SYNTHETIC STUDIES ON TUMOR PROMOTERS & INHIBITORS: ANTI AIDS DRUG

肿瘤促进剂的综合研究

• 批准号: 7369015
• 负责人: PAUL Anthony WENDER
• 金额: $ 6.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369015
• 关键词: SYNTHETIC; STUDIES; TUMOR; PROMOTERS; INHIBITORS

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。该提案描述了继续开展综合研究计划的计划，该计划涉及合成、机制/作用模式、生物学和计算机建模研究，旨在了解肿瘤促进（人类健康问题）的分子基础、蛋白激酶的调节和生物化学C（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，以及更广泛的癌症和医学研究中感兴趣的分子。拟对五个项目进行调查。一项主要的后续研究将针对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）的合成，并研究其肿瘤促进活性的结构基础。第二个主要项目针对树脂毒素的合成和生化作用模式，树脂毒素是已知最有效的刺激物之一，是研究神经元受体的令人兴奋的探针，也是开发用于缓解神经痛的新药的先导。疼痛。第三项主要研究涉及钙磷蛋白的合成和生化作用模式，钙磷蛋白是一种新型光激活佛波酯拮抗剂，也是开发新型抗艾滋病药物的潜在先导。第四个主要项目侧重于环状二酰基甘油 (cDAG)，这是一种新的有效 PKC 激活剂家族，合成新的代谢稳定的 cDAG 类似物，并研究这些分子和其他在脂双层中发挥作用的分子的脂质结构如何影响PKC同工酶识别的亲和力和选择性。最后一个主要项目旨在通过使用光亲和标记、合成、计算机建模和 NMR 研究来定义 PKC 调控域的三级结构。总体而言，该研究项目预计将在化学、生物学和医学领域具有重要价值。