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.

本申请概述了一项继续开发 喹诺卡星和萘甲霉素的统一合成方法 DNA活性异喹啉生物碱家族。这些物质沿着 有了最近分离的四唑胺，就有希望成为潜在的 抗肿瘤药物，因为它们有抑制核酸的能力 DNA模板水平上的合成。在这方面，切实可行 这些物质及其同系物的不对称路线 需要有对映体纯形式才能进行进一步的研究 最终利用它们与天然核酸的相互作用 序列。 下一个供资期间的具体目标包括： 1.硫代酰亚胺共轭氮杂环丙烷的光化学探索 以及生成的不对称甲亚胺的环加成行为 耶利德斯。 2.分子内酰亚胺/硫代酰亚胺烯化反应作为一种新型催化剂的评价 1-取代的不对称合成的一般方法 二氢异喹啉。 3.新化合物四氮唑胺的不对称合成及结构鉴定 一种在结构上与奎诺卡星相似的抗肿瘤抗生素 和抗肿瘤活性。 4.分子内环加成反应策略的优化(即 合理的系绳修改)，以支持拟议的 萘啶霉素的合成研究。 5.完成氰环素A和氰环素的不对称合成 基于这种分子内1，3-偶极环加成反应的萘霉素 协议。 6.设计(分子模拟)、不对称合成和评价 一类新的C2对称DNA交联剂的合成 奎诺卡星。