STRATEGIES FOR THE SYNTHESIS OF ANTITUMOR COMPOUNDS

抗肿瘤化合物的合成策略

• 批准号: 6137432
• 负责人: JEFFREY D WINKLER
• 金额: $ 26.94万
• 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/6137432
• 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：（主要研究者）本提案针对 开发新的方法来构建自然发生的 具有重要生物活性的物质。 的主要目标之一 这项研究计划继续是光化学的发展， 有机合成方法学 乙烯基乙酰胺 光环化加成-逆Mannich断裂-Mannich闭合序列 导致了一种高效合成曼扎明的方法， 生物碱，具有重要的抗肿瘤特性。 的一个主要 拟议延长期的目标是完成以下综合工作： manzamine使用光化学方法在我们的实验室开发。 分子内二氧杂环己烯酮光环加成反应提供了独特的 方法为大会的巨大戟烷二萜，建立 关键的“内外”立体化学关系， 是生物活动所必需的。 这种方法已经成功地 应用于合成高纯度的第一种巨大戟烷类似物， 蛋白激酶C，一个重要的细胞信号系统的亲和配体。 考虑到蛋白激酶C激活剂诱导的生物反应， 这种酶的抑制剂的开发可能导致治疗剂 可用于治疗慢性炎性和增殖性疾病。 巨大戟醇的全合成及新类似物的合成与研究 是建议更新期的第二个主要目标。