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 制定一般策略和方法的合成方法 具有抗癌活性的天然产品。 在 这些研究，有必要发明新的合成方法和 探索现有的范围和局限性。 具体而言，是有前途的抗肿瘤ANSA的新颖而统一的条目 将开发MacRocyles MacBecin（NSC 330500）和草食霉素。 这 策略具有足够的灵活性，以允许从 相关大环乳糖的晚期常见中间体 Geldanamycin，它是DNA依赖性RNA聚合酶的抑制剂。 Macbecin表现出明显的抗肿瘤活性，但没有抗纯活动 活性，而金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 开发用于构建TrisubStated的新合成方法 烯烃。 实现立体选择添加的策略 将探索乳糖的有机金属试剂。 最后，新的 从中衍生出的Furans和Hydropyranones的应用 将开发无环阵列的不对称合成。 抗癌生物碱的两种不同的合成方法 已配制了氨基酸氨酸，含素和胰腺蛋白酶。 将利用异核Diels-Alder反应进行开发 轻松地进入了外星和光学上的氨基细胞质亚基 纯形。 器官化学和根治性环化方法论 然后将编组作为三环的关键步骤 环系统。 异性恋中不对称合成的一些新方面 Diels-Alder反应将被探讨 自由基环化和有机疗法化学。 选定的自然存在目标的合成方法是 设计为足够灵活和高效，以便类似 随时准备研究结构活动关系。 选定 化合物将提交给C.P. Eli Lilly Company Starks，Inc。， Upjohn Company，Abbott Laboratories和Dupont放映 生物活性和具有有希望的抗癌活性的化合物 将提交给国家癌症进一步生物学研究所 评估。