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

J Med Chem. 1992 Dec 25;35(26):4875-84. doi: 10.1021/jm00104a014.

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Citric acid analogues (+/-)-12a,b and (+/-)-17a,b, where one of the primary carboxylates has been replaced by a sulfoximinoyl and a 3-(3-hydroxy-beta-lactamyl) moiety, respectively, have been synthesized and evaluated as inhibitors of ATP-citrate lyase.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

MeSH terms

  • ATP Citrate (pro-S)-Lyase / antagonists & inhibitors*
  • Animals
  • Citrates / chemical synthesis*
  • Citrates / chemistry
  • Citrates / pharmacology
  • Humans
  • Hypolipidemic Agents / chemical synthesis*
  • Hypolipidemic Agents / chemistry
  • Hypolipidemic Agents / pharmacology
  • Oximes / chemical synthesis*
  • Oximes / chemistry
  • Oximes / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Citrates
  • Hypolipidemic Agents
  • Oximes
  • ATP Citrate (pro-S)-Lyase