Cornified envelope formation by anthralin, simple analogues, and related anthracenones.
The ability of the antipsoriatic anthralin to induce HaCaT keratinocyte differentiation was investigated and correlated with its potency to inhibit proliferation of keratinocytes. To determine the structural requirements for this effect, anthralin and seventeen simple analogues or related anthracenones were examined for their ability to induce the formation of cornified envelope as a marker of terminal differentiation. Covalently cross-linked protein was measured as a key feature of this process. Induction of keratinocyte differentiation was significant at a concentration of 0.5 microM anthralin after 48 h exposure. The presence of the 1,8-dihydroxy groups is a critical determinant of cross-linking activity, since removing or exchanging these groups prevented the induction of keratinocyte differentiation. Furthermore, at least one hydrogen atom at the 10-position of anthralin is required. Moreover, anthralin, anthralin dimer, and anthralin triacetate exhibited antiproliferative and antirespiratory activity at concentrations required to induce keratinocyte differentiation, suggesting a causality between these effects. In addition, cornified envelope formation was observed for a number of related anthracenones at concentrations as low as 1-5 microM. In general, compounds containing benzoyl substituents, independent of the position in the anthralin nucleus, were more potent than those having benzyl substituents. Only marginal differences in cross-linking potency were observed within a number of phenylpropionyl substituted analogues, suggesting that the ability to induce keratinocyte differentiation is independent of the nature of substituents at the side chain.
Müller
K
K
Westfälische Wilhelms-Universität Münster, Institut für Pharmazeutische Chemie, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Reindl
H
H
D000287:Administration, Topical; D000875:Anthralin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D012867:Skin / Q000166:cytology* / Q000187:drug effects; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000875:Anthralin