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: 2181173
• 负责人: DANIEL F HARVEY
• 金额: $ 13.24万
• 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 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2181173
• 关键词: alkylating agents; antineoplastics; carbene; carbopolycyclic compound; chemical structure function; chemical synthesis; diacylglycerols; diterpenes; heavy metals; metal complex; phorbols; protein kinase C; receptor binding; tumor promoters

DESCRIPTION: The goal of this revised renewal project is to develop transition-metal carbene complex-based approaches to polycyclic systems. It is noted that this methodology will allow for the rapid construction of a variety of polycyclic frameworks, many of which are found in biologically active natural products and that many of the ring systems accessible with this methodology are not readily accessible with existing methodology. The principal investigator states that current efforts are focused on the further expansion of this methodology as well as on the application of these strategies to the synthesis of several medicinally relevant targets. He notes that of particular interest is the construction of the tricyclic ring skeleton of the tiglane and daphnane diterpenes and that members of these classes of compounds have been widely studied, primarily because of their ability to promote tumor formation. It is indicated that 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. It is noted that structure-activity studies of this type are currently not feasible due to the absence of general routes to the phorbol skeleton. The principal investigator states that in addition, an approach to the DNA alkylating subunit of CC-1065 and the duocarmycins will be developed. He indicates that 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.

描述：这个修订后的更新项目的目标是开发 基于过渡金属卡宾配合物的多环系统方法。 值得注意的是，这种方法将允许快速构建 多种多环骨架，其中许多存在于 具有生物活性的天然产物和许多环系统 使用此方法无法轻松访问 现有的方法论。 首席研究员表示，目前 工作重点还在于进一步扩展该方法 至于将这些策略应用于合成几种 医学相关目标。 他指出，特别令人感兴趣的是 tiglane的三环骨架的构建和 瑞香二萜和此类化合物的成员 被广泛研究，主要是因为它们能够促进肿瘤 形成。 表明佛波酯的类似物将是 构建并用于探测佛波醇结合的性质 蛋白激酶 C 的二酰甘油结合位点的酯，它们的 生物受体。 值得注意的是，该化合物的结构-活性研究 由于缺乏通用路线，目前这种类型不可行 佛波醇骨架。 首席研究员表示，在 此外，CC-1065 的 DNA 烷基化亚基的方法和 将开发duocarmycins。 他表示，这种做法是 预计将提供对各种衍生品的普遍访问 CC-1065 和双卡霉素将增强我们对 这些强大的抗肿瘤药物的作用机制。