AZINOMYCINS--TOTAL SYNTHESIS AND MECHANISM OF ACTION

阿齐霉素--全合成及作用机制

• 批准号: 6172420
• 负责人: ROBERT S COLEMAN
• 金额: $ 21.29万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6172420
• 关键词: DNA damage; adduct; antineoplastic antibiotics; aziridines; biological products; carbopolycyclic compound; chemical structure function; crosslink; drug design /synthesis /production; naphthalenes; stereochemistry

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.

偶氮霉素A和B是有效且有效的抗肿瘤剂 来自链霉菌。 他们的生物活动属于他们的能力 以共价烷基化和随后的交联双链DNA。 这些代理商对这些代理没有发展的工作 自然来源的可用性差，由于它们的化学物质 不稳定。 该提议的目的是阐明分子 细胞毒性和抗肿瘤表达涉及的细节 这些药物通过天然产物的总合成而进行的活性 以及一系列结构和功能的合理设计的系列 相关代理。 前所未有的结构，复杂的功能化，独特的 分子作用机理和有效的抗肿瘤活性使得 偶氮霉素有吸引力的研究目标。 主要理由 合成努力在于结构和 与功能相关的药物用于阐明细节 这些药物与DNA的共价相互作用。 开发了方法 在合成工作的过程中，将用于设计和合成 探索DNA交叉的化学事件的代理 链接。 收敛的合成方法将五个小 一系列酯，酰胺和烯烃键形成事件中的片段 并将成为模块化构造的关键 探索基于结构功能关系的分子 在偶氮霉素骨架上。