SULFINYL KETIMINES

磺酰酮亚胺

基本信息

批准号：
3196467
负责人：
DUY H HUA
金额：
$ 9.47万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-05-01 至 1994-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3196467
关键词：
DNA RNA antiAIDS agent antineoplastics biological products castanospermine drug design /synthesis /production drug metabolism drug screening /evaluation neoplasm /cancer pharmacology neoplastic cell propane pyridoindole quinolizine stereoisomer tissue /cell culture yohimbine

项目摘要

In the course of studies involving the enantioselective synthesis of biologically active alkaloids, we have prepared chiral alpha-sulfinyl ketimines. The anions of these ketimines undergo in situ 1,4-addition/ring closure reactions with alpha-ene esters, 1,3-diiodopropane, and 3-chloro-2- chloromethylpropene. We propose to study the asymmetric addition reactions of the anions of various chiral alpha-sulfinyl ketimines and substituted acyclic and cyclic alpha-ene esters, and other electrophiles, and the stereoselective reduction of the resulted beta-sulfinyl enamides and enamines. The utilization of these reactions in the asymmetric syntheses of indolizidines [e.g., (+)-castanospermine and (-)-slaframine], quinolizidines [e.g., (-)-lupinine], pyrrolizidines [e.g., (+)-yohimbine and 18,19-dihydrousambarine], and beta-carboline alkaloids [e.g., (-)- emetine] will be studies. The synthesized natural products, their synthetic intermediates, and analogs will be tested for antitumor activity using in vitro tissue culture systems in Dr. Dolores Takemoto's laboratory (co-investigator), and anti-AIDS activities in Dr. V.L. Narayanan's laboratory, Drug Synthesis & Chemistry Branch, National Cancer Institute. The proposed synthetic schemes are general and should provide many useful biologically active synthetic intermediates and analogues. The cytotoxic activity in vitro against cancer cells (P388, P815, and L1210 cells), the toxicity towards normal cells, and the mechanism of actions (in vitro; DNA, RNA, and protein inhibitions) of these compounds will be studied.

在涉及对映选择性合成的研究过程中生物活性生物碱，我们已经制备了手性α-磺胺基酮。这些酮的阴离子会在原位1,4添加/环发生与α-烯酯，1,3-二二丙烷和3-氯-2-的闭合反应氯甲基丙烯。我们建议研究不对称的添加反应各种手性α-磺胺基酮的阴离子和取代无环和环状α-烯酯以及其他电力酯，以及立体选择性降低所得的β-硫烯基烯敏和搪瓷。这些反应在不对称合成中的利用吲哚衍定[例如（+） - castanospermine和（ - ） - slaframine]，喹啉苷[例如，（ - ） - 卢彭氨酸]，吡咯烷类[例如，（+） - Yohimimbine 和18,19-二氢糖[]和β-碳酸酯生物碱[e.g，（ - ） - Emetine]将是研究。合成的天然产品，它们合成中间体和类似物将测试抗肿瘤活性在Takemoto博士的实验室中使用体外组织培养系统（共同投资者）和V.L.博士的反辅助活动纳拉亚南的国家癌症研究所的药物合成与化学分支实验室。提出的合成方案是一般的，应该提供许多有用的生物活性合成中间体和类似物。细胞毒性在体外对癌细胞（p388，p815和L1210细胞）的体外活性，对正常细胞的毒性以及作用机理（体外； DNA，将研究这些化合物的RNA和蛋白质抑制）。