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At least 163 records · Page 9Linked to original sources
PubMed1994

Antipsoriatic anthrones with modulated redox properties. 2. Novel derivatives of chrysarobin and isochrysarobin--antiproliferative activity and 5-lipoxygenase inhibition.

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).

Administration, Topical↗
PubMed1993

Antipsoriatic anthrones with modulated redox properties. 1. Novel 10-substituted 1,8-dihydroxy-9(10H)-anthracenones as inhibitors of 5-lipoxygenase.

The syntheses, the biological evaluation, and the structure-activity relationships of a novel series of 1,8-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.

Administration, Topical↗
PubMed2001

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.

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 a highly potent inhibitor of LTB(4) biosynthesis in addition to its excellent antiproliferative activity. SARs of these inhibitors of both keratinocyte growth and LTB(4) biosynthesis with respect to the nature of the para-substitution in the 10-phenylacetyl side chain are discussed. Third, the compounds were also evaluated for their ability to induce the formation of cornified envelope protein in keratinocytes. Cross-linking of cellular protein as a marker of terminal differentiation of keratinocytes was observed for many 10-arylacetyl analogues at concentrations required to arrest cell growth. This newly uncovered activity of the novel anthracenones suggests antipsoriatic potential with respect to disturbance of keratinocyte differentiation, in addition to hyperproliferative and inflammatory aspects of psoriasis.

Acetanilides↗
PubMed1996

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.

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.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1997

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.

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.

Animals↗