Antipsoriatic Anthrones with Modulated Redox Properties, 1. Novel 10-Substituted 1,8-Dihydroxy-9(10H)-anthracenones as Inhibitors of 5-Lipoxygenase

摘要

The syntheses, the biological evaluation, and the structure-activity relationships of a novel seriesudof l,8-dihydroxy-9(10H)-anthracenones bearing acyl-, alkyl-, or alkylidene-linked aromaticudsubstituents in the 10-position are described. The phenylacyl and phenylalkylidene analogs wereudfar more potent inhibitors of 5-lipoxygenase (5-LO) from bovine polymorphonuclear leukocytesud(IC50 values in the 10- 7 M range) than the antipsoriatic drug anthralin, whereas phenylalkyl analogsudwere only weak inhibitors. Among the active compounds were both potent generators of hydroxyludradicals, as determined by deoxyribose degradation, and strong reducers of the stable free radicalud2,2-diphenyl-1-picrylhydrazyl (DPPH). However, several derivatives of this series maintainedud5-LO inhibitory activity but did not generate hydroxyl radicals and were not reactive with DPPH .udIn particular, phenylacyl analogs were also 6 times more efficient in inhibition of lipid peroxidationudin model membranes than anthralin. Structure-activity relationships have shown that the presenceudof free phenolic groups in the attached aromatic ring is beneficial but not required for 5-LOudinhibitory potency. The inhibitory potency in the 10-phenylacyl series increased with the lengthudof the acyl chain with three methylene units being the optimum, suggesting a specific enzymeudinteraction which would not be expected for nonspecific redox inhibitors.