STRATEGIES FOR THE SYNTHESIS OF ANTITUMOR COMPOUNDS

描述：(首席调查员)这项建议是针对 开发新的方法建设自然发生的 具有重要生物活性的物质。的主要目标之一 这项研究计划将继续发展光化学 有机合成方法论。乙二醇胺 光环加成-逆Mannich裂解-Mannich闭合序列 导致了一种高效地合成甘露糖胺的方法 生物碱，具有重要的抗肿瘤作用。其中一个主要的 拟议续期的目标是完成综合 使用我们实验室开发的光化学方法学。 分子内二恶酮光环加成反应提供了一种独特的 异庚烷二萜的组装方法，建立了 关键的“内-外”立体化学关系 是生物活动所必需的。这种方法论已经成功地应用于 应用于合成第一个高纯度的金刚烷类似物 蛋白激酶C的亲和配体，一个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， 这种酶的抑制剂的开发可能导致治疗药物的出现。 用于治疗慢性炎症性和增生性疾病。 吲哚酚的全合成及新型类似物的合成与研究 是拟议续期的第二个主要目标。

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.