Anthralin Inhibition of Mouse Epidermal Arachidonic Acid Lipoxygenase In Vitro

Bedord, Charles J.; Young, J. M.; Wagner, Bonnie M.

doi:10.1111/1523-1747.ep12523249

Cited by 54 publications

(9 citation statements)

References 20 publications

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“…The recovery of the internal standard PGB 2 was used to correct for losses during sample preparation. Molar absorption coefficients (M" 1 cm* 1 ) of 28,650 for PGB 2 and 50,000 for LTB 4 at 270 nm and 29,500 for 5-HETE at 232 nm were used 6) .…”

Section: Reversed-phase High-performance Liquid Chromatography 2 ®mentioning

confidence: 99%

Anthralin derivatives—inhibition of 5‐lipoxygenase—antipsoriatic efficacy

Tanzer

Braun

Seidel

et al. 1991

Archiv der Pharmazie

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Inhibition of 5-lipoxygenase by anthralin (1) and 41 derivatives is determined: the acids 38 and 39, the lactones 40-42 and 9-anthrone (8) are the most potent inhibitors, the lactone 41 reaching the efficacy of nordihydroguaiaretic acid (NDGA). The results were correlated with the hydrophilic/lipophilic balance of the test compounds and their clinical efficacy as far as known. There is no correlation between the "minimum structure" of Krebs and SchalteggeP^ concerning antipsoriatic activity and the inhibitory effects against 5-lipoxygenase. Dithranol-Derivate: Hemmung der 5-Lipoxygenase und antipsoriatische WirksamkeitDie Hemmung der 5-Lipoxygenase durch Dithranol (1) und 41 Derivate wird bestimmt: die Säuren 38 und 39, die Laktone 40-42 und 9-Anthron (8) sind die stärksten Inhibitoren, das Lakton 41 erreicht die Wirksamkeit der Nordihydroguajaretsäure. Die Ergebnisse werden mit den hydrophilen/lipophilen Eigenschaften der Verbindungen und -soweit bekannt -mit deren klinischer Wirksamkeit in Beziehung gesetzt: es besteht keine Korrelation zwischen der sog. "antipsoriatischen Minimalstruktur" nach Krebs und SchalteggeP^ und der Hemm wirkung auf die 5-Lipoxygenase.Psoriasis is a common chronic inflammatory and proliferative skin disease with unknown aetiology. An important feature is the abnormal metabolism of arachidonic acid, particularly by the lipoxygenase pathways. Lesional skin contains increased concentrations of arachidonic acid, 12-HETE and LTB 4 , whereas the cyclooxygenase-products PGF^ and PGE2 are only modestly elevated 1 *. LTB 4 and 12-HETE are potent chemoattractans for human polymorphonuclear leukocytes (PMNs) 2) , which are part of a characteristic inflammatory infiltrate and were suggested to play an important physiologic role in cutaneous lesion of psoriasis 3 *. In the present study structure-activity relationships concerning the in vitro 5-lipoxygenase inhibitory activity of various anthrone derivatives and related compounds were investigated. The results were compared with the antipsoriatic properties of the compounds according to the "minimum structure" concept by Krebs and SchalteggeP\ Anthralin (dithranol Materials and Methods

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Section: Reversed-phase High-performance Liquid Chromatography 2 ®mentioning

confidence: 99%

Anthralin derivatives—inhibition of 5‐lipoxygenase—antipsoriatic efficacy

Tanzer

Braun

Seidel

et al. 1991

Archiv der Pharmazie

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“…21 * 22 The biosynthesis of eicosanoids occurs via the formation of free radicals. 23 Therefore, compounds with antioxidant properties would be expected to be potential inhibitors of 5-LO.…”

mentioning

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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“…In the present experiment dithranol was applied to the skin as a suspension in a mixed cellulose ester film which restricted the spread of the drug from the experimental area and facilitated its removal after 12 h. The clinical response and changes in PGE2 concentration followed a similar pattern to the previous results for dithranol in yellow soft paraffin. In contrast, 12-HETE had risen at 12 h (P < 0.05), then declined in all subjects at 48 h before again increasing significantly at 72 h. Dithranol is reported to inhibit 12-lipoxygenase, but not cyclo-oxygenase, activity in epidermal homogenates (Bedord et al, 1983). The rise in 12-HETE during the mobilisation of arachidonic acid from phospholipids in the inflammatory reaction to dithranol may be suppressed to some extent by the inhibition of 12-lipoxygenase activity as the concentration of dithranol in the skin increases.…”

Section: Controlmentioning

confidence: 78%

Lipoxygenase products of arachidonic acid in human inflamed skin.

Black¹,

Barr²,

Wong³

et al. 1985

Brit J Clinical Pharma

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Monohydroxy acids (HETEs) and leukotriene B4 (LTB4) metabolites of arachidonic acid were measured in skin of healthy volunteers after ultraviolet B irradiation, and in the uninvolved skin of psoriatics after topical dithranol application. Exudate was collected from suction bullae on control and inflamed abdominal skin, and analysed for 12‐HETE and PGE2 by GC‐MS and LTB4 by bioassay. 12‐HETE and PGE2 were raised at 24 h but not at 72 h after u.v.B irradiation: control and 24 h values were 13.7 and 41.5 ng ml‐1 (P less than 0.05, n = 6) for 12‐HETE respectively, and 4.5 and 30.2 ng ml‐1 (P less than 0.01, n = 6) for PGE2. Dithranol application raised PGE2 levels from 23.1 ng ml‐1 in control exudate to 62 ng ml‐1 (P less than 0.01, n = 6) at 24 h before declining to base levels at 72 h. However, 12‐HETE was raised at 72 h (200 ng ml‐1, P less than 0.01, n = 5) but not at 24 h (104 ng ml‐1) compared to control levels (50 ng ml‐1, n = 5). The levels of the LTB4 were low (less than 100 pg ml‐1), and no significant increases were observed. Arachidonic acid in inflamed skin can be metabolised by the cyclo‐oxygenase and lipoxygenase pathway. It is probable that the lipoxygenase product 12‐HETE is involved in these inflammatory reactions.

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Anthralin Inhibition of Mouse Epidermal Arachidonic Acid Lipoxygenase In Vitro

Cited by 54 publications

References 20 publications

Anthralin derivatives—inhibition of 5‐lipoxygenase—antipsoriatic efficacy

Anthralin derivatives—inhibition of 5‐lipoxygenase—antipsoriatic efficacy

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

Lipoxygenase products of arachidonic acid in human inflamed skin.

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