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

Roland E. Dolle, David McNair, Markj Hughes, Lawrence I. Kruse, Drake Eggelston, Barbara A. Saxty, Timothy N.C. Wells, Pieter H.E. Groot

Research output: Contribution to journalArticle

16 Scopus citations

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Citric acid analogues (±)-12a,b and (±)-17a,b, where one of the primary carboxylates has been replaced by a sulfoximinoyl and a 3-(3-hydroxy-β- lactamyl) moiety, respectively, have been synthesized and evaluated as inhibitors of ATP-citrate lyase.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.

Original languageEnglish
Pages (from-to)4875-4884
Number of pages10
JournalJournal of Medicinal Chemistry
Volume35
Issue number26
DOIs
StatePublished - Dec 1 1992
Externally publishedYes

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