ATP-citrate lyase as a target for hypolipidemic intervention. Sulfoximine and 3-hydroxy-β-lactam containing analogues of citric acid as potential tight-binding inhibitors

Citric acid analogues (±)-12a,b and (±)-17a,b, where one of the primary carboxylates has been replaced by a sulfoximinoyl and a 3-(3-hydroxy-β- lactamyl) moiety, respectively, have been synthesized and evaluated as inhibitors of ATP-citrate lyase. The design of these inhibitors was based on methionine sulfoximine and tabtoxinine β-lactam, potent, tight-binding inhibitors of glutamine synthetase. Both ATP-citrate lyase and glutamine synthetase employ phosphate-carboxylate anhydrides as a method for carboxylate activation during catalysis. Only one diastereomer, (±)-12a, displayed weak, reversible inhibition, while the remaining citrate analogues (±)-12b and (±)-17a,b were inactive against the lyase. No time-dependent inactivation of the enzyme was observed.