Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2.
Group VIA calcium-independent phospholipase A(2) (GVIA iPLA(2)) has recently emerged as a novel pharmaceutical target. We have now explored the structure-activity relationship between fluoroketones and GVIA iPLA(2) inhibition. The presence of a naphthyl group proved to be of paramount importance. 1,1,1-Trifluoro-6-(naphthalen-2-yl)hexan-2-one (FKGK18) is the most potent inhibitor of GVIA iPLA(2) (X(I)(50) = 0.0002) ever reported. Being 195 and >455 times more potent for GVIA iPLA(2) than for GIVA cPLA(2) and GV sPLA(2), respectively, makes it a valuable tool to explore the role of GVIA iPLA(2) in cells and in vivo models. 1,1,1,2,2,3,3-Heptafluoro-8-(naphthalene-2-yl)octan-4-one inhibited GVIA iPLA(2) with a X(I)(50) value of 0.001 while inhibiting the other intracellular GIVA cPLA(2) and GV sPLA(2) at least 90 times less potently. Hexa- and octafluoro ketones were also found to be potent inhibitors of GVIA iPLA(2); however, they are not selective.
Kokotos
George
G
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece. gkokotos@chem.uoa.gr
Hsu
Yuan-Hao
YH
Burke
John E
JE
Baskakis
Constantinos
C
Kokotos
Christoforos G
CG
Magrioti
Victoria
V
Dennis
Edward A
EA
D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry; D005461:Fluorine; D054522:Group VI Phospholipases A2 / Q000037:antagonists & inhibitors*; D006801:Humans; D007659:Ketones / Q000494:pharmacology* / Q000627:therapeutic use; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D054512:Phospholipases A2, Calcium-Independent / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
C587596:1,1,1-trifluoro-6-(naphthalen-2-yl)hexan-2-one; D004791:Enzyme Inhibitors; D007659:Ketones; D009281:Naphthalenes; D005461:Fluorine; D054522:Group VI Phospholipases A2; D054512:Phospholipases A2, Calcium-Independent