title: Structure-activity relationship studies of 3-dodecanoylindole-2-carboxylic acid inhibitors of cytosolic phospholipase A2alpha-mediated arachidonic acid release in intact platelets: variation of the keto moiety.
abstract: Recently we found that 1-methyldodecanoylindole-2-carboxylic acid (1) and 1-[2-(4-carboxyphenoxy)ethyl]-3-dodecanoylindole-2-carboxylic acid (4) were inhibitors of the cytosolic phospholipase A2alpha (cPLA2alpha)-mediated arachidonic acid release in calcium ionophore A23187-stimulated human platelets with IC50-values of 4.8 microM (1) and 0.86 microM (4). We have now replaced the 3-acyl residue of these compounds by alkylated sulfinyl-, sulfony-, sulfinamoyl-, sulfamoyl-, carbonylamino-, or carbonylaminomethyl-substituents. Structure-activity relationship studies revealed that the pronounced cellular activity of 4 strongly depends on the presence of the 3-acyl moiety. Surprisingly, when testing 4 and its derivatives in an assay with the isolated cPLA2, none of these compounds showed an inhibitory potency at 10 microM indicating that they do not inhibit cPLA2alpha in the cells by a direct interaction with the active site of the enzyme.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62 D-48149 Münster, Germany.
authors.forename: Afshin
authors.initials: A
authors.lastname: Ghasemi
authors.forename: Alwine Schulze
authors.initials: AS
authors.lastname: Elfringhoff
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism*; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054513:Group IV Phospholipases A2; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C438979:3-dodecanoylindole-2-carboxylic acid; D004791:Enzyme Inhibitors; D007211:Indoles; D016718:Arachidonic Acid; D000001:Calcimycin; D010741:Phospholipases A; D054513:Group IV Phospholipases A2