Azinomycins - Total Synthesis and Mechanism of Action

阿嗪霉素 - 全合成和作用机制

• 批准号: 6693794
• 负责人: ROBERT S COLEMAN
• 金额: $ 27.73万
• 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 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693794
• 关键词: Streptomyces; alkylation; antineoplastic antibiotics; aziridines; binding sites; cell line; chemical models; chemical structure; chemical synthesis; computer simulation; crosslink; cytotoxicity; drug discovery /isolation; epoxides; high performance liquid chromatography; molecular dynamics; nuclear magnetic resonance spectroscopy; nucleic acid sequence

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.

描述（由申请人提供）：阿齐霉素 A 和 B 是从链霉菌中分离出来的强效且有效的抗肿瘤剂。它们的生物活性在于共价烷基化并随后交联双链 DNA 的能力。 由于天然来源的可用性较差且化学不稳定，因此尚未对天然药物进行开发工作。该提案的目的是通过天然产物的全合成和合理设计的一系列结构和功能相关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。 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阿齐霉素成为有吸引力的研究目标。合成工作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键、酰胺键和烯烃键形成事件中的五个小片段聚集在一起，这将是多种分子模块化构建的关键，可用于探索基于阿齐霉素骨架的结构-功能关系。