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Klaus Müller - One of the best experts on this subject based on the ideXlab platform.
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antipsoriatic anthrones with modulated redox properties 4 synthesis and biological activity of novel 9 10 dihydro 1 8 dihydroxy 9 oxo 2 anthracenecarboxylic and hydroxamic acids
Journal of Medicinal Chemistry, 1997Co-Authors: Klaus Müller, Helge PrinzAbstract:A novel series of carboxylic and hydroxamic acids based on 1,8-dihydroxy-9(10H)-anthracenone were synthesized from 8-hydroxy-1-methoxy-9,10-anthracenedione as the key intermediate and evaluated both in the bovine polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay and in the HaCaT keratinocyte proliferation assay for their enzyme inhibitory and antiproliferative activity, respectively. The most potent inhibitors in both assays were the N-methylated hydroxamic acids 5d-8d with straight chain alkyl spacers. Incorporation of these structural features on the anthracenone pharmacophore resulted in increased inhibitory activity against 5-LO while the antiproliferative activity was retained. In addition, prooxidant properties as measured by deoxyribose degradation and cytotoxicity as assessed by LDH release were largely reduced as compared with the antipsoriatic Anthralin. Contrary to Anthralin, antioxidant properties were observed as documented by the reactivity of the novel compounds against free radicals and inhibition of lipid peroxidation in model membranes.
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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
Journal of Medicinal Chemistry, 1996Co-Authors: Klaus Müller, Hsu Shan Huang, Wolfgang WiegrebeAbstract: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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Reduction of nitroxides by Anthralin and some of its derivatives
Free radical biology & medicine, 1995Co-Authors: Slavko Pečar, Milan Schara, Klaus Müller, Wolfgang WiegrebeAbstract:In DMSO solution, Anthralin and its C-10 monosubstituted derivatives reduce nitroxides to the corresponding hydroxylamine derivatives, which are not further transformed. The reaction rate depends on the solvent used, the nitroxide, and the structure of the reducer. It is faster in DMSO than in DMF, piperidine type of nitroxides are reduced faster than the pyrrolidine type, and the substitution on C-10 of Anthralin has a significant influence on the reaction rate. Anthralin derivatives without protons at C-10 are not able to reduce nitroxides.
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Antipsoriatic anthrones with modulated redox properties. 2. Novel derivatives of chrysarobin and isochrysarobin--antiproliferative activity and 5-lipoxygenase inhibition.
Journal of medicinal chemistry, 1994Co-Authors: Klaus Müller, P. Leukel, Klaus Ziereis, Ingo GawlikAbstract:A novel series of 2- and 3-substituted 1,8-dihydroxy-9(10H)-anthracenones were synthesized and tested for their inhibitory activity against 5-lipoxygenase (5-LO) in bovine polymorphonuclear leukocytes and the growth of human keratinocytes. Structure-activity relationships are discussed with respect to the following redox properties of the compounds: reactivity against 2,2-diphenyl-1-picrylhydrazyl, generation of hydroxyl radicals as measured by deoxyribose degradation, and inhibition of lipid peroxidation in model membranes. Inhibition of cell proliferation seemed to be related to these properties, whereas 5-LO inhibition was not. Within a class of structural analogs the activity against 5-LO, which was markedly improved as compared to that of the antipsoriatic drug Anthralin, correlated well with the overall lipophilicity. Even though a number of compounds in this series enhanced oxidative damage to nonlipid molecules such as deoxyribose, their antioxidant properties predominate in membrane lipids. Among the prooxidant compounds were also the most potent antiproliferative agents (IC50 values in the 10(-7) M range).
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antipsoriatic anthrones with modulated redox properties 1 novel 10 substituted 1 8 dihydroxy 9 10h anthracenones as inhibitors of 5 lipoxygenase
Journal of Medicinal Chemistry, 1993Co-Authors: Klaus Müller, Dieter Gurster, Susanne Piwek, Wolfgang WiegrebeAbstract: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-1-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.
Wolfgang Wiegrebe - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Medicinal Chemistry, 1996Co-Authors: Klaus Müller, Hsu Shan Huang, Wolfgang WiegrebeAbstract: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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Reduction of nitroxides by Anthralin and some of its derivatives
Free radical biology & medicine, 1995Co-Authors: Slavko Pečar, Milan Schara, Klaus Müller, Wolfgang WiegrebeAbstract:In DMSO solution, Anthralin and its C-10 monosubstituted derivatives reduce nitroxides to the corresponding hydroxylamine derivatives, which are not further transformed. The reaction rate depends on the solvent used, the nitroxide, and the structure of the reducer. It is faster in DMSO than in DMF, piperidine type of nitroxides are reduced faster than the pyrrolidine type, and the substitution on C-10 of Anthralin has a significant influence on the reaction rate. Anthralin derivatives without protons at C-10 are not able to reduce nitroxides.
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antipsoriatic anthrones with modulated redox properties 1 novel 10 substituted 1 8 dihydroxy 9 10h anthracenones as inhibitors of 5 lipoxygenase
Journal of Medicinal Chemistry, 1993Co-Authors: Klaus Müller, Dieter Gurster, Susanne Piwek, Wolfgang WiegrebeAbstract: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-1-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.
Wiegrebe Wolfgang - One of the best experts on this subject based on the ideXlab platform.
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UV/Vis and fluorescence study on Anthralin and its alkylated derivatives
'Elsevier BV', 1998Co-Authors: Sellmer Andreas, Wiegrebe Wolfgang, Terpetschnig Ewald, Wolfbeis, Otto S.Abstract:Anthralin 1 and some of its C-10 or O-alkylated derivatives were investigated by UV/VIS- and fluorescence spectroscopy in different solvents and buffer systems, respectively. The effects of substituents on the formation of Anthralin anion as well as the constitution of the resulting anions confirm that C-H acidity at position 10 is necessary for the formation of a fully aromatic anionic form. It is concluded that the resulting anion 1a is the pharmacologically active species of the antipsoriatic Anthralin. Tautomerism of the neutral molecule is not observable
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Modification of DNA bases by Anthralin and related compounds
'Elsevier BV', 1995Co-Authors: Müller K., Leukel P., Mayer K.k., Wiegrebe WolfgangAbstract:Modification of bases in calf thymus DNA by treatment with the antipsoriatic drug Anthralin was studied. The products of DNA bases were identified and their yields measured by gas chromatography-mass spectrometry with selected ion monitoring. Treatment of calf thymus DNA with Anthralin significantly enhanced the amount of modified bases above control levels. Purine bases were modified to products identical with those known to be typical of DNA damage induced by hydroxyl radicals. The yields of Fapy-adenine, 8-hydroxyadenine, Fapy-guanine, and 8-hydroxyguanine were maximally increased at an Anthralin concentration of 75 μM. A variety of structural analogues of Anthralin were also tested at 75 μM and were either weaker or stronger hydroxylating agents. It is likely that damage to DNA bases induced by anthrones contributes to their antiproliferative activity. The pharmacological implications of these characteristics of the action of Anthralin on DNA bases are discussed
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Acidity and Stability of 10-Substituted 1,8-Dihydroxy-9(10H)-anthracenones
'Wiley', 1995Co-Authors: Müller K., Wiegrebe WolfgangAbstract:The decomposition of 10-substituted Anthralin derivatives in dimethyl sulfoxide and ethanol was determined. While 10-ω-phenylalkylidene derivatives were thoroughly stable, 10-ω-phenylacyl-substituted compounds were slowly degraded to danthron and the corresponding carboxylic acids. However, the stability of these derivatives was markedly improved as compared to that of Anthralin. Determination of the pKa values showed that the ω-phenylacyl derivatives were somewhat stronger acids than Anthralin, while ω-phenylalkylidene-substitutiong enerally leaves the acidity of the Anthralin part unchanged. Die Zersetzung 10-substituiertex Anthralinderivate in Dimethylsulfoxid und Ethanol wurde bestimmt. Während 1 0-ω-Phenylalkyliden-Derivate stabil waren, wurden 10-ω-PhenyIacyl-subsituierte Verbindungen langsam zu Dantron und den entspr. Carbonsiiuren abgebaut. Dennoch war die Stabilitiit dieser Verbindungen im Vergleich zu Anthralin wesentlich höher. Die Bestimmung der pKkWerte zeigte, daB die ω-Phenylacyl-Derivate etwas stärker sauer als Anthralin sind, während ω-Phenylalkyliden-Substitution im allgemeinen die Acidität des Anthralin-Anteils nicht verändert
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A Convenient Synthesis of 14C-Anthralin
'Wiley', 1994Co-Authors: Huang H.s., Müller K., Mayer K.k., Wiegrebe WolfgangAbstract:Anthralin [1,8-dihydroxy-9(10H)-anthracenone] is among the most widely used drugs in the topical treatment of psoriasis1). However, not much is known concerning its mode of action at the molecular level, although a variety of cellular targets have been implicated both in the main and side effects of Anthralin2 ). In particular, the interaction of Anthralin with proteins has long been recognized to occur3 , 4 ) and there has been renewed interest in this topic, mostly directed toward the investigation whether enzyme inhibition by Anthralin is related to oxygen radicalmediated damage of proteins5 ) . In order to gain a more profound understanding of the interaction between this drug and cellular targets, Anthralin labelled with a non-exchangeable radioisotope in a suitable position was highly desirable. Furthermore, this labelled compound might serve as a useful starting material for the synthesis of analogues labelled in the anthrone nucleus. Since structural modification of Anthralin has provided compounds with improved biological activity6 '7), labelled compounds are required for studies on skin penetration and metabolism of these future drugs. Although routes to 14C-Anthralin have already been described8,9), each of these methods suffers from too many synthetic steps, or the use of hazardous 14C-sources1 ) . In this paper, we describe a short and efficient synthesis of l,8-dihydroxy-[10-14C]-9(10H)-anthracenone
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Electron-impact Induced and Thermal Decomposition of Dithranol Derivatives, I: Thermolysis of 10-Phenylthio-dithranol in the Mass Spectrometer
'Wiley', 1994Co-Authors: Huang H. S., Mayer K. K., Wiegrebe WolfgangAbstract:Dithranol (Anthralin; 1,8-dihydroxy-9-anthrone) and its derivatives bearing a variety of substituents in the 10-position are of actual interest in research on psoriasis1). In connection herewith 10-alkylthio- and 10-arylthio-1,8- dihydroxy-9(10H)-anthracenones were synthetized and used for antipsoriatic activity2,3)
Helge Prinz - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Structure–Activity Relationships of Lapacho Analogues. 2. Modification of the Basic Naphtho[2,3‑b]furan-4,9-dione, Redox Activation, and Suppression of Human Keratinocyte Hyperproliferation by 8‑Hydroxynaphtho[2,3‑b]thiophene-4,9-diones
2014Co-Authors: Sven Bannwitz, Helge Prinz, Dirk Krane, Silke Vortherms, Tobias Kalin, Cathrin Lindenschmidt, Nader Zahedi Golpayegani, Jan Tentrop, Klaus MüllerAbstract:The basic structure of linearly anellated lapacho quinones, naphtho[2,3-b]furan-4,9-dione (7), was modified in the search for novel agents against keratinocyte hyperproliferation. The synthesis and structure–activity relationships of several heterocycle-fused naphthoquinones as well as a full range of 2- and 7-substituted derivatives of one of these, 8-hydroxynaphtho[2,3-b]thiophene-4,9-dione (8a), are described. Out of a total of 71 analogues, particularly 2-thenoyl-substituted 26l, 2-nicotinoyl-substituted 26m, and 2-oxadiazole-substituted 35a compared favorably with the antipsoriatic agent Anthralin. Their potency for suppression of keratinocyte hyperproliferation, which was evaluated using HaCaT cells as a model, was combined with comparably low membrane-damaging effects toward keratinocytes, as established by the release of lactate dehydrogenase activity from the cytoplasm of the cells. With respect to the mechanism of action, redox activation of lapacho quinones by one- and two-electron reduction in isolated enzymatic assays was studied, and their potential to generate superoxide was confirmed in the keratinocyte-based hyperproliferation assay
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antipsoriatic anthrones with modulated redox properties 4 synthesis and biological activity of novel 9 10 dihydro 1 8 dihydroxy 9 oxo 2 anthracenecarboxylic and hydroxamic acids
Journal of Medicinal Chemistry, 1997Co-Authors: Klaus Müller, Helge PrinzAbstract:A novel series of carboxylic and hydroxamic acids based on 1,8-dihydroxy-9(10H)-anthracenone were synthesized from 8-hydroxy-1-methoxy-9,10-anthracenedione as the key intermediate and evaluated both in the bovine polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay and in the HaCaT keratinocyte proliferation assay for their enzyme inhibitory and antiproliferative activity, respectively. The most potent inhibitors in both assays were the N-methylated hydroxamic acids 5d-8d with straight chain alkyl spacers. Incorporation of these structural features on the anthracenone pharmacophore resulted in increased inhibitory activity against 5-LO while the antiproliferative activity was retained. In addition, prooxidant properties as measured by deoxyribose degradation and cytotoxicity as assessed by LDH release were largely reduced as compared with the antipsoriatic Anthralin. Contrary to Anthralin, antioxidant properties were observed as documented by the reactivity of the novel compounds against free radicals and inhibition of lipid peroxidation in model membranes.
Dieter Gurster - One of the best experts on this subject based on the ideXlab platform.
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antipsoriatic anthrones with modulated redox properties 1 novel 10 substituted 1 8 dihydroxy 9 10h anthracenones as inhibitors of 5 lipoxygenase
Journal of Medicinal Chemistry, 1993Co-Authors: Klaus Müller, Dieter Gurster, Susanne Piwek, Wolfgang WiegrebeAbstract: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-1-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.
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hydroxyl radical damage to dna sugar and model membranes induced by Anthralin dithranol
Biochemical Pharmacology, 1993Co-Authors: Klaus Müller, Dieter GursterAbstract:Abstract The antipsoriatic anthrones Anthralin and butantrone caused degradation of the DNA sugar deoxyribose in the presence of ferric salt. The degradation was substantially inhibited by iron-binding hydroxyl radical scavengers, iron chelators, superoxide dismutase (SOD) and catalase, suggesting a mechanism in which antipsoriatic anthrones generate hydroxyl radicals via the Fenton reaction or an iron-catalysed Harber-Weiss reaction. Butantrone was markedly less efficient at generating hydroxyl radicals than Anthralin. Using bovine brain phospholipid liposomes as model membranes to study the effects of antipsoriatic anthrones on lipid peroxidation, the peroxidation of liposomal membranes in the presence of ferric salt was maximally enhanced by Anthralin and butantrone at 12.5 and 5 μM, respectively. Higher concentrations of the drugs resulted in less peroxidation. Chain-breaking antioxidants and iron chelators strongly decreased Anthralin-enhanced lipid peroxidation, suggesting the involvement of hydroxyl, peroxyl or alkoxyl radicals. In contrast to their stimulatory effects on liposomal membrane peroxidation, both Anthralin and butantrone diminished Fe 3+ /ascorbate-induced lipid peroxidation in liposomes. Butantrone was more effective as an inhibitor of lipid peroxidation than was Anthralin. The antioxidant properties of antipsoriatic anthrones were determined in terms of their reactivities with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). Antioxidant activity of antipsoriatic anthrones requires the presence of free hydroxyl groups at C-1 and C-8 and at least one hydrogen atom at C-10 of the anthrone nucleus. The role of active oxygen species produced by antipsoriatic anthrones and the biological effects on cellular targets are discussed with respect to the mode of action and manifestation of side effects of these drugs.