Design, Synthesis and Biological Evaluation of 6H-Benzimidazo1′,2′:1,2pyrido3,4- b indole Derivatives as TDP1 Inhibitors: Potent Synergistic Agents with Topotecan against Cervical Cancer

Cervical cancer remains a major global threat to women's health. Topotecan (TPT), a topoisomerase I (TOP1) inhibitor, is widely used for advanced or recurrent disease; however, its efficacy is compromised by tyrosyl-DNA phosphodiesterase 1 (TDP1)-mediated DNA repair. Moreover, effective TDP1 inhibitors remain limited. In this study, we modified the lead compound 3b based on the 6H-benzimidazo1',2':1,2pyrido3,4-bindole scaffold to synthesize derivatives. Derivative 16b exhibited the most potent TDP1 inhibitory activity (IC50 = 1.52 ± 0.34 μM). Molecular docking and dynamics simulations revealed that 16b simultaneously occupied TDP1's catalytic and DNA-binding domains. Furthermore, 16b synergized with TPT to suppress HeLa cell proliferation. This effect was likely mediated by enhanced DNA damage, induced apoptosis, S-phase cell cycle arrest, and potentially ferroptosis. In vivo, the combination treatment significantly inhibited tumor growth in cervical cancer xenograft models. These findings identify 16b as a promising TDP1 inhibitor with potential to enhance TPT-based therapy.