Structure-based design, synthesis, and biological studies of new anticancer norindenoisoquinoline topoisomerase I inhibitors.

On the basis of the superimposition of the crystal structures of norindenoisoquinoline 5 and topotecan (2) bound in the topoisomerase I-DNA covalent complex, as well as molecular docking and quantum chemical calculations, the substituted norindenoisoquinoline 14a was designed by transporting the 9-dimethylaminomethyl group of topotecan to the 10-position of the norindenoisoquinoline 5. The desired compound 14a was synthesized and found to possess topoisomerase I inhibitory activity that was slightly better than that of the starting compound 5. A focused set of 10-substitued norindenoisoquinoline analogues were then synthesized. The imidazole-substituted compound 14c was highly cytotoxic when evaluated in a series of human leukemia, ovarian, and breast cancer cells.