Regio/stereochem defined, diol epoxide adducted ras

区域/立体化学定义，二醇环氧化物加合 ras

• 批准号: 6434263
• 负责人: MAHESH K LAKSHMAN
• 金额: $ 14.61万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6434263
• 关键词: DNA repair; adduct; benzopyrenes; carbopolycyclic compound; carcinogen testing; chemical carcinogen; chemical carcinogenesis; chemical synthesis; circular dichroism; epoxides; gene mutation; mutagen testing; mutagens; nuclear magnetic resonance spectroscopy; nucleic acid structure; oligonucleotides; oncogenes; phenanthrene; stereochemistry

DESCRIPTION: This proposal is a request for support for a beginning investigator's program in the area of chemical carcinogenesis by polycyclic aromatic hydrocarbons (PAHs). PAHs, by virtue of being ubiquitous environmental pollutant, pose a cancer threat to humans. Many members of this class undergo metabolic activation to four reactive diol epoxides. In the presence of DNA, these metabolites bind largely to purine residues forming covalent lesions. Formation of covalent diolepoxide-DNA adducts is implicated as the first step in the biological cascade that ultimately leads to mutagenesis and tumorigenesis. Although structural features o f the hydrocarbon metabolites associated with high carcinogenic activity have been known for quite some time, recent studies have become focused on answering questions on DNA adduct structure and biology subsequent to DNA binding by these metabolites. Of the four metabolically produced isomeric diol epoxides of any hydrocarbon, only one isomer exhibits high tumorigenic activity. However, all four diol epoxides alkylate DNA producing a total of 16 adducts. Thus a question that is central to the overall understanding of chemical carcinogenesis lies in determining how isomeric DNA adducts affect local DNA structure and enzymatic replication of repair. In order to address this question, it then becomes necessary to have a set of probes for physical, biochemical and biological experimentation. To date all 16 adducts of any PAH are not available for comprehensive, comparative studies. The PI proposes rational, highly diastereoselective syntheses of all 16 epoxide adducts of two structurally different PAHs benzo[a]pyrene and benzo[c]phenanthrene, within uniform, biologically important DNA sequence contexts. The differences in PAH structure provide a test for the generality of the syntheses, while uniformity of sequence context provides for comparisons and generalizations of structural and biological effects. For this study, the PI has chosen the human ras sequences (N-ras protooncogene codons 60-62 for A modification at codon 61 and c-Ki-ras protooncogene codons 11-13 for G modification at codon 12), both of which are purine rich. This study will therefore provide 16 N-ras and 16c-Ki-ras oligomers with two stereoisomers of two PAH diol epoxides. In and of itself, this is a nontrivial, previously accomplished task. The PI will then undertake evaluation of thermal denaturation, UV and CD properties of the PAH modified duplexes with normal targets and targets having mismatched bases opposite the lesion. The latter is important because it is believed that misincorporation opposite an adduct could be critical to the mutagenic event. Since structural information can be derived from NMR studies, the syntheses are designed to produce sufficient materials for this. The PI will also collaborate with other groups and the topics to be addressed are (a) NMR analyses, (b) possibly x-ray structures, (c) mutation analyses, (d) DNA repair, and (e) fluorescence studies.

描述：本提案是对开始支持的请求 多环化学致癌领域的研究人员计划 芳香烃(PAHs)。多环芳烃，因为它是无处不在的环境 污染物，对人类构成癌症威胁。这一类的许多成员都经历了 对四种反应性二醇环氧化物的代谢活化。在DNA的存在下， 这些代谢物主要与嘌呤残基结合，形成共价损伤。 共价双环氧化物-DNA加合物的形成是第一步 在生物级联中，最终导致突变和 肿瘤发生学。尽管碳氢化合物代谢物的结构特征 与高致癌活性相关已经知道了很长一段时间， 最近的研究集中于回答有关DNA加合物的问题 DNA与这些代谢物结合后的结构和生物学。中的 任何碳氢化合物的四种代谢生成的同分异构体二醇环氧化物，只有一种 异构体具有很高的致瘤活性。然而，所有四种二元醇环氧化物 使DNA烷基化，总共产生16个加合物。因此，这是一个核心问题 对化学致癌的全面理解在于确定如何 异构体DNA加合物对局部DNA结构和酶促复制的影响 修理。为了解决这个问题，就有必要有一个 一套用于物理、生化和生物实验的探头。到目前为止 任何多环芳烃的所有16个加合物都不能用于全面的、比较的 学习。PI提出了合理的、高度非对映选择性的所有合成 16两种结构不同的多环芳烃的环氧化物加合物苯并[a]芘和 苯并[c]菲，在均匀的、具有生物重要性的DNA序列中 上下文。多环芳烃结构的差异为其通用性提供了测试 合成，而序列上下文的一致性提供了比较 以及对结构和生物效应的概括。在这项研究中， PI已经选择了人类ras序列(A的N-ras原癌基因密码子60-62 G细胞原癌基因密码子61和c-ki-ras密码子11-13的修饰 密码子12处的修饰)，两者都富含嘌呤。这项研究将 因此提供了16个N-ras和16c-ki-ras齐聚物，其中两个立体异构体 两个多环芳烃二醇环氧化物。就其本身而言，这是一个不平凡的问题，以前 完成了任务。然后，PI将进行热力评估 多环芳烃修饰双链体的变性、紫外光和CD性质 靶点和靶点与病变相反的碱基不匹配。后者是 这一点很重要，因为人们认为与加成词相对的错误并入可能 对诱变事件起到关键作用。由于可以推导出结构信息 根据核磁共振研究，这些合成被设计成能够产生足够的材料 为了这个。PI还将与其他小组合作，并讨论以下主题 涉及(A)核磁共振分析，(B)可能的x射线结构，(C)突变 分析、(D)DNA修复和(E)荧光研究。

项目成果

Evaluation of the enantiomeric resolution of 7,8-dihydroxy-7,8-dihydrobenzo[a]-pyrene and its 6-fluoro and 6-bromo derivatives on polysaccharide-derived stationary phases.

评估 7,8-二羟基-7,8-二氢苯并[a]-芘及其 6-氟和 6-溴衍生物在多糖衍生固定相上的对映体拆分。

• DOI: 10.1021/jo020607t
• 发表时间: 2003
• 期刊: The Journal of organic chemistry.
• 作者: Zajc,Barbara;Grahek,Rok;Kocijan,Andrej;Lakshman,MaheshK;Kosmrlj,Janez;Lah,Jure
• 通讯作者: Lah,Jure

Synthesis of pyrene and benzo[a]pyrene adducts at the exocyclic amino groups of 2'-deoxyadenosine and 2'-deoxyguanosine by a palladium-mediated C-N bond-formation strategy.

通过钯介导的 C-N 键形成策略在 2-脱氧腺苷和 2-脱氧鸟苷的环外氨基处合成芘和苯并[a]芘加合物。

• DOI: 10.1021/jo030113b
• 发表时间: 2003
• 期刊: The Journal of organic chemistry.
• 作者: Lakshman,MaheshK;Ngassa,FelixN;Bae,Suyeal;Buchanan,DennisG;Hahn,Hoh-Gyu;Mah,Heduck
• 通讯作者: Mah,Heduck

Palladium-catalyzed synthesis of carcinogenic polycyclic aromatic hydrocarbon epoxide-nucleoside adducts: the first amination of a chloro nucleoside.

钯催化合成致癌多环芳烃环氧化物-核苷加合物：氯核苷的第一次胺化。

• DOI: 10.1021/ol027084w
• 发表时间: 2003
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Lakshman,MaheshK;Gunda,Padmaja
• 通讯作者: Gunda,Padmaja