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.