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.

该提议是针对开发新方法的 建造重要的物质 生物活性。 基于乙烯基酰胺的三个研究领域 本文概述了光化学：1）乙烯基的扩展 酰胺光细胞载体/恢复曼尼克碎片/环闭合 旁喹啉环系统合成的顺序； 2） 将三级乙烯基酰胺的光载载细胞应用于A 最近发现的曼氮胺抗肿瘤生物碱的结构； 3）对新型合成的范围和局限性的研究 基于乙烯基酰胺的光化学的杂环。 紫杉醇（NSC-125973）是一种异常有希望的癌症化学治疗 具有异常广泛的有效抗血性和 抑制肿瘤活性。 这是唯一已知促进的植物产品 微管的组装并抑制小管蛋白拆卸过程 因此，似乎是新类癌症的原型 化学治疗剂。 两种构建的方法 在此中描述了紫杉烷二萜的碳环环系统 建议：1）分子内二恶英的应用 光细胞载体与紫杉醇类似物的合成和自然合成 出租车发生； 2）发展高度收敛的方法 用于基于grob的紫杉烷二萜的合成 分子内酮 - 烯烃环载体的碎片。 本文概述的生物学合成的策略 活性天然产物在Diels-Alder反应中具有对应物， 阳离子多烯环化和芳烃环加成反应。 多个碳碳键和相当大的立体化学 信息是在单个合成操作中生成的。 方法 用于建造甘氮胺生物碱和紫杉烷二萜 在本提案中概述了这一点的巨大潜力 合成具有药物重要物质的方法。