SYNTHESIS OF CHEMICALLY ACTIVATED DNA-CLEAVING AGENTS

我们建议设计和合成一类新的DNA裂解剂 基于最近发现的一种化学反应，它形成了一种碳- 在生理温度下以双自由基为中心。最初，身体上的- 将对基本重排进行有机研究，以期 降低活化势垒(从而降低反应温度) 形成双自由基。从这项研究中学到的原则将 用于设计一系列化合物，这些化合物是 双基前驱物质。也就是说，在用各种试剂处理后 (化学活化)这些化合物将转化为一种物种 它会在37℃或更低的温度下迅速重排成双自由基。 然后结合功能将被合并到我们的合成化合物中，并 这些杂交结构的DNA切割特性将被研究。 我们的目标是生产新的合成材料，这将启动 用外源试剂处理时选择性地切割DNA。 重要的是，我们的底物可以被设计成由细胞激活 “试剂”，如谷胱甘肽。人们希望这些化合物能形成 这是一种新型抗生素的基础。

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.