2. Academic Validation
  3. Sinomenine derivative 1f suppresses glioblastoma through inducing both apoptosis mediated by intrinsic pathway and necroptosis mediated by TNF-α/NF-κB/MAPK signaling pathway

Sinomenine derivative 1f suppresses glioblastoma through inducing both apoptosis mediated by intrinsic pathway and necroptosis mediated by TNF-α/NF-κB/MAPK signaling pathway

  • Eur J Med Chem. 2026 Feb 15:304:118535. doi: 10.1016/j.ejmech.2025.118535.
Bin Jiang 1,  Fang Xu 2,  Juan Liu 1,  Xiaoxue Li 2,  Wanxin Cao 2,  Huijuan Song 1,  Siyuan Zhang 1,  Yuxuan Zhao 2,  Weifeng Li 1,  Zhiwen Yue 1,  Siting Liu 1,  Sijia Yan 1,  Ruifang Zheng 3,  Jinhua Wang 4,  Jianguang Li 5,  Tengfei Ji 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
  • 3 Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi, 841100, China.
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 5 Xinjiang Second Medical College, Karamay, 834000, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi, 841100, China. Electronic address: [email protected].
PMID: 41475072 DOI: 10.1016/j.ejmech.2025.118535
Abstract

Glioblastoma (GBM) is the most prevalent and aggressive primary malignant brain tumor. Currently, there is a severe lack of drugs to treat GBM. In the study, we established the configuration of novel enantiomeric compounds of sinomenine derivatives through chemical synthesis and X-ray diffraction analysis. Based on this structural characterization, we designed and synthesized a series of sinomenine derivatives and evaluated their antiproliferative activity in GBM cell lines. Among them, compound 1f exhibited notable antiproliferative activity and was amenable to large-scale synthesis. Mechanistic studies reveal that compound 1f induces mitochondria-dependent Apoptosis. Furthermore, we also found that compound 1f induced Necroptosis by activating the TNF-α/NF-κB/MAPK signaling pathway. Inducing dual modes of cell death is beneficial for overcoming drug resistance associated with reliance on a single death pathway. In addition, with favorable blood-brain barrier (BBB) permeability, compound 1f was found to inhibit the growth of orthotopic GBM and improve the survival rate. These results suggest that compound 1f may be a promising candidate with an excellent safety profile for the treatment of GBM.

Keywords

Anti-GBM; Apoptosis; Necroptosis; Sinomenine derivatives; Synthesis; TNF-α.

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