SYNTHETIC STUDIES ON TUMOR PROMOTERS & INHIBITORS: POTENTIAL ANTI AIDS DRUG DVMT

本提案描述了继续执行 综合研究计划，涉及合成、机理/模式 行动，生物学和计算机建模研究， 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（一种新的 新药开发的目标），癌症的合理设计 基于蛋白激酶C的化疗剂，更一般地， 在癌症和医学研究中的重要分子。 五 提出了供调查的项目。 一项重大的继续研究 将致力于合成佛波醇和巨大戟二萜醇类似物， 已知最有效的肿瘤促进剂，并在一项调查中， 其肿瘤促进活性的结构基础。 第二主 该项目是针对的合成和生物化学的行动模式， 树脂毒素，已知的最有效的刺激物之一，一种令人兴奋的 研究enuronal受体的探针，以及 开发缓解神经痛的新药。 第三个主要 研究涉及的努力针对合成和生化模式 calphostin的作用，一种新的，光活化佛波酯 拮抗剂和开发新的抗艾滋病药物的潜在领导者 毒品 第四个主要项目集中在环状二酰基甘油 （cDAGs），一个新的家族的有效的PKC激活剂，对合成的 新的代谢稳定的cDAG类似物，并在研究 这些和其他分子中的脂质结构如何在脂质中起作用 双分子层影响PKC同工酶的亲和力和选择性 识别. 最后一个主要项目旨在界定第三产业 PKC的调节结构域的结构，通过使用 光亲和标记、合成、计算机莫德林和NMR研究。 总的来说，这项研究计划预计将具有重大价值 在化学、生物学和医学上。

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 enuronal 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 modling, and NMR studies. Overall, this research program is expected to be of significant value in chemistry, biology, and medicine.