NATURAL AND NONNATURAL DNA-CLEAVING AGENTS

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It is proposed to synthesize and study natural and nonnatural members of a class of compounds capable of forming biradicals under physiological conditions with the tandem goals (1) to increase our understanding of the detailed mechanisms by which these substances cleave DNA and function as antitumor agents; and (2) to provide by chemical synthesis new structures for study as potential DNA cleaving agents and as leads for the design of new antitumor agents. This is a multifaceted program which is composed of the following subdivisions: (a) Synthesis of Neocarzinostatin Chromophore, its Aglycone, and Nonnatural Derivatives of the Chromophore Core; (b) Synthesis and Study of Dynemicin and Related Structures; (c) Design and Synthesis of Nonnatural DNA Cleaving Agents; (d) Mechanistic Studies of Natural and Nonnatural DNA Cleaving Agents.