ONCOGENE-DIRECTED SYNTHESIS--CEPHALOSTATIN CANCER DRUGS

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This proposal seeks to prepare new synthetic anticancer agents for the purpose of biological definition of the minimum pharmacophore present in the trisdecacyclic pyrazine family of cephalostatins. Five main objectives of this four-year proposal are: (1) Synthesis of optically active symmetrical trisdecacyclic pyrazine analogs bearing all of the functionality of the "upper" spiroketal of cephalostatin 1; (2) Synthesis of optically active symmetrical trisdecacyclic pyrazine analogs bearing all of the functionality of the "lower" spiroketal of cephalostatin 1; and (3) Synthesis of optically active unsymmetrical trisdecacyclic pyrazine and pyridine analogs bearing all of the functionality of both spiroketals of cephalostatin 1; (4) An essential feature of this research features using the synthetic cephalostatin analogs to find selective inhibitors of human tumor subsets caused by particular oncogenes; and (5) Compare in vitro oncogene-guided anticancer agent assessment with the current NIH in vitro 60 tumor panel.