SYNTHETIC STUDIES ON TUMOR PROMOTERS AND INHIBITORS

这项提案描述了继续进行全面的 涉及综合、机理/行动模式的研究计划， 生物学和计算机模拟研究，旨在了解 促进肿瘤的分子基础(一个人类健康问题)， 蛋白激酶C(新靶点)的调节和生物化学 药物开发)，癌症化疗药物的合理设计 基于蛋白激酶C，以及更广泛的感兴趣的分子 癌症和医学研究。提出了五个项目， 调查。一项主要的继续研究将针对 最有效的肿瘤--佛波醇和吲哚类似物的合成 已知的启动子，并对其结构基础进行调查 它们的促肿瘤活性。第二个主要项目是 松脂毒素的合成及其生化作用模式 已知的最强刺激物，一种令人兴奋的研究 神经元受体，以及开发新药的领头羊 缓解神经痛。第三项主要研究涉及定向努力 在钙磷蛋白的合成和生化作用模式上，一种新的， 光激活佛波酯拮抗剂和潜在的先导 开发新的抗艾滋病药物。第四个主要项目是重点 一类新的有效PKC家族--环二酰甘油(CDAGs) 激活剂，合成代谢稳定的新的CDAG类似物， 以及关于这些和其他生物中的脂质结构是如何 作用于脂双层的分子影响亲和力和亲和力 PKC同工酶识别的选择性。最后一个重大项目寻求 通过以下方式定义PKC监管域的三级结构 光亲和标记、合成、计算机模拟和核磁共振的应用 学习。总体而言，这项研究计划预计将具有重要意义 在化学、生物和医学方面的价值。

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.