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

DNA 裂解 1,3 DIOXO 1,2 二硫杂环己烷的研究

• 批准号: 6118504
• 负责人: Kent S Gates
• 金额: $ 0.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6118504
• 关键词: biological products; biomedical resource; neoplasm /cancer; spectrometry

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 .

该研究旨在阐明其机制 与抗肿瘤抗生素莱那霉素相关的 1,3-二氧代-1,2-二硫戊环 (1)切割脱氧核糖核酸(DNA)。 体外实验表明 LM 的 DNA 切割是由添加的硫醇触发的，但并不 涉及部首。 重要的是，我们发现S-脱氧莱霉素 (2) 不表现出生物活性并且不切割DNA 体外实验。 由此看来，不寻常的 LM 切割 DNA 需要 1,3-二氧代-1,2-二硫戊环 (3)。 此时，LM切割DNA的化学机制是 对于这种化学反应完全未知，也没有详细的建议 被做了。 在我们的前期工作中，我们已经确定了简单的、 合成 1,3-二氧代-1,2-二硫戊环，与莱纳霉素一样，可切割 DNA 以硫醇依赖性方式。 我们在此描述的工作有三个 主要目标：我们将（1）调查结构要求 二氧二硫戊烷对 DNA 的切割，(2) 确定化学机制 二氧二硫戊环通过其切割DNA，(3)设计并合成新型 利用二氧二硫戊环的硫醇触发 DNA 切割剂 “核。” 为了实现这些目标，我们将综合一系列 类似地，我们系统地改变了功能 二氧二硫杂环戊烷环系统。 我们将为（或 通过研究这些的反应性来反对）我们提出的机制 DNA 的类似物和化学模型反应。 我们计划申请 我们通过以下方式获得有关 DNA 切割的信息 二氧二硫戊环用于设计新型 DNA 切割剂 将这个 DNA 切割官能团与 DNA 结合部分结合起来 知道亲和力和特异性。