title: ATP-citrate lyase as a target for hypolipidemic intervention. Sulfoximine and 3-hydroxy-beta-lactam containing analogues of citric acid as potential tight-binding inhibitors.
abstract: Citric acid analogues (+/-)-12a,b and (+/-)-17a,b, where one of the primary carboxylates has been replaced by a sulfoximinoyl and a 3-(3-hydroxy-beta-lactamyl) moiety, respectively, have been synthesized and evaluated as inhibitors of ATP-citrate lyase.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 beta-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.
authors: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals Ltd., The Frythe, Welwyn, Hertfordshire, U.K.
authors: R E
authors: RE
authors: Dolle
authors: D
authors: D
authors: McNair
authors: M J
authors: MJ
authors: Hughes
authors: L I
authors: LI
authors: Kruse
authors: D
authors: D
authors: Eggelston
authors: B A
authors: BA
authors: Saxty
authors: T N
authors: TN
authors: Wells
authors: P H
authors: PH
authors: Groot
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors*; D000818:Animals; D002951:Citrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002951:Citrates; D000960:Hypolipidemic Agents; D010091:Oximes; D001275:ATP Citrate (pro-S)-Lyase