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


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 ?-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 ?-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.

SUBMITTER: Dedaki C 

PROVIDER: S-EPMC6767909 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Dedaki Christina C   Kokotou Maroula G MG   Mouchlis Varnavas D VD   Limnios Dimitris D   Lei Xiaoyong X   Mu Carol T CT   Ramanadham Sasanka S   Magrioti Victoria V   Dennis Edward A EA   Kokotos George G  

Journal of medicinal chemistry 20190312 6


Ca<sup>2+</sup>-independent phospholipase A<sub>2</sub> (GVIA iPLA<sub>2</sub>) 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<sub>2</sub> inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA<sub>2</sub> inhibitors based on the β-lactone ring. This functionality  ...[more]

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