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.

本申请概述了一个持续发展的计划， 奎奴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。 这些物质沿着 与最近分离的四唑明，举行的承诺，作为潜在的 因为它们能够抑制核酸， 在DNA模板水平上合成。 在这方面，务实 这些物质及其同系物的不对称途径， 对映体纯形式需要进一步研究， 最终利用它们与天然核酸的相互作用 序列的 下一个供资期的具体目标包括： 1. 硫代酰亚胺共轭氮杂环丙烷的光化学研究 以及不对称甲亚胺的环加成行为 叶立德 2. 分子内酰亚胺/硫代酰亚胺烯化反应作为一种新的 不对称合成1-取代 二氢异喹啉。 3. 新化合物四唑明的不对称合成及结构鉴定 一种抗肿瘤抗生素，其结构与奎诺卡辛相似 和抗肿瘤活性。 4. 分子内环加成策略的优化（即， 合理的系绳修改），以支持拟议的 萘啶霉素的合成研究。 5. 完成了氰环素A的不对称合成， 基于这种分子内1，3-偶极环加成的萘啶霉素 议定书 6.设计（分子建模），不对称合成和评估 一类新的C2-对称DNA交联剂， 奎奴卡辛