STRATEGIES FOR THE SYNTHESIS OF ANTI-TUMOR COMPOUNDS

抗肿瘤化合物的合成策略

• 批准号: 3179953
• 负责人: JEFFREY D WINKLER
• 金额: $ 29.37万
• 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/3179953
• 关键词: alkaloids; antineoplastics; biological products; 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.

该提案旨在开发新方法 构建具有重要意义的天然物质 生物活性。 基于插烯酰胺的三个研究领域 本文概述了光化学：1）插烯的延伸 酰胺光环加成/逆曼尼希碎裂/闭环 全氢喹啉环系的合成顺序； 2） 插烯叔酰胺光环加成反应在光环加成反应中的应用 最近发现的曼扎明抗肿瘤生物碱的构建； 3）研究新型合成的范围和局限性 基于插烯酰胺光化学的杂环。 紫杉醇 (NSC-125973) 是一种非常有前途的癌症化疗药物 具有异常广谱的有效抗白血病药物 肿瘤抑制活性。 它是唯一已知可促进 微管组装并抑制微管蛋白分解过程 因此，它似乎是一类新癌症的原型 化疗剂。 构建的两种方法 紫杉烷二萜的碳环系统描述于 提案：1）分子内二恶烯酮的应用 光环加成法合成紫杉醇类似物和天然产物 发生紫杉素； 2）开发高度收敛的方法 用于基于 Grob-like 的紫杉烷二萜的合成 分子内乙烯酮-烯烃环加合物的断裂。 本文概述的生物合成策略 活性天然产物在第尔斯-阿尔德反应中具有对应物， 阳离子多烯环化、芳烃-烯烃环加成反应。 多个碳碳键和相当多的立体化学 信息是在单个合成操作中生成的。 方法 用于构建曼扎明生物碱和紫杉烷二萜 该提案中概述的内容证明了该方案的巨大潜力 重要药用物质的合成方法。