title: Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2.
abstract: 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.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece. gkokotos@chem.uoa.gr
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
authors.forename: Yuan-Hao
authors.initials: YH
authors.lastname: Hsu
authors.forename: John E
authors.initials: JE
authors.lastname: Burke
authors.forename: Constantinos
authors.initials: C
authors.lastname: Baskakis
authors.forename: Christoforos G
authors.initials: CG
authors.lastname: Kokotos
authors.forename: Victoria
authors.initials: V
authors.lastname: Magrioti
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
mesh_terms: 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
chemical_list: 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