[Partially hydrogenated aryl-1,2/1,4-anthraquinone derivatives, 5-lipoxygenase inhibitors with arotinoid structure].
The combination of 5-LOX inhibition and retinoid activity in one molecule could be an interesting pharmacological tool to influence psoriasis. Thus we synthesized compounds with arotinoid structure by anellation of the 5-LOX inhibitors 1 and 2 with 1,1,4,4-tetramethylcyclohexane. A key step was the CuCl-MeCN-O2 oxidation of tetrahydroanthracenol 13 to the corresponding 1,2-anthraquinone 14 which could be converted to the analogous 2-hydroxy-1,4-anthraquinone 19 by Thiele-Winter reaction followed by oxidation. The halogenated quinones 9 and 21 were arylated with 2,6-di-tertbutylphenol and demethylated or hydrolyzed to the target compounds 3 and 4 which were tested in comparison with the non-anellated 5-LOX inhibitors 1 and 2 for LOX inhibition in activated human granulocytes and for antioxidative activity by the method of Popov with the chemiluminometer Photochem. The results are discussed in relation to the corresponding logP values. The 1,2-quinones 1 and 3 are more potent 5-LOX inhibitors than their 1,4-analogues 2 and 4, the tetrahydroanthraquinon derivatives 3 and 4 are less potent than the naphthoquinones 1 and 2. All compounds are devoid of any activity in cell differentiation as compared to retinoic acid as indicated by the NBT test with HL-60 leukemia cells.
Wurm
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Institut für Pharmazie, Freien Universität Berlin, Germany. Rehiwer@zedat.fu-berlin.de
Probst
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Schwandt
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D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000494:pharmacology; D009580:Nitroblue Tetrazolium; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000187:drug effects
D000880:Anthraquinones; D000975:Antioxidants; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D009580:Nitroblue Tetrazolium