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.

阿齐霉素 A 和 B 是分离的强效抗肿瘤药物 来自链霉菌。 他们的生物活性在于他们的能力 共价烷基化并随后交联双链 DNA。 由于这些药物的 天然来源的可用性较差，并且由于其化学成分 不稳定。 该提案的目的是阐明分子 涉及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发挥活性 以及一系列结构和功能上合理设计的 相关代理。 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 阿齐霉素是有吸引力的研究目标。 主要理由 综合努力在于结构性和 功能相关的试剂用于阐明细节 这些试剂与 DNA 的共价相互作用。 开发方法论 在合成过程中将用于设计和合成 用于探索 DNA 交叉化学事件的试剂 链接。 聚合合成方法将五个小 一系列酯、酰胺和烯烃键形成事件中的片段 并将成为各种模块化建设的关键 分子，用于探索结构-功能关系 在阿奇霉素骨架上。