1. β‑Lactones: A Novel Class of Ca2+-Independent Phospholipase A2 (Group VIA iPLA2) Inhibitors with the Ability To Inhibit β‑Cell Apoptosis
- Author
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Dedaki, Christina, Kokotou, Maroula G, Mouchlis, Varnavas D, Limnios, Dimitris, Lei, Xiaoyong, Mu, Carol T, Ramanadham, Sasanka, Magrioti, Victoria, Dennis, Edward A, and Kokotos, George
- Subjects
Diabetes ,Autoimmune Disease ,Metabolic and endocrine ,Animals ,Apoptosis ,Cytokines ,Drug Design ,Humans ,Inflammation Mediators ,Insulin-Secreting Cells ,Lactones ,Phospholipase A2 Inhibitors ,Phospholipases A2 ,Calcium-Independent ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry - 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.
- Published
- 2019