title: Synthesis of polyfluoro ketones for selective inhibition of human phospholipase A2 enzymes.
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.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Baskakis
authors.forename: Victoria
authors.initials: V
authors.lastname: Magrioti
authors.forename: Naomi
authors.initials: N
authors.lastname: Cotton
authors.forename: Daren
authors.initials: D
authors.lastname: Stephens
authors.forename: Violetta
authors.initials: V
authors.lastname: Constantinou-Kokotou
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
mesh_terms: D002244:Carbon / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005466:Fluorocarbons; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008956:Models, Chemical; D054510:Phospholipases A2, Cytosolic / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: C533806:1,1,1,2,2-pentafluoro-7-phenylheptan-3-one; D004791:Enzyme Inhibitors; D005466:Fluorocarbons; D007659:Ketones; D008823:Micelles; D010743:Phospholipids; D002244:Carbon; D054510:Phospholipases A2, Cytosolic