β-Lactones: A Novel Class of Ca 2+ -Independent Phospholipase A 2 (Group VIA iPLA 2 ) Inhibitors with the Ability To Inhibit β-Cell Apoptosis

Academic Article

Abstract

  • Ca 2+ -independent phospholipase A 2 (GVIA iPLA 2 ) has gained increasing interest recently as it has been recognized as a participant in biological processes underlying diabetes development and autoimmune-based neurological disorders. The development of potent GVIA iPLA 2 inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA 2 inhibitors based on the β-lactone ring. This functionality in combination with a four-carbon chain carrying a phenyl group at position-3 and a linear propyl group at position-4 of the lactone ring confers excellent potency. trans-3-(4-Phenylbutyl)-4-propyloxetan-2-one (GK563) was identified as being the most potent GVIA iPLA 2 inhibitor ever reported (X I (50) 0.0000021, IC 50 1 nM) and also one that is 22 000 times more active against GVIA iPLA 2 than GIVA cPLA 2 . It was found to reduce β-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Dedaki C; Kokotou MG; Mouchlis VD; Limnios D; Lei X; Mu CT; Ramanadham S; Magrioti V; Dennis EA; Kokotos G
  • Start Page

  • 2916
  • End Page

  • 2927
  • Volume

  • 62
  • Issue

  • 6