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 1-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 norindenolsoquinoline 5. The desired compound 14a wits 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 it series of human leukemia, ovarian, and breast cancer cells.