On the photobiological properties of chimeras combining quaternary ammonium derivatives of retinoic amides and psoralen. A study with cultured human keratinocytes.
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.
Lartillot
Véronique
V
INSERM U532, Institut de Recherche sur la Peau, Hôpital Saint-Louis, Paris cedex, France.
Risler
Arnaud
A
Andriamialisoa
Zo
Z
Giraud
Michel
M
Sá e Melo
Teresa
T
Michel
Laurence
L
Santus
René
R
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004338:Drug Combinations; D005363:Ficusin / Q000627:therapeutic use; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D008027:Light; D015227:Lipid Peroxidation / Q000187:drug effects / Q000528:radiation effects; D011701:PUVA Therapy / Q000379:methods*; D000644:Quaternary Ammonium Compounds / Q000627:therapeutic use; D014212:Tretinoin / Q000031:analogs & derivatives / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004338:Drug Combinations; D000644:Quaternary Ammonium Compounds; D014212:Tretinoin; D005363:Ficusin