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: 6271777
• 负责人: DANIEL F HARVEY
• 金额: $ 5.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6271777
• 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.

该项目的目标是开发过渡金属卡宾配合物- 基于多环系统的方法。该方法将允许 快速构建各种多环框架，其中许多 存在于具有生物活性的天然产物中。很多戒指 用这种方法访问的系统不容易用 现有的方法论。目前的工作重点是进一步扩大 以及这些策略的应用 几个医学相关靶标的制备。特别是 感兴趣的是三环骨架的构建 提利亚烷和瑞香二萜。这些化合物类别的成员 已被广泛研究，主要是因为它们能够促进 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的二酰甘油结合位点及其生物学特性 受体。目前还没有这种类型的结构/活性研究 由于缺乏通往佛波醇骨架的一般途径，因此可行。在 此外，CC-1065 的 DNA 烷基化亚基的方法和 将开发duocarmycins。这种方法预计将提供 一般可获取 CC-1065 和 duocarmycins 的多种衍生物 这将增强我们对这些作用机制的理解 强大的抗肿瘤剂。