STRATEGIES FOR THE SYNTHESIS OF ANTITUMOR COMPOUNDS

抗肿瘤化合物的合成策略

• 批准号: 2090166
• 负责人: JEFFREY D WINKLER
• 金额: $ 30.33万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2090166
• 关键词: alkaloids; antineoplastics; biological products; chemical addition; drug design /synthesis /production; heterocyclic compounds; paclitaxel; photochemistry; quinoline

This proposal is directed towards the development of new approaches to the construction of naturally occurring substances with important biological activity. Three areas of research based on vinylogous amide photochemistry are outlined herein: 1) the extension of the vinylogous amide photocycloaddition/retro-Mannich fragmentation/ring closure sequence to the synthesis of perhydroquinoline ring systems; 2) the application of the photocycloaddition of tertiary vinylogous amides to a construction of the recently discovered manzamine antitumor alkaloids; and 3) a study of the scope and limitations of a novel synthesis of heterocycles based on the photochemistry of vinylogous amides. Taxol (NSC-125973) is an exceptionally promising cancer chemotherapeutic agent with an unusually broad spectrum of potent antileukemic and tumor-inhibiting activity. It is the only plant product known to promote the assembly of microtubules and inhibit the tubulin disassembly process and, thus, appears to be the prototype of a new class of cancer chemotherapeutic agents. Two approaches for the construction of the carbocyclic ring system of the taxane diterpenes are described in this proposal: 1) the application of the intramolecular dioxenone photocycloaddition to the synthesis of taxol analogs and the naturally occurring taxusin; and 2) the development of a highly convergent approach for the synthesis of the taxane diterpenes based on a Grob-like fragmentation of an intramolecular ketene-olefin cycloadduct. The strategies that are outlined herein for the synthesis of biologically active natural products have counterparts in the Diels-Alder reaction, cationic polyene cyclization, and arene-olefin cycloaddition reaction. More than one carbon-carbon bond and considerable stereochemical information is generated in a single synthetic operation. The approaches for the construction of the manzamine alkaloids and the taxane diterpenes outlined in this proposal attest to the considerable potential of this methodology for the synthesis of medicinally important substances.

这项建议旨在开发新的方法，以 构建具有重要意义的自然生成物质 生物活性。基于乙烯基酰胺的三个研究领域 这里概述了光化学：1)葡萄属植物的延伸 酰胺光环加成/逆Mannich裂解/环关闭 全氢喹啉环系的合成序列；2) 叔乙烯基酰胺类化合物的光环加成反应 新近发现的甘露糖胺抗肿瘤生物碱的构建； 以及3)一种新的合成方法的范围和局限性的研究 基于乙烯基酰胺类化合物光化学的杂环化合物。 紫杉醇(Nsc-125973)是一种非常有前途的癌症化疗药物 一种具有异常广谱的有效抗白血病和 抑瘤活性。它是目前已知的唯一一种能促进 微管的组装和抑制微管蛋白的拆解过程 因此，它似乎是一种新的癌症的原型 化疗药物。建设社会主义和谐社会的两种途径 本文描述了紫杉烷二萜的碳环环系统。 建议：1)分子内二恶酮的应用 紫杉醇类似物和天然产物的光环加成反应 发生紫杉醇；以及2)开发高度收敛的方法 基于Grob-like的紫杉烷二萜化合物的合成 分子内烯酮-烯烃环加成物的裂解。 这里概述的用于生物合成的策略 活性天然产物在Diels-Alder反应中具有对应物， 阳离子多烯环合反应和芳烃-烯烃环加成反应。 不止一个碳-碳键和相当多的立体化学物质 信息在一次合成操作中产生。这些方法 用于构建甘露糖胺生物碱和紫杉烷二萜 这项提案中概述的内容证明了这一点的巨大潜力 药用重要物质的合成方法学。