Topoisomerase poisoning activity of novel disaccharide anthracyclines

Doxorubicin and idarubicin are very effective anticancer drugs in the treat ment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs r ecently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for the ir poisoning effects of human topoisomerase I and topoisomerases II alpha a nd II beta Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topo isomerases II alpha and II beta The axial orientation of the second sugar r elative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at lo w levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellula r topoisomerase I content. The results are relevant for the full understand ing of the molecular mechanism of topoisomerase poisoning by anticancer dru gs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I.