Synthesis and biological evaluation of novel 10-benzyl-substituted 4,5-dichloro-10H-anthracen-9-ones as inhibitors of keratinocyte hyperproliferation.
A series of 10-substituted 4,5-dichloro-10H-anthracen-9-ones were synthesized in the search for novel agents against keratinocyte hyperproliferation. The antiproliferative activity of these novel anthrones was evaluated using the human keratinocyte line HaCaT as the primary test system. Structure-activity relationships with respect to the nature and position of the substituents at the benzyl moiety were studied, with a 3-hydroxy-4-methoxy-substitution pattern being the most potent (IC(50) = 0.7 μM) and comparable to the potency of the antipsoriatic anthralin. In contrast to anthralin, inhibition of keratinocyte hyperproliferation was not mediated by damage to the keratinocyte membrane, as the activity of lactate dehydrogenase released from the cytoplasm was in the control range. These findings may be rationalized as a benefit of the ineffectiveness of the novel anthrones to interact with the free radical 2,2-diphenyl-1-picrylhydrazyl.
Kratz
Ulrich
U
Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Hittorfstraße 58-62, D-48149 Münster, Germany.
Prinz
Helge
H
Müller
Klaus
K
D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
D000873:Anthracenes