SYNTHETIC STUDIES ON TUMOR PROMOTERS AND INHIBITORS

这一新的应用包括合成、机制、作用模式、计算机模拟和生化研究，目的是了解肿瘤促进和蛋白激酶C(PKC)选择性调节的分子基础；开发癌症预防的新途径；开发新的有效方法和策略，用于合成新的和有效的癌症治疗线索和更广泛的癌症和药物研究中感兴趣的化合物，并研究这些线索的新作用模式；开发令人兴奋的新型药物转运体；以及开发用于快速多样化、分析、分离和识别治疗线索的新途径。PKC的异常激活与人类癌变的促癌阶段有关。这项研究试图了解肿瘤促进的分子基础，并调查其普遍性，这是开发癌症预防方案所必需的。由于PKC抑制也与目前正在进行临床试验的癌症治疗药物的作用方式有关，本研究也为合理开发新的抗肿瘤药物和治疗策略提供了基础。PKC还与心血管疾病、神经病理性疼痛、病毒感染和HIV表达有关。更广泛地说，这项研究提供了对努力了解正常和异常细胞功能的基本价值的信息。建议的项目包括：1)开发复杂分子合成的新方法和策略，针对结构新颖和生物化学独特的癌症化疗新先导化合物格地马克林，它可能涉及通过PKC选择性结合调节细胞周期；2)研究一类非常有用的新的PKC多肽替代品和有效的新型PKC激活剂，包括一类新的超强佛波酯、钙磷蛋白和环二酰甘油，旨在阐明这些新的治疗先导的结合和功能的结构基础，以及PKC同工酶选择性激活剂和抑制剂的开发；3)合成和研究劳利马利德，这是一种激动人心的癌症化疗先导化合物，最近发现其功能类似紫杉醇，但在多药耐药细胞系中保持其活性；4)一类令人兴奋的新型分子转运体的合成和评估，它增强了原本无法进入细胞或只能很差地摄取药物的候选药物的摄取，这一项目可能在化疗中产生广泛的后果；5)开发一种新的策略，用于治疗先导化合物的多样化和基于受体的分析、分离和鉴定如此产生的最佳化合物。总体而言，这一计划有望在化学、生物和医学方面具有重要价值。

This renewal application involves synthetic, mechanistic, mode of action, computer modeling, and biochemical studies directed at understanding the molecular basis of tumor promotion and of protein kinase C (PKC) selective regulation; at the development of new approaches to cancer prevention; at the development of novel and effective methods and strategies for the synthesis of new and potent cancer therapeutic leads and more generally compounds of interest in cancer and medicinal research and at the investigation of the novel mode of action of these leads; at the development of an exciting new class of drug transporters; and at the development of a novel approach for the rapid diversification, assay, separation, and identification of therapeutic leads. Abnormal PKC activation is implicated in the tumor promotion stage of human carcinogenesis. This research seeks to understand the molecular basis for tumor promotion and to investigate its generality, as required for the development of protocols for cancer prevention. Since PKC inhibition is also implicated in the mode of action of cancer therapeutic agents now in clinical trials, this research also provides the basis for rational approaches to new anti-tumor agents and therapeutic strategies. PKC is also implicated in cardiovascular disease, neuropathic pain, viral infection, and HIV expression. More generally, this research provides information of fundamental value in efforts to understand normal and abnormal cell function. Proposed projects include: 1) the development of new methods and strategies for complex molecule synthesis directed at the total synthesis and mode of action of gnidimacrin, a structurally novel and biochemically unique new lead for cancer chemotherapy that putatively involves cell cycle regulation through PKC selective binding; 2) studies on a highly useful new class of peptide surrogates of PKC and on potent and novel PKC activators including a new ultrapotent class of phorbol esters, calphostin and cyclic diacyl glycerols aimed at elucidation of the structural basis for the binding and function of these novel therapeutic leads and the development of isozyme selective activators and inhibitors of PKC; 3) studies on the synthesis and investigation of laulimalide, an exciting cancer chemotherapeutic lead recently found to function like taxol but which retains its activity in multidrug resistant cell lines; 4) the synthesis and evaluation of an exciting new class of molecular transporters that enhance the uptake of drug candidates that otherwise cannot get into cells or do so only poorly, a project of potentially broad consequence in chemotherapy; 5) the development of a novel strategy for the diversification of a therapeutic lead and for the receptor based assay, separation, and identification of the best compounds so produced. Overall, this program is expected to be of significant value in chemistry, biology, and medicine.