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−1cm−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 μM) as compared with that of the cinnamic acid derivative–psoralen chimeras (LD50≥ 50 μM). 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.