Antipsoriatic anthrones with modulated redox properties. 3. 10-thio-substituted 1,8-dihydroxy-9(10H)-anthracenones as inhibitors of keratinocyte growth, 5-lipoxygenase, and the formation of 12(S)-HETE in mouse epidermis.
The synthesis of a series of 1,8-dihydroxy-9(10H)-anthracenones bearing sulfur-linked substituents in the 10-position is described. These compounds were evaluated for their ability to inhibit the growth of the human keratinocyte cell line HaCaT and the 5- and 12-lipoxygenase enzymes in bovine polymorphonuclear leukocytes and mouse epidermal homogenate, respectively. In addition, the following redox properties of the compounds were determined: reactivity against 2,2-diphenyl-1-picrylhydrazyl, generation of hydroxyl radicals as measured by deoxyribose degradation, and inhibition of lipid peroxidation in model membranes. Compounds 4e and 4h of this series compare favorably in the cellular assays with the antipsoriatic anthralin. They have the combined inhibitory action against leukotriene B4 and 12(S)-HETE formation and are highly potent antiproliferative agents against keratinocyte growth. In contrast to anthralin, 4h, 1,8-dihydroxy-10-[(4-hydroxyphenyl)thio]-9(10H)-anthracenone, is not cytotoxic as documented by the LDH activity released from cytoplasm of keratinocytes and does not enhance lipid peroxidation in model membranes.
Müller
K
K
Institut für Pharmazie, Universität Regensburg, Germany.
Huang
H S
HS
Wiegrebe
W
W
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D000875:Anthralin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy*
D000975:Antioxidants; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000875:Anthralin