ASYMMETRIC SYNTHESIS OF BIOACTIVE ALKALOIDS

生物活性生物碱的不对称合成

• 批准号: 3295499
• 负责人: PHILIP P GARNER
• 金额: $ 14.34万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 1995-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3295499
• 关键词: alkaloids; antineoplastic antibiotics; aziridines; azo compounds; chemical addition; chemical conjugate; chemical reaction; chemical structure function; chemical synthesis; crosslink; drug design /synthesis /production; imides; isoquinolines; molecular asymmetry; nucleic acid sequence; photochemistry; piperidine; thiols

This application outlines a program for the continued development of a unified synthetic approach to the quinocarcin and naphthyridinomycin families of DNA reactive isoquinoline alkaloids. These substances along with the recently isolated tetrazomine, hold promise as potential antineoplastic agents because of their ability to inhibit nucleic acid synthesis at the DNA template level. In this context, practical asymmetric routes to these substances and their congeners in enantiomerically pure form are required for further investigation and eventual exploitation of their interaction with native nucleic acid sequences. Specific aims for the next funding period include: 1. Exploration of the photochemistry of thioimide-conjugated aziridines and the cycloaddition behavior of the resultant unsymmetrical azomethine ylides. 2. The evaluation of intramolecular imide/thioimide olefination as a new general method for the asymmetric synthesis of 1-substituted dihydroisoquinolines. 3. Asymmetric synthesis and structure elucidation of tetrazomine, a new antitumor antibiotic which resembles quinocarcin in both its structure and antitumor activity. 4. Optimization of the intramolecular cycloaddition strategy (i.e. rational tether modification) in support of the proposed naphthyridinomycin synthetic studies. 5. Completion of an asymmetric synthesis of cyanocycline A and naphthyridinomycin based on this intramolecular 1,3-dipolar cycloaddition protocol. 6. The design (molecular modelling), asymmetric synthesis, and evaluation of a new class of C2-symmetric DNA cross-linking agents based on quinocarcin.

该应用程序概述了一个持续开发的计划 喹诺卡星和萘啶霉素的统一合成方法 DNA 反应性异喹啉生物碱家族。 These substances along 最近分离出的四唑明，有望发挥潜力 抗肿瘤剂，因为它们具有抑制核酸的能力 DNA模板水平的合成。 In this context, practical 这些物质及其同系物的不对称途径 需要对映体纯形式进行进一步研究和 最终利用它们与天然核酸的相互作用 序列。 下一个资助期的具体目标包括： 1. 硫代酰亚胺共轭氮丙啶的光化学探索 以及所得不对称偶氮甲碱的环加成行为 ylides. 2. 分子内酰亚胺/硫代酰亚胺烯化作为新能源的评价 1-取代的不对称合成的通用方法 dihydroisoquinolines. 3. 新型药物四唑明的不对称合成及结构解析 抗肿瘤抗生素，其结构与喹诺酮相似 and antitumor activity. 4. 分子内环加成策略的优化（即 合理的系链修饰）支持所提出的 naphthyridinomycin synthetic studies. 5.完成氰环素A和的不对称合成 基于分子内 1,3-偶极环加成的萘啶霉素 协议。 6. 设计（分子建模）、不对称合成和评价 基于C2对称DNA交联剂的新型一类 quinocarcin.