NEW APPROACHES TO PREPARATION OF CARCINOGENIC/DEOXYNUCLEOSIDE ADDUCT

通过苯并[α]芘的化学致癌作用是 致癌物质对肿瘤的诱导作用。BP被代谢成二元醇环氧化物 (BPDE)与正常DNA失效时共价结合到构象上 正在处理。对这些立体化学同质的大量研究 脱氧核苷-BPDE衍生物是持续BPDE必不可少的 致癌研究，然而，目前的方法不能提供 足够的数量。这些拟议研究的目标是 开发制备非对映异构体纯的新方法， 用于这些研究的BPDE-脱氧核苷加合物。我们建议改善至 改进了非外消旋BPDE的制备方法，并引入了一种 一种新的、通用的方法将其偶联到顺式和反式BPDE- 脱氧核苷加合物。提出了两个独立的战略，用于 改进BPDE合成：(I)一种新的pi堆积策略 非对映选择性非致癌中间体的合成和(Ii) 9，10-二氢BP的不对称环氧化反应将是有效的 通过已知的合成步骤转化为BPDE。作为这方面的第二个推动力 研究计划中，我们将研究7，8-环氧基-7，8，9，10-环氧丙烷的胺化反应。 具有脱氧核苷外环氨基功能的四氢BP。这些 努力为以后的BPDE改性的合成提供了一个模型 脱氧核苷和修饰的寡核苷酸。我们将扩大 这些研究的调查结果的范围到编制相关的 多环芳烃二醇环氧化物(例如， 菲等)以及它们与DNA的共价加成产物。作为一种 这个项目的重要副产品，我们将建立一个坚实的基础 用于设计和实现立体选择方法，该方法 包括圆周率-圆周率的相互作用。

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.