SYNTHESIS AND STUDY OF TUMOR PROMOTERS AND INHIBITORS

肿瘤促进剂和抑制剂的合成与研究

• 批准号: 6240509
• 负责人: DANIEL F HARVEY
• 金额: $ 1.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240509
• 关键词: alkylating agents; analog; antineoplastic antibiotics; antineoplastics; biological products; carbene; chemical structure function; diacylglycerols; drug design /synthesis /production; heavy metals; heterocyclic polycyclic compound; infrared spectrometry; mass spectrometry; metal complex; method development; nuclear magnetic resonance spectroscopy; phorbols; protein kinase C; sphingosine; tumor promoters

The goal of this project is to develop transition metal carbene complex- based approaches to polycyclic systems. This methodology will allow for the rapid construction of a variety of polycyclic frameworks, many of which are found in biologically active natural products. Many of the ring systems accessible with this methodology are not readily accessible with existing methodology. Current efforts are focused on the further expansion of this methodology, as well as on the application of these strategies to the preparation of several medicinally relevant targets. Of particular interest is the construction of the 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 will be constructed and used to probe the nature of the binding of phorbol esters to the diacylglycerol binding site of protein kinase C, their biological receptor. Structure/activity studies of this type are currently not feasible due to the absence of general routes to the phorbol skeleton. In addition, an approach to the DNA alkylating subunit of CC-1065 and the duocarmycins will be developed. This approach is expected to provide general access to a variety of derivatives of CC-1065 and the duocarmycins that will enhance our understanding of the mechanism of action of these powerful antitumor agents.

该项目的目的是开发过渡金属碳复合物 - 基于多环系统的方法。这种方法将允许 快速构建各种多环形框架，许多 在生物活性天然产物中发现。许多戒指 使用此方法可访问的系统不容易访问 现有方法。当前的努力集中在进一步的扩展上 这种方法以及这些策略的应用 制备几个与药物相关的目标。特别 兴趣是建造三环环骨架 Tigliane和Daphnane Diterpenes。这些化合物的成员 已经广泛研究了，主要是因为它们的促进能力 肿瘤形成。将构建佛波酯的类似物，并 用于探测佛波酯与 蛋白激酶C的二酰基甘油结合位点，其生物学 受体。目前没有这种类型的结构/活动研究 由于缺乏通往佛波尔骨架的一般路线，因此可行。在 另外，一种CC-1065和CC-1065的DNA烷基化亚基的方法 Duocarmycins将开发。这种方法有望提供 一般访问CC-1065和Duocarmycins的各种衍生物 这将增强我们对这些行动机制的理解 强大的抗肿瘤代理。