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首页> 外文学位 >Part I. Investigations of DNA damage mechanisms of azinomycin analogs and the natural product leinamycin. Part II. Biologically relevant chemical reactions of 1,2-dithiole-3-thiones as cancer preventive agents.
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Part I. Investigations of DNA damage mechanisms of azinomycin analogs and the natural product leinamycin. Part II. Biologically relevant chemical reactions of 1,2-dithiole-3-thiones as cancer preventive agents.

机译：第一部分：阿奇霉素类似物和天然产物莱那霉素的DNA损伤机理研究。第二部分1,2-二硫代-3-硫酮作为癌症预防剂的生物学相关化学反应。

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Part I. Azinomycin is known to cause DNA crosslink formation. It has been proposed that reaction at aziridine residue proceeds alkylation of DNA by epoxide of azinomycin. Because epoxides are known to be efficient DNA alkylation agents (eg. pluramycin), and it seems likely that naphthalene binds to DNA, we examined whether formation of epoxide adducts in azinomycin could occur independent of aziridine reaction. More importantly, the epoxide-only metabolite of azinomycin is formed in vivo and retains potent biological activities. We find the left half of azinomycin B, containing only the epoxide moiety of the natural product, modifies guanosines in DNA with high efficiency. UV-vis, DNA unwinding, viscosimetry and fluorescence experiments indicate the naphthalene ring intercalates into DNA. The sequence specificity of azinomycin analogs is also discussed. Relying on these results, we are able to provide insights about the DNA crosslinking properties of the natural product azinomycin B.;Leinamycin is a structurally novel antitumor agent that is bioactivated by reaction with cellular thiols. It has been shown that thiol attack on leinamycin triggers DNA damage by two unprecedented mechanisms. Herein, we provide evidence of an interesting bioactivation pathway in which hydrolysis of the 1,2-dithiolan-3-one 1-oxide heterocycle in leinamycin generates a reactive episulfonium ion species that alkylates DNA. DNA alkylation by leinamycin triggered by other nucleophiles was also investigated. In addition, leinamycin has a unique and previously unknown 18-membered macrocycle, its DNA-binding properties are both mechanistically interesting and biologically important. The results of UV-Vis DNA titration, DNA alkylation efficiency of ds-DNA vs. ss-DNA support for the noncovalent association of leinamycin with DNA. We have suggested the thialzole dieneone portion of leinamycin may bind DNA by intercalation. The sequence specificity of DNA alkylation by leinamycin supports the notion that this compound binds noncovalently to double stranded DNA via intercalation.;Part II. Because prevention is the most desirable approach for fighting cancer, we are investigating the biologically relevant chemical properties of chemoprotective agents. 1,2-Dithiole-3-thiones are a promising class of chemoprotective agents that operate through induction of phase II enzymes. Dithiolethiones are currently in clinical trials as cancer preventive agents. Oltipraz (5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione) has been used to protect against carcinogenic effects of aflatoxin and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, which are known mutagens. Elucidation of the chemical events underlying the selective induction of phase II enzymes is crucial for understanding existing chemoprotective agents and for development of novel anticarcinogenic agents. Our goal is to define the nature of the chemical reactions of dithiolethiones with thiols under mimics of physiological conditions. We find that dithiolethiones could mediate thiol dimerization and lead to other types of thiol modifications. Such modifications of protein thiol groups could be relevant to signal transduction processes involved in the cellular chemoprotective response.
机译：第一部分。已知阿奇霉素会导致DNA交联形成。已经提出在氮丙啶残基上的反应通过阿奇霉素的环氧化物进行DNA的烷基化。因为已知环氧化物是有效的DNA烷基化剂（例如，普拉霉素），而且萘似乎与DNA结合，所以我们检查了阿奇霉素中是否会发生环氧加合物的形成，而与氮丙啶反应无关。更重要的是，阿奇霉素的仅环氧化物代谢物在体内形成并保留了强大的生物活性。我们发现阿奇霉素B的左半部分仅包含天然产物的环氧化物部分，可高效修饰DNA中的鸟苷。紫外可见，DNA展开，粘度测定和荧光实验表明萘环嵌入DNA中。还讨论了阿奇霉素类似物的序列特异性。依靠这些结果，我们能够提供有关天然产物阿奇霉素B的DNA交联特性的见解。莱那霉素是一种结构新颖的抗肿瘤剂，通过与细胞硫醇反应而被生物激活。已经表明，硫醇对莱那霉素的攻击通过两种前所未有的机制触发了DNA损伤。在这里，我们提供了一个有趣的生物激活途径的证据，其中莱纳霉素中的1,2-二硫杂-3--3-一环氧化物的水解产生了使DNA烷基化的反应性epi离子物种。还研究了由其他亲核试剂引发的莱那霉素引起的DNA烷基化。此外，莱那霉素具有独特的，以前未知的18元大环，其DNA结合特性在机理上很有意义，而且在生物学上也很重要。 UV-Vis DNA滴定的结果，ds-DNA与ss-DNA的DNA烷基化效率支持莱纳霉素与DNA的非共价结合。我们已经提出莱纳霉素的噻唑二烯酮部分可能通过嵌入结合DNA。莱那霉素对DNA烷基化的序列特异性支持以下观点：该化合物通过插层非共价结合至双链DNA。第二部分。因为预防是对抗癌症的最理想方法，所以我们正在研究化学保护剂的生物学相关化学性质。 1,2-二硫代-3-硫酮是一种有前途的化学保护剂，可通过诱导II期酶起作用。二硫代噻酮目前正在临床试验中作为癌症预防剂。 Oltipraz（5-（2-吡嗪基）-4-甲基-1,2-二硫基-3-硫酮）已被用来预防黄曲霉毒素和2-氨基-1-甲基-6-苯基咪唑的致癌作用[4,5 -b]吡啶，是已知的诱变剂。阐明选择性诱导II期酶的化学事件对于理解现有的化学保护剂和开发新型抗癌剂至关重要。我们的目标是定义在生理条件下模拟二硫代硫酮与硫醇的化学反应的性质。我们发现二硫代硫酮可介导硫醇二聚化并导致其他类型的硫醇修饰。蛋白质硫醇基团的这种修饰可能与细胞化学保护反应中涉及的信号转导过程有关。

著录项

  • 作者

    Zang, Hong.;

  • 作者单位

    University of Missouri - Columbia.;

  • 授予单位 University of Missouri - Columbia.;
  • 学科 Organic chemistry.;Biochemistry.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 212 p.
  • 总页数 212
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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