- Synthesis of polyfluoro ketones for selective inhibition of human phospholipase A2 enzymes
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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 observed promiscuity of known PLA2 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 iPLA2, 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 iPLA2 (XI(50) = 0.0073). Furthermore, we conclude that the introduction of an additional fluorine atom at the α′ position of a trifluoromethyl ketone constitutes an important strategy for the development of new potent GVIA iPLA2 inhibitors.
- Baskakis, Constantinos,Magrioti, Victoria,Cotton, Naomi,Stephens, Daren,Constantinou-Kokotou, Violetta,Dennis, Edward A.,Kokotos, George
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experimental part
p. 8027 - 8037
(2009/11/30)
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- PERFLUOROKETONE COMPOUNDS AND USES THEREOF
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Novel perfluoroketone compounds of formula [I] and [Ia] are described Also described are uses thereof, such as for inhibition of phospholipase A2 activity. Therapeutic uses thereof are also described, such as for the treatment of neural conditions and / or inflammatory conditions, such as demeyelmatmg (e.g., multiple sclerosis) and neural injury (e.g., spinal cord injury).
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Page/Page column 44
(2008/12/04)
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