2. Academic Validation
  3. Design, synthesis, and biological evaluation of Pseudolaric acid B derivatives as Ferroptosis inducers in Colon Cancer cells

Design, synthesis, and biological evaluation of Pseudolaric acid B derivatives as Ferroptosis inducers in Colon Cancer cells

  • Bioorg Chem. 2025 Sep:164:108852. doi: 10.1016/j.bioorg.2025.108852.
Lu Zhang 1,  Yu-Xia Wang 1,  Jin-Zi Chen 1,  Feng Bao 1,  Qi-Mei Tan 1,  Ya-Lin Li 1,  Ling-Yi Kong 2,  Jian-Guang Luo 3,  Chen Chen 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Basic Medical Research Innovation Center for Anti-Cancer Drugs, Ministry of Education, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
  • 2 State Key Laboratory of Natural Medicines, Basic Medical Research Innovation Center for Anti-Cancer Drugs, Ministry of Education, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
  • 3 State Key Laboratory of Natural Medicines, Basic Medical Research Innovation Center for Anti-Cancer Drugs, Ministry of Education, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: luojg@cpu.edu.cn.
  • 4 State Key Laboratory of Natural Medicines, Basic Medical Research Innovation Center for Anti-Cancer Drugs, Ministry of Education, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: chenchen1601@126.com.
PMID: 40795665 DOI: 10.1016/j.bioorg.2025.108852
Abstract

The inhibition of Glutathione Peroxidase 4 (GPX4) is an effective strategy to suppress the proliferation of tumor cells by inducing Ferroptosis. To obtain GPX4 inhibitors, we designed and synthesized 34 pseudolaric acid B (PAB) derivatives. The results of the cytotoxicity test showed that compound 30 significantly inhibited the proliferation of colon Cancer cells (HCT-116 and HT-29). Importantly, 30-induced cytotoxicity was reversed by Ferroptosis inhibitors (ferrostatin-1 and deferoxamine). Enzyme activity assays demonstrated that compound 30 significantly inhibited GPX4 enzymatic activity. Further flow cytometry experiments showed that 30 significantly increased the level of lipid Reactive Oxygen Species in HCT-116 cells. Correspondingly, 30 modulated the levels of other Ferroptosis indicators, such as Fe2+, MDA, and GSH in HCT-116 cells. The Western blot results displayed that 30 inhibited the protein expression of GPX4 in a dose and time-dependent manner, which was reversed by MG132 (a Proteasome Inhibitor), suggesting that 30 suppressed the protein level of GPX4 by promoting GPX4 protein degradation. These results suggest that 30 is a Ferroptosis inducer through the inhibition of GPX4, exhibiting the potential for treatment of colon Cancer.

Keywords

Colon cancer; Ferroptosis; GPX4; Lipid ROS; Pseudolaric acid B derivatives.

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