Structural optimization of benzophenanthridinone and benzophenanthridine Tyrosyl-DNA phosphodiesterase 1 inhibitors and their radiosensitizing activity.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a potential radiotherapeutic target for cancer treatment. Herein, two series of analogues, benzophenanthridinone derivatives and benzophenanthridine derivatives, were designed and synthesized based on the reported TDP1 inhibitor NTD119B showing strong radiosensitization in vitro and in vivo. The structural modification gave seventeen analogues with stronger TDP1 inhibitory activity than NTD119B (IC50 = 6.9 μM). B11 showed the most potent TDP1 inhibition (IC50 = 1.2 ± 0.7 μM), 5.8-fold greater than NTD119B. Colony formation assays showed four TDP1 inhibitors A6, A26, B1, B7 showing stronger radiosensitizing activity than NTD119B in HCT116 cells. Further studies demonstrate that A6 targets TDP1 in cells and suppresses NHEJ repair activity, enhancing ionizing radiation-induced DNA damage resulting in a strong radiosensitizing activity both in HCT116 cells and xenografts animal model. The structure-activity relationship for TDP1 inhibition is also analyzed.