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 activity was compared with that of 4-(hydroxymethyl)benzopsoralen (BP). 5-(Hydroxymethyl)benzopsoralen (7b), 11-(hydroxymethyl)benzopsoralen (7c), and 11-(diethylaminomethyl)benzopsoralen (8c) induced marked antiproliferative effects in mammalian cells by simple incubation in the dark; this activity appeared to be related to their ability to inhibit topoisomerase II. Benzopsoralens appeared to be more active, especially BP and 7c, upon UVA activation. Compounds carrying a methyl group at the 4 position together with a hydroxymethyl or diethylaminomethyl at the 8 position (7d and 8d, respectively) were also effective, although to a lower extent; instead, a substituent at the 3 position canceled all activity. Benzopsoralens did not induce interstrand 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 absence of any phototoxicity on the skin. For these features, benzopsoralens seem to be interesting potential drugs for PUVA photochemotherapy and photopheresis. The activity shown in the dark is not sufficient for their possible use as antitumor drugs, but it does offer a new model for the study of topoisomerase inhibitors.
Chilin
A
A
Department of Pharmaceutical Sciences and Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR, Padova, Italy.
Marzano
C
C
Guiotto
A
A
Manzini
P
P
Baccichetti
F
F
Carlassare
F
F
Bordin
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects; D004271:DNA, Fungal / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008730:Methoxsalen / Q000737:chemistry / Q000494:pharmacology; D009152:Mutagenicity Tests; D009154:Mutation; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012867:Skin / Q000528:radiation effects; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D015003:Yeasts / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects
C090414:4-hydroxymethyl-4',5'-benzopsoralen; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004271:DNA, Fungal; D004791:Enzyme Inhibitors; D011564:Furocoumarins; D017319:Photosensitizing Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA; D008730:Methoxsalen