8-Halo-substituted naphtho[2,3-b]thiophene-4,9-diones as redox-active inhibitors of keratinocyte hyperproliferation with reduced membrane-damaging properties.

A series of 8-chloronaphtho[2,3-b]thiophene-4,9-diones and also some 8-bromo analogues were prepared. The compounds were evaluated for their potencies to suppress keratinocyte hyperproliferation using the human keratinocyte line HaCaT as the primary test system. Structure-activity relationship studies revealed that replacement of the phenolic group of an earlier series with an 8-halogen atom retained the inhibitory potency against keratinocyte hyperproliferation with IC50 values in the submicromolar range. 8-Chloro-substitution led to inhibitors that were more potent than their bromo analogues. Concomitantly, halo-substitution eliminated membrane-damaging properties as assessed by LDH release from the cytoplasm of the keratinocytes which, in contrast, were induced by the corresponding phenolic analogues. Finally, selective compounds were characterized for their ability to participate in redox cycling to generate superoxide in enzymatic and keratinocyte-based studies.

Synthesis and structure-activity relationships of lapacho analogues. 2. Modification of the basic naphtho[2,3-b]furan-4,9-dione, redox activation, and suppression of human keratinocyte hyperproliferation by 8-hydroxynaphtho[2,3-b]thiophene-4,9-diones.

The basic structure of linearly anellated lapacho quinones, naphtho[2,3-b]furan-4,9-dione (7), was modified in the search for novel agents against keratinocyte hyperproliferation. The synthesis and structure-activity relationships of several heterocycle-fused naphthoquinones as well as a full range of 2- and 7-substituted derivatives of one of these, 8-hydroxynaphtho[2,3-b]thiophene-4,9-dione (8a), are described. Out of a total of 71 analogues, particularly 2-thenoyl-substituted 26l, 2-nicotinoyl-substituted 26m, and 2-oxadiazole-substituted 35a compared favorably with the antipsoriatic agent anthralin. Their potency for suppression of keratinocyte hyperproliferation, which was evaluated using HaCaT cells as a model, was combined with comparably low membrane-damaging effects toward keratinocytes, as established by the release of lactate dehydrogenase activity from the cytoplasm of the cells. With respect to the mechanism of action, redox activation of lapacho quinones by one- and two-electron reduction in isolated enzymatic assays was studied, and their potential to generate superoxide was confirmed in the keratinocyte-based hyperproliferation assay.