Differential inhibition of human secretory and cytosolic phospholipase A2.
The roles and relative contributions of secretory and cytosolic phospholipases A2 in physiology and pathology are not precisely known. In a search for differential inhibitors of these enzymes, which could serve as tools to clarify this issue, we evaluated the potencies of reference compounds and three series of new compounds, viz. substrate analogues, 1,2-amino alcohols and enolized beta-tricarbonyl derivatives, as inhibitors of secretory phospholipase A2 from human polymorphonuclear leukocytes (sPLA2) and of cytosolic phospholipase A2 from human U937 cells (cPLA2). With few exceptions, the compounds selected are potent inhibitors of sPLA2 with IC50 values (concentration inhibiting 50%) in the low micromolar range. Inhibition of cPLA2 was only observed with some phosphate-free substrate analogues, with 1,2-amino alcohols and two of seven reference compounds. These results suggest that inhibition of secretory and of cytosolic phospholipases A2 are independent effects. Several inhibitors could be identified with a marked selectivity for sPLA2.
Märki
F
F
Research Department, Ciba-Geigy Limited, Basel, Switzerland.
Breitenstein
W
W
Beriger
E
E
Bernasconi
R
R
Caravatti
G
G
Francis
J E
JE
Paioni
R
R
Wehrli
H U
HU
Wiederkehr
R
R
D000605:Amino Alcohols / Q000737:chemistry / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D014407:Tumor Cells, Cultured
D000605:Amino Alcohols; D010741:Phospholipases A; D054467:Phospholipases A2