Human DNA topoisomerase I poisoning activity of bis-1-aminomethylnaphtalenes. A correlation with their cytotoxic activity.

Symmetrical bis-1-aminmoethylnaphtalenes, a group of compounds that demonstrated cytotoxicity towards human tumor cell lines, showed human topoisomerase I poisoning activity. The compounds tested were: N,N'-bis-1-naphthylmethyl-1,6-hexanediamine (1a), N,N'-bis-1-naphthylmethyl-1,8-octanediamine (1b), N,N'-bis-1-naphthylmethyl-1,12-dodecanediamine (1c), N,N'-bis-1-naphthylmethyl-4,4-bipiperidine (2) and N-(1-naphthylmethyl)-N'-dimethyl-1,3-diaminepropane dichlorhydrate (3). All showed human topoisomerase I inhibition by producing protein-linked DNA breaks. The most active were 1a, 1b, 1c with a percentage stimulation of DNA cleavage of 75, 84 and 70% at 100 micrograms/ml, respectively. Compounds 2 and 3 were moderately active as poisons of topoisomerase I activity, the former showing 58% stimulation of DNA cleavage at 100 micrograms/ml and the latter a 24% stimulation. The correlation observed between topoisomerase I poisoning and in vitro cytotoxic activity suggests that this could be a possible mechanism for the cytotoxicity observed in tumor cell lines.