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  3. Discovery, structural modification and structure-activity relationship study of Echinulin derivatives as tyrosyl-DNA phosphodiesterase 1 inhibitors and their potential antitumor activity

Discovery, structural modification and structure-activity relationship study of Echinulin derivatives as tyrosyl-DNA phosphodiesterase 1 inhibitors and their potential antitumor activity

  • Eur J Med Chem. 2025 Nov 15:298:118040. doi: 10.1016/j.ejmech.2025.118040.
Chuan-Sheng Yao 1,  Jiaqi Zhu 2,  Xiang Gao 1,  Ao Chen 1,  Yue-Wen Li 1,  Wen-Ya Liu 1,  Li-Shuang Guo 1,  Yong-Chun Wu 2,  Cui-Xian Zhang 3,  Xi-Xin He 4,  Lin-Kun An 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
  • 3 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. Electronic address: zhangcuixian@gzucm.edu.cn.
  • 4 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. Electronic address: mark07@gzucm.edu.cn.
  • 5 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: 40782471 DOI: 10.1016/j.ejmech.2025.118040
Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme and a potential antitumor target. Inhibiting TDP1 can potentiate the efficacy of both chemotherapy and radiotherapy. Herein, we report the discovery of the natural product Echinulin as a novel TDP1 inhibitor (IC50 = 5.6 μM). The structural modification of Echinulin gave fifty-one derivatives. The evaluation of TDP1 inhibition indicated that eight derivatives 20, 25, 26, 27, 33, 64, 66, and 67 showed higher TDP1 inhibitory activity than Echinulin. 33 exhibited the highest TDP1 potency with an IC50 value of 0.90 μM, and a strong synergistic effect with camptothecin in human skin melanoma SK-Mel-2 cells, but not in three Cancer cells A549, HCT-116, MCF-7, and non-cancerous Ges-1 cells. Structure-activity relationship (SAR) and the hypothetical binding mode of 33 with TDP1 protein were also analyzed. These results highlight that the Echinulin scaffold is a novel chemotype for the development of TDP1 inhibitors.

Keywords

Antitumor; Echinulin; Natural product; SAR study; Topoisomerase; Tyrosyl-DNA phosphodiesterase.

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