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Open Access Methylierte 2-Aryl-1,4-naphthochinonderivate, 5-Lipoxygenase-Inhibitoren mit reduzierter antioxidativer Aktivität

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2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-1,4-naphthochinon (1) ist ein selektiver 5-Lipoxygenase (5-LOX)-Inhibitor mit großer antioxidativer Aktivität (AOA). Um zu prüfen, ob diese Aktivität dem Mechanismus der 5-LOX-Hemmung entspricht (5-LOX-Inhibitor vom Redox-Typ), wurden die im benzoiden Molekülteil mono- und dimethylierten Analoga von 1, 57–66, und die entsprechenden 3-Methoxyderivate 47–56 synthetisiert. Diese Verbindungen wurden auf ihre 5-LOX-Hemmung mit humanen Granulozyten und chemiluminometrisch auf ihre AOA im Vergleich mit dem Standard 1 untersucht. Die Synthese der Testsubstanzen erfolgte über folgende Sequenz: Diels-Alder-Reaktion von 1,4-Benzochinon (2) mit den Buta-1,3-dienen 3–8, Bromierung der 1,4-Naphthochinone 9–14, Arylierung mit 2,6-Di-tert-butylphenol und Bromsubstitution der Aryl-bromnaphthochinone 33–46 durch Methoxy- und Hydroxyfunktionen. Ein Schlüsselschritt ist die sc Trennung der Regioisomerengemische 25/2631/32. Die potentesten 5-LOX-Inhibitoren (IC50 = 1–3 μM) besitzen Methylfunktionen in 5-/8-Position und zeigen deutlich geringere AOA als 1. 5-LOX-Hemmung und AOA sind in der untersuchten Verbindungsklasse folglich nicht positiv korreliert.

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 25/2631/32. 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.
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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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