SYNTHESIS AND STUDY OF TUMOR PROMOTERS & INHIBITORS

肿瘤促进剂的合成与研究

• 批准号: 2181171
• 负责人: DANIEL F HARVEY
• 金额: $ 10.53万
• 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 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2181171
• 关键词: antineoplastics; biological products; 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.

该项目的目标是开发一种基于费歇尔卡宾的方法 多环系统的合成。 如果成功的话，这种新方法 将允许快速构建几个复杂的生物 主动目标结构。 这项研究的初始阶段将涉及 原位生成的费歇尔乙烯基碳烯反应性的一般研究 复合物。 捕获这些反应性过渡金属配合物 取代的烯烃或其他不饱和部分应提供快速 访问各种新颖的环系统。 特别令人感兴趣的是 将该方法应用于构建基本三环 提利亚烷和瑞香二萜的环骨架。 这些成员 化合物类别已被广泛研究，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 的二酰甘油结合位点。结构/活性 由于缺乏相关资料，此类研究目前尚不可行 佛波醇骨架的一般路线。 此外，类似物 鞘氨醇，已被发现具有蛋白激酶 C 的功能 抑制剂，将被合成以确定其化学性质 与激活佛波酯的蛋白激酶 C 的关系。 我们希望 通过这些研究我们将能够开发出更好的 了解调节的生化控制机制 蛋白激酶C的活性