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 c ould be an interesting pharmacological tool to influence psoriasis. Thus we synthezised 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-O-2 oxidation of the tetrahydroanthracenol 13 to the correspondin g 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 h alogenated quinones 9 and 21 were arylated with 2,6-di-tert-butylphenol and demethylated or hydrolyzed to the target compounds 3 and 4 which were test ed in comparison with the non-anellated 5-LOX inhibitors 1 and 2 for LOX in hibition in activated human granulocytes and for antioxidative activity by the method of Popov with the chemiluminometer Photochem(R). 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, t he tetrahydroanthraquinon derivatives 3 and 4 are less potent than the naph thoquinones 1 and 2. All compounds are devoid of any activity in cell diffe rentiation as compared to retinoic acid as indicated by the NBT test with H L-60 leukemia cells.