ONCOGENE-DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG

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This proposal seeks: to utilize a new unsymmetrical pyrazine coupling to complete the total synthesis and determine the biological activity of C- 14',15' dihydrocephalostatin 1; to develop new chemistry of symchiral Beta-nitroacetonide anions in order to prepare and test the unnatural cephalostatin/ritterazine hybrid "cephalozine alpha"; to further explore the nitroacetonide methodology to synthesize the 6/6 spiroketal domain of the extremely potent anticancer agents altohyrtins A-C. If C-14',15' dihydrocephalostatin 1 does not have subnanomolar activity, the total synthesis of cephalostatin 1 will be undertaken using chemistry developed in conjunction with the synthesis of cephalozine alpha. A pseudocombinatorial approach will be employed to rapidly assess the activity of thirty new trisdecacyclic pyrazines; a series of vinyl ethers will be generated and tested in order to evaluate oxonium intermediates as the species responsible for anticancer activity of the cephalostatins, ritterazines, and the new steroidal antineoplastic OSW-1. The relationship between steroid biosynthesis inhibitor activity and anticancer activity will be explored for cephalostatin 7. Several photoaffinity-labeled analogs of cephalostatin 1 and/or cephalostatin 7 will be prepared in order to try to identify the biological target of the cephalostatins. Gram quantities of the best agent will be synthesized as a prelude to toxicological and human Phase I clinical trials.