NEW APPROACHES TO PREPARATION OF CARCINOGENIC/DEOXYNUCLEOSIDE ADDUCT

制备致癌/脱氧核苷加合物的新方法

• 批准号: 6240215
• 负责人: George Raymond NEGRETE
• 金额: $ 10.6万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240215
• 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

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[α]芘的化学致癌作用是 致癌物诱发肿瘤。 BP代谢为二醇环氧化物 （BPDE）共价结合到构象与正常DNA的故障 处理. 对这些立体化学均相的充分研究 脱氧核苷-BPDE衍生物对于持续BPDE是必需的 致癌研究，然而，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， 用于这些研究的BPDE-脱氧核苷加合物。 我们建议改善， 改进非外消旋BPDE的制备以及引入 将其偶联成顺式和反式BPDE的新的通用方法， 脱氧核苷加合物。 提出了两个独立的战略， 改进BPDE合成：（i）一种新的，π-堆叠策略， 非致癌中间体的非对映选择性合成，和（ii） 9，10-二氢BP的不对称环氧化，这将是有效的 通过已知的合成步骤转化为BPDE。 作为第二个推力， 研究计划，我们将研究胺化7，8-环氧-7，8，9，10- 具有脱氧核苷环外氨基官能团的四氢BP。 这些 这些努力是后来合成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，以编写有关 多环芳烃二醇环氧化物（例如萘， 菲等）以及它们与DNA的共价加成产物。 作为 作为该计划的重要副产品，我们将建立一个坚实的基础， 用于设计和实施立体选择性方法， 包括π-π相互作用。