Naphtho[2,3-f]indole-5,10-dione aminoalkyl derivatives: A new class of topoisomerase I inhibitors

Abstract

Naphtho[2,3-f]indole-5,10-dione aminoalkyl derivatives in cytotoxic concentrations inhibit topoisomerase I, which is an important factor of antitumor activity of compounds of this chemical class. The degree of topoisomerase I inhibition with naphtho[2,3-f]indole-5,10-dione derivatives depends on the structure and position of active (aminoalkyl) groups. The mechanism of topoisomerase I inhibition with aminoalkylnaph-tho[2,3-f]indole-5,10-diones differs from specific blocking of the catalytic activity of the enzyme and depends on interactions of these compounds with DNA.

Mannich bases in medicinal chemistry and drug design

“…Replacement of phenolic hydroxyl groups R 1 in 63 (R ¼ dimethylamino) by 2-aminoethyleneamino moieties led to mixed results, as the potency improved for some of the cell lines and declined for others, but the sensitivity of multidrug resistant breast cancer cells to these modified candidates was completely lost [86]. Furthermore, candidate 63 (R ¼ quinuclidin-3ylamino, R 1 ¼ OH) was shown to inhibit topoisomerase I-mediated relaxation of DNA, but the suppression of the topoisomerase I activity is presumably the leading although probably not the only factor contributing to cytotoxicity of Mannich bases of naphtho [2,3-f]indole-5,10-diones [87]. Preobrazhenskaya et al have also shown that a series of single and double Mannich bases 64 (R 1 ¼ H or dialkylaminomethyl) of 3,4-bis(indol-1-yl)maleimides ( Fig.…”