STRATEGIES FOR THE SYNTHESIS OF ANTITUMOR COMPOUNDS

抗肿瘤化合物的合成策略

• 批准号: 2467941
• 负责人: JEFFREY D WINKLER
• 金额: $ 28.37万
• 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 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2467941
• 关键词: alkaloids; antineoplastics; chemical addition; drug design /synthesis /production; heterocyclic compounds; paclitaxel; photochemistry; quinoline

DESCRIPTION: (Principal Investigator's) This proposal is directed towards the development of new approaches to the construction of naturally occurring substances with important biological activity. One of the major goals of this research program continues to be the development of photochemical methodology in organic synthesis. The vinylogous amide photocycloaddition-retro-Mannich fragmentation-Mannich closure sequence leads to a highly efficient approach to the synthesis of the manzamine alkaloids, which have important antitumor properties. One of the major goals of the proposed renewal period is to complete the synthesis of manzamine using the photochemical methodology developed in our laboratory. The intramolecular dioxenone photocycloaddition reaction provides a unique approach for the assembly of the ingenane diterpenes, with the establishment of the critical "inside-outside" stereochemical relationship that is necessary for biological activity. This methodology has been successfully applied to the synthesis of the first ingenane analogs that are high affinity ligands for protein kinase C, an important cell signalling system. Given the biological responses induced by activators of protein kinase C, the development of inhibitors of this enzyme may lead to therapeutic agents useful in the treatment of chronic inflammatory and proliferative diseases. The total synthesis of ingenol and the synthesis and study of novel analogs is the second major goal for the proposed renewal period.

描述：（首席研究员）该提案针对 开发构建自然发生的新方法 具有重要生物活性的物质。 的主要目标之一 该研究计划继续发展光化学 有机合成方法论。 插烯酰胺 光环加成-逆转录-曼尼希碎裂-曼尼希闭合序列 导致一种高效合成曼扎胺的方法 生物碱，具有重要的抗肿瘤特性。 主要之一 拟议更新期的目标是完成综合 曼扎明使用我们实验室开发的光化学方法。 分子内二恶烯酮光环加成反应提供了独特的 组装 ingenane 二萜的方法，并建立 关键的“内-外”立体化学关系 生物活性所必需的。 该方法已成功 应用于合成第一个高含量的马六烷类似物 蛋白激酶 C 的亲和配体，一种重要的细胞信号系统。 鉴于蛋白激酶 C 激活剂诱导的生物反应， 这种酶抑制剂的开发可能会导致治疗药物的出现 可用于治疗慢性炎症和增殖性疾病。 巨大戟二萜醇的全合成及新型类似物的合成与研究 是拟议续展期间的第二个主要目标。