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 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.