MITOMYCIN SYNTHESIS AND NITRONE-BASED METHODOLOGY

丝裂霉素的合成和硝基方法

• 批准号: 3165300
• 负责人: ROBERT M. COATES
• 金额: $ 7.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-04-01 至 1986-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165300
• 关键词: N hydroxylation; chemical structure function; cyclic amine; drug design /synthesis /production; hydroxamate; hydroxylamine; mitomycins; nitrone

The utility of mitomycin C in cancer chemotherapy has been limited by its toxic side effects. An objective of this project is to develop chemical methods to synthesize new mitomycin analogues for evaluation as antitumor agents. Target compounds include C-homo mitosenes, 1,2-aziridino mitosenes, and pyrroloindolines bearing the characteristic 9a-oxy group of the mitomycins with or without additional substitution at positions 1,2,9 and 10. Another aspect of this research is the development of new synthetic methodology based on nitrones or their tautomers, N-vinylhydroxylamines. Procedures for intramolecular alpha-functionalization via [3,3]- and [2,3] sigmatropic rearrangements of N-vinylhydroxylamine derivatives are to be explored. Nitrones of esters (alpha-oxy-nitrones and alpha-thionitrones) are to be prepared and their alpha-functionalizing rearrangements and cycloaddition reactions will be studied. The use of N-chiral nitrones for asymmetric alpha-functionalization and for the preparation of chiral amines by stereo-selective addition of carbon nucleophiles is proposed.

丝裂霉素 C 在癌症化疗中的应用因其自身的作用而受到限制。 毒副作用。 该项目的目标是开发化学 合成新丝裂霉素类似物用于抗肿瘤评价的方法 代理。 目标化合物包括 C-同型核糖体、1,2-氮丙啶基 mitosenes 和带有特征 9a-氧基的吡咯并吲哚啉 在位置 1、2、9 有或没有额外取代的丝裂霉素 10. 这项研究的另一个方面是开发新的 基于硝酮或其互变异构体的合成方法， N-乙烯基羟胺。 分子内的程序 通过 [3,3]- 和 [2,3] σ 重排进行 α 功能化 N-乙烯基羟胺衍生物有待探索。 酯的硝基 （α-氧硝酮和α-硫硝酮）的制备及其 α-功能化重排和环加成反应将 研究过。 N-手性硝酮在不对称反应中的应用 α-官能化和用于制备手性胺 提出了碳亲核试剂的立体选择性加成。