William Kish

Honors in Chemistry

Major: Chemistry

Supervisor: Christopher Halkides, Chemistry and Biochemistry

Synthesis and Characterization of Several Enzyme Inhibitors

Several potential enzyme inhibitors were synthesized, purified and characterized by NMR spectroscopy. Attempts were made to synthesize inhibitors of aspartate -β-semialdehyde dehydrogenase(ASADH), including phosphonomethylcysteine, PMC, catechol rhodanine acetic acid, CRAA, and trifluoroethylcysteine-sulfoxide, TFEC-S. Various NMR experiments were conducted on PMC, CRAA and TFEC. The CRAA and PMC reactions and purifications led to pure products. However, oxidation of TFEC to TFEC-S using sodium meta periodate seems to have failed. CRAA was sent to a collaborator, Dr. Ronald Viola to be tested as an inhibitor of ASADH where it exhibited minor inhibition capabilities (K_i in the mM range). Phosphonomethylhomocysteine, PMHC, a glutamylphosphate analog, was synthesized, purified and characterized by ³¹P, ¹H and ¹³C NMR. PMHC was oxidized to its sulfoxide and sulfone derivatives using hydrogen peroxide and these products were also characterized by ³¹P and ¹³C NMR. Also, an attempt to make the sulfoxide using sodium meta periodate was conducted that resulted in formation of the sulfoxide, the sulfone and an unknown compound. Samples of PMHC, PMHC-S and PMHC-SO were sent to a collaborator, Dr. Owen Griffith, to be tested as inhibitors of various enzymes (results pending). Finally, Phosphonomethyltriflate, PMT, was synthesized and characterized by ¹H NMR. This PMT will be used at a later date as an enzyme alkylating reagent or as a starting material for reactions of PMC or PMHC.