SYNTHESIS OF CHEMICALLY ACTIVATED DNA-CLEAVING AGENTS

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We propose to design and synthesize a new class of DNA cleaving agents based on a recently discovered chemical reaction which forms a carbon- centered biradical at physiological temperatures. Initially, a physical- organic study of the basic rearrangement will be conducted with a view towards lowering the activation barrier (and thus the reaction temperature) for formation of the biradical. The principles learned in this study will be used in the design of a series of compounds that are latent forms of the biradical precursor. That is, upon treatment with various reagents (chemical activation) these compounds will be transformed into a species which will rapidly rearrange to a biradical at or below 37o C. A DNA binding function will then be incorporated into our synthetic compounds and the DNA cleaving properties of these hybrid structures will be studied. Our goal is to produce new synthetic materials which will initiate the selective cleavage of DNA upon treatment with an exogenous reagent. Importantly, our substrates can be designed for activation by a cellular "reagent" such as glutathione. It is hoped that these compounds will form the basis for a new class of antibiotics.