STRATEGIES FOR THE SYNTHESIS OF ANTICANCER AGENTS

抗癌剂的合成策略

• 批准号: 3195600
• 负责人: STEPHEN MARTIN
• 金额: $ 9.48万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3195600
• 关键词: DNA directed RNA polymerase; Diels Alder reaction; alkaloids; antineoplastics; chemical structure function; drug design /synthesis /production; drug screening /evaluation; furans; lactams; organometallic compounds; pyrans; reverse transcriptase inhibitors

The principal objective of the program of research outlined herein is the development of general strategies and methods for the syntheses of selected natural products possessing anticancer activity. During the course of these studies, it will be necessary to invent new synthetic methods and to explore the scope and limitations of existing ones. Specifically, a novel and unified entry to the promising antitumor ansa macrocyles macbecin (NSC 330500) and herbimycin will be developed. The strategy is endowed with sufficient flexibility to allow preparation from advanced, common intermediates of the related macrocyclic lactam geldanamycin, which is an inhibitor of DNA-dependent-RNA polymerase. Macbecin exhibits significant antitumor activity but not antitublinic activity, and geldanamycin is an inhibitor of a reverse transcriptase. One of the methodological challenges of these endeavors will be the design and development of new synthetic methods for the construction of trisubstituted olefins. Tactics for achieving the stereoselective addition of organometallic reagents to lactols will be explored. Finally, new applications of the use of furans and hydropyranones derived therefrom in asymmetric synthesis of acyclic arrays will be developed. Two different synthetic approaches to the anticancer alkaloids lycoricidine, narciclasine, and pancratistatin have been formulated. Hetero Diels-Alder reactions will be exploited for the development of a facile entry to the aminocyclitol subunit in both racemic and optically pure form. Organocuprate chemistry and radical cyclization methodology will then be marshalled as key steps for the construction of the tricyclic ring system. Some new aspects of asymmetric synthesis in hetero Diels-Alder reactions will be explored as will some interesting facets of radical cyclization and organocuprate chemistry. The synthetic approaches to the selected naturally-occurring targets are designed to be sufficiently flexible and efficient so that analogues may be readily prepared for study of structure-activity relationships. Selected compounds will be submitted to C.P. Starks, Inc., the Eli Lilly Company, the Upjohn Company, Abbott Laboratories, and DuPont for screening for biological activity, and compounds having promising anticancer activity will be submitted to the National Cancer Institute for further biological evaluation.

本文概述的研究计划的主要目标是 开发合成选定物质的一般策略和方法 具有抗癌活性的天然产物。 期间 这些研究，有必要发明新的合成方法并 探索现有的范围和局限性。 具体来说，有前途的抗肿瘤 ansa 的新颖且统一的条目 将开发大环麦克贝星（NSC 330500）和除草霉素。 这 战略具有足够的灵活性，可以从 相关大环内酰胺的高级、通用中间体 格尔德霉素是一种 DNA 依赖性 RNA 聚合酶抑制剂。 Macbecin 具有显着的抗肿瘤活性，但不具有抗微管蛋白活性 活性，格尔德霉素是逆转录酶的抑制剂。 一 这些努力的方法论挑战将是设计和 开发构建三取代的新合成方法 烯烃。 实现立体选择性加成的策略 将探索用于乳醇的有机金属试剂。 最后，新 呋喃和由其衍生的氢吡喃酮在医药中的用途 将开发非循环阵列的不对称合成。 抗癌生物碱的两种不同合成方法 已配制出石蒜苷、水仙环素和pancratistatin。 杂狄尔斯-阿尔德反应将被用于开发 轻松进入外消旋和光学形式的氨基环醇亚基 纯粹的形式。 有机铜化学和自由基环化方法 然后将作为建设三环的关键步骤 环系统。 异质不对称合成的一些新方面 将探讨狄尔斯-阿尔德反应以及一些有趣的方面 自由基环化和有机铜酸盐化学。 所选天然目标的合成方法是 设计得足够灵活和高效，以便类似物可以 为研究结构-活性关系做好准备。 已选择 化合物将提交给 C.P.斯塔克斯公司、礼来公司、 Upjohn 公司、雅培实验室和杜邦公司进行筛选 生物活性和具有潜在抗癌活性的化合物 将提交给国家癌症研究所进行进一步的生物学研究 评估。