation of bovine serum albumin, histone, and an estrogen receptor, thus opening a new application of enediynes as chemical proteases. Recently, Peterson et al.117 has reported the synthesis and reactivity of imidazole-fused cyclic enediynes toward photoinduced BC. The more conformationally rigid analogues gave higher yields of cycloaromatized products upon irradiation

2880 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 47. Fate of the Diradical in the Presence of Glycine-d2 (Jones)

Kar and Basak Scheme 49. Photo-activated Imidazole-Fused Enediynes (Peterson)

Scheme 48. Photo-activated Enediyne-Amino Acid Conjugates (Jones) Scheme 50. Photo-BC of Diethynyl Sulfide (Matzger)

Scheme 51. Photo-activated Fluoropyridinyl Enediyne (Alabugin)a

at ambient temperature. For example, the bicyclic analogue 5.035 was shown to undergo photo-BC to produce the cycloaromatized product 5.037 (Scheme 49) and consequently to induce single-strand breaks in supercoiled DNA at micromolar concentrations. An interesting variation of BC has been reported by the Matzger group118 in the photochemistry of diethynyl sulfide. Photo-irradiation of bis(phenylethynyl) sulfide 5.038 in hexane in the presence of 1,4-CHD produced 3,4-diphenylthiophene through the presumed intermediacy of the 2,5didehydrothiophene diradical 5.039 (Scheme 50). This constitutes the first example of a 5-membered ring cycloaromatization exploiting the aromaticity of heterocyclic rings, such as thiophene.

a 5.041A, X ) Y ) H; 5.041B, X ) Y ) Me; 5.041C, X ) Cl, Y ) H; 5.041D, X ) H, Y ) Cl.

5.2. Category 2: Activation of Enediynes via Photo-induced Electron Transfer Alabugin et al.119,120 have recently shown that bistetrafluoropyridinyl ethynyl benzenes 5.041A-5.041D, a class of photo-activated benzenes, smoothly undergo a novel C1-C5 photochemical cyclization to provide isomeric indenes 5.042 and 5.043 (Scheme 51). It has been suggested that the cycloaromatization follows a different mechanism than that operating in normal BC. The key step in this is the photoinduced electron transfer from 1,4-CHD to the singlet excited


state of the enediyne. The presence of strongly electronwithdrawing tetrafluoropyridinyl (TFP) substituents renders the photo-induced electron transfer from 1,4-CHD to the singlet state of enediyne highly exothermic. Unlike the cyclization of neutral enediynes, the C1-C5 cyclization of enediyne radical anions 5.046 leads to an intermediate 5.049 stabilized by resonance involving cyclopentadienyl anions, which makes the cyclization mode possible (Scheme 52). Scheme 52. Probable Mechanism for the Formation of Indenes (Alabugin)a


penetration by near-infrared (IR) photons. Two possible approaches can be adopted to shift the excitation wavelength required for photo-BC beyond λ > 600 nm. The most obvious design involves the synthesis of enediynes with extended π conjugation, which, in addition to synthetically challenging, may also run into solubility problems. Alternatively, long-wavelength electronic transition with considerable absorptivity can be generated via metal-to-ligand charge transfer (MLCT) within compounds where both the metal oxidation state and donor/acceptor redox potentials have been properly chosen. Zaleski et al.122a has elegantly demonstrated this concept via the photochemistry of a novel vanadium (V) metalloenediyne compound 5.054A of a 4,5-bis(phenylethynyl) benzene 1,2-diol ligand. The metalloenediyne exhibited strong ligand-to-metal charge transfer (LMCT) transitions in the near-IR region because of low redox potentials of the high valent vanadium center and the easily oxidizable metalbinding motif. DSC and resonance Raman spectroscopy showed that these LMCTs can be successfully used to photothermally activate the metalloenediyne toward BC. Thus, compound 5.054A in the solid state, upon laser excitation at 785 or 1064 nm, is photothermally activated toward BC to produce the insoluble polymeric material 5.056A. It may be noted that the compound was inert to BC upon electronic excitation in the UV spectral region (Scheme 53). Scheme 53. Photo-excitation via Ligand-to-Metal Charge Transfer (Zaleski)

a

For R refer to Scheme 51.

This is inferred after calculating the energies of the starting enediyne, the TS, and the radical product formed by photochemical cyclization. It is also interesting to note that an enediyne-lysine conjugate 5.041E has been shown to possess some degree of sequence-selective binding and cleavage of DNA.121

5.3. Category 3: Photo-excitation of Enediyne Metal Complexes via Ligand-to-Metal or Metal-to-Ligand Charge Transfer One important goal toward the development of drugs to be used for photodynamic therapy is the use of longer excitation wavelengths. This will ensure enhanced tissue

Photo-BC can also be prompted by MLCT. Zaleski et al.122b have reported that photolysis of copper complexes of Cu(bpod)2PF6 (5.054B) and Cu(bpod)2(NO3)2 (5.054C) (bpod ) cis-1,8-bis(pyridine-3-oxy)oct-4-ene-2,6-diyne) yielded BC of bound ligands. In contrast, the uncomplexed ligand and Zn(bpod)2(CH3COO)2 compound (5.054D) were photochemically inert under the same conditions (Scheme 54). The observed BC of the compounds 5.054B and 5.054C has been ascribed because of MLCT. It is also important to note that the intermediates produced upon photolysis degrade both pUC19 plasmid DNA as well as a 25 base pair doublestranded oligonucleotide via C-4′ hydrogen-atom abstraction. Both single- and double-strand cleavages were observed in micromolar concentrations.

2882 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 54. Photo-excitation via Metal-to-Ligand Charge Transfer (Zaleski)a

Kar and Basak Scheme 55. Reactivity of Benzene-Fused Enediyne and Its Ru Complex (O’Connor)

ring-like epoxide. As a consequence, the enediynes get activated toward BC under ambient conditions. A very thought-provoking and elegant choice of model compound was reported by Nicolaou and his group124 that resulted in the chemistry as depicted in Scheme 56. ComScheme 56. Activation of the Dynemicin Model by Photodeprotection (Nicolaou)

a

(a) 1,4-CHD or 2-propanol, CH3CN and (b) EDTA, DMF‚H2O, CH2Cl2.

The above example depicted nicely how a metal ion can facilitate photo-BC. An interesting variation whereby the photo-BC is completely shutdown upon metal complexation is provided in the next example.123 Thus, the parent benzene-fused enediyne 5.057 undergoes photo-BC upon irradiation to produce the cycloaromatized product. The ruthenium complex 5.058, however, did not produce any cyclized product upon similar photo-irradiation, thus highlighting the importance of the electronic effect in controlling the BC kinetics (Scheme 55). The reluctance of compound 5.058 to undergo cycloaromatization (relative to 5.057) is most likely due to decreased aromaticity in the incipient 1,4-diradical, which would be generated from 5.058.

5.4. Category 4: Photo-activation of Locked or Acyclic Enediyne The basis of this design depends upon the use of photocleavable protecting groups that mask the nucleophilic character of an amine or a phenolic hydroxyl group. Upon photolysis, the protecting group falls off, liberating the free amine or phenol. Flow of electrons takes place, with the net result being the release of strain by the opening of a strained

pound 5.061 under photolytic conditions got converted into the diol 5.064 via the intermediacy of the quinone-methide 5.063 formed by epoxide ring opening. With the release of strain, the compound 5.064 underwent BC. The addition of an external nucleophile, such as EtOH or EtSH, led to the isolation of the cycloaromatized product. Another design based on similar lines of thought was devised by Wender et al.,125 who synthesized a 5-nitroveratryloxy (N-Voc)-protected dynemicin analogue 5.065 (Scheme 57). This photochemically activable analogue was shown to undergo cycloaromatization upon irradiation with wavelengths greater than 300 nm. The ability of this compound to effect DNA cleavage was also demonstrated. Incidentally,

Unnatural Enediynes and Related Analogues Scheme 57. Activation of the Dynemicin Model by Photodeprotection (Wender)a

Chemical Reviews, 2007, Vol. 107, No. 7 2883 Scheme 58. Azetidinyl Acyclic Enediynes Activated through Ring Opening (Basak)

propargylic halide (Scheme 58). Among these, the enediyne, which can form a 10-membered ring after ring opening under basic conditions, showed antibacterial activity against β-lactamase-producing strain. Previously, the moderate DNA-cleaving activity of monocyclic 10-membered enediynes with one nitrogen atom replacing a nonenediynyl carbon was reported from our laboratory.127 However, one problem associated with these compounds is their inherent instability under ambient conditions. Thus, it would be appropriate if an acyclic molecule could be designed that is stable at biological temperatures but is convertible to a cyclic 10-membered enediyne after a triggering reaction. This in situ generated enediyne should then be capable of showing DNA cleavage (Scheme 59). Scheme 59. Strategy for the Triggering of Acyclic Enediynes by Photodeprotection (Basak)

a

(a) THF-MeOH and (b) AcCl, THF, MeOH.

the enediyne 5.065 is also activated toward thermal BC by treatment with acid, which opens up the epoxide. Thus, the molecule is equipped with a dual triggering mechanism (pH as well as light). The design of molecules with an acyclic framework to be activated in a similar way is based on the fact that cyclic 10-membered azaenediyne spontaneously cyclizes under ambient conditions with a decent half-life (t1/2 ) 36 h at 30 °C). Taking a cue from this fact, a new design strategy has been adopted in which an acyclic enediyne having an amino group in one arm of the enediyne is protected in the form of N-Voc or β-lactam. Cleavage of N-Voc or opening of the β-lactam ring releases the nucleophilic nitrogen, which then undergoes intramolecular attack to close the cycle. The latter with appropriate size then undergoes BC, and the resulting diradical shows DNA cleavage or antibacterial property. The first example in this category, which was triggered by base and not by photo-irradiation, was reported from our laboratory. It is discussed here because the approach ultimately led to the idea of photodeprotection. The series of monocyclic β-lactam-based enediynes 5.072 were synthesized126 having an electrophilic center in the form of a

Consideration of all of these points led us to the design of the enediyne 5.076, where the group R1 satisfies two criteria: (a) it suppresses the nucleophilicity of the nitrogen, and (b) it is removed by photolysis. The N-Voc protecting group128 is ideal for this purpose. The compound 5.082 upon irradiation at 365 nm was able to induce single-strand cleavage of plasmid DNA, thus lending support to our hypothesis (Scheme 60).127 It may be mentioned that the

2884 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 60. Proposed Mechanism of DNA Cleavage after Photodeprotection (Basak)a

Kar and Basak Scheme 61. Photochemical in Situ Generation of Enediyne (Popik)

a Lane 1, DNA; lane 2, DNA plus 5.082 (10 µM) (24 h) plus hν (365 nm); lane 3, DNA plus 5.082 (10 µM) (24 h).

ketone 5.082 also caused partial DNA damage under nonirradiating conditions; however, the efficiency of cleavage was ∼2.5 times less. This ruled out the cleavage via the Maxam-Gilbert mechanism as the major pathway.

5.5. Category 5: Activation of the Prodrug via Photolysis of Cyclopropenone/Diazoketone In this strategy, a reactive enediyne system is protected with a group that arrests the spontaneity of BC under ambient conditions of a monocyclic enediyne. Although cobalt carbonyl complexation of the acetylenic moiety is a commonly used protecting group,129 the difficulty in the removal of such a group under photochemical conditions precluded its use. Recently, Popik et al.130a have used cyclopropenone as a photocleavable protecting group to lock a benzene-fused enediyne system 5.087. Irradiation led to cheletropic removal of carbon monoxide with consequent generation of enediyne 5.088, which then underwent BC. It may be noted that the acetylene-protected enediyne 5.087 is thermally stable, showing no sign of decomposition even after heating at 84 °C for 7 days. In a more recent report, Popik et al.130b have demonstrated that the p-quinonoid cyclopropenone-containing enediyne prodrug 5.087A can be activated by photolysis via a single- or two-photon transfer to the enediyne. The latter undergoes BC at 40 °C with a half-life of 88 h (Scheme 61). Similar to the MSC, eneyne-ketones can also undergo similar cyclization chemistry to form a phenoxy diradical. The latter reaction also takes place under ambient conditions similar to the MSC. On the basis of this, the research group of Nakatani and Saito131 synthesized the diazoketone 5.092 via Sonogashira coupling followed by the reaction with diazomethane or methyldiazomethane with the acid chloride 5.091. The resulting diazoketone, upon photo-irradiation (high-pressure Hg lamp), rearranges into the ketene 5.094, which, being conjugated to the eneyne system, undergoes cycloaromatization to produce the phenoxy diradical 5.095 (Scheme 62). The latter was shown to induce cleavage of ds plasmid DNA (pBR322).

Scheme 62. Activation through Conversion of Eneyne-Ketene (Saito)a

a R ) H (50%), hν at 313 nm; R ) CH (64%), hν at 295 nm. (a) 3 RCHN2, ether.

5.6. Category 6: Activation via Photo-isomerization of Azobenzene-Based Enediynes and Sulfones Conformational changes can bring about significant perturbation in the kinetics of BC. In a pioneering work, Ko¨nig et al.132 had earlier reported that, for a bipyridyl enediyne 5.097, a decrease in the distance between the acetylenes


undergoing covalent connection (c and d distance) upon complexation to mercury(II) brings about a remarkable increase in the reactivity toward BC (Scheme 63).

Chemical Reviews, 2007, Vol. 107, No. 7 2885 Scheme 65. Rationale behind Triggering through E-Z Isomerization (Basak)a

Scheme 63. Activation of Bipyridyl Enediynes by Chelation to Hg2+ (Ko1 nig)a

a

d1 > d2 and Tcis < Ttrans.

Scheme 66. Synthesis of Aryl-Fused Azo Enediyne (Basak)a

a

(a) Hg(OCOCF3)2.

We envisioned that similar conformational changes might be achieved if a group capable of switching between E and Z configurations is incorporated in an enediyne moiety (Scheme 64). Azo compounds are well-known to exist in Scheme 64. Phototriggering through E-Z Isomerization of Azo Enediynes (Basak)a

a (a) MsCl, Et N, DCM, 0 °C, 15-20 min; (b) LiBr, THF, 3-4 h; and 3 (c) anhydrous Cs2CO3, rt, 3-4 h, dry DMF.

a

T1 is expected to be higher than T2.

two isomeric forms Z and E. Their reversible isomerization, induced by light or heat, has been exploited for photoresponsive host molecules,133 polymers,134 and liquid crystals.135 Very recently, a light-driven hairpin formation in a peptide backbone using azo functionality136a and incorporation of a photo-isomerizable amino acid into proteins in Escherichia coli have been achieved.136b Besides, a tetrameric sugar-based azobenzene that gels water at different pH values has also been reported.136c Consideration of all of these led us to

design azo-based enediyne systems represented by the general structure 5.099. These molecules should exist in the thermally stable E isomer. Photo-isomerization to the Z isomer 5.100 is expected to bring down the c and d distance (Scheme 64), which should lead to an increase in reactivity. A similar observation is expected for enediynes 5.103 and 5.105 containing E or Z double bonds in a constrained macrocycle (Scheme 65). With this background, the cyclic enediynes 5.111 and 5.116 containing stable E-azo moiety (azoenediynes) were synthesized.137 The key step is the double N-alkylation to form the cyclic network (Schemes 66 and 67). These compounds upon irradiation with long-wavelength UV isomerize to the Z compounds 5.117 and 5.118, which can be thermally re-isomerized to the E compounds (Scheme 68). Reactivity studies toward BC using DSC predictably indicate higher reactivity for the Z isomers. These studies provide a novel way to modulate the reactivity of enediynes under thermal or photochemical conditions. With an appropriately sized enediyne, there could be a possibility of inducing BC upon irradiation under ambient conditions. Encouraged by our success in effecting a change in BC kinetics by E to Z photo-isomerization, a novel cyclic

2886 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 67. Synthesis of Nonaromatic Azo Enediyne (Basak)a

Kar and Basak Scheme 69. Possible Reaction Pathway (Basak)

a (a) MsCl, Et N, DCM, 0 °C, 15-20 min; (b) LiBr, THF, rt, 12 h; (c) 3 NaH, dry THF, reflux for 4 h; and (d) Cs2CO3, DMF.

Scheme 68. Thermal Reactivity of Azo Enediynes (Basak)

bispropargyl sulfone 5.119 containing stable E-azo moiety has also been synthesized. The compound upon irradiation with long UV (350 nm) isomerized to the Z compounds 5.120, which, similar to the previous case, can be thermally re-isomerized to the E compounds. The E isomer 5.119 upon treatment with Et3N equilibrates to the mono-allenic sulfone 5.119A. The latter has been trapped with 1 equiv of MeOH as indicated by the appearance of a peak at m/z 413 corresponding to (M + MeOH + H)+. The formation of bisallene 5.121 could not be seen during the base treatment. On the other hand, a similar treatment of the corresponding Z isomer forms the monoallene 5.120A first, which subsequently further isomerized to the unstable bisallene 5.122; the latter finally underwent decomposition presumably via the Garratt-Braverman pathway (Scheme 69). The formation of bisallene in this case has been proven by the appearance of a peak at m/z 445 corresponding to the addition of 2 equiv of MeOH. Incubation with plasmid DNA also indicated higher DNA-cleavage efficiency (∼2.5 times) for the Z isomer (Figure 6).138 The incubation, however, had to be carried for a short time because of the thermal re-isomerisation problem. A similar increase in DNA-cleavage activity of a related sulfone with an extra conjugation was also observed for the Z isomer 5.135 as compared to the E analogue 5.134 (Schemes 70 and 71 and Figure 7). It is pertinent to mention here that Dai et al.139,140 have earlier reported efficient photo-inducible DNA-cleaving ability of propargylic sulfone 5.136 conjugated to the


Chemical Reviews, 2007, Vol. 107, No. 7 2887 Scheme 71. Synthesis of Unsaturated Bispropargyl Sulfones (Basak)a

Figure 6. DNA-cleavage experiment of compounds 5.119 and 5.120 after 1.5 h of incubation at 37 °C. Lane 1, control DNA in TAE buffer (pH 8.5, 0.4 µm/bp) (7 µL) plus CH3CN (10 µL); lane 2, DNA in TAE buffer (pH 8.5, 0.4 µm/bp) (7 µL) plus Z-sulfone 5.120 (0.02 mM, 2.5 h) in CH3CN (5 µL); lane 3, DNA in TAE buffer (pH 8.5, 0.4 µm/bp) (7 µL) plus E-sulfone 5.119 (0.02 mM, 2.5 h) in CH3CN (5 µL). Scheme 70. Synthesis of Azo Bispropargyl Sulfones (Basak)a

a (a) TsCl, Et N, DCM, 0 °C; (b) Cs CO , CH CN, 50 °C, 24 h; (c) 3 2 3 3 MsCl, Et3N, DCM, 0 °C; (d) Na2S, 9H2O (adsorbed in basic alumina), CH2Cl2-EtOH (2:5), rt, 1 h; and (e) mCPBA, NaHCO3, DCM, from 0 °C to rt, 2 h.

anthraquinone moiety (Scheme 72). From DNA-cleavage studies using different anthraquinone-based sulfones, it was concluded that appropriate spatial arrangement between the activated allenic sulfone and nucleobase, which is derived from an efficient intercalation, leads to a substantial amount of DNA cleavage via alkylation of the nucleobase and photoinduced one-electron oxidation of guanine bases.

6. Concluding Remarks Since the first chemical as well as theoretical evaluation of dependence of kinetics of BC on various parameters, such as proximity effects (Nicolaou) and molecular-strain difference (Magnus and Snyder), significant advances have been made in the area of designing new enediynes in which the BC is controlled by subtle changes in pH or by photo-

a (a) Cs CO , CH CN; (b) PPTs, EtOH; (c) MsCl, Et N, DCM; (d) Na S, 2 3 3 3 2 EtOH-DCM, rt, 1 h; and (e) mCPBA, DCM, rt, 2 h.

irradiation. New pH-based systems, which show BC even at room temperature in the presence of an acid or a base, have been designed and synthesized. The sensitivity of cancer cells toward pH and the fact that photo-irradiation can be targeted specifically to a tumor cell, by directing the laser light through fiber-optic cables, generate a lot of potential in these molecules to be elaborated into chemotherapeutic agents. The cable can be inserted through an endoscope into


Kar and Basak

M.K. takes this opportunity to express her deepest gratitude to A.B., her project supervisor and present head of the department, and last but not the least, she thanks her father, for giving her life in the first place, for the education with aspects from both arts and sciences, and for unconditional support and encouragement to pursue her interests. Figure 7. DNA-cleavage experiment of compounds 5.134 and 5.135 after 2.5 h of incubation at 20 °C. Lane 1, control DNA in TAE buffer (pH 8.5, 0.4 µm/bp) (7 µL) plus CH3CN (10 µL); lane 2, DNA in TAE buffer (pH 8.5, 0.4 µm/bp) (7 µL) plus E-sulfone 5.134 (0.02 mM, 2.5 h) in CH3CN (5 µL); lane 3, DNA in TAE buffer (pH 8.5, 0.4 µm/bp) (7 µL) plus Z-sulfone 5.135 (0.02 mM, 2.5 h) in CH3CN (5 µL). Scheme 72. Anthraquinone-Based Propargyl Sulfone (Dai)

the affected organ, such as the lungs or esophagus, to treat cancer in these organs. Considerable progress is expected in this direction in the near future, and it may not be a wild dream to predict the approval of some of these molecules or analogues as actual clinical agents. However, there are obstacles to achieve that expectation. The light needed to activate the enediynes and related systems cannot pass through more than one-third of an inch of tissue. For this reason, photodynamic therapy is generally used to treat tumors on or under the skin or on the lining of internal organs or cavities. The therapy is less effective for large tumors because light cannot pass into these tumors and is totally ineffective to treat cancers that have metastasized. These points need to be kept in mind when designing new enediynes with light-triggering devices.

7. Acknowledgement The author (A.B.) expresses heartfelt thanks to all of the past and present research scholars for carrying out work on enediynes in his laboratory. A.B. is also indebted to his wife Nupur for her constant encouragement and to his son and daughter for habituating with their father not at home for most of the time. The Department of Science and Technology and Council of Scientific and Industrial Research, Government of India, are thanked for funding the projects on enediynes and providing fellowship to M.K. (CSIR-NET).

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