Müller, K., Gürster, D., Piwek, S. and Wiegrebe, Wolfgang
(1993)
Antipsoriatic Anthrones with Modulated Redox Properties, 1. Novel 10-Substituted 1,8-Dihydroxy-9(10H)-anthracenones as Inhibitors of 5-Lipoxygenase.
European Journal of Medicinal Chemistry 36 (25), pp. 4099-4107.
Date of publication of this fulltext: 12 Jul 2010 07:53
Abstract
The syntheses, the biological evaluation, and the structure-activity relationships of a novel series
of l,8-dihydroxy-9(10H)-anthracenones bearing acyl-, alkyl-, or alkylidene-linked aromatic
substituents in the 10-position are described. The phenylacyl and phenylalkylidene analogs were
far more potent inhibitors of 5-lipoxygenase (5-LO) from bovine polymorphonuclear leukocytes
(IC50 values in ...
Abstract
The syntheses, the biological evaluation, and the structure-activity relationships of a novel series
of l,8-dihydroxy-9(10H)-anthracenones bearing acyl-, alkyl-, or alkylidene-linked aromatic
substituents in the 10-position are described. The phenylacyl and phenylalkylidene analogs were
far more potent inhibitors of 5-lipoxygenase (5-LO) from bovine polymorphonuclear leukocytes
(IC50 values in the 10- 7 M range) than the antipsoriatic drug anthralin, whereas phenylalkyl analogs
were only weak inhibitors. Among the active compounds were both potent generators of hydroxyl
radicals, as determined by deoxyribose degradation, and strong reducers of the stable free radical
2,2-diphenyl-1-picrylhydrazyl (DPPH). However, several derivatives of this series maintained
5-LO inhibitory activity but did not generate hydroxyl radicals and were not reactive with DPPH .
In particular, phenylacyl analogs were also 6 times more efficient in inhibition of lipid peroxidation
in model membranes than anthralin. Structure-activity relationships have shown that the presence
of free phenolic groups in the attached aromatic ring is beneficial but not required for 5-LO
inhibitory potency. The inhibitory potency in the 10-phenylacyl series increased with the length
of the acyl chain with three methylene units being the optimum, suggesting a specific enzyme
interaction which would not be expected for nonspecific redox inhibitors.
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