High level quantum-chemical computations on the cyclizations of enyne allenes

摘要

The ring-closure reactions of the eneediyne and enyne-allene moiteties of the natural antitumor antibiotics neocarzinostatin (1), calicheamicin (4), and dynemicin (5) are held responsible for the DNA-cleavage abilities of these potent pharmacophors. Noeocarzinostatin, first isolated from Streptomyces carzinostaticus in 1961 [1], consists of the key chromophore 1 (Fig. 1.1) bound to a 113-amino acid apoprotein. [2,3] The enediyne moitey of 1 is activated by a thiol nucleophile, rearranges to enyne-cumulene 2, and cyclizes to the highly reactive biradical 3 (Fig. 1.1), a reaction akin to the Myers-Saito cyclization. [4] Since 1 binds to the minor groove of DNA, [5-7] 3 is able to abstract hydrogens from adenine or thymine moieties [8] leading to cell damage. While calicheamicin 4 and dynemicin 5 (Fig. 1.1) undergo Bergman cyclizations to give rise to 1,4-didehydrobenzene biradicals, the neocarizinostatin chromophore 1 reacts differently.