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Synthesis of Polyfluoro Ketones for Selective Inhibition of Human Phospholipase A2 Enzymes

Synthesis of Polyfluoro Ketones for Selective Inhibition of Human Phospholipase A2 Enzymes

Constantinos Baskakis, Victoria Magrioti, Naomi Cotton, Daren Stephens, Violetta Constantinou-Kokotou, Edward A Dennis, George Kokotos

J Med Chem. 2008 Dec 25;51(24):8027-37.

PMID: 19053783

Abstract:

The development of selective inhibitors for individual PLA(2) enzymes is necessary in order to target PLA(2)-specific signaling pathways, but it is challenging due to the observed promiscuity of known PLA(2) inhibitors. In the current work, we present the development and application of a variety of synthetic routes to produce pentafluoro, tetrafluoro, and trifluoro derivatives of activated carbonyl groups in order to screen for selective inhibitors and characterize the chemical properties that can lead to selective inhibition. Our results demonstrate that the pentafluoroethyl ketone functionality favors selective inhibition of the GVIA iPLA(2), a very important enzyme for which specific, potent, reversible inhibitors are needed. We find that 1,1,1,2,2-pentafluoro-7-phenyl-heptan-3-one (FKGK11) is a selective inhibitor of GVIA iPLA(2) (X(I)(50) = 0.0073). Furthermore, we conclude that the introduction of an additional fluorine atom at the alpha' position of a trifluoromethyl ketone constitutes an important strategy for the development of new potent GVIA iPLA(2) inhibitors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1071000980	FKGK11		1071000-98-0	Price

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