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

肿瘤促进剂的综合研究

• 批准号: 6308817
• 负责人: PAUL A WENDER
• 金额: $ 0.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6308817
• 关键词: AIDS; biological products; biomedical resource; immunology; infection; inflammation; lymphatic system; spectrometry; structural biology; virus

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.

本提案描述了继续执行 涉及综合、机械/模式的综合研究计划 行动、生物和计算机模拟研究的目标是 了解促进肿瘤的分子基础(人类健康 问题)，蛋白激酶C的调节和生物化学(一种新的 新药开发的靶点)，癌症的合理设计 基于蛋白激酶C的化疗药物，以及更一般的 癌症和医学研究中感兴趣的分子。五 建议进行调查的项目。一项重大的持续研究 将针对佛波醇和吲哚类似物的合成， 已知的最有效的肿瘤促进剂，在对 它们具有促肿瘤活性的结构基础。第二个大调 该项目针对的是合成和生化作用模式 树脂毒素，已知的最强刺激物之一，令人兴奋 神经肽受体研究的探索性和先导性 用于缓解神经痛的新药的开发。第三个专业 研究涉及到针对合成和生化模式的努力 钙磷蛋白的作用，一种新的，可光激活的佛波酯 拮抗剂和新抗艾滋病药物开发的潜在引领者 毒品。第四个主要项目集中在环二酰甘油。 一种新的有效的PKC激活剂家族(CDAGs)对合成 新的代谢稳定的CDAG类似物，以及对其的研究 这些分子和其他分子中的脂质结构如何在脂质中发挥作用 双分子层对PKC同工酶亲和力和选择性的影响 承认。最后一个重大项目寻求定义第三世界 PKC调节域的结构通过使用 光亲和标记、合成、计算机建模和核磁共振研究。 总体而言，这项研究计划预计将具有重大价值 在化学、生物和医学方面。