This proposal describes plans for the continuation of a research program involving synthesis, computer modeling, mechanistic/mode of action, biological, and spectroscopic studies focused on compounds of demonstrated or potential importance in cancer research and chemotherapy. It is the objective of this program to develop fundamentally new methods and strategies for the synthesis of such compounds, to elucidate the structural basis for their mode of action, and to test and exploit these new findings in the rational design of new cancer chemotherapeutic agents or compounds of interest in cancer research. Five projects are proposed for investigation during the continuation period. A major continuation study focusing on taxol, a promising chemotherapeutic agent recently approved for the treatment of ovarian and metastatic breast cancers, will be directed at the development of practical syntheses of taxol and its analogs, the elucidation of its molecular mode of action, and at the design of simplified, potentially superior clinical candidates. A second major project is directed at the continuation of our studies on novel DNA cleaving reagents and potential chemotherapeutic agents, focusing on a highly potent and readily synthesized new class of dynemicin analogs and on new classes of DNA cleaving agents that operate through the inducible generation of aryl radicals. A third major effort is directed at the elucidation of the molecular mode of action and the synthesis of simplified analogs of the highly potent marine natural product bryostatin, an exceptionally promising cancer chemotherapeutic agent now in clinical trials for the treatment of solid tumors. A fourth project is directed at the synthesis and evacuation of a new class of bioresponse modulators that induce the synthesis and expression of tumor associated antigens in human breast cancer cells, an activity that could be exploited in enhancing the performance of monoclonal-drug conjugates in cancer chemotherapy. A fifth project seeks to establish an understanding of the structural and functional role of RACKs (receptors for activated C kinases), a newly discovered class of proteins of fundamental importance in cellular signal transduction and new targets for the design of novel cancer chemotherapeutic agents. Overall, this research program is expected-to be of significant value in chemistry, biology, and medicine.
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