ASYMMETRIC SYNTHESIS OF BIOACTIVE ALKALOIDS

生物活性生物碱的不对称合成

• 批准号: 2179549
• 负责人: PHILIP P GARNER
• 金额: $ 13.71万
• 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/2179549
• 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程序 奎诺卡蛋白和萘霉素的统一合成方法 DNA反应性异喹啉生物碱的家族。 这些物质一直存在 使用最近隔离的四氮嗪，保持承诺为潜力 抗塑剂，因为它们具有抑制核酸的能力 DNA模板级别的合成。 在这种情况下，实用 这些物质及其同类物的不对称路线 进一步调查需要对映异构体形式和 最终剥削其与天然核酸的相互作用 序列。 下一个资金期的具体目标包括： 1。探索硫酰亚胺 - 偶联的阿佐赖丁的光化学 以及最终的不对称偶氮胺的环载行为 ylides。 2。分子内酰亚胺/硫酰亚胺烯烃作为新的评估 一般方法，是1-取代的不对称合成的 二氢异喹啉。 3。非对称合成和结构阐明四阿唑胺，一种新的 抗肿瘤抗生素类似于喹啉素的结构 和抗肿瘤活性。 4。优化分子内环加成策略（即 理性的束缚修改）支持所提出的 萘霉素合成研究。 5。完成氰环素A的不对称合成和 基于这种分子内的1,3-二极化环载菌素的萘霉素 协议。 6。设计（分子建模），不对称合成和评估 基于一类新的C2对称DNA交联剂 奎诺卡辛。