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  • Title: [Inhibition of the arachidonic acid cascade by aza-2-aryl-1,4-naphthoquinone derivatives].
    Author: Richwien A, Wurm G.
    Journal: Pharmazie; 2004 Dec; 59(12):906-12. PubMed ID: 15638076.
    Abstract:
    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.
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