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）：硫霉素A和B是从链霉菌分离的有效且有效的抗肿瘤剂。它们的生物学活性属于它们共价烷基化和随后交联双链DNA的能力。 由于自然来源的可用性和化学不稳定性，因此没有关于自然药物的发展工作。该提案的目的是通过全天然产物的总合成以及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，独特的分子作用机理和有效的抗肿瘤活性使硫霉素具有吸引力的研究目标。合成工作的主要基本原理在于结构和功能相关的药物用于阐明这些药物与DNA共价相互作用的细节。在合成工作过程中开发的方法将用于设计和合成探索DNA交联的化学事件的药物。一种收敛的合成方法将一系列酯，酰胺和烯烃键形成事件中的五个小片段汇集在一起​​，并且将是多种分子模块化结构的关键，这些分子可以探索基于硫代霉素骨架的结构 - 功能关系。