Synthesis of 5,9- and 5,8-Diaminoalkoxy Substituted Benzophenanthridinone Analogues as Tyrosyl-DNA Phosphodiesterase 1 Inhibitors and Their Radiosensitizing Activity

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a potential target for cancer chemotherapy and radiotherapy. There are a few reports on TDP1 inhibitors used in chemotherapy, but no report on their use in radiotherapy. Herein, we designed and synthesized a series of titled analogues. Twelve analogues showed high TDP1 inhibitory activity. Among them, 18 (IC₅₀ = 6.9 μM) showed strong radiosensitization in colorectal cancer cells, and could suppress tumor growth in the HCT116 xenograft animal model combined with X-ray radiation, and exhibited low acute toxicity with good pharmacokinetic (PK) parameters, implying that 18 is worth further clinical research. Further studies indicated that 18 could target cellular TDP1 and suppress NHEJ repair activity for radiation-induced DNA damage, resulting in cancer cell death. Additionally, 18 could also increase the expression of PIG3, resulting in an enhancement of radiation-induced cellular ROS and mitochondrial dysfunction. Our studies provide a novel cancer treatment strategy combining TDP1 inhibitors and radiotherapy.