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We report three as yet undescribed, critical features of the interaction of the enediyne antitumor antibiotic esperamicin A1 (ESP A l ) with DNA. First, results from hydrodynamic and spectroscopic studies revealed an intercalative binding mode conferred by the deoxyfucose-anthranilate of ESP A l . An intercalative binding mode is consistent with earlier observations of nucleosome linker-selective DNA damage by ESP A1 [Yu, L. et al. J. Biol. Chem. 1994,269,4144-415 11. While capable of adopting a planar structure, the N-(2-methoxyacrylyl)anthranilate group would represent an unusual intercalator, which by itself has no apparent affinity for DNA, yet contributes 1-2 kcallmol to the binding energetics of ESP A l . Second, bistranded DNA lesions, which consist of a direct strand break opposite an abasic site, represent 20-25% of ESP Al-mediated DNA damage. Finally, sequencing gel analysis and tritium abstraction studies revealed that the deoxyfucose-anthranilate caused a switch in the chemistry of ESP Al-mediated DNA damage from 4'-hydrogen abstraction to 1'. We propose that intercalation of the anthranilate of ESP A1 alters the minor groove position of the diradical form of the drug and causes a switch in the hydrogen abstraction in bistranded lesions; the predominance of single-strand lesions associated with ESP A1 may be the result of the altered positioning or intramolecular quenching of one of the drug radicals.

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