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

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 <b>86</b> (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 <b>86</b> 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 <b>92</b>, the water-soluble prodrug of <b>86</b>, exhibited no apparent toxicity. Furthermore, <b>92</b> significantly reduced the tumor volume and tumor weights in lung cancer CDX and PDX models. These findings suggested that <b>92</b> deserved further studies as a potential candidate for the ultimate discovery of effective anti-lung cancer agents.