Photobiological activity of certain new methylazapsoralens.

ABSTRACT

The photobiological activity of a series of psoralen isosters carrying a nitrogen atom at 8 position, new potential drugs for the photochemotherapy of hyperproliferative skin diseases, have been studied; the more active derivatives appeared to be 5,4'-dimethyl-8-azapsoralen and 3,4,4'-trimethyl-8-azapsoralen which induced a strong inhibition of DNA synthesis in Ehrlich ascites cells, very similar to that provoked by 8-methoxypsoralen, the furocoumarin at present used in photochemotherapy. Such compounds induced a small amount of inter-strand DNA cross-links and were non phototoxic when assayed on guinea-pig skin; however, both derivatives appeared to be highly mutagenic in E. coli WP2 TM6. This strain contains the plasmid R46 and it is proficient in DNA repair, and therefore monoadducts do not should be mutagenic in such a strain. Because the first steps of excision, which remove monoadducts, and of the main cross-link repair use the same enzymes (produced by the uvrABC complex), in the presence of a great number of monofunctional lesions, it is possible that there are not sufficient enzyme molecules for removing cross-links according this pathway, which could be repaired by a second one, uvrABC independent and based on glycosilase activity, which works at reduced levels and is much less accurate.