On the photobiological properties of chimeras combining quaternary ammonium derivatives of retinoic amides and psoralen. A study with cultured human keratinocytes.

Abstract

The effectiveness of the combination of retinoids with 8-methoxypsoralen (8-MOP) and ultraviolet-A (UV-A) light in the treatment of some cutaneous proliferative diseases has motivated the synthesis of new "chimera-type" molecules built from psoralen derivatives and retinoic amides and related molecules. The chimeras result from the combination of 8-(3-bromopropyloxy)-psoralen with amides prepared by reacting 4-amino-pyridine with 13E- and 13Z-retinoic acids or a "retinoid-like" derivative with an alkene chain of only three double bonds. The synthesis of chimeras built with the 8-(3-bromopropyloxy)-psoralen and the amide of cinnamic acid or its 4-methoxy derivative has also been carried out. In contrast to 8-MOP, all the chimeras exhibit strong molar absorptivities in the range 20 000-40 000 M(-1) cm(-1) in the 340-390 nm UV-A region. The "retinoid-like"- and retinoid-psoralen chimeras are characterized by a marked dark toxicity toward proliferating NCTC 2544 keratinocytes (with a lethal dose corresponding to 50% cell survival [LD50] of 1-5 microM) as compared with that of the cinnamic acid derivative-psoralen chimeras (LD50 > or = 50 microM). This toxicity leads to alteration of the mitochondrial membrane potential. At nontoxic concentrations, the chimeras demonstrate effective psoralens + UV-A-induced photocytotoxicity. They are moderate photosensitizers of membrane lipid peroxidation. Cell apoptosis is a major photocytotoxic process as suggested by the fluorescence-activated cell-sorting technique using annexin-fluorescein isothiocyanate and propidium iodide as apoptotic markers.