SYNTHETIC STUDIES ON TUMOR PROMOTERS AND INHIBITORS

本提案阐述了继续开展全面的 涉及合成、作用机理/模式的研究计划， 生物学和计算机建模研究，旨在了解 肿瘤促进的分子基础（人类健康问题）， 蛋白激酶C的调节和生物化学（新的靶点） 药物开发），癌症化疗药物的合理设计 基于蛋白激酶C，以及更一般地， 癌症和医学研究。 五个项目建议 调查 一项主要的继续研究将针对 合成佛波醇和巨大戟醇类似物， 启动子已知，并在调查的结构基础， 它们的肿瘤促进活性。 第二个主要项目是针对 树脂毒素合成和生化作用方式， 已知的最有效的刺激物，一个令人兴奋的研究探针， 神经元受体，并为开发新的药物， 缓解神经痛。 第三项主要研究涉及努力， 在calphostin的合成和生物化学作用模式，一种新的， 光激活佛波醇酯拮抗剂和潜在的铅 开发抗艾滋病新药。 第四个主要项目是 环二酰基甘油（cDAGs），一种新的强效PKC家族， 活化剂，对新的代谢稳定的cDAG类似物的合成， 以及对这些和其他细胞中脂质结构的研究 在脂质双层起作用的分子影响亲和力， PKC同工酶识别的选择性。 最后一个主要项目旨在 定义PKC调节域的三级结构， 使用光亲和标记、合成、计算机建模和NMR 问题研究 总的来说，这项研究计划预计将具有重要意义。 在化学、生物学和医学上的价值。

This proposal describes plans for the continuation of a comprehensive research program involving synthesis, mechanistic/mode of action, biological, and computer modeling studies directed at understanding the molecular basis of tumor promotion (a human health problem), the regulation and biochemistry of protein kinase C (a novel target for new drug development), the rational design of cancer chemotherapeutic agents based on protein kinase C, and more generally of molecules of interest in cancer and medicinal research. Five projects are proposed for investigation. A major continuation study will be directed at the synthesis of phorbol and ingenol analogues, the most potent tumor promoters known, and at an investigation of the structural basis for their tumor promoting activity. A second major project is directed at the synthesis and biochemical mode of action of resiniferatoxin, one of the most potent irritants known, an exciting probe for the study of neuronal receptors, and a lead for the development of new drugs for relief of neuralgic pain. A third major study involves efforts directed at the synthesis and biochemical mode of action of calphostin, a new, light-activatable phorbol ester antagonist and a potential lead for the development of new anti-AIDS drugs. A fourth major project is focussed on cyclic diacyl glycerols (cDAGs), a new family of potent PKC activators, on the synthesis of new metabolically stable cDAG analogues, and on the investigation of how lipid structure in these and other molecules functioning at lipid bilayers affects the affinity and selectivity of PKC isozyme recognition. A final major project seeks to define the tertiary structure of the regulatory domain of PKC through the use of photoaffinity labeling, synthesis, computer modeling, and NMR studies. Overall, this research program is expected to be of significant value in chemistry, biology, and medicine.