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

Müller, Klaus; Huang, Hsu Shan; Wiegrebe, Wolfgang

doi:10.1021/jm960259l

Cited by 30 publications

(21 citation statements)

References 59 publications

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“…This was assessed by the activity of LDH (lactate dehydrogenase) released into the culture medium, which is commonly used as an indicator of plasma membrane damage [9,38].…”

Section: Biological Assay Methodsmentioning

confidence: 99%

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Structure–activity relationship studies of acridones as potential antipsoriatic agents. 1. Synthesis and antiproliferative activity of simple N-unsubstituted 10H-acridin-9-ones against human keratinocyte growth

Putic

Stecher

Prinz

et al. 2010

European Journal of Medicinal Chemistry

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A series of N-unsubstituted hydroxy-10H-acridin-9-ones were synthesized and evaluated for inhibitory action against HaCaT keratinocyte growth, in order to explore their potential as antipsoriatic agents. For structure-activity relationship studies, the number and position of the hydroxyl groups were modified, the oxygen functions substituted or replaced, or additional functional groups were introduced into the acridone scaffold. 1,8-Dihydroxy-10H-acridin-9-one (4), which is an aza-analogue of the antipsoriatic anthralin, was only marginally active. However, 1,3-dihydroxy-substituted 5ee was the most potent acridone within this series and inhibited keratinocyte growth with an IC(50) value comparable to that of anthralin. In contrast to anthralin, nearly all members of the acridone series were devoid of radical generating properties, which were determined by their capability to interact with the free radical 2,2-diphenyl-1-picrylhydrazyl. Structures with a phenolic hydroxyl or an aromatic amine arranged ortho or para to the acridone NH group were exceptions. Also in contrast to anthralin, membrane-damaging effects as documented by the release of lactate dehydrogenase into the culture medium were not observed for acridones.

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“…This was assessed by the activity of LDH (lactate dehydrogenase) released into the culture medium, which is commonly used as an indicator of plasma membrane damage [9,38].…”

Section: Biological Assay Methodsmentioning

confidence: 99%

“…The assay was performed as described [9,38]. HaCaT cells were incubated with the test compounds (2 mM) for 4 h at 37 C. Extracellular LDH activity was measured using the UV method with pyruvate and NADH and is expressed in mU/ml.…”

Section: Lactate Dehydrogenase Releasementioning

confidence: 99%

Structure–activity relationship studies of acridones as potential antipsoriatic agents. 1. Synthesis and antiproliferative activity of simple N-unsubstituted 10H-acridin-9-ones against human keratinocyte growth

Putic

Stecher

Prinz

et al. 2010

European Journal of Medicinal Chemistry

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“…Moreover, the preliminary ESR studies revealed that the reduction power of anthracenones substituted with an electron-withdrawing group in the C-10 position is impeded, whereas that of 10-thio derivatives is increased. 16,17) The reaction undergoes a nucleophilic substitution at the 1 and 5 positions with the appropriate thiols in the presence of sodium methoxide and THF at room temperature or after reflux for 1 to 2 h to generate this structural class of anthraquinones. The mechanism for the reaction may be rationalized assuming that thiols are ionized by sodium methoxide as nucleophiles undergo nucleophilic substitution.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis of Symmetrical 1,5-bis-thio-Substituted Anthraquinones for Cytotoxicity in Cultured Tumor Cells and Lipid Peroxidation.

Huang

Chiou

Chiu

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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The synthesis of a series of anthraquinone moieties bearing symmetrical sulfur-linked substituents in the 1 and 5 positions is described. These compounds were evaluated for their ability to inhibit the growth of suspended rat glioma C6 cells and human hepatoma G2 cells, respectively. In addition, the redox property of the compounds was determined based on the inhibition of lipid peroxidation in model membranes. Compounds 2a and 2h in this series compared favorably and exhibited the most potent cytotoxicity (0.02, 0.05 m mM) against C6 cells in the XTT colorimetric assay. As far as redox properties are concerned, all bis-thio-anthraquinones show potential lipid peroxidation in model membranes very close to that of mitoxantrone (MX), and 2a, 2d, 2e, 2i, 2j, and 2k have more potential than that of MX. The lack of cytotoxicity of compound 2i cannot be related to lipid peroxidation, but the steric and electronic properties of the side-chain substituent maybe impair effective recognition of the cleavable complex. In contrast to MX, 2a and 2h are cytotoxic in rat glioma C6 cells and do not enhance lipid peroxidation in model membranes.

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“…Calibration was performed as described. 20) Log P values as a measure of lipophilicity are given in Table 1.…”

Section: 5-dichloro-9(10h)-anthracenone (2)mentioning

confidence: 99%

Studies on Anthracenes. 1. Human Telomerase Inhibition and Lipid Peroxidation of 9-Acyloxy 1,5-Dichloroanthracene Derivatives.

Huang

Hwang

Jen

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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The synthetically useful approaches to 9-acyloxy 1,5-dichloroanthracene derivatives are reported. The system selectively reduces the carbonyl group flanked by the peri substituents of the anthracenediones to give the corresponding 1,5-dichloro-9(10H)-anthracenone. Simple regioselective acylation of anthracenone is applied with appropriate acyl chlorides in CH 2 Cl 2 with catalytic amount of pyridine to give the novel 9-acyloxy 1,5-dichloroanthracene derivatives. Considerable interest has developed in the mechanism of how anthracenone achieves this desirable selectivity. In an attempt to understand the mechanism of this reaction, solid-state structures of anthracene derivatives have been obtained. In addition, the inhibition of lipid peroxidation in model membranes was determined as was their ability to inhibit the telomere-addition function of the human telomerase enzyme together with their inhibition of the Taq polymerase enzyme. In contrast to (؉)-a a-tocopherol, 3b, 3c, 3d, 3g, and 3i do not enhance lipid peroxidation in model membranes. Implications for 9-acyloxy 1,5-dichloroanthracene analogues as potential anticancer agents are discussed.

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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

Cited by 30 publications

References 59 publications

Structure–activity relationship studies of acridones as potential antipsoriatic agents. 1. Synthesis and antiproliferative activity of simple N-unsubstituted 10H-acridin-9-ones against human keratinocyte growth

Structure–activity relationship studies of acridones as potential antipsoriatic agents. 1. Synthesis and antiproliferative activity of simple N-unsubstituted 10H-acridin-9-ones against human keratinocyte growth

Synthesis of Symmetrical 1,5-bis-thio-Substituted Anthraquinones for Cytotoxicity in Cultured Tumor Cells and Lipid Peroxidation.

Studies on Anthracenes. 1. Human Telomerase Inhibition and Lipid Peroxidation of 9-Acyloxy 1,5-Dichloroanthracene Derivatives.

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