Plans are presented for the continuation of a comprehensive program involving synthesis, computer modelling, mode of action, bioassay, and degradation studies on tumor promoters. Emerging evidence suggests that, in addition to carcinogens, tumor promoters represent significant cancer risk factors in human carcinogenesis. It is the objective of this project to establish new chemistry and synthetic expertise in this previously unstudied area and through these efforts and computer modelling and bioassay techniques to contribute to our understanding of tumor promotion and carcinogenesis, thereby ultimately providing a scientific foundation for rational approaches to cancer prevention. Because the molecular mechanism of promotion is intimately involved in basic cell biochemistry including signal transduction and growth, these studies are expected to provide insight on normal and abnormal cell function and on recent medicinal leads based on protein kinase C. The synthetic goals for this project are selected in part to elucidate the structural requirements for tumor promotion. To achieve these goals a synthesis of the most potent tumor promoter- -phorbol myristate acetate will be completed. Alternative approaches to related tiglianes needed for modelling and bioassay studies, including 13-deoxy- and 13-deoxy-phorbol, are also planned. Synthetic expertise in the unexplored daphnane promoter area will be developed and focussed initially on the synthesis of resiniferatoxin. A biomimetic approach to the ingenanes will also be investigated. Plans are also presented for syntheses of structurally modified promoters and a new class of diacyl glycerol analogs. Computer modelling and bioassays will be performed in conjunction with these and related projects in order to establish the structural basis for the potent biological activities of the promoters and PKC activators.
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