Anthralin derivatives—inhibition of 5‐lipoxygenase—antipsoriatic efficacy

Abstract

Inhibition of 5-lipoxygenase by anthralin (1) and 41 derivatives is determined: the acids 38 and 39, the lactones 40-42 and 9-anthrone (8) are the most potent inhibitors, the lactone 41 reaching the efficacy of nordihydroguaiaretic acid (NDGA). The results were correlated with the hydrophilic/lipophilic balance of the test compounds and their clinical efficacy as far as known. There is no correlation between the "minimum structure" of Krebs and SchalteggeP^ concerning antipsoriatic activity and the inhibitory effects against 5-lipoxygenase. Dithranol-Derivate: Hemmung der 5-Lipoxygenase und antipsoriatische WirksamkeitDie Hemmung der 5-Lipoxygenase durch Dithranol (1) und 41 Derivate wird bestimmt: die Säuren 38 und 39, die Laktone 40-42 und 9-Anthron (8) sind die stärksten Inhibitoren, das Lakton 41 erreicht die Wirksamkeit der Nordihydroguajaretsäure. Die Ergebnisse werden mit den hydrophilen/lipophilen Eigenschaften der Verbindungen und -soweit bekannt -mit deren klinischer Wirksamkeit in Beziehung gesetzt: es besteht keine Korrelation zwischen der sog. "antipsoriatischen Minimalstruktur" nach Krebs und SchalteggeP^ und der Hemm wirkung auf die 5-Lipoxygenase.Psoriasis is a common chronic inflammatory and proliferative skin disease with unknown aetiology. An important feature is the abnormal metabolism of arachidonic acid, particularly by the lipoxygenase pathways. Lesional skin contains increased concentrations of arachidonic acid, 12-HETE and LTB 4 , whereas the cyclooxygenase-products PGF^ and PGE2 are only modestly elevated 1 *. LTB 4 and 12-HETE are potent chemoattractans for human polymorphonuclear leukocytes (PMNs) 2) , which are part of a characteristic inflammatory infiltrate and were suggested to play an important physiologic role in cutaneous lesion of psoriasis 3 *. In the present study structure-activity relationships concerning the in vitro 5-lipoxygenase inhibitory activity of various anthrone derivatives and related compounds were investigated. The results were compared with the antipsoriatic properties of the compounds according to the "minimum structure" concept by Krebs and SchalteggeP\ Anthralin (dithranol Materials and Methods

Structure‐function relationship of new anthralin derivatives assayed for growth inhibition and cytotoxicity in human keratinocyte cultures

“…Also not in favor of the "minimum structure" concept was the finding that the topically applied antiproliferatively active 1,8-diacetoxy-anthracene was not converted to a compound with a free C-l hydroxy group 40) . In contrast to the results with the HaCaT keratinocytes we recently found nonphenolic anthrones to be more active as inhibitors of arachidonic acid lipoxygenase from bovine polymorphonuclear leucocytes than anthralin, suggesting a different mode of action 42) .…”

“…8 and 9 also show activity similar to that of anthralin in the inhibition of leucotriene production; the acids 6 and 7, however, were more potent than anthralin. Their IC5o-values for 5-lipoxygenase-inhibition were found to be between 5 and 10 |iM (anthralin: IC 50 « 40 |iM) 42) . Concerning anthralin derivatives bearing acyl chains of different length at C- 10 Mustakallio 43M) has already stated that at this position substituents less bulky than glucose do not hamper antiproliferative activity.…”

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

“…Both metabolites are not effective in 5-LO inhibition. 22 ' 39 Contrary to anthralin, compounds 4p and 7j of our series were not appreciably degraded during the 5-LO assay, and they were not hydrolyzed to anthralin.…”

Syntheses of Anthracenones. 2. Preparation of 1,8-Dimethoxy- (Dimethylanthralin) and 4,5-Dihydroxy-9(10H)-anthracenone (Isoanthralin): A Revision

“…In light of these findings some biological studies on anthralin derivatives have to be reconsidered, since in each of these studies − the putative anthracenone 2a was prepared from 3 according to the method of Attree and Perkin . Confirmation of the position of the methoxy groups is therefore necessary before conclusions are drawn from the results of experiments which are performed to determine the structural features necessary for antipsoriatic activity.…”