Action mechanism and molecular design of biologically active enediyne compounds

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The enediyne antibiotics possess unprecedented chemical structure, potent anticancer activity, and a fascinating mode of bioligical action.In order to clarify the action mechanism of a new enediyne antibiotic C-1027 isolated in Japan, we investigated the C-1027 chromophore-d (GTATC)_2 interaction mode by high resolution NMR method. The NMR results clearly indicate both intercalation and minor groove binding modes with the enediyne chromophore. In the NOESY spectra, the disruption of the sequential connectivities of the base and sugar protons strongly supports intercalative binding at the T_4-A_5 step. The NMR observation is also consistent with intercalation of the benzoxazolinate at the (T_4・A_3)-(A_5・T_2) step. The complex model shows that the DNA oligomer remains in a B-form conformation, although minor groove width (6.04*) are somewhat widened by the occupation of the bulky chromophore. On the other hand, we designed and synthesized 9-membered masked enediyne analogues with DNA intercalator and/or sugar moiety. These new compounds gave high DNA cleaving activity and sequence-specific cleavage. In particular, the sugar attached enediyne analogues are of great promise in respect of antitumor activity and bio-targeting.