FUNDAMENTAL STUDIES OF 1,4-DEHYDROBENZENE DIRADICALS

1,4-脱氢苯双基的基础研究

• 批准号: 3304735
• 负责人: ROBERT G BERGMAN
• 金额: $ 12.58万
• 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 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3304735
• 关键词: DNA damage; antineoplastic antibiotics; benzene; 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.

这项提案概述了对 1，5-己二炔-3-烯环合成1，4-脱氢苯二基 触发双链切割的本质转变 最近发现的几种抗生素的DNA，esperamicins和 Calicheamicins。有人提出，DNA切割反应是 通过将抗生素结合到小凹槽中而启动 双螺旋DNA，随后发生一系列反应，导致 药物中1，5-己二炔-3-烯体系的环化反应 取代的1，4-脱氢苯二基中间体。《激进派》 以脱氧核糖的中间抽象氢为中心 核酸的主干，导致生物聚合物的裂解。 尽管这些结果刺激了几个领域的研究 旨在合成和研究埃司帕米星和阿司匹林的实验室 目前，针对Calicheamicin模型系统的研究工作很少 研究环化或环化的基本性质 1，4-脱氢苯为中间体。这类问题 将在本提案概述的工作中处理的问题包括：(A) 寻求更好地了解影响经济增长的因素 1，5-己二炔-3-烯基-1，4-脱氢苯的反应速率和热力学 环化反应；(B)寻求对化学更好的理解， 分子的结构、热力学性质和自旋态 1，4-脱氢苯；(C)结构变化对苯环的影响 双基的化学；(D)检测和分析方法的发展 直接研究中间体；(E)双基与的关系 替代结构，如闭环结构和两性离子结构 1，4-脱氢苯；和(F)使用与下列反应有关的反应的可能性 1，5-己二炔-3-烯环合生成其他芳香族二自由基 类似于1，4-脱氢苯。中寻求的基本信息 这项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 芳香族双自由基中间体的裂解。