SYNTHESIS AND STUDY OF TUMOR PROMOTERS & INHIBITORS

肿瘤促进剂的合成与研究

• 批准号: 3467627
• 负责人: DANIEL F HARVEY
• 金额: $ 8.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3467627
• 关键词: antineoplastics; carbene; chemical carcinogen; chemical structure function; cycloalkene; diacylglycerols; diterpenes; drug design /synthesis /production; enzyme induction /repression; heterocyclic polycyclic compound; phorbols; protein kinase; saturated /unsaturated bonds; sphingosine

The goal of this project is to develop a Fischer carbene based approach to the synthesis of polycyclic systems. If successful, this new methodology will allow for the rapid construction of several complex biologically active target structures. The initial phase of this research will involve a general study of the reactivity of in situ generated Fischer vinylcarbene complexes. Trapping of these reactive transition-metal complexes with substituted olefins or other unsaturated moieties should provide rapid access to a variety of novel ring systems. Of particular interest is the application of this methodology to the construction of the basic tricyclic ring skeleton of the tigliane and daphnane diterpenes. Members of these classes of compounds have been widely studied, primarily because of their ability to promote tumor formation. Analogs of the phorbol esters to the diacylglycerol binding site of protein kinase C. Structure/activity studies of this type are currently not feasible due to the absence of general routes to the phorbol skeleton. In addition, analogs of sphingosine, which has been found to function as a protein kinase C inhibitor, will be synthesized to determine the chemical nature of its relationship to the protein kinase C activating phorbol esters. We hope that through these studies we will be able to develop a better understanding of the biochemical control mechanisms that regulate the activity of protein kinase C.

该项目的目的是开发一种基于Fischer Carbene的方法 多环系统的合成。 如果成功，这种新方法 将允许在生物学上快速构建几个复合物 主动目标结构。 这项研究的初始阶段将涉及 一般研究原位产生的Fischer乙烯基碳酸盐的反应性 复合物。 这些反应性过渡金属复合物与 取代的烯烃或其他不饱和部分应提供快速 访问各种新型环系统。 特别感兴趣的是 将此方法应用于基本三环 Tigliane和daphnane diterpenes的环骨架。 其中的成员 广泛研究了一类化合物，主要是因为它们 促进肿瘤形成的能力。 佛波酯的类似物 蛋白激酶C的二酰基甘油结合位点C结构/活性 由于没有 通往佛波尔骨骼的一般路线。 另外，类似 鞘氨醇，已被发现充当蛋白激酶C 抑制剂将合成以确定其化学性质 与蛋白激酶C激活佛波酯的关系。 我们希望 通过这些研究，我们将能够更好地发展 了解调节的生化控制机制 蛋白激酶C的活性。