NEW SYNTHETIC REACTIONS FOR ACTIVE PRINCIPLES

活性原理的新合成反应

• 批准号: 3338300
• 负责人: SAMUEL J DANISHEFSKY
• 金额: $ 24.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-01-01 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3338300
• 关键词: antihypercholesterolemic agent; antihypertensive agents; castanospermine; chemical group; chemical structure function; chemical substitution; drug design /synthesis /production; mass spectrometry; molecular rearrangement; neuropharmacologic agent; nuclear magnetic resonance spectroscopy; quinoline; stereochemistry; sugar alcohols

In this program we propose to investigate the synthesis and chemistry of a series of natural products of biological interest. It is expected that from this work will emerge new reactions of value to chemical synthesis, new modes of strategic analysis of synthetic problems, and new access to compounds worthy of evaluation in several biological settings. The natural products which form the goal structures around which the program is organized are: (i) compactin-mevinolin and a Fusarium derived metabolite, (ii) heptelidic acid, (iii) rishirilide. (iv) aflavinine, (v) erythrina alkaloids, (vi) zincophorin, (vii) A-58365A, (viii) castanospermine, (ix) apramycin, and (x) amauromine. The general chemical issues which will be of significant concern with respect to these targets are: (a) the lactonic enolate version of the Claisen rearrangement, (b) free radical cyclization reactions of nitrogen containing compounds, (c) the 2+2+2 cyclization reaction, (d) the aldimine- diene cyclocondensation reaction, and (e) radical substitution reactions of aryl and allylic silanes and stannanes. Among the sorts of biological activities manifested by the goal systems are: inhibition of cholesterol biosynthesis, hypotensive responses, inhibition of glyceraldehyde-3-phosphate dehydrogenase, inhibition of plasmin inhibitors, trimming enzyme inactivators, ACE inhibitors, and inhibition of phytohemeagglutinin response.

在这个程序中，我们建议调查的合成和 一系列具有生物学意义的天然产物的化学。 预计这项工作将产生新的反应， 化学合成的价值，战略分析的新模式， 合成问题，以及获得值得 在几个生物环境中进行评估。 形成目标结构的天然产物， 该计划是有组织的是：（一）compactin-mevinolin和一个 镰刀菌衍生的代谢物，（ii）庚内酯酸，（iii） 利舍瑞林。 (iv)黄曲霉素，（v）刺桐生物碱，（vi） （vii）A-58365 A，（viii）栗精胺，（ix） 安普霉素，和（x）苦黑素。 一般的化学问题， 在实现这些目标方面将引起重大关切的是： (a)克莱森重排的内酯烯醇化物形式，（B） 含氮自由基环化反应 化合物，（c）2+2+2环化反应，（d）醛亚胺- 二烯环缩合反应，和（e）自由基取代 芳基和烯丙基硅烷与锡烷的反应。 中 目标系统所表现的生物活动有： 胆固醇生物合成的抑制，水肿反应， 甘油醛-3-磷酸脱氢酶抑制，抑制 纤溶酶抑制剂、修整酶灭活剂、ACE 抑制剂，以及响应中的植物血红素的抑制。