Novel 10-substituted antipsoriatic anthrones as inhibitors of epidermal 12-lipoxygenase and lipid peroxidation in membranes

Müller, Klaus; Gawlik, Ingo

doi:10.1016/0006-2952(95)02114-0

Cited by 16 publications

(17 citation statements)

References 55 publications

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“…44,45 Anthralin showed higher selectivity for epidermal 12-LO versus the platelet enzyme (IC 50 values are 9 and 30 µM, respectively). 22 With psoriasis as target for therapy, potential 12-LO inhibitors have to be evaluated using epidermal 12-LO. 21 In this study we used epidermal strips from mouse skin to investigate the effects of the novel 10-thiosubstituted analogs.…”

Section: Inhibition Of 12(s)-hete Formationmentioning

confidence: 99%

Antipsoriatic Anthrones with Modulated Redox Properties. 3. 10-Thio-Substituted 1,8-Dihydroxy-9(10H)-anthracenones as Inhibitors of Keratinocyte Growth, 5-Lipoxygenase, and the Formation of 12(S)-HETE in Mouse Epidermis

1996

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The synthesis of a series of 1,8-dihydroxy-9(10H)-anthracenones bearing sulfur-linked substituents in the 10-position is described. These compounds were evaluated for their ability to inhibit the growth of the human keratinocyte cell line HaCaT and the 5- and 12-lipoxygenase enzymes in bovine polymorphonuclear leukocytes and mouse epidermal homogenate, respectively. In addition, the following redox properties of the compounds were determined: reactivity against 2,2-diphenyl-1-picrylhydrazyl, generation of hydroxyl radicals as measured by deoxyribose degradation, and inhibition of lipid peroxidation in model membranes. Compounds 4e and 4h of this series compare favorably in the cellular assays with the antipsoriatic anthralin. They have the combined inhibitory action against leukotriene B4 and 12(S)-HETE formation and are highly potent antiproliferative agents against keratinocyte growth. In contrast to anthralin, 4h, 1,8-dihydroxy-10-[(4-hydroxyphenyl)thio]-9(10H)-anthracenone, is not cytotoxic as documented by the LDH activity released from cytoplasm of keratinocytes and does not enhance lipid peroxidation in model membranes.

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Section: Inhibition Of 12(s)-hete Formationmentioning

confidence: 99%

Antipsoriatic Anthrones with Modulated Redox Properties. 3. 10-Thio-Substituted 1,8-Dihydroxy-9(10H)-anthracenones as Inhibitors of Keratinocyte Growth, 5-Lipoxygenase, and the Formation of 12(S)-HETE in Mouse Epidermis

1996

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“…12-HETE stimulates keratinocyte proliferation and induces histological changes characteristic of psoriasis [19][20][21] . Based on this information, we evaluated the ability of the novel compounds to inhibit the 12-LO pathway in epidermal homogenate of mice [22] .…”

Section: Biological Evaluationmentioning

confidence: 99%

“…To exclude oxidation of arachidonic acid by a nonspecific free radical mechanism which affords racemic 12-HETE, the absolute stereochemistry of 12-HETE was determined by chiral phase HPLC to confirm the presence of the S-enantiomer [22] .…”

Section: Inhibition Of 12(s)-hete Biosynthesismentioning

confidence: 99%

“…Preparation of the epidermal homogenate from NMRI-mice and the epidermal 12-LO assay were performed as described [22] . Test compounds were preincubated for 5 min at 37 °C, and the concentration of 12(S)-HETE formed after 10 min was measured by reversed-phase HPLC analysis.…”

Section: Inhibition Of 12(s)-hete Biosynthesismentioning

confidence: 99%

“…Test compounds were preincubated for 5 min at 37 °C, and the concentration of 12(S)-HETE formed after 10 min was measured by reversed-phase HPLC analysis. 12(S)-HETE was analyzed by chiral phase chromatography as described [22] .…”

Section: Inhibition Of 12(s)-hete Biosynthesismentioning

confidence: 99%

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10-α-Aminoacyl-9(10H)-anthracenones: Inhibition of 12(S)-HETE Biosynthesis and HaCaT Cell Growth

Müller¹,

Breu²

1999

Arch. Pharm. Pharm. Med. Chem.

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1,8‐Dihydroxy‐9(10H)‐anthracenones with a 10‐α‐aminoacyl group were synthesized using either a mixed‐anhydride coupling method or Boc‐protected oxazolidinediones. The novel anthracenones were evaluated as inhibitors of the biosynthesis of 12(S)‐hydroxyeicosatetraenoic acid (12(S)‐HETE) in epidermal homogenate of mice and for inhibition of the growth of HaCaT keratinocytes. These cells were also tested for their susceptibility for the action of the most potent members of this series on plasma membrane integrity, in order to confirm that inhibition of cell growth is not a result of membrane damage induced by prooxidants released from anthracenones. Hydroxyl‐radical generation as measure of the prooxidant potential of the compounds was determined by deoxyribose degradation. The most potent analogues of this series were equally potent as anthralin against 12(S)‐HETE biosynthesis and keratinocyte proliferation, while oxygen‐radical generation and the resulting damage to cell membrane was strongly reduced as compared to the antipsoriatic drug.

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Potent Antipsoriatic Agents: A Facile Preparation of Acylated Derivatives from Dithranol in a Mild Basic Reaction

Liang

2004

J Chinese Chemical Soc

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Treatment of dithranol 1 with various equivalents of acetyl chloride and Et3N in THF at room temperature afforded the corresponding acylated derivatives, such as 1‐acetyloxy‐ and 1,8‐diacetyloxy‐9(10H)‐anthracenones, 6a, and 6b, as well as 1,8,9‐triacetyloxyanthracene 7a, and 1,8,9‐triacetyloxy‐10‐acetylanthracene 7b. 1,8‐Bis(trimethylacetyloxy)‐9(10H)‐anthracenone 6c was also obtained in high yield by using pivaloyl chloride during the mild acylation.

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Novel 10-substituted antipsoriatic anthrones as inhibitors of epidermal 12-lipoxygenase and lipid peroxidation in membranes

Cited by 16 publications

References 55 publications

Antipsoriatic Anthrones with Modulated Redox Properties. 3. 10-Thio-Substituted 1,8-Dihydroxy-9(10H)-anthracenones as Inhibitors of Keratinocyte Growth, 5-Lipoxygenase, and the Formation of 12(S)-HETE in Mouse Epidermis

Antipsoriatic Anthrones with Modulated Redox Properties. 3. 10-Thio-Substituted 1,8-Dihydroxy-9(10H)-anthracenones as Inhibitors of Keratinocyte Growth, 5-Lipoxygenase, and the Formation of 12(S)-HETE in Mouse Epidermis

10-α-Aminoacyl-9(10H)-anthracenones: Inhibition of 12(S)-HETE Biosynthesis and HaCaT Cell Growth

Potent Antipsoriatic Agents: A Facile Preparation of Acylated Derivatives from Dithranol in a Mild Basic Reaction

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