Synthesis and Biological Activities of 11‐ and 12‐Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB and Tyrosyl‐DNA Phosphodiesterase 1 Inhibitors

Abstract Herein, a series of 11‐ or 12‐substituted benzophenanthridinone derivatives was designed and synthesized for the discovery of dual topoisomerase IB (TOP1) and tyrosyl‐DNA phosphodiesterase 1 (TDP1) inhibitors. Enzyme‐based assays indicated that two compounds 12 and 38 showed high TOP1 inhibitory potency (+++), and four compounds 35, 37, 39 and 43 showed good TDP1 inhibition with IC 50 values ranging from 10 to 18 μM. 38 could induce cellular TOP1cc formation, resulting in the highest cytotoxicity against HCT‐116 cells (0.25 μM). The most potent TDP1 inhibitor 43 (10 μM) could induce cellular TDP1cc formation and enhance topotecan‐induced DNA damage and showed strong synergistic cytotoxicity with topotecan in both MCF‐7 and MCF‐7/TDP1 cells.