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

DNA 切割 1,3-二氧代-1,2-二硫杂环己烷

• 批准号: 6019029
• 负责人: Kent S Gates
• 金额: $ 9.59万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6019029
• 关键词: DNA damage; alkanes; analog; antineoplastic antibiotics; chemical cleavage; chemical models; chemical structure function; chemical synthesis; dithiol

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.

我们在本提案中描述的研究旨在阐明

项目成果

DNA alkylation by leinamycin can be triggered by cyanide and phosphines.

氰化物和膦可以引发莱纳霉素的 DNA 烷基化作用。

• DOI: 10.1016/s0960-894x(01)00196-2
• 发表时间: 2001
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Zang,H;Breydo,L;Mitra,K;Dannaldson,J;Gates,KS
• 通讯作者: Gates,KS

DNA binding and alkylation by the "left half" of azinomycin B.

• DOI: 10.1021/bi001998d
• 发表时间: 2000-11
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: H. Zang;K. Gates