The relevance of secondary radicals in the mode of action of anthralin

Lambelet, Pierre; Ducret, F.; Löliger, J.; Maignan, J.; Reichert, Uwe; Shroot, Braham

doi:10.1016/0891-5849(90)90026-f

Cited by 15 publications

(12 citation statements)

References 21 publications

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“…17 Hence, inhibitors which lack hydroxyl-radical formation may be expected to be devoid of skin-irritating properties. Furthermore, redox inhibitors are oxidized during their action on LO.…”

Section: Discussionmentioning

confidence: 99%

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

Müller

Gürster²,

Piwek³

et al. 1993

J. Med. Chem.

112

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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.

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Section: Discussionmentioning

confidence: 99%

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

Müller

Gürster²,

Piwek³

et al. 1993

J. Med. Chem.

112

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“…Therefore, generation of the radical by means of these rather harsh conditions may not be relevant to the biological situation. EPR spectra that have been attributed to AN* have also been observed in solutions of peroxidizing lipids (39,40) and in strongly alkaline aqueous solutions (41) containing anthralin. In the present study we have utilized the EPR spin trapping technique (42) to investigate the generation of anthralin-derived radicals under more physiological conditions.…”

Section: Introductionmentioning

confidence: 76%

Detection and characterization of 9-anthron-10-yl radicals formed by antipsoriatic and tumor-promoting 9-anthrones in aqueous buffers

Hayden

Chignell²

1993

Chem. Res. Toxicol.

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Certain 1,8-dihydroxy-9-anthrones have been used for the topical treatment of psoriasis for over seventy-five years. The therapeutic usefulness of these compounds is limited, however, by side effects including severe skin inflammation and staining. Antipsoriatic 9-anthrones are also tumor promoters in mouse skin. The chemical mechanisms underlying the biological properties of 9-anthrones are believed to involve the generation of free radical products such as 9-anthron-10-yl radicals or secondary oxygen radicals such as O2.- or OH.. However, the specific role that 9-anthron-10-yl radicals may play in mediating the biological effects of 9-anthrones is uncertain because these species have not been detected in biological systems. In the present study we have used the EPR spin trapping technique to demonstrate for the first time the formation of the 1,8-dihydroxy-9-anthron-10-yl radical in aqueous buffers. Additionally, in order to gain information concerning the role of 9-anthron-10-yl radicals in tumor promotion and antipsoriatic activities, we have used this technique to investigate the formation of these radical species by a series of 9-anthrones of known tumor-promoting and antipsoriatic activities. All of the 9-anthrones studied formed spin adducts with 3,5-dibromo-4-nitrosobenzenesulfonic acid in aqueous buffers. The formation of these adducts was pH-dependent, being favored at alkaline pH.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…A mechanism of the oxidative degradation of anthralin proposed by Hayden and Chignell [12] starts with the forrrjation of the anthralin anion, which further reacts witli oxygen to form the 1,8-dihydroxy-9-anthronl()_yl_radical and the superoxide anion. How this oxidative metaholism leads to hiologic damage remains to he elucidated and is an area of continuing investigation [11,12,13,18].…”

Section: Discussionmentioning

confidence: 99%

“…In this paper, we focused our attention on anthralin (1,8-dihydroxy-9-anthrone; dithranol), which is widely used for the topical treatment of psoria,sis [10], It is well known that anthralin is a labile drug that is easily oxidized to the corresponding quinone, a dimer, and finally to ether-insoluble compounds, the so-called "dithranol-brown" [11], The involvement of free radicals in the oxidation of anthralin has been demonstrated in solutions using EPR spectroscopy and EPR spin trapping [12,13], The in vitro formation of antbralin radicals in isolated pig skin also has been demonstrated, including the use of carbon-13-labeled anthralin. These studies resulted in significant line-broadening, .supporting the direct involvement of anthralin in the formation of the radicals [14], The authors attributed the single line (g = 2,0028) to the anthronyl radical, although no hyperfine splitting was observed, Anthralinderived radicals in the skin of nude mice also were observed iit vitro by Fuchs and Packer [15], The detected signal had a g-factor of 2,0036 and a line width of 6 gauss, with no observable hyperfine splitting.…”

mentioning

confidence: 99%

In Vivo Detection of Anthralin-Derived Free Radicals in the Skin of Hairless Mice by Low-Frequency Electron Paramagnetic Resonance Spectroscopy

Mäder

Bačić

Swartz

1995

Journal of Investigative Dermatology

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Free radicals were directly detected in vivo in the skin of hairless mice by low-frequency electron paramagnetic resonance spectroscopy after topical application of anthralin under pertinent therapeutic conditions. The electron paramagnetic resonance signal intensity increased steadily, reaching a maximum after about 1 d and decreased slowly in the foUoiving days, probably because of desquamation of the skin. We conclude from the spectroscopic features (single line with a line width of 6 gauss; g = 2.0036) and from the pharmacokinetic pattern that the observed signal arises from tbe final products of anthralin metabolism (ether-insoluble polymeric structures-"antbralin brown"). Two potential antioxidants, vitamin E and the spin trap tert-butylpbenylnitrone, decreased the amount of tbe anthralin-derived radical that was formed. Neither vitamin E radicals nor tert-butylphenylnitrone spin adducts were observed. We suggest tbat electron paramagnetic resonance is a valuable tool for tbe noninvasive and direct iti vivo monitoring of drug-induced radical formation in the skin under therapeutic conditions.

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The relevance of secondary radicals in the mode of action of anthralin

Cited by 15 publications

References 21 publications

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

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

Detection and characterization of 9-anthron-10-yl radicals formed by antipsoriatic and tumor-promoting 9-anthrones in aqueous buffers

In Vivo Detection of Anthralin-Derived Free Radicals in the Skin of Hairless Mice by Low-Frequency Electron Paramagnetic Resonance Spectroscopy

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