[Influence of 2-aryl-3-halogen/3-hydroxy-1,4-naphthoquinones with salicylic and cinnamic acid partial structures on the arachidonic acid cascade].
Searching for more potent 5-lipoxygenase (LO) inhibitors one tert-butyl group of the selective 5-LO-inhibitor 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-1,4-naphthoquinone (1) was substituted by polar functions (-CHO, -COOH, -CH=CH-COOR, -CH2-CH2-COOR). At the same time the 5-LO selectivity of the new compounds within the arachidonic acid cascade was investigated. For this 12-LO- and COX-1-assays with activated human platelets were used. Screening the test compounds new selective 5-LO-inhibitors (4, 9 and 16) and a COX-1-inhibitor (10) as well as dual 5-LO/COX-1- (23) and 12-LO/COX-1- (12) inhibiting compounds were found. Obviously in this class of compounds 5-LO and 12-LO inhibition are mutually excluded for a structural reason. In addition to the well known 3-chloro- (19) and 3-bromo- (20) analogues of 1 the 3-fluoro- (22), 3-iodo- (23) and the 3-carbonitrile- (24) derivatives were synthesized. All 3-halogen compounds, except 23 and the nitrile, are potent non selective inhibitors of all three enzymes. Causative for this unselectivity is the inhibition of the arachidonic acid release by inhibition of the cytosolic phospholipase A2 (cPLA2) with the exception of 24.
Richwien
A
A
Institut für Pharmazie der Freien Universität Berlin, Germany. rehiwer@zedat.fu-berlin.de
Wurm
G
G
D016718:Arachidonic Acid / Q000378:metabolism*; D001773:Blood Cells / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002934:Cinnamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012459:Salicylates / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002934:Cinnamates; D006219:Halogens; D007202:Indicators and Reagents; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D009285:Naphthoquinones; D010975:Platelet Aggregation Inhibitors; D012459:Salicylates; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases