title: 2-Oxoamide inhibitors of phospholipase A2 activity and cellular arachidonate release based on dipeptides and pseudodipeptides.
abstract: 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.
authors.affiliation: Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis, Athens, Greece.
authors.forename: Efrosini
authors.initials: E
authors.lastname: Barbayianni
authors.forename: Daren
authors.initials: D
authors.lastname: Stephens
authors.forename: Andrej
authors.initials: A
authors.lastname: Grkovich
authors.forename: Victoria
authors.initials: V
authors.lastname: Magrioti
authors.forename: Yuan-Hao
authors.initials: YH
authors.lastname: Hsu
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Dolatzas
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kalogiannidis
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
mesh_terms: 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
chemical_list: D004151:Dipeptides; D011725:Pyridines; D016718:Arachidonic Acid; C034960:oxoamide; D054510:Phospholipases A2, Cytosolic; D054497:Phospholipases A2, Secretory