INVESTIGATION OF DNA CLEAVING 1,3 DIOXO 1,2 DITHIOLANES

这项研究旨在阐明 与抗肿瘤抗生素雷诺霉素相关的1，3-二氧代-1，2-二硫杂环戊烷 (1)裂解脱氧核糖核酸。体外实验表明 添加硫醇会触发LM对DNA的切割，但不会 牵涉到激进分子。重要的是，人们发现S-脱氧莱诺霉素 (2)无生物活性，不切割DNA。 体外实验。因此，似乎不寻常的 1，3-二氧代-1，2-二硫杂环(3)是LM切割DNA所必需的。 目前，LM切割DNA的化学机制是 完全未知，也没有关于这种化学的详细建议 已经做好了。在我们的初步工作中，我们已经确定了简单的， 合成的1，3-二氧代-1，2-二硫杂环戊烷，与雷诺霉素一样，可以裂解DNA 以硫醇依赖的方式。我们在这里描述的工作有三个 主要目标：我们将(1)调查 二氧二硫杂环戊烷对DNA的切割作用，(2)确定其化学机制 二氧杂二硫杂环戊烷对DNA的切割作用；(3)设计合成新型化合物 利用二氧二硫杂环戊烷的硫醇引发的DNA裂解剂 “核心。”为了实现这些目标，我们将综合一系列 类比，其中我们系统地更改 二氧二硫杂环己烷体系。我们将为(或)提供证据 反对)我们提出的机制，通过研究这些反应的活性 与DNA和化学模型反应中的类似物。我们计划申请 我们获得的关于DNA被切割的信息 二氧二硫杂环戊烷用于设计新型DNA裂解剂 将该DNA裂解官能团与DNA结合部分结合 了解亲和力和专一性。

The research is designed to elucidate the mechanism by which 1,3-dioxo-1,2-dithiolanes related to anti-tumor antibiotic leinamycin (1) cleave deoxyribonucleic acid (DNA). In vitro experiments showed that DNA-cleavage by LM is triggered by added thiol, but does not involve radicals. Importantly, it was found that S-deoxyleinamycin (2) displays no biological activity and does not cleave DNA in in vitro experiments. Thus, it appears that the unusual 1,3-dioxo-1,2-dithiolane ring (3) is required for DNA-cleavage by LM. At this time, the chemical mechanism of DNA cleavage by LM is completely unknown and no detailed proposals for this chemistry have been made. In our preliminary work, we have identified simple, synthetic 1,3-dioxo-1,2-dithiolanes that, like leinamycin, cleave DNA in a thiol-dependent manner. The work we describe herein has three main goals: we will (1) investigate the structural requirements for DNA cleavage by dioxodithiolanes, (2) determine the chemical mechanism by which dioxodithiolanes cleave DNA, (3) design and synthesize novel thiol-triggered DNA-cleaving agents that utilize the dioxodithiolane "core." In order to meet these goals, we will synthesize a series of analogs in which we systematically alter the functionality on the dioxodithiolane ring system. We will produce evidence for (or against) our proposed mechanism by studying the reactivity of these analogs with DNA and in chemical model reactions. We plan to apply the information that we gain regarding the cleavage of DNA by dioxodithiolanes toward the design of novel DNA-cleaving agents that combine this DNA-cleaving functional group with a DNA-binding moiety of know affinity and specificity .