LIOST

利奥斯特

• 批准号: 2183065
• 负责人: ROBERT G BERGMAN
• 金额: $ 13.34万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2183065
• 关键词: DNA damage; antineoplastic antibiotics; benzene; chemical addition; chemical binding; chemical kinetics; chemical reaction; chemical structure function; chemical substitution; chemical synthesis; cyclization; electron spin resonance spectroscopy; electronic spectra; fluorohydrocarbon; free radicals; infrared spectrometry; intermolecular interaction; lasers; molecular rearrangement; molecular site; photochemistry; stereochemistry; thermodynamics; ultraviolet spectrometry

This proposal outlines a study of the fundamental aspects of the cyclization of 1,5-hexadiyne-3-enes to 1,4-dehydrobenzene diradicals, the essential transformation that triggers the double-stranded cleavage of DNA by several recently discovered antibiotics, the esperamicins and calicheamicins. It has been proposed that the DNA cleavage reaction is initiated by binding of the antibiotic into the minor groove of double-helical DNA, followed by a series of reactions that result in cyclization of the 1,5-hexadiyne-3-ene system in the drug to a substituted 1,4-dehydrobenzene diradical intermediate. The radical centers in this intermediate abstract hydrogen from the deoxyribose backbone of the nucleic acid, resulting in cleavage of the biopolymer. Although these results have stimulated research in several laboratories aimed at the synthesis and study of esperamicin and calicheamicin model systems, there, is little work under way directed at studying the fundamental properties of the cyclization or of the 1,4-dehydrobenzene inter-mediates themselves. Questions of this type that will be addressed in the work outlined in this proposal include: (a) the search for a better understanding of the factors that influence the rate and thermodynamics of the 1,5-hexadiyne-3-ene-to-1,4-dehydrobenzene cyclization; (b) the search for a better understanding of the chemistry, structure, thermodynamic properties and spin states of 1,4-dehydrobenzenes; (c) the effect of structural changes on the chemistry of the diradical; (d) the developments of methods to detect and study the intermediate directly; (e) the relationship of the diradical to alternative structures, such as ring-closed and zwitterionic 1,4-dehydrobenzenes; and (f) the potential for using reactions related to the 1,5-hexadiyne-3-ene cyclization to generate other aromatic diradicals analogous to 1,4-dehydrobenzene. The fundamental information sought in this proposal should be directly useful to workers interested in the chemical and biological properties of antibiotics that induce DNA cleavage by aromatic diradical intermediates.

这项建议概述了对《公约》基本方面的研究， 将1，5-己二炔-3-烯环化为1，4-脱氢苯双自由基， 触发双链切割的必要转化 最近发现的几种抗生素，esperamicins和 加利车霉素。 已经提出DNA切割反应是 通过将抗生素结合到 双螺旋DNA，随后发生一系列反应， 将药物中的1，5-己二炔-3-烯系统环化成 取代的1，4-脱氢苯双自由基中间体。 激进 这个中间体的中心从脱氧核糖中提取氢 在一些实施方案中，所述方法包括将所述生物聚合物与所述核酸的主链连接，从而导致所述生物聚合物的裂解。 虽然这些结果刺激了一些研究， 旨在合成和研究埃斯帕霉素的实验室， 加利车霉素模型系统，在那里，很少有针对 研究环化反应的基本性质 1，4-脱氢苯本身作为中间体。 这类问题 本提案所述工作将涉及的问题包括： 寻求更好地了解影响经济增长的因素， 1，5-己二炔-3-烯合成1，4-脱氢苯的反应速率和热力学 环化;（B）寻求对化学的更好理解， 结构、热力学性质和自旋态 1，4-脱氢苯;（c）结构变化对 （d）发展的方法，以检测和 直接研究中间体;（e）双自由基与 替代结构，例如闭环和两性离子 1，4-脱氢苯;和（f）利用与下列物质有关的反应的潜力： 1，5-己二炔-3-烯环化生成其它芳族双自由基 类似于1，4-脱氢苯。 所寻求的基本信息 这一建议应该对有兴趣的工人直接有用， 诱导DNA的抗生素的化学和生物学特性 通过芳族双自由基中间体裂解。