NEW APPROACHES TO PREPARATION OF CARCINOGENIC/DEOXYNUCLEOSIDE ADDUCT

制备致癌/脱氧核苷加合物的新方法

基本信息

批准号：
6107288
负责人：
George Raymond NEGRETE
金额：
$ 5.68万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 1999-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6107288
关键词：
adduct benzopyrenediol epoxide carbopolycyclic compound chemical carcinogen chemical carcinogenesis chemical models chemical synthesis cis trans isomerization conformation high performance liquid chromatography method development nucleoside analog nucleosides organic chemicals racemization stereochemistry stereoisomer

项目摘要

Chemical carcinogenesis via benzo[alpha]pyrene is the archetypal model for the carcinogen induction of tumors. BP is metabolized to diol epoxides (BPDE) that covalently bind to conformation with the failure of normal DNA processing. Ample studies of these stereochemically homogeneous deoxynucleosides-BPDE derivatives are essential for continuing BPDE carcinogenesis studies, however present methods are unable to deliver sufficient quantities. The objective of these proposed studies is the development of new methods for the preparation of diastereomerically pure, BPDE-deoxynucleoside adducts for these studies. We propose to improve to improve both the preparation of nonracemic BPDE as well as introduce a novel, general method for its coupling into both cis and trans BPDE- deoxynucleoside adducts. Two independent strategies are proposed for improving BPDE synthesis: (i) a novel, pi-stacking strategy for the diastereoselective synthesis of non-carcinogenic intermediates and (ii) the asymmetric epoxidation of 9,10-dihydro BP, which will be efficiently converted to BPDE by known synthetic steps. As a second thrust of this research program, we will investigate the amination of 7,8-epoxy-7,8,9,10- tetrahydro BP with deoxynucleoside exocyclic amino functions. These efforts are a model for the later synthesis of BPDE-modified deoxynucleosides and modified-oligodeoxynucleotides. We will broaden the scope of the findings in these studies to the preparation of related polycyclic aromatic hydrocarbon diol epoxides (e.g. naphthalene, phenanthrene, etc.) and their covalent addition products with DNA. As an important byproduct of this program, we will establish a firm foundation for the design and implementation of stereoselective methods that incorporate pi-pi interactions.

通过苯并芘的化学致癌作用是典型模型致癌物质诱发肿瘤。 BP 代谢为二醇环氧化物 (BPDE) 与正常 DNA 失效的构象共价结合加工。对这些立体化学同质的大量研究脱氧核苷-BPDE衍生物对于持续BPDE至关重要致癌研究，但目前的方法无法提供足够的数量。这些拟议研究的目的是开发制备非对映体纯的新方法，用于这些研究的 BPDE-脱氧核苷加合物。我们建议改进为改进非外消旋 BPDE 的制备并引入新颖、通用的方法，可将其偶联到顺式和反式 BPDE- 脱氧核苷加合物。提出了两个独立的策略改进 BPDE 合成：(i) 一种新颖的 pi 堆叠策略非对映选择性合成非致癌中间体和 (ii) 9,10-二氢BP的不对称环氧化反应可有效通过已知的合成步骤转化为BPDE。作为本次活动的第二个推动力研究计划，我们将研究7,8-环氧-7,8,9,10-的胺化具有脱氧核苷环外氨基功能的四氢BP。这些的努力是后来合成 BPDE 修饰的模型脱氧核苷和修饰的寡脱氧核苷酸。我们将扩大这些研究结果的范围，以准备相关的多环芳烃二醇环氧化物（例如萘，菲等）及其与DNA的共价加成产物。作为一个该计划的重要副产品，我们将建立坚实的基础用于设计和实施立体选择性方法结合 pi-pi 相互作用。