SYNTHETIC STUDIES ON TUMOR PROMOTERS & INHIBITORS: ANTI AIDS DRUG

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。该提案描述了继续进行综合研究计划的计划，该计划涉及合成、作用机制/模式、生物学和计算机建模研究，旨在了解肿瘤促进的分子基础。（一个人类健康问题），蛋白激酶C的调节和生物化学（新药开发的新靶点），基于蛋白激酶C的癌症化疗药物的合理设计，更广泛地说，是癌症和医学研究中感兴趣的分子。提出了五个项目进行调查。一个主要的继续研究将针对合成佛波醇和巨大戟二萜醇类似物，已知的最有效的肿瘤促进剂，并在其肿瘤促进活性的结构基础的调查。第二个主要项目是针对树脂毒素的合成和生化作用模式，树脂毒素是已知的最强刺激物之一，是研究神经元受体的令人兴奋的探针，也是开发缓解神经痛新药的先导。第三项主要研究涉及针对calphostin的合成和生物化学作用模式的努力，calphostin是一种新的光活化佛波酯拮抗剂，是开发新的抗艾滋病药物的潜在领导者。第四个主要项目是集中在环状二酰基甘油（cDAGs），一个新的家庭的有效的PKC激活剂，对新的代谢稳定的cDAG类似物的合成，并在这些和其他分子的脂质结构如何在脂质双层功能影响的亲和力和选择性的PKC同工酶识别的调查。最后一个主要项目是通过光亲和标记、合成、计算机莫德林和核磁共振研究来确定PKC调控域的三级结构。总的来说，这项研究计划预计将在化学，生物学和医学方面具有重要价值。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 rec epto rs, 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.