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Klaus Muller - One of the best experts on this subject based on the ideXlab platform.
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Structure-activity relationship studies of acridones as potential Antipsoriatic agents. 2. Synthesis and antiproliferative activity of 10-substituted hydroxy-10H-acridin-9-ones against human keratinocyte growth.
European journal of medicinal chemistry, 2010Co-Authors: Aleksandar Putic, Lambert Stecher, Helge Prinz, Klaus MullerAbstract:Abstract A series of 10-substituted hydroxy-10 H -acridin-9-ones were synthesized and studied as potential Antipsoriatic agents. The antiproliferative activity of the novel derivatives, which can be considered as aza-analogues of the Antipsoriatic drug anthralin, was determined using the human keratinocyte cell line HaCaT. Structure–activity relationships with respect to the nature of the N-substituent at the acridone scaffold were delineated. Release of lactate dehydrogenase (LDH) was used to exclude non-specific cytotoxic effects. As compared to anthralin, N-substitution of the acridone scaffold in the target compounds provided agents devoid of radical producing properties, which was documented by their ineffectiveness to interact with the free radical 2,2-diphenyl-1-picrylhydrazyl. This was in excellent agreement with the data obtained from the LDH assay in which the novel compounds did not induce membrane damage. Benzyl substitution at the 10-position yielded keratinocyte growth inhibitory activity in the low micromolar range. The most potent inhibitor of keratinocyte hyperproliferation was compound 8a having an N-methyl group and a 1,3-dihydroxy arrangement at the acridone scaffold, with an IC 50 value comparable to that of anthralin.
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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.
European journal of medicinal chemistry, 2010Co-Authors: Aleksandar Putic, Lambert Stecher, Helge Prinz, Klaus MullerAbstract: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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Antipsoriatic anthrones with modulated redox properties. 5. Potent inhibition of human keratinocyte growth, induction of keratinocyte differentiation, and reduced membrane damage by novel 10-arylacetyl-1,8-dihydroxy-9(10H)-anthracenones.
Journal of medicinal chemistry, 2001Co-Authors: Klaus Muller, Hans Reindl, Klaus BreuAbstract:The synthesis and structure−activity relationships (SARs) of a series of novel 10-arylacetyl-1,8-dihydroxy-9(10H)-anthracenones are described. Acylation of anthralin with either the appropriate arylacetyl chlorides or arylacetic acids in the presence of pyridine or via the coupling agent dicyclohexylcarbodiimide (DCC), respectively, furnished this structural class of Antipsoriatic agents. Potential Antipsoriatic activity was evaluated in complementary assays specifically addressed to three important aspects of psoriasis. First, several compounds were identified which are equally potent as inhibitors of human keratinocyte growth as the Antipsoriatic agent anthralin. Furthermore, improved ratio of antiproliferative activity to cytotoxicity is demonstrated by the reduced potential of the novel analogues to induce membrane damage, which is a benefit of their reduced ability to generate oxygen radicals as documented by deoxyribose degradation. Second, analogue 3o bearing a hydroxamate functional group was also...
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Current status and recent developments in anthracenone Antipsoriatics.
Current pharmaceutical design, 2000Co-Authors: Klaus MullerAbstract:Treatment of psoriasis is rapidly changing, and there have been dramatic additions such as topical vitamin D analogs and a topical retinoid to the therapeutic armamentarium in recent years. Even though drug therapy is often inadequate and serves only to abate the skin disorder, anthralin of the anthracenone Antipsoriatics clears the rash totally. Of all Antipsoriatic agents, anthralin has proven to be the most remarkably consistent and time-honored drug for treating the disease, However, anthralin therapy is accompanied by inflammation and staining of the nonaffected skin surrounding a psoriatic lesion. A large body of evidence has shown that the biochemical basis for its mechanism of action at the molecular level is related to its redox chemistry leading to the production of oxygen radicals. These can react with all classes of biological macromolecules and are involved in the principal cellular effects of the anthracenones, This article will focus on current strategies to minimize the potential of skin inflammation by anthralin and the underlying concepts of controlling and manipulating oxygen-radical generation which are essential for the rational design of novel anthracenones. Various studies have show n that by altering the structure of anthralin the in vitro profile can be markedly altered from an only moderate 5-lipoxygenase inhibitor to a more potent inhibitor of this enzyme, which may reflect improved activity against the inflammatory component of psoriasis while the antiproliferative activity is retained, The structural change is also accompanied by significantly diminished oxygen-radical generation and proinflammatory action on the skin, In particular, derivatives bearing a phenylacyl substituent in the critical 10-position of the anthracenone molecule have a favorable overall profile for achieving improved topical therapy of psoriasis.
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Potential Antipsoriatic agents: lapacho compounds as potent inhibitors of HaCaT cell growth.
Journal of natural products, 1999Co-Authors: Klaus Muller, And Andreas Sellmer, Wolfgang WiegrebeAbstract:A number of lapacho compounds, representing the most common constituents of the inner bark of Tabebuia impetiginosa, together with some synthetic analogues, were evaluated in vitro against the growth of the human keratinocyte cell line HaCaT. With an IC(50) value of 0.7 microM, beta-lapachone (4) displayed activity comparable to that of the Antipsoriatic drug anthralin. 2-Acetyl-8-hydroxynaphtho[2,3-b]furan-4,9-dione (7), which was prepared in a four-step synthesis from 2,8-dihydroxy-1, 4-naphthoquinone, was the most potent inhibitor among the known lapacho-derived compounds and inhibited cell growth with an IC(50) value of 0.35 microM. Furthermore, other active constituents of lapacho inhibited keratinocyte growth, with IC(50) values in the range of 0.5-3.0 microM. However, as already observed with anthralin, treatment of HaCaT cells with these potent lapacho compounds also caused remarkable damage to the plasma membrane. This was documented by leakage of lactate dehydrogenase into the culture medium, which significantly exceeded that of the vehicle control. Because of their potent activity against the growth of human keratinocytes, some lapacho-derived compounds appear to be promising as effective Antipsoriatic agents.
P.c.m. Van De Kerkhof - One of the best experts on this subject based on the ideXlab platform.
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An update on vitamin D3 analogues in the treatment of psoriasis
Skin pharmacology and applied skin physiology, 1998Co-Authors: P.c.m. Van De KerkhofAbstract:Vitamin D3 analogues have revolutionized the topical treatment of psoriasis during the last decade. The mode of action of this ligand for the vitamin D3 receptor is via modulation of the transcription of genes with vitamin D3 response elements in their promoter region. Vitamin D3 analogues cause inhibition of various aspects of cutaneous inflammation and epidermal proliferation with enhancement of normal keratinization. In vivo, active vitamin D3 analogues proved to have a substantial Antipsoriatic effect. Calcipotriol (50 micrograms/g in ointment or cream), tacalcitol (4 micrograms/g in ointment) and calcitriol (3 micrograms/g in ointment) have been shown to have an Antipsoriatic effect in placebo-controlled studies. The most extensive body of information on comparative studies and on combination therapies is available for the analogue calcipotriol. So far, calcipotriol is available as a routine treatment in most countries, whereas tacalcitol has been registered in Japan and some European countries. From the available data in the literature we may conclude that calcipotriol is a first-line treatment for psoriasis and is advantageous in the combination with several other Antipsoriatic treatments such as topical corticosteroids, PUVA, cyclosporin and acitretin. Tacalcitol 4 micrograms/g as a once-daily principle is effective in psoriasis. Comparative studies will indicate the position of the existing and new vitamin D3 analogues.
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The epidermis as a target for Antipsoriatic treatment; the Nijmegen view
Journal of Dermatological Treatment, 1997Co-Authors: P.c.m. Van De Kerkhof, C.j.m. Van Der Vleuten, Marie-jeanne P. Gerritsen, E.m.g.j. De JongAbstract:The modes of action of Antipsoriatic treatments can be studied in in vitro in models, in vivo models or during treatment of psoriatic plaques. During the last decade research programmes in Nijmegen have focused on the epidermis as a target for Antipsoriatic treatments. The present communication reviews aspects of epidermal growth and inflammation during the treatment of psoriasis. Both in vitro and in vivo data are reviewed. All established Antipsoriatic treatments have been proved to inhibit epidermal proliferation in vitro and in vivo, except for cyclosporin. Cyclosporin is a selective immunomodulatory treatment in vivo. In contrast to the in vitro situation, during treatment of psoriatic plaques in vivo a rather consistent pattern is observed for all Antipsoriatic treatments with a reduction of involucrin-, transglutaminase-and keratin 16-positive cell layers and an increase in the number of filaggrin-positive cell layers. The various Antipsoriatic treatments differ mainly with respect to the modulatio...
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Multiparameter flow cytometry as a tool to evaluate Antipsoriatic therapy
The British journal of dermatology, 1997Co-Authors: C.p. Glade, P.e.j. Van Erp, Jan B.m. Boezeman, P.c.m. Van De KerkhofAbstract:Objective comparison of different Antipsoriatic therapies requires quantitative assessment of disease severity. However, clinical assessment with the widely used Psoriasis Area and Severity Index (PASI) introduces inaccuracy. An alternative is the quantitative analysis of different epidermal cell parameters using multiparameter flow cytometry. Our aim in the present study was to compare the clinical and flow cytometric approach to monitor disease activity and to evaluate Antipsoriatic efficacy. Clinical scores for erythema, induration and scaling were assessed and biopsies for flow cytometric analysis were obtained from the psoriatic plaques of 89 patients before and after treatment with different therapeutic regimens consisting of vitamin D3 analogues and corticosteroids. In total, 219 epidermal cell suspensions were analysed using triple-labelling, with the simultaneous staining of markers for epidermal proliferation (DNA dye TO-PRO-3), differentiation (antikeratin 10), and inflammation (antivimentin). Correlation analysis was performed on 166 paired values obtained from 83 patients. A highly significant correlation was observed between erythema and the percentage of vimentin-positive cells, between scaling and the percentage of keratin 10 positive keratinocytes, and between induration and the number of basal keratinocytes in the S- and G2M phase, when all 166 biopsies were assessed. The correlation remained in the same range if the analysis was restricted to the 83 pretreatment biopsies. In contrast to the clinical scores, the flow cytometric analysis permitted a clear separation between the antiproliferative and anti-inflammatory or keratinization-enhancing effects of Antipsoriatic treatment. The vitamin D3 analogues proved to exert a mainly antiproliferative effect. The combination of calcipotriol and a topical corticosteroid improved all cell biological markers substantially, and clobetasol monotherapy had a powerful effect on these markers. In conclusion, multiparameter flow cytometry has been shown to be a sensitive tool to evaluate the growth inhibiting, anti-inflammatory and keratinization-enhancing effects of Antipsoriatic therapies.
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the immunohistochemical effect of a hydrocolloid occlusive dressing duoderm e in psoriasis vulgaris
Dermatology, 1993Co-Authors: I M J J Van Vlijmenwillems, A Chang, J B M Boezeman, P.c.m. Van De KerkhofAbstract:The topical application of a hydrocolloid occlusive dressing (HCD) has been shown in various studies to have an Antipsoriatic effect as monotherapy but especially in combination with a topical corticosteroid. The aim of the present study was to assess the effect of 3 weeks of HCD monotherapy at the immunohistochemical level. Ten patients were treated. Before and after treatment, a biopsy was taken, and immunohistochemical stainings were carried out with markers for epidermal growth, keratinization, inflammation and endothelium. Suprabasal expression of keratin 16, the number of cycling epidermal cells and the number of polymorphonuclear leucocytes and T lymphocytes tended to decrease during treatment. The endothelial markers did not change during HCD treatment. This study confirms the Antipsoriatic effect of HCD and demonstrates that its effect upon some markers of inflammation, epidermal proliferation and keratinization is modest.
Satyendra Kumar Pandey - One of the best experts on this subject based on the ideXlab platform.
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organocatalytic asymmetric tandem α aminooxylation henry reactions for the synthesis of 1 2 diols total synthesis of l threo sphinganine
European Journal of Organic Chemistry, 2017Co-Authors: Yuvraj Garg, Ramandeep Kaur, Satyendra Kumar PandeyAbstract:A novel and rapid asymmetric syntheses of 1,2-diol derivatives anti- and syn-β,γ-dihydroxynitroalkanes via organocatalyzed tandem α-aminooxylation-Henry reactions are described. The targeted diol derivatives are synthesized in good yields, with excellent enantio- and low to moderate diasteroselectivities under mild conditions. Synthesis of an antineoplastic and Antipsoriatic drug (-)-L-threo-sphinganine demonstrate the synthetic utility of the fragments generated in the title reaction.
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Organocatalytic Asymmetric Tandem α‐Aminooxylation–Henry Reactions for the Synthesis of 1,2‐Diols: Total Synthesis of (–)‐l‐threo‐Sphinganine
European Journal of Organic Chemistry, 2017Co-Authors: Yuvraj Garg, Ramandeep Kaur, Satyendra Kumar PandeyAbstract:A novel and rapid asymmetric syntheses of 1,2-diol derivatives anti- and syn-β,γ-dihydroxynitroalkanes via organocatalyzed tandem α-aminooxylation-Henry reactions are described. The targeted diol derivatives are synthesized in good yields, with excellent enantio- and low to moderate diasteroselectivities under mild conditions. Synthesis of an antineoplastic and Antipsoriatic drug (-)-L-threo-sphinganine demonstrate the synthetic utility of the fragments generated in the title reaction.
Yuvraj Garg - One of the best experts on this subject based on the ideXlab platform.
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organocatalytic asymmetric tandem α aminooxylation henry reactions for the synthesis of 1 2 diols total synthesis of l threo sphinganine
European Journal of Organic Chemistry, 2017Co-Authors: Yuvraj Garg, Ramandeep Kaur, Satyendra Kumar PandeyAbstract:A novel and rapid asymmetric syntheses of 1,2-diol derivatives anti- and syn-β,γ-dihydroxynitroalkanes via organocatalyzed tandem α-aminooxylation-Henry reactions are described. The targeted diol derivatives are synthesized in good yields, with excellent enantio- and low to moderate diasteroselectivities under mild conditions. Synthesis of an antineoplastic and Antipsoriatic drug (-)-L-threo-sphinganine demonstrate the synthetic utility of the fragments generated in the title reaction.
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Organocatalytic Asymmetric Tandem α‐Aminooxylation–Henry Reactions for the Synthesis of 1,2‐Diols: Total Synthesis of (–)‐l‐threo‐Sphinganine
European Journal of Organic Chemistry, 2017Co-Authors: Yuvraj Garg, Ramandeep Kaur, Satyendra Kumar PandeyAbstract:A novel and rapid asymmetric syntheses of 1,2-diol derivatives anti- and syn-β,γ-dihydroxynitroalkanes via organocatalyzed tandem α-aminooxylation-Henry reactions are described. The targeted diol derivatives are synthesized in good yields, with excellent enantio- and low to moderate diasteroselectivities under mild conditions. Synthesis of an antineoplastic and Antipsoriatic drug (-)-L-threo-sphinganine demonstrate the synthetic utility of the fragments generated in the title reaction.
Nithyanantham Muruganantham - One of the best experts on this subject based on the ideXlab platform.
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Antipsoriatic activity of extracts and fractions obtained from memecylon malabaricum leaves
Journal of Pharmacy and Pharmacology, 2012Co-Authors: Sangai Palanisamy Dhanabal, Nithyanantham Muruganantham, Kh Basavaraj, Asish Wadhwani, Nonavinakere Mannar ShamasundarAbstract:Objectives This study involves the evaluation of Memecylon malabaricum Cogn. (Melastomataceae) leaves for Antipsoriatic activity. Methods Aqueous extract, hydroalcoholic extract and their fractions of M. malabaricum leaves were evaluated for in-vivo Antipsoriatic activity by mouse tail test and for in-vitro Antipsoriatic activity using HaCaT cells, lipoxygenase inhibition and thymidine phosphorylase inhibition assays. Extracts and fractions were evaluated for total phenol and flavonoid contents. HPTLC was used for screening and fingerprint analysis of the extracts and active fraction. Key findings M. malabaricum hydroalcoholic extract (MMHA) and water fraction of MMHA (MMHAW) produced significant (P < 0.05) percent orthokeratosis in the mouse tail test. All samples except MMHA showed a significant (P < 0.05) reduction in epidermal thickness in the mouse tail test when compared with control. Maximum activity against HaCaT cells was shown by chloroform fraction of MMHA (MMHAC). The M. malabaricum decoction (MMD) and water fraction of MMD (MMDW) showed equally good inhibition of lipoxygenase. In thymidine phosphorylase inhibition assay only MMD showed activity. Conclusions The findings of this investigation reveal that the leaves of M. malabaricum have good Antipsoriatic potential, which provides scope for further detailed research in to this plant for psoriasis.
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Antipsoriatic activity of extracts and fractions obtained from Memecylon malabaricum leaves.
The Journal of pharmacy and pharmacology, 2012Co-Authors: Sangai Palanisamy Dhanabal, Nithyanantham Muruganantham, Kh Basavaraj, Asish Wadhwani, Nonavinakere Mannar ShamasundarAbstract:Objectives This study involves the evaluation of Memecylon malabaricum Cogn. (Melastomataceae) leaves for Antipsoriatic activity. Methods Aqueous extract, hydroalcoholic extract and their fractions of M. malabaricum leaves were evaluated for in-vivo Antipsoriatic activity by mouse tail test and for in-vitro Antipsoriatic activity using HaCaT cells, lipoxygenase inhibition and thymidine phosphorylase inhibition assays. Extracts and fractions were evaluated for total phenol and flavonoid contents. HPTLC was used for screening and fingerprint analysis of the extracts and active fraction. Key findings M. malabaricum hydroalcoholic extract (MMHA) and water fraction of MMHA (MMHAW) produced significant (P
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Antipsoriatic activity and Cytotoxicity of ethanolic extract of Psoralia corylifolia seeds
2012Co-Authors: Lalitha Priyanka Dwarampudi, S.p. Dhanabal, Shanmugam R, Nithyanantham MurugananthamAbstract:Plan: Traditionally in India and China, Psoralia corylifolia seed decoction used for treating psoriasis. However, the Antipsoriatic activity of Psoralia corylifolia seeds has not been scientifically evaluated using mouse tail model. Methodology: Ethanolic extract of Psoralia corylifolia seeds were analyzed by high performance thin layer chromatography (HPTLC) .The In vivo Antipsoriatic activity of 95% of ethanolic extract of Psoralia corylifolia seeds was done by using mouse tail model for psoriasis and In vitro Antipsoriatic activity was carried out by Sulphorhodamine B (SRB) assay using HaCaT human keratinocyte cell lines. Outcome: HPTLC fingerprinting revealed the presence of gallic acid. The ethanolic extract shown IC50 255 µg/ml, with good antiproliferant activity when compared with Asiaticoside as positive control with potent IC50 value of 20.13 µg/ml. Psoralia corylifolia seed extract showed an overall Antipsoriatic activity of 75.87%, when compared with standard tazarot gel activity 87.94% by using mouse tail model, confirmed its traditional use in psoriasis treatment.
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Evaluation of the Antipsoriatic activity of Aloe vera leaf extract using a mouse tail model of psoriasis.
Phytotherapy research : PTR, 2011Co-Authors: S.p. Dhanabal, Lalitha Priyanka Dwarampudi, Nithyanantham Muruganantham, R. VadivelanAbstract:Aloe vera gel is used traditionally for the treatment of skin diseases, including psoriasis. An ethanolic extract of the gel was assessed for Antipsoriatic activity using a mouse tail model of psoriasis. The extract produced a significant differentiation in the epidermis, as seen from its degree of orthokeratosis (85.07 ± 3.36%) when compared with the negative control (17.30 ± 4.09%). This was equivalent to the effect of the standard positive control, tazarotene (0.1%) gel, which showed a 90.03 ± 2.00% degree of orthokeratosis. The ethanolic extract of Aloe vera leaf gel also produced a significant increase in relative epidermal thickness when compared with the control group, whereas the standard tazarotene showed no change. Taken together, the extract showed an overall Antipsoriatic activity of 81.95%, compared with 87.94 for tazarotene, in the mouse tail model for psoriasis.