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. 2010 May 13;53(9):3602-10.
doi: 10.1021/jm901872v.

Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2

George Kokotos  1 , Yuan-Hao Hsu, John E Burke, Constantinos Baskakis, Christoforos G Kokotos, Victoria Magrioti, Edward A Dennis
Affiliations

Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2

George Kokotos et al. J Med Chem. .

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.

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Figures

Figure 1
Figure 1
Some known inhibitors of GVIA iPLA2.
Figure 2
Figure 2
GVIA iPLA2 % inhibition at 0.091 mole fraction of inhibitor in mixed micelles (top) and XI(50) values (bottom). Standard error (n = 3) for average % inhibition and XI(50) values for all synthesized compounds is indicated.
Figure 3
Figure 3
Dose–response curves for GVIA iPLA2 inhibition by inhibitors 12g and 12i. Inhibition of the activity of human GVIA iPLA2 was tested on mixed-micelles containing 100 μM PAPC and 400 μM Triton X-100. Inhibition curves were generated using Graphpad Prism with a non-linear regression targeted at symmetrical sigmoidal curves based on plots of % inhibition versus log(inhibitor concentration). The reported XI(50) values were calculated from the resultant plots.
Figure 4
Figure 4
Model for the binding mode of fluoroketone inhibitors in the active-site crevice of GVIA iPLA2.
Scheme 1
Scheme 1
Reagents and conditions: (a) (i) (COCl)2, CH2Cl2, (ii) (C3F7CO)2O, pyridine, CH2Cl2.
Scheme 2
Scheme 2
Reagents and conditions: (a) C2H5OOCCH=CHCH2P(=O)(OC2H5)2, LiOH, THF; (b) (i) NaOH, 1,4-dioxane; (c) DMAP, NMM, WSCI•HCl, CH3ONHCH3 •HCl, CH2Cl2; (d) CF3CF2I, CH3Li•LiBr, Et2O.
Scheme 3
Scheme 3
Reagents and conditions: (a) (i) (COCl)2, CH2Cl2, (ii) (CF3CO)2O or (C2F5CO)2O or (C3F7CO)2O, pyridine, CH2Cl2; (b) C2H5OOCCH=CHCH2P(=O)(OC2H5)2, LiOH, THF; (c) H2, 10% Pd/C; (d) NaOH, CH3OH; (e) Br(CH2)3COOEt, K2CO3, acetone.
Scheme 4
Scheme 4
Reagents and conditions: (a) DAST, CH2Cl2 or (CH3OCH2CH2)2NSF3, CH2Cl2; (b) (i) (CH3)3SiCF3, CsF, CH3OCH2CH2OCH3 or (CH3)3SiCF3, TBAF, toluene, (ii) conc. HCl or TBAF, CH3COOH, THF.
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