This renewal application involves synthetic, mechanistic, mode of action, computer modeling, and biochemical studies directed at the design, synthesis, biological evaluation and development of new cancer chemotherapeutic leads and of new drug delivery systems. These studies seek to advance our understanding of the molecular basis for the selective regulation of protein kinase C (PKC), targets of interest in cancer chemotherapy, to develop novel and practical synthetic approaches to promising chemotherapeutic leads, especially those that exhibit new modes of action, and more generally compounds of interest in cancer and medical research, and to advance an exciting new class of transporters for drug and probe delivery. Section D.1 describes a continuation of plans using computer assisted design, synthesis, and biological assays including real time translocation studies of PKC fusion proteins for the study of the daphnane gnidimacrin, a new and promising cancer chemotherapeutic lead that operates through a novel mechanism putatively involving the regulation of cell cycling through the selective modulation of PKC. Section D.2 describes our complementary efforts to access synthetically and broadly the chemotherapeutically promising members of the daphnane family and to begin to elucidate the basis for their unusual potency and therapeutically promising biological activity. Section D.3 describes plans for the synthesis and biological evaluation of daphnane-tigliane hybrids, a totally new structural class of potential therapeutic leads designed to probe factors that control selective translocation of PKC. Section D.4 describes plans for the advancement of our studies on laulimalide, a cancer chemotherapeutic lead that functions like taxol but binds to a novel microtubule site and exhibits therapeutically promising activity against taxol resistant cancer cell lines. Section D.5 describes plans to identify new molecular transporters, to evaluate their performance in real time in an in vivo assay of tissue selective entry and to explore a new concept for tissue selective entry of molecular transporters based on tissue activatable transporters.
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