Lipidization of gelsemine facilitates its cellular uptake and anti-tumor activity

Gelsemine possesses an unique structure and diverse pharmacological properties; however, its practical application is severely limited due to its low activity and safety. In this work, we designed and synthesized three series of lipidated gelsemines, significantly improving their antiproliferative activity against cancer cells. Structure-activity relationship studies have shown that the antiproliferative activity depends on the lipid chain length, with modifications of medium-chain lipids being the most effective. GB5, with a C15-chain lipid, exhibited the most potent activity and selectivity in HT-29 cells (IC₅₀ = 0.48 ± 0.03 μM, SI = 12.5), and was even superior to 5-fluorouracil (5-FU, IC₅₀ = 3.63 ± 0.61 μM, SI = 0.4). Cell fluorescence imaging assays demonstrated that the modification of medium-chain lipids promoted the cellular uptake of gelsemine derivatives and their localization in lysosomes. Further pharmacological studies indicated that GA6 and GB5 arrested the cell cycle in the G0/G1 phase, raised ROS levels, triggered ferroptosis, and promoted apoptosis via ROS-mediated MAPK/NF-κB/p53 signaling pathways in HT-29 cells. In vivo xenograft tumor model experiments have shown that GA6 and GB5 have anti-tumor efficacy comparable to that of 5-FU. These results will significantly advance the pharmacological research of gelsemine-like compounds.