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

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

  • Eur J Med Chem. 2026 Sep 5:313:118907. doi: 10.1016/j.ejmech.2026.118907.
De-Xuan Hu 1,  Yue-Wen Li 2,  Ao Chen 2,  Chao Qin 3,  Jian-Qiang Zhang 2,  Zi-Qiong Liang 2,  Keli Agama 4,  Yves Pommier 4,  Huaiming Wang 5,  Lin-Kun An 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; Chengdu Medical College, Chengdu, 610500, China.
  • 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; Guangdong Institute for Drug Control, Guangzhou, 510663, China.
  • 4 Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States.
  • 5 Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. Electronic address: wanghm7@mail.sysu.edu.cn.
  • 6 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, China. Electronic address: lssalk@mail.sysu.edu.cn.
PMID: 42070448 DOI: 10.1016/j.ejmech.2026.118907
Abstract

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.

Keywords

Benzophenanthridine; Benzophenanthridinone; Cancer resistance; DNA damage; Radiosensitivity; Tyrosyl-DNA phosphodiesterase.

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