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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，我们制备了手性α-亚磺酰基酮亚胺。这些酮亚胺的阴离子进行原位 1,4-加成/环化与α-烯酯、1,3-二碘丙烷和3-氯-2-发生闭环反应氯甲基丙烯。我们建议研究不对称加成反应各种手性α-亚磺酰基酮亚胺的阴离子和取代的无环和环状α-烯酯，以及其他亲电子试剂，以及所得β-亚磺酰烯酰胺的立体选择性还原和烯胺。这些反应在不对称合成中的应用吲哚里西啶[例如，(+)-栗精胺和(-)-地黄明]，喹啉西啶[例如，(-)-羽扇豆碱]、吡咯西啶[例如，(+)-育亨宾] 和 18,19-二氢桑巴碱]和 β-咔啉生物碱 [例如，(-)- 依米丁]将进行研究。合成的天然产物，它们合成中间体和类似物将进行抗肿瘤活性测试在 Dolores Takemoto 博士的实验室中使用体外组织培养系统（共同研究员），以及 V.L. 博士的抗艾滋病活动。纳拉亚南的国家癌症研究所药物合成与化学分部实验室。所提出的合成方案是通用的，应该提供许多有用的生物活性合成中间体和类似物。细胞毒性体外对抗癌细胞（P388、P815 和 L1210 细胞）的活性，对正常细胞的毒性及其作用机制（体外；DNA，将研究这些化合物的 RNA 和蛋白质抑制作用。