Regio/stereochem defined, diol epoxide adducted ras

区域/立体化学定义，二醇环氧化物加合 ras

基本信息

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
项目类别：
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

项目摘要

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：此提案是对开始的支持请求多环化学致癌领域的研究者计划芳香烃（PAH）。 PAHs，由于在环境中普遍存在污染物，对人类构成癌症威胁。这个班级的许多成员都经历过代谢活化为四种反应性二醇环氧化物。在DNA存在的情况下，这些代谢物主要与嘌呤残基结合，形成共价损伤。第一步是形成共价二醇环氧化物-DNA 加合物在最终导致突变的生物级联反应中肿瘤发生。尽管碳氢化合物代谢物的结构特征与高致癌活性有关已经知道很长一段时间了，最近的研究重点是回答有关 DNA 加合物的问题这些代谢物与 DNA 结合后的结构和生物学。的任何碳氢化合物代谢产生的四种异构二醇环氧化物，只有一种异构体表现出高致瘤活性。然而，所有四种二醇环氧化物烷基化 DNA 总共产生 16 个加合物。因此一个核心问题是对化学致癌作用的整体理解在于确定如何异构体 DNA 加合物影响局部 DNA 结构和酶促复制维修。为了解决这个问题，就需要有一个用于物理、生化和生物实验的探针组。迄今为止任何 PAH 的所有 16 种加合物均无法用于全面、比较研究。 PI 提出了所有的合理的、高度非对映选择性的合成 16 两种结构不同的多环芳烃苯并[a]芘和苯并[c]菲，位于统一的、生物学上重要的DNA序列中上下文。 PAH结构的差异为通用性提供了检验合成，而序列上下文的一致性提供了比较以及结构和生物效应的概括。对于本研究， PI 选择了人类 ras 序列（A 的 N-ras 原癌基因密码子 60-62） G 密码子 61 和 c-Ki-ras 原癌基因密码子 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 16 N-ras 和 16c-Ki-ras 寡聚物以及两种立体异构体两个 PAH 二醇环氧化物。就其本身而言，这是一个不平凡的事情，以前已完成任务。然后 PI 将进行热评估 PAH 修饰双链体与正常双链体的变性、UV 和 CD 特性目标和与病变相对的碱基不匹配的目标。后者是重要的是因为人们相信加合物对面的错误掺入可能对诱变事件至关重要。由于可以导出结构信息根据核磁共振研究，合成的目的是生产足够的材料为了这。 PI 还将与其他小组和主题进行合作涉及 (a) NMR 分析，(b) 可能的 X 射线结构，(c) 突变分析，(d) DNA 修复，以及 (e) 荧光研究。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.
影响因子：
0
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.
影响因子：
0
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。