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

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

  • J Med Chem. 2025 May 8;68(9):9323-9340. doi: 10.1021/acs.jmedchem.4c02951.
De-Xuan Hu 1 2 3,  Chao Qin 1,  Li-Shuang Guo 1,  Wen-Ya Liu 1,  Zi-Qiong Liang 1,  Ye Cao 1,  Chuan-Sheng Yao 1,  Yingqi Wei 4,  Xin Yue 5,  Md Rasel Al Mahmud 6,  Keli Agama 6,  Huaiming Wang 4,  Yves Pommier 6,  Lin-Kun An 1 2 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 2 State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 3 School of Pharmacy, Chengdu Medical College, Chengdu 610500, China.
  • 4 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 5 The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.
  • 6 Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 7 Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou 510006, China.
PMID: 40298128 DOI: 10.1021/acs.jmedchem.4c02951
Abstract

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.

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