Azinomycins - Total Synthesis and Mechanism of Action

描述（由申请人提供）：azinomycin A和B是从链霉菌中分离出来的强效抗肿瘤药物。它们的生物活性在于其共价烷基化和随后交联双链DNA的能力。由于天然制剂难以从天然来源获得，而且其化学性质不稳定，因此没有对其进行开发工作。本研究的目的是通过天然产物的全合成和合理设计一系列结构和功能相关的药物来阐明这些药物表达细胞毒性和抗肿瘤活性的分子细节。前所未有的结构、复杂的功能化、独特的分子作用机制和有效的抗肿瘤活性使其成为研究的热点。合成努力的主要原理在于构建结构和功能相关的试剂，用于阐明这些试剂与DNA共价相互作用的细节。在合成过程中开发的方法将用于设计和合成试剂，以探索DNA交联周围的化学事件。聚合合成方法将一系列酯、酰胺和烯烃键形成事件中的5个小片段聚集在一起，将成为探索基于阿嗪霉素骨架的结构-功能关系的各种分子的模块化构建的关键。

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.