AZINOMYCINS--TOTAL SYNTHESIS AND MECHANISM OF ACTION

阿奇霉素A和B是分离得到的强效抗肿瘤剂 链霉菌 它们的生物活性在于 共价烷基化并随后交联双链DNA。 目前还没有关于这些药物的开发工作，因为它们 天然来源的可用性较差，并且由于其化学物质 不稳定 这项建议的目的是阐明分子 细胞毒性和抗肿瘤表达的细节 这些试剂通过天然产物的全合成而产生的活性 以及一系列结构和功能上合理设计的 相关代理商 前所未有的结构，复杂的功能，独特的 分子作用机制和有效的抗肿瘤活性，使 azinomycins吸引人的研究目标。 主要理由是 综合努力在于建设结构和 功能相关的试剂，用于阐明 这些试剂与DNA的共价相互作用。 制定方法 在综合努力的过程中，将用于设计和综合 探索DNA交叉周围化学事件的试剂- 链接。 一个融合的综合方法汇集了五个小的 在一系列酯、酰胺和烯烃键形成事件中的片段 并将成为各种模块化结构的关键， 探索结构-功能关系的分子 在阿奇霉素骨架上。

Azinomycins A and B are potent and effective antitumor agents isolated from Streptomyces. Their biological activity resides in their ability to covalently alkylate and subsequently cross-link double stranded DNA. There has been no developmental work on these agents because of their poor availability from natural sources and because of their chemical instability. The aim of this proposal is to elucidate the molecular details involved in the expression of cytotoxicity and antitumor activity by these agents through total synthesis of the natural products and a rationally designed series of structurally and functionally related agents. The unprecedented structure, intricate functionalization, unique molecular mechanism of action, and effective antitumor activity make the azinomycins attractive targets for study. The major rationale for synthetic efforts lies in the construction of structurally and functionally related agents for use in elucidation of the detail of covalent interaction of these agents with DNA. Methodology developed in the course of synthetic efforts will be used to design and synthesize agents with which to explore the chemical events surrounding DNA cross- linking. A convergent synthetic approach brings together five small fragments in a series of ester, amide, and olefin bond formation events and will be the key to the modular construction of a variety of molecules with which to explore structure-function relationships based on the azinomycin skeleton.