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

[摘要]：The development of selective inhibitors for individual PLA2 enzymes is necessary in order to target PLA2-specific signaling pathways, but it is challenging due to the obsd. promiscuity of known PLA2 inhibitors. This work presents the development and application of a variety of synthetic routes to produce pentafluoro, tetrafluoro, and trifluoro derivs. of activated carbonyl groups in order to screen for selective inhibitors and characterize the chem. properties that can lead to selective inhibition. Thus, the pentafluoroethyl ketone functionality favors selective inhibition of the GVIA iPLA2, a very important enzyme for which specific, potent, reversible inhibitors are needed. Also, 1,1,1,2,2-pentafluoro-7-phenylheptan-3-one (FKGK11) is a selective inhibitor of GVIA iPLA2. It is concluded that the introduction of an addnl. fluorine atom at the a' position of a trifluoromethyl ketone constitutes an important strategy for the development of new potent GVIA iPLA2 inhibitors.

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