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: 2392077
• 负责人: DANIEL F HARVEY
• 金额: $ 14.33万
• 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 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2392077
• 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：经过修订的续订项目的目标是开发 基于多环体系的基于过渡金属碳复合物的方法。 注意，这种方法将允许快速构建 在各种多环形框架中，其中许多都在 生物活跃的天然产物和许多环系统 使用这种方法可访问 现有方法。 主要研究者指出目前 努力也集中在这种方法的进一步扩展上 就像将这些策略应用于合成几个 药物相关目标。 他指出，特别感兴趣的是 Tiglane和Tiglane的三环环骨架的构造 流浪汉二萜和这些化合物的成员具有 被广泛研究，主要是因为它们促进肿瘤的能力 形成。 表明佛波尔酯的类似物将是 构建并用于探测佛波的结合的性质 酯到蛋白激酶C的二酰基甘油结合位点，它们 生物受体。 值得注意的是，对此的结构活动研究 由于没有通用路线，目前不可行 佛波尔骨骼。 主要研究人员指出 另外，一种CC-1065和CC-1065的DNA烷基化亚基的方法 Duocarmycins将开发。 他指出这种方法是 预计将提供一般的访问 CC-1065和Duocarmycins将增强我们对 这些强大的抗肿瘤剂的作用机理。