AZINOMYCINS--TOTAL SYNTHESIS AND MECHANISM OF ACTION

阿奇霉素A和B是分离出来的高效抗肿瘤药物 来自链霉菌。它们的生物活性在于它们的能力 共价烷基化并随后使双链DNA交联。 目前还没有关于这些药物的开发工作，因为它们 来自自然来源的可获得性很差，因为它们的化学物质 不稳定。这项提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来发挥活性 以及结构和功能上设计合理的一系列 相关人员。 史无前例的结构，错综复杂的功能，独特的 分子作用机制和有效的抗肿瘤活性使 阿奇霉素类是很有吸引力的研究对象。主要的理由是 综合发力在于结构上的建设和 用于阐明其细节的功能相关试剂 这些试剂与DNA的共价相互作用。已开发的方法 在合成的过程中，会用来设计和合成 用来探索围绕DNA的化学事件的试剂- 链接。一种收敛的综合方法将五个小 一系列酯、酰胺和烯键形成事件中的碎片 并将成为各种模块化结构的关键 用于探索结构-功能关系的分子 在阿奇霉素的骨架上。

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.