2. Academic Validation
  3. Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells

Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells

  • Bioorg Chem. 2024 Sep:150:107594. doi: 10.1016/j.bioorg.2024.107594.
Jian-Fei Zhang 1,  Li-Hong Hong 1,  Shi-Ying Fan 1,  Ling Zhu 1,  Zhan-Peng Yu 1,  Chen Chen 2,  Ling-Yi Kong 3,  Jian-Guang Luo 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: chenchen1601@126.com.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
  • 4 Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: luojg@cpu.edu.cn.
PMID: 38941701 DOI: 10.1016/j.bioorg.2024.107594
Abstract

Inhibition of human Dihydroorotate Dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of Cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human Cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted Anticancer effects by inducing Ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by Ferroptosis inhibitors. This was supported by the intracellular growth or decline of Ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential Anticancer properties warranting development.

Keywords

Cytotoxic; Ferroptosis; Lipid peroxidation; Piperine derivatives; hDHODH inhibitors.

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