β-Lactones: A Novel Class of Ca2+-Independent Phospholipase A2 (Group VIA iPLA2) Inhibitors with the Ability To Inhibit β-Cell Apoptosis

  • J Med Chem. 2019 Mar 28;62(6):2916-2927. doi: 10.1021/acs.jmedchem.8b01216.
Christina Dedaki  1 ,  Maroula G Kokotou  1  2 ,  Varnavas D Mouchlis  2 ,  Dimitris Limnios  1  2 ,  Xiaoyong Lei ,  Carol T Mu  2 ,  Sasanka Ramanadham ,  Victoria Magrioti  1 ,  Edward A Dennis  2 ,  George Kokotos  1
Affiliations
  • 1. Laboratory of Organic Chemistry, Department of Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis, Athens 15771 , Greece.
  • 2. Department of Chemistry and Biochemistry and Department of Pharmacology, School of Medicine , University of California, San Diego , La Jolla, San Diego , California 92093-0601 , United States.
PMID: 30798607 DOI: 10.1021/acs.jmedchem.8b01216
Abstract

CA2+-independent Phospholipase A2 (GVIA iPLA2) 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 iPLA2 inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA2 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 iPLA2 inhibitor ever reported ( XI(50) 0.0000021, IC50 1 nM) and also one that is 22 000 times more active against GVIA iPLA2 than GIVA cPLA2. 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.

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