Fatty acid synthase (FAS) has gained increased attention in the development of new antineoplastic therapy. Overexpression of FAS in various cancers of the breast, prostate, endometrium, and colon have made this enzyme a selective target for the development of new and potent inhibitors. Selective inhibition of the beta-ketoacyl synthase (KS) by cerulenin and more recently C75 has lead to the inactivation of fatty acid synthesis and apoptosis. Synthesis of several thiolphosphonate, phosphonate, and phosphinic analogs will be carried out and tested as potential transition state inhibitors of the p-ketoacyl synthase of FAS. Attachment of a hydrocarbon chain (varying in length and unsaturation) and modified pantetheine or cysteine ligands to the phosphorous are strategies that will be used to mimic the transition states of the two reactions catalyzed by KS. An alternative strategy to the selective inhibition of KS consists of synthesizing and studying fluorinated analogs of methylmalonyl CoA as a potential mechanism-based inhibitors. Trifluoromethyl malonyl-CoA analogs and a class of cyclic difluoromethylene analogs will be synthesized. Steady-state kinetics will be used to determine magnitude and type of inhibition. Synthesis of """"""""C-labeled analogs will be carried out in order to identify the stoichlometry and mode of inactivation. The effects of these analogs on human cancer cells will also be studied in vitro and in vivo. Development of 'inhibitors of FAS, such as those targeted herein, may provide alternative and/or more effective anticancer therapy and provide further insight into the mechanism by which inhibition of fatty acid synthesis produces its antitumor effect.
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