Azapsoralens: new potential photochemotherapeutic agents for psoriasis.
New bioisoters of psoralen, obtained by replacing carbon 8 of the central benzene ring with a nitrogen, were studied from the photochemical, photobiological and phototherapeutic points of view. In particular, 4,4'-, 4',5'-dimetyl, 4,4',5'-trimethyl and 3,4,4',5'-tetramethylazapsoralen were studied. The crystal and molecular structure of 4,4',5'-trimethylazapsoralen, obtained by X ray diffraction, was also reported. Like psoralen, these compounds form a molecular complex with DNA, undergoing intercalation inside the double helix of the macromolecule. When irridiated with long ultraviolet light (365 nm), the intercalated drug photoconjugates covalently to the macromolecule, forming mono- and diadducts. The photobinding rate show the following order of magnitude: 4,4',5'-trimetylazapsoralen (4,4',5'-TMAP) = 3,4,4',5'-tetramethylazapsoralen (3,4,4',5'-TMAP) greater than 4',5'-dimethylazapsoralen (4',5'-DMAP) = 4,4'-dimethylazapsoralen (4,4'-DMAP). The DNA photobinding rate of 8-methoxypsoralen (8-MOP), taken as reference compound, is similar to that of the two dimetylazapsoralens but lower than tri- and tetramethyl derivatives. The ability of azapsoralens to form cross-links in DNA is lower than that of 8-MOP. However, capacity to induce cross-links does not parallel the DNA photobinding rate; it is higher for trimethyl derivate and lower for tetramethylazapsoralen. Azapsoralens show evident antiproliferative activity. The trimethyl derivative is the most active, followed by tetrametyl, both these compounds showing activity slightly higher than that of 8-MOP. The two dimethylderivatives are less active. The mautagenic activity of azapsoralens on E. coli WP2 TM6 is lower than that of 8-MOP in the same conditions. The new compounds do not show any skin phototoxicity on guinea pig skin. On the basis of its DNA photobinding, antiproliferative activity, mutagenicity and lack of skin phototoxicity, 4,4',5'-TMAP was chosen for clinical evaluation. Clinical results obtained by topical treatment of psoriatic plaques reveal evident therapeutic effectiveness and clearing is between good and moderate, although 8-MOP, used as reference compound, is more effective.
Vedaldi
D
D
Department of Pharmaceutical Sciences of the University, Padova, Italy.
Caffieri
S
S
Miolo
G
G
Dall'Acqua
F
F
Baccichetti
F
F
Guiotto
A
A
Benetollo
F
F
Bombieri
G
G
Recchia
G
G
Cristofolini
M
M
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects; D003956:Dialysis; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005260:Female; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D009153:Mutagens / Q000633:toxicity; D010778:Photochemotherapy; D011565:Psoriasis / Q000188:drug therapy*; D051381:Rats; D012995:Solubility; D013941:Thymine / Q000737:chemistry; D014961:X-Ray Diffraction
D001372:Aza Compounds; D003432:Cross-Linking Reagents; D011564:Furocoumarins; D009153:Mutagens; D004247:DNA; D013941:Thymine