SYNTHESIS OF BRIDGED AND POLYCYCLIC ANTITUMOR AGENTS

桥联和多环抗肿瘤剂的合成

• 批准号: 3165061
• 负责人: ANDREW S KENDE
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-06-30 至 1992-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165061
• 关键词: antineoplastics; beta lactam antibiotic; bridged cyclic compound; colchicine; diterpenes; drug design /synthesis /production; heterocyclic compounds; heterocyclic polycyclic compound; lactones; methoxyindole; podophyllin; quinones; stereochemistry

The long-term objectives of our research are to discover new chemical strategies and tactics for the synthesis of complex natural products. Our focus is on the synthesis of structures known or likely to have in vivo anticancer activity. We propose to carry out the first total synthesis of a natural taxane diterpene, taxusin, and to construct close analogs of the clinical anticancer drug taxol. We outline a novel synthesis of the drug Fredericamycin A (currently under development by NCI) and of the antimitotic agent colchicine, both employing radical coupling cyclizations. Also proposed are chiral syntheses of the new antitumor antibiotics oxazolomycin and neooxazolomycin. We described a stereocontrolled chiral approach to the in vivo antitumor macrocyclic antibiotic Lankacidin C based on the intramolecular rearrangement of an optically active Beta-lactam intermediate. Applications of the thermal and Pd (II)-mediated cycloalkenylation methodologies developed in our group are tested in proposed syntheses of the terpenes hirsutic acid, patchoulenone and sanadaol. General syntheses of Gelsemium aldaloids, in particular gelsedine and gelsemine, are anticipated based on recent results from our laboratories involving the stereocontrolled intramolecular cyclizations of acetal derivatives of N-methoxy oxindoles.

我们研究的长期目标是发现新的 合成配合物的化学策略 天然产品。 我们的重点是结构的合成 已知或可能具有体内抗癌活性。 我们建议 首次全合成天然紫杉烷类二萜， 紫杉醇，并构建临床抗癌药物紫杉醇的类似物， 药物紫杉醇。 我们概述了一种新的合成药物 Fredericamycin A（目前正在由NCI开发）和 抗有丝分裂剂秋水仙碱，两者都采用自由基偶联 循环 还提出了新的手性合成 抗肿瘤抗生素恶唑霉素和新恶唑霉素。 我们 描述了一种立体控制的手性方法， 抗肿瘤大环抗生素Lankacidin C， 光学活性β-内酰胺分子内重排 中间体 热和Pd（II）介导的 环烯基化方法在我们的小组开发的测试 在萜类化合物多毛酸、广藿香酮的建议合成中， 和Sanadaol。 钩吻生物碱的一般合成 特别是钩吻素和钩吻素， 我们的实验室最近的结果涉及立体控制 N-甲氧基缩醛衍生物的分子内环化反应 羟吲哚。