title: New potent and selective polyfluoroalkyl ketone inhibitors of GVIA calcium-independent phospholipase A2.
abstract: Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as an important pharmaceutical target. Selective and potent GVIA iPLA2 inhibitors can be used to study its role in various neurological disorders. In the current work, we explore the significance of the introduction of a substituent in previously reported potent GVIA iPLA2 inhibitors. 1,1,1,2,2-Pentafluoro-7-(4-methoxyphenyl)heptan-3-one (GK187) is the most potent and selective GVIA iPLA2 inhibitor ever reported with a XI(50) value of 0.0001, and with no significant inhibition against GIVA cPLA2 or GV sPLA2. We also compare the inhibition of two difluoromethyl ketones on GVIA iPLA2, GIVA cPLA2, and GV sPLA2.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Greece.
authors.forename: Victoria
authors.initials: V
authors.lastname: Magrioti
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Nikolaou
authors.forename: Annetta
authors.initials: A
authors.lastname: Smyrniotou
authors.forename: Ishita
authors.initials: I
authors.lastname: Shah
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: D005461:Fluorine / Q000737:chemistry; D054522:Group VI Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D064801:Phospholipase A2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007659:Ketones; D064801:Phospholipase A2 Inhibitors; D020033:Protein Isoforms; D005461:Fluorine; D054522:Group VI Phospholipases A2
keywords: GVIA iPLA(2); Inhibitor; Pentafluoroethyl ketones; Phospholipase A(2); Polyfluoroalkyl ketone
references.citation: Trends Biochem Sci. 1999 Aug;24(8):311-6
references.pmid: 10431175
references.citation: Biochim Biophys Acta. 2005 Jul 15;1735(2):119-29
references.pmid: 15967714
references.citation: J Biol Chem. 1995 Jan 6;270(1):445-50
references.pmid: 7814408
references.citation: PLoS One. 2013;8(3):e59267
references.pmid: 23533611
references.citation: Lipids. 2001 Jul;36(7):689-700
references.pmid: 11521967
references.citation: Biochemistry. 2006 Jan 24;45(3):1061-73
references.pmid: 16411783
references.citation: Biochem Pharmacol. 2008 Oct 30;76(9):1059-67
references.pmid: 18775417
references.citation: J Biol Chem. 1997 Mar 28;272(13):8576-80
references.pmid: 9079688
references.citation: J Biol Chem. 1999 May 14;274(20):13915-27
references.pmid: 10318801
references.citation: J Biol Chem. 2004 Apr 16;279(16):16488-94
references.pmid: 14761945
references.citation: J Am Chem Soc. 2013 Jan 30;135(4):1330-7
references.pmid: 23256506
references.citation: J Biol Chem. 2013 Jan 18;288(3):1806-13
references.pmid: 23209293
references.citation: J Biol Chem. 1991 Mar 15;266(8):5268-72
references.pmid: 2002059
references.citation: Brain. 2009 May;132(Pt 5):1221-35
references.pmid: 19218359
references.citation: J Biol Chem. 1997 Nov 14;272(46):29317-21
references.pmid: 9361012
references.citation: J Med Chem. 2008 Dec 25;51(24):8027-37
references.pmid: 19053783
references.citation: Biochim Biophys Acta. 2006 Nov;1761(11):1344-50
references.pmid: 16962822
references.citation: J Biol Chem. 2004 Jun 11;279(24):25024-38
references.pmid: 15007070
references.citation: Cell Signal. 2005 Sep;17(9):1052-62
references.pmid: 15993747
references.citation: J Med Chem. 2010 May 13;53(9):3602-10
references.pmid: 20369880
references.citation: Cardiovasc Res. 2009 May 1;82(2):240-9
references.pmid: 19074824
references.citation: Curr Drug Targets. 2008 Aug;9(8):683-97
references.pmid: 18691015
references.citation: Prog Lipid Res. 2006 Nov;45(6):487-510
references.pmid: 16814865
references.citation: Expert Opin Ther Pat. 2013 Mar;23(3):333-44
references.pmid: 23294257
references.citation: J Biol Chem. 1994 Mar 25;269(12):9227-33
references.pmid: 8132660
references.citation: Eur J Biochem. 2000 Dec;267(24):7118-27
references.pmid: 11106423
references.citation: Chem Rev. 2011 Oct 12;111(10):6130-85
references.pmid: 21910409
references.citation: Cell. 1991 Jun 14;65(6):1043-51
references.pmid: 1904318
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8527-31
references.pmid: 7667324
references.citation: J Biol Chem. 2001 Apr 20;276(16):13198-208
references.pmid: 11278673
references.citation: J Med Chem. 2004 Jul 1;47(14):3615-28
references.pmid: 15214789
references.citation: J Med Chem. 2006 May 4;49(9):2821-8
references.pmid: 16640343
references.citation: Cardiovasc Drugs Ther. 2009 Feb;23(1):49-59
references.pmid: 18931897
references.citation: J Biol Chem. 1997 Mar 28;272(13):8567-75
references.pmid: 9079687
references.citation: Expert Opin Ther Pat. 2010 Jan;20(1):1-18
references.pmid: 20021282
references.citation: J Med Chem. 2007 Aug 23;50(17):4222-35
references.pmid: 17672443
references.citation: J Lipid Res. 2010 Mar;51(3):525-34
references.pmid: 19741254
references.citation: Biochim Biophys Acta. 1996 Jul 12;1302(1):55-60
references.pmid: 8695655
references.citation: Biochimie. 2010 Jun;92(6):627-37
references.pmid: 20083151
references.citation: J Biol Chem. 1997 Jun 27;272(26):16069-72
references.pmid: 9195897