Methylierte 2-Aryl-1,4-naphthochinonderivate, 5-Lipoxygenase-Inhibitoren mit reduzierter antioxidativer Aktivität
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-bromo-naphthoquinones 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 μM) 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.
Document Type: Research Article
Affiliations: 1: Institut für Pharmazie der Freien Universität Berlin, Königin-Luise-Str. 2–4, Berlin, D-14195, Germany, Email: [email protected] 2: Institut für Pharmazie der Freien Universität Berlin, Berlin, Germany
Publication date: August 1, 2003
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