A. Chilin et al., Synthesis and biological activity of (Hydroxymethyl)- and (diethylaminomethyl)benzopsoralens, J MED CHEM, 42(15), 1999, pp. 2936-2945
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.