Synthesis and biological activity of (Hydroxymethyl)- and (diethylaminomethyl)benzopsoralens

Some benzopsoralens, carrying a hydroxymethyl or a diethylaminomethyl group at the 3, 5, 8, and 11 positions, were prepared, and their biological acti vity was compared with that of 4-(hydroxymethyl)benzopsoralen (BP). 5-(Hydr oxymethyl)benzopsoralen (7b), 11-(hydroxymethyl)benzopsoralen (7c), and 11- (diethylaminomethyl)benzopsoralen (8c) induced marked antiproliferative eff ects in mammalian cells by simple incubation in the dark; this activity app eared to be related to their ability to inhibit topoisomerase II. Benzopsor alens appeared to be more active, especially BP and 7c, upon WA activation. Compounds carrying a methyl group at the 4 position together with a hydrox ymethyl Or diethylaminomethyl at the 8 position (7d and 8d, respectively) w ere also effective, although to a lower extent; instead, a substituent at t he 3 position canceled all activity. Benzopsoralens did not induce interstr and cross-links in DNA in vitro, as seen in the induction of cytoplasmic << petite>> mutations and double-strand breaks in yeast. This behavior is also compatible with their low mutagenic activity in E. coli WP2 and with the a bsence of any phototoxicity on the skin. For these features, benzopsoralens seem to be interesting potential drugs for PUVA photochemotherapy and phot opheresis. The activity shown in the dark is not sufficient for their possi ble use as antitumor drugs, but it does offer a new model for the study of topoisomerase inhibitors.