10-Benzoyl-1,8-dihydroxy-9(10H)-anthracenones: Synthesis and biological properties

Müller, Klaus; Altmann, Reinhold; Prinz, Helge

doi:10.1016/s0223-5234(98)80010-x

Cited by 17 publications

(6 citation statements)

References 17 publications

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“…In the case of 10-benzoyl analogs these methods fail, and the desired compounds are best prepared by reaction of anthralin diacetate (12) and benzoyl chlorides in the presence of sodium hydride in THF, which affords the pertinent enol esters. Hydrolysis using aqueous sodium hydroxide in ethanol affords the desired 10-benzoylanthralins [76,116].…”

Section: Substitution At the Oxygen Functionsmentioning

confidence: 99%

Current Status and Recent Developments in Anthracenone Antipsoriatics

Müller

2000

CPD

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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 shown 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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Section: Substitution At the Oxygen Functionsmentioning

confidence: 99%

Current Status and Recent Developments in Anthracenone Antipsoriatics

Müller

2000

CPD

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“…In co-drug design, the selection of therapeutic moieties is restricted to those with complementary functional groups which can form a biologically labile bond [ 7 ]. Several dithranol derivatives have been prepared and studied, mostly involving modification at the C-10 methylene group with the aim of diminishing oxygen-radical formation, reducing staining or irritation, and/or improving anti-proliferative properties [ 12 , 14 , 15 , 16 ]. Given the clinical efficacy of dithranol and potential for derivatization with biologically labile ester functional groups at the C-1 and C-8 hydroxyl groups, carboxylic acid containing drugs with clinical applications in psoriasis that could be formulated as a dithranol ester co-drug were investigated.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis

2013

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Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, Vmax = 10.3 µM·min−1 and Km = 65.1 µM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis.

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“…Apart from the therapeutic benefits, dithranol causes undesirable side effect such as unpleasant inflammation of the skin surrounding the treated psoriatic plaques [1] because it can undergo complex transformations in the human body [2]. Much work has been directed to reduce this clinical side effect by acylation of dithranol at its 10-position [3], and acylation or alkylation of its 1,8-dihydroxys and/or the 9-hydroxy of its tautomer, i.e., 1,8,9-trihydroxyanthracene [3,4]. However, no major advance has been achieved in this aspect, and little effort has been made to explore the unknown reactivities of dithranol which might be associated to this side effect [5].…”

Section: Introductionmentioning

confidence: 99%

Multiple reactivities of dithranol towards 1-alkynyl Fischer carbene complexes (CO)5MC(OEt)CCPh (M=Cr, W) – Efficient chemical synthesis of aromatic polyketides

Luo

2009

Journal of Organometallic Chemistry

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10-Benzoyl-1,8-dihydroxy-9(10H)-anthracenones: Synthesis and biological properties

Cited by 17 publications

References 17 publications

Current Status and Recent Developments in Anthracenone Antipsoriatics

Current Status and Recent Developments in Anthracenone Antipsoriatics

Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis

Multiple reactivities of dithranol towards 1-alkynyl Fischer carbene complexes (CO)5MC(OEt)CCPh (M=Cr, W) – Efficient chemical synthesis of aromatic polyketides

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