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.