SYNTHESIS OF BRIDGED AND POLYCYCLIC ANTITUMOR AGENTS

桥联和多环抗肿瘤剂的合成

基本信息

批准号：
3165069
负责人：
ANDREW S KENDE
金额：
$ 20.11万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
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/3165069
关键词：
antineoplastics beta lactam antibiotic bridged cyclic compound colchicine diterpenes drug design /synthesis /production heterocyclic compounds heterocyclic polycyclic compound lactones methoxyindole paclitaxel podophyllin quinones stereochemistry

项目摘要

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复杂化合物的化学策略和策略天然产品。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二萜，紫杉素，并构建临床抗癌的密切类似物药物紫杉醇。我们概述了该药物的新合成 Fredericamycin A（目前由 NCI 开发）和抗有丝分裂剂秋水仙碱，两者均采用自由基偶联环化。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。我们描述了体内立体控制手性方法抗肿瘤大环抗生素兰卡西丁C 光学活性β-内酰胺的分子内重排中间的。热介导和 Pd (II) 介导的应用我们小组开发的环烯基化方法经过测试在萜烯毛酸、广藿烯酮的拟议合成中和沙那多。钩吻醛醛酮的一般合成特别是钩麻碱和钩麻碱，预计基于我们实验室的最新结果涉及立体控制 N-甲氧基缩醛衍生物的分子内环化羟吲哚。