Azinomycins - Total Synthesis and Mechanism of Action

说明(申请人提供)：偶氮霉素A和B是从链霉菌中分离出来的有效的抗肿瘤药物。它们的生物活性在于它们能够共价烷基化并随后使双链DNA交联。由于天然来源的可获得性很差，而且化学不稳定，目前还没有关于这些天然制剂的开发工作。这项建议的目的是通过全合成天然产物和一系列合理设计的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所涉及的分子细节。其前所未有的结构、复杂的功能、独特的分子作用机制和有效的抗肿瘤活性使其成为研究的靶点。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被用来设计和合成试剂，用来探索围绕DNA交联的化学事件。一种收敛的合成方法将一系列酯、酰胺和烯键形成事件中的五个小片段聚集在一起，将是探索基于阿奇霉素骨架的结构-功能关系的各种分子的模块结构的关键。

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.