HaCaT keratinocyte cultures were exposed to twelve hydrophilic anthralin derivatives 1 to 12 with substituents at C-l and C-8 of the anthrone skeleton, of one H at C-10 and of both H's at C-10 by lacton rings ( fig. 1). After 3 uM treatment growth was determined by cellular protein content, ^-thymidineand 14 C-amino-acid-uptake and cytotoxicity by the release of cytoplasmic LDH into the culture medium.-In comparison to acetone control (100%) anthralin suppressed mean protein content, as well as DNA-and protein-synthesis to 33, 28, and 21%, respectively, and the drug revealed an enzyme release of 660%. In relation to the parent drug we found similar cell growth inhibitory effects of compounds 4, 6, 8, 9, 10, and 12. Deriv. 4, 8, and 10 were, however, to some extent less cytotoxic than anthralin, whereas deriv. 6, 9, and 12 were in the same range. An extreme suppression of growth parameters which differed from the anthralin effect by a factor 0.5-0.8 was caused by deriv. 11, showing the same cytotoxicity. Deriv. 1, 2, 3,5, and 7 did not demonstrate any cytotoxicity. Concerning growth parameters, deriv. 2 induced a slight stimulation, deriv. 3 and 7 were completely ineffective, deriv. 1 and 5 induced slightly to moderately inhibited proliferation but both being much less effective than anthralin. These data indicate that the "minimum structure" concept by Krebs and Schaltegger -claiming l-hydroxy-9-anthrone as a precondition for clinical antipsoriatic potency -is not valid at least in cell-biological tests and point toward possible usefulness of some experimental model compounds as alternative antipsoriatics.

The title compounds are not available by hydrolysis of the pertinent esters on 10-(o-Carboxyacy1)-Derivate des Dithranols a preparative scale. Therefore, they were prepared by base catalyzed condensation of dicarboxylic acid dichlorides or succinic acid monobenzylesterchloride, respectively, with dithranol (1). Their IC5o-values for glucosedphosphate dehydrogenase are lower than that of dithranol (1). whilst 10ethyldithranol (6) and the o-(wcarboxyalkyl)-derivatives 8 and 9 are weaker inhibitors.Die Titelverbindungen sind nicht aus den entspr. Estem praparativ z u m glich, sondern wurden aus Dicarbons;iureciichlonden bzw. Bemsteins;iuremonobenzylesterchlond und Dithmnol(1) hergestellt. Die ICS-Werte dieser Substanzen fiir Glucose-6-phosphat--Dhydrogenase sind kleiner als der von Dithranol (1). 10-Ethyldithranol (6) und die o-(o-Carboxyalkyl)-Dnvate 8 und 9 sind dagegen schwkhere Inhibitoren.10-Acyl-derivatives of dithranol(1) have been introduced as antipsoriatic agents by Musrakallio", bulantrone (2b) being the most effective compound of a series with 2 to 5 and with 14 Catoms in the C-10 side chain'). According to Kreh.?' the C-10-acylated dithranol derivatives are considered to be pro-drugs on account of their phenlylogous P-dicarbonyl moiety.

The syntheses of dithranol derivatives with co-carboxyalkyl side chains at C-2 (and C-7) or co-methoxycarbonylacyl-substituents at C-10, respectively, are described. Hydrophile DithranolderivateDie Herstellung von Dithranolderivaten mit co-Carboxyalkyl-Seitenketten an C-2 (und C-7) bzw. mit co-Methoxycarbonylacyl-Substituenten an C-10 wird beschrieben.We have reported a) upon the inhibition of glucose-6-phosphate-dehydrogenase by dithranol (l) 1 ), b) upon the UV-spectra of 1 and its anion 2 ) and c) upon the active oxygen species generated by l-C-10-anion 3 ). These experiments were hampered by the low degree of solubility of 1 in aqueous buffer systems.Here we describe the syntheses of hydrophilic derivatives of 1 which will be used as model compounds for further experiments in the context of the problems a)-c) mentioned above. B) C-2 (and C-7) Substituted Dithranol Derivatives2-(2-carboxyethyl)-dithranol 7 was obtained by ether cleavage, saponification, decarboxylation, and reduction of the anthraquinone 8 6) with SnCl 2 in a one-pot-reaction according to AuterhoffX Chrysazin (9) when being treated with an excess of (HO) 2 CH-COOH/NaOH/Na-dithionite according to Marschalk® yielded thebis-(carboxymethyl)-dihydroxyanthraquinone 10 as a very polar, crude material which was methylated to 11 for characterization. Under Auterhoffs reductive conditions^ 11 was converted to 2,7-bis-(carboxymethyl)-dithranol 12.Analogously to the reaction of chrysazin (9) its mono-methyl ether 13 6) was converted with (HO) 2 CH-COOH to the mono-carboxymethyl-derivative 14, which was reduced to the carboxymethyldithranol 15 with concomittant ether cleavage. A) C-10-Acylated Dithranol DerivativesC-10-acylated derivatives of 1 have been investigated thoroughly by Mustakallio et al. 4) mainly under clinical aspects, butantrone (2) being the most potent compound of this series. Unfortunately 2 is not suitable for our purposes. So we converted 1 into the esters 3 and 4, respectively, by acylation with co-methoxycarbonyl-propionyl chloride 5) or the homologous co-methoxycarbonyl-butyryl chloride.Besides the main components 3 and 4 the phenyl ester 5 arose as a side product. -1 reacted with succinyl chloride yielding the lactone 6.

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

The derivatives (III) and (V) are prepared from dithranol (I) via base‐catalyzed acylation using conventional methods.