[Inhibition of the arachidonic acid cascade by aza-2-aryl-1,4-naphthoquinone derivatives].
Inhibition of the arachidonic acid cascade by aza-2-aryl-1,4-naphthoquinone derivatives To find more potent 5-lipoxygenase(LO)-inhibitors than the up to now studied 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-1,4-naphthoquinone derivatives the analogous aza-1,4-naphthoquinones 14, 15, 16/17 as well as the 3-bromo precursors 7, 8, 9/10 and 11 were synthesized. The naphtho[2,1-b][1,4]thiazin derivative 21 was included in this investigation as a quinone imine. Beside 5-LO inhibition the influence on 12-LO, COX-1 and cPLA2 was determined to investigate the selectivity of the compounds within the arachidonic acid cascade. To test the biochemical properties human granulocytes (5-LO) and human platelets (12-LO/COX-1 and cPLA2) were used. All 3-bromo compounds inhibit completely the arachidonic acid cascade by blocking the cPLA2. The 3-methoxy derivatives of the quinoline quinones 12 and 13 and the 3-hydroxyisoquinoline mixture 16/17 show 5-LO selectivity. 13 inhibits 5-LO selectively, 12 is a dual 5-LO/COX-1-inhibitor and 16/17 are dual 12-LO/COX-1-inhibitors. To verify the hypothesis that the hydroxylated 2-aryl-1,4-benzoquinone structure is the pharmacophore for 5-LO-inhibition within the class of 2-aryl-1,4-naphtho- and -aza-naphthoquinones the 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,4-benzoquinones 24-28 were synthesized. It was shown that the 5-methoxy and 5-hydroxy compounds 24 and 27 are highly selective and potent 5-LO-inhibitors.
Richwien
A
A
Institut für Pharmazie der Freien Universität Berlin, Germany.
Wurm
G
G
D016718:Arachidonic Acid / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008565:Membrane Proteins; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D010740:Phospholipases / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D009285:Naphthoquinones; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010740:Phospholipases