2-Oxoamide inhibitors of phospholipase A2 activity and cellular arachidonate release based on dipeptides and pseudodipeptides.
A series of 2-oxoamides based on dipeptides and pseudodipeptides were synthesized and their activities towards two human intracellular phospholipases A(2) (GIVA cPLA(2) and GVIA iPLA(2)) and one human secretory phospholipase A(2) (GV sPLA(2)) were evaluated. Derivatives containing a free carboxyl group are selective GIVA cPLA(2) inhibitors. A derivative based on the ethyl ester of an ether pseudodipeptide is the first 2-oxoamide, which preferentially inhibits GVIA iPLA(2). The effect of 2-oxoamides on the generation of arachidonic acid from RAW 264.7 macrophages was also studied and it was found that selective GIVA cPLA(2) inhibitors preferentially inhibited cellular arachidonic acid release; one pseudodipeptide gave an IC(50) value of 2muM.
Barbayianni
Efrosini
E
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis, Athens, Greece.
Stephens
Daren
D
Grkovich
Andrej
A
Magrioti
Victoria
V
Hsu
Yuan-Hao
YH
Dolatzas
Panagiotis
P
Kalogiannidis
Dimitrios
D
Dennis
Edward A
EA
Kokotos
George
G
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D054510:Phospholipases A2, Cytosolic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004151:Dipeptides; D011725:Pyridines; D016718:Arachidonic Acid; C034960:oxoamide; D054510:Phospholipases A2, Cytosolic; D054497:Phospholipases A2, Secretory