Antipsoriatic anthrones with modulated redox properties. 1. Novel 10-substituted 1,8-dihydroxy-9(10H)-anthracenones as inhibitors of 5-lipoxygenase

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-l-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.Psoriasis is a widespread, chronic inflammatory and scaling skin disease, mainly characterized by increased cell proliferation of the epidermis.

Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer

“…S1). Chemicals belonging to the 10-benzylidene-10H-anthracen-9-one family have been previously implicated in some biological processes including inhibition of tubulin polymerization (21,38,39). However, this does not seem to be the mechanism of action observed in this work, as there was no correlation between antitubulin activity and either androgen displacement or androgen receptor transcriptional inhibition.…”

Current Status and Recent Developments in Anthracenone Antipsoriatics

“…10). In support of this, an ESR investigation of electronic and conformational effects in similarly substituted phenoxyl radicals revealed that the rotational barrier of a 4-methylthio substituted phenoxyl radical was eight-fold of the active methylene protons at C-10 was replaced by acyl substituents which permit control over the release of active oxygen species [106]. In this case, pairs of identical substituents act on the radical of a 10-acyl derivative, which gives rise to three mesomeric forms 40a-c (Fig.…”

“…This indicates that substitution of both hydrogen atoms at C-10 prevents free radical formation and produces inactive compounds. This is also documented by the lack of 5-LO inhibitory action by the 10,10'-dibenzylated 39, which is devoid of radical generating properties [106]. By contrast, 10-acyl substituted anthralin analogs retained their antipsoriatic activity and gave rise to free radicals [107,108], although their ESR signals were much weaker than that of anthralin.…”

3‐Alkyl‐ and 3‐Aryl‐(7‐oxo‐7H‐furo[3, 2‐g]chromen‐5‐yl)alkanoic Acids as Inhibitors of Leukotriene B4 Biosynthesis

“…The potential dark inhibitory activity of the compounds against LTB 4 biosynthesis was evaluated using calcium ionophore activated bovine polymorphonuclear leukocytes (PMNL) [22,23]. Furthermore, in addition to determining their lipophilicity, the photoreactive potential of the new of furocoumarins was also investigated through the capacity of the compounds to photobleach RNO [24].…”

“…The furocoumarins were investigated in vitro for their ability to inhibit LTB 4 production by calcium ionophore A23187 stimulated PMNL [22,23]. Results are expressed as percentage of inhibition of LTB 4 production at a concentration of 10 µM (Table 6).…”