2. Academic Validation
  3. Identification of Melampomagnolide B Derivatives as Triggers of Cuproptosis, Ferroptosis, and Apoptosis for Treatment of Lung Cancer

Identification of Melampomagnolide B Derivatives as Triggers of Cuproptosis, Ferroptosis, and Apoptosis for Treatment of Lung Cancer

  • J Med Chem. 2026 Apr 9;69(7):8255-8284. doi: 10.1021/acs.jmedchem.5c03682.
Yongping Bai 1,  Liping Chen 1,  Huaxu Liu 2,  Wanjing Feng 1,  Yue Chen 2 3,  Yahui Ding 2 3,  Quan Zhang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300350, People's Republic of China.
  • 2 College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, People's Republic of China.
  • 3 Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300071, People's Republic of China.
PMID: 41906470 DOI: 10.1021/acs.jmedchem.5c03682
Abstract

Herein, we described the design and synthesis of a series of melampomagnolide B-dithiocarbamate hybrids and the evaluation of their anti-lung Cancer activities. The most active compound 86 (IC50 = 0.46 μM) exhibited a highly potent inhibitory effect on NCI-H820 cells, with a 44-fold increase compared to the natural product melampomagnolide B (IC50 = 20.43 μM). Compound 86 mediated mitochondrial dysfunction, promoted ROS generation to disrupt redox homeostasis, and eventually induced Apoptosis, Ferroptosis, and Cuproptosis in lung Cancer cells in vitro and in vivo. Preliminary toxicity assessment indicated that compound 92, the water-soluble prodrug of 86, exhibited no apparent toxicity. Furthermore, 92 significantly reduced the tumor volume and tumor weights in lung Cancer CDX and PDX models. These findings suggested that 92 deserved further studies as a potential candidate for the ultimate discovery of effective anti-lung Cancer agents.

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