DNA CLEAVING 1,3-DIOXO-1,2-DITHIOLANES

我们在这项提案中描述的研究旨在阐明 1，3-二氧代-1，2-二硫杂环戊烷的抗肿瘤作用机制 抗生素雷诺霉素(1)裂解脱氧核糖核酸(DNA)。离体 实验表明，添加硫醇可触发LM对DNA的切割，但 不涉及激进分子。重要的是，发现S- 脱氧莱那霉素(2)没有生物活性，也不切割DNA 在体外实验中。因此，看起来不寻常的3-二氧杂-1，2- 二硫杂环(3)是光镜切割DNA所必需的。在这个时候， LM切割DNA的化学机制完全未知，也没有 对这种化学反应提出了详细的建议。在这份提案中，我们 提出了1，3-二氧代-1，2-二氧基-1，2-二氧基-1，3-二氧基-1，2-脱氧核糖核酸裂解的一般机制 二硫杂环戊烷。 在我们的初步工作中，我们已经确定了简单的合成1，3-二氧杂- 1，2-二硫杂环戊烷，像雷诺霉素一样，在硫醇依赖的 举止。我们在这里描述的工作有三个主要目标；我们将(1) 通过研究DNA裂解的结构要求 二氧二硫杂环戊烷，(2)决定化学机理 二氧二硫杂环戊烷裂解DNA，(3)设计合成新型硫醇化合物-- 触发了利用二氧二硫杂环戊烷“核心”的DNA裂解剂。 为了达到这些目标，我们将在 我们系统地改变二氧二硫杂环戊烷上的官能团 振铃系统。我们将拿出支持(或反对)我们提议的证据 通过研究这些类似物与DNA和In的反应性来研究其机制 化学模型反应。我们计划应用我们所获得的信息 关于二氧二硫杂环己烷对DNA的切割 结合该DNA裂解官能团的新型DNA裂解剂 具有已知亲和力和特异性的DNA结合部分。 我们认为1，3-二氧代-1，2-二硫杂环戊烷的化学机理 裂解DNA特别令人感兴趣，因为二氧代二硫杂环戊烷似乎是 一种新的化学类别的DNA裂解剂。

The research we describe in this proposal is designed to elucidate the mechanism by which 1,3-dioxo-1,2-dithiolanes related to antitumor 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 ,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 this proposal we suggest general mechanisms for the cleavage of DNA by 1,3-dioxo-1,2- dithiolanes. 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 dioxodiathiolane "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 mechanisms by studying athe 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 known affinity and specificity. We fell that the chemical mechanism by which 1,3-dioxo-1,2-dithiolanes cleave DNA is of particular interest, because dioxodithiolanes appear to be a new chemical class of DNA-cleaving agents.