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.
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