Azinomycins - Total Synthesis and Mechanism of Action

描述（由申请方提供）：阿奇霉素A和B是从链霉菌中分离的强效和有效的抗肿瘤剂。它们的生物活性在于它们共价烷基化并随后交联双链DNA的能力。 由于从自然来源获得的天然制剂很少，而且其化学性质不稳定，因此没有对天然制剂进行开发。本提案的目的是阐明参与表达的细胞毒性和抗肿瘤活性的这些代理商通过全合成的天然产物和合理设计的一系列结构和功能相关的代理商的分子细节。 azinomycins具有前所未有的结构，复杂的功能化，独特的分子作用机制，以及有效的抗肿瘤活性，这使得azinomycins成为引人注目的研究目标。合成努力的主要理由在于构建结构和功能相关的试剂，用于阐明这些试剂与DNA的共价相互作用的细节。在合成努力的过程中开发的方法将用于设计和合成试剂，以探索围绕DNA交联的化学事件。一个收敛的合成方法汇集了五个小片段在一系列的酯，酰胺和烯烃键形成事件，将是关键的模块化建设的各种分子，探索结构-功能关系的基础上的azinomycin骨架。

DESCRIPTION (provided by applicant): 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 the natural 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 details 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 of the azinomycin skeleton.