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 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.
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1 December 2003
On the Photobiological Properties of Chimeras Combining Quaternary Ammonium Derivatives of Retinoic Amides and Psoralen. A Study with Cultured Human Keratinocytes
Teresa Sá e Melo,
Photochemistry and Photobiology
Vol. 78 • No. 6
Vol. 78 • No. 6