1.7.3.12. Role of Hybridization on the Kinetics of Bergman Cyclization (BC)
1.7.3.12.1. Role of Hybridization in Natural Enediynes
The first enediyne natural products are the calicheamicins and esperamicins. They belong to separate family of enediynes but share the same enediyne-containing bicyclic core [7.3.1] (Figure 17) as well as similar mode of biological action.
Extensive in vitro studies suggest that the biological action of these molecules starts with the reorganization and site specific binding to the DNA followed by the attack of a nucleophile (e.g. glutathione) at the central sulfur atom of the trisulfide moiety to generate the thiolate (Scheme 30). The geometry of the molecule enables this thiolate to undergo Michael addition to the enone producing a dihydrothiophene (C). As a consequence, hybridization of the bridgehead carbon changes from sp2 to sp3 which allows the enediyne to undergo BC with concomitant generation of diradical as a rate-determining step.
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The reactive diradical (C) is capable, and well positioned, to abstract two hydrogen atoms, one from the C5' position of deoxycytidine and the other from a ribose position of the opposing strand. The DNA radicals so generated then proceed to react with molecular oxygen leading to double strand cleavages. Townsend et al. have demonstrated the existence of the dihydrothiophene intermediate by 1H-NMR. They have also measured the half-life of this intermediate which came out to be about 4.5 s at 37 oC (Scheme 30).
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Like calicheamicins, the esperamicins (E) also exerts their biological action by damaging DNA. The mechanism of the DNA-cleavage by Esperamicins A1 is identical to that of the cleavage by calicheamicin 
. Esperamicin A1, however, exhibits less sequence selectivity than calicheamicin and shows preference in the order T > C > A > G and results in both single and double strand cuts.
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Figure 18. The natural enediyne Esperamicin A1 (E). |