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.