[Methylated 2-aryl-1,4-naphtoquinone derivatives with diminished antioxidative activity].
Methylated 2-aryl-1,4-naphtoquinone derivatives with diminished antioxidative activity 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-1,4-naphthoquinone (1) is a selective 5-lipoxygenase (5-LOX) inhibitor possessing high antioxidative activity (AOA). In order to study the question if this activity corresponds to the mechanism of the 5-LOX inhibition (redox type 5-LOX inhibitor) the analogues 57-66 and their 3-methoxy derivatives 47-56 of the reference compound 1 were synthezised. These compounds are mono- and dimethylated within the benzoid molecular moiety which were tested for their 5-LOX inhibiting activity using human granulocytes and for their AOA by a chemiluminometric method. The synthesis of the test compounds runs in the following manner: Diels-Alder reaction of 1,4-benzoquinone (2) with the buta-1,3-dienes 3-8, bromination of the 1,4-naphthoquinones 9-14, arylation with 2,6-di-tert-butylphenol and substitution of bromine of the aryl-bromonaphthoquinones 33-46 by methoxy and hydroxy functions. A key step is the cc separation of the regioisomeric mixtures 25/26-31/32. The most potent 5-LOX inhibitors (IC50 = 1-3 microM) possess methylfunctions in 5-/8-position and show markedly diminished AOA compared with 1. 5-LOX inhibition and AOA in this class of compounds hence are not positively correlated.
Wurm
G
G
Institut für Pharmazie der Freien Universität Berlin, Germany. rehiwer@zedat.fu-berlin.de
Schwandt
S
S
D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006098:Granulocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007975:Leukotriene B4 / Q000096:biosynthesis; D008055:Lipids / Q000737:chemistry; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D010777:Photochemistry; D013329:Structure-Activity Relationship
D000975:Antioxidants; D007202:Indicators and Reagents; D008055:Lipids; D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D007975:Leukotriene B4
Methylierte 2-Aryl-1,4-naphthochinonderivate, 5-Lipoxygenase-Inhibitorenmit reduzierter antioxidativer Aktivität.Untersuchungen an 1,4-Naphthochinonen, 28. Mitt.