SYNTHETIC STUDIES ON TUMOR PROMOTERS & INHIBITORS: ANTI AIDS DRUG

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项建议描述了一项综合性研究计划的继续计划，该计划涉及合成、机理/作用模式、生物学和计算机模拟研究，旨在了解促进肿瘤的分子基础(人类健康问题)、蛋白激酶C(新药开发的新靶点)的调节和生物化学、基于蛋白激酶C的癌症化疗药物的合理设计，以及更广泛地说，癌症和药物研究中感兴趣的分子。提出了五个项目进行调研。一项主要的继续研究将针对佛波醇和吲哚类似物的合成，这是已知的最有效的肿瘤促进剂，并调查它们促进肿瘤活性的结构基础。第二个重大项目是关于树脂毒素的合成和生化作用模式，它是已知的最有效的刺激物之一，是研究神经兴奋的一个令人兴奋的探测器，也是开发缓解神经痛的新药的先导。第三项主要研究涉及Calphostin的合成和生化作用模式，Calphostin是一种新的、可光激活的佛波酯拮抗剂，也是开发新的抗艾滋病药物的潜在先导。第四个主要项目集中在环二酰甘油(CDAGs)，一个新的有效的PKC激活剂家族，合成新的代谢稳定的CDAG类似物，以及研究这些分子和其他作用于脂双层的分子中的脂结构如何影响PKC同工酶识别的亲和力和选择性。最后一个主要项目寻求通过使用光亲和标记、合成、计算机建模和核磁共振研究来定义PKC调节域的三级结构。总体而言，这项研究计划有望在化学、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.