@article{Li2026, 
author = {Tianze Li and Chenxi Jiang and Qihao Li and Min-min Hu and Yabo Li and Yao Yang and Yunbao Ma and Yongcui Wang and Jijun Chen},
title = {Discovery of dimeric costunolide-triazole conjugates as antihepatoma agents via integrating dimerization and molecular hybridization},
year = {2026},
journal = {Chinese Journal of Natural Medicines},
volume = {24},
number = {8},
pages = {1006-1014},
keywords = {Antihepatoma activity, Costunolide, Triazole, Dimers, Glucose-6-phosphate dehydrogenase (G6PD), Mechanism},
url = {https://www.sciopen.com/article/10.1016/S1875-5364(26)61098-9},
doi = {10.1016/S1875-5364(26)61098-9},
abstract = {Costunolide, a natural germacranolide sesquiterpenoid, exhibits only moderate anti-HCC activity. To enhance its efficacy and tumor selectivity, a series of 37 dimeric costunolide-1,2,3-triazole conjugates was designed and synthesized by integrating dimerization and molecular hybridization strategies. Evaluation of their antiproliferative effects on HepG2, Huh-7, and SK-Hep-1 cells suggested that 25 compounds were more potent than either costunolide or sorafenib. The most active dimer 19 exhibited significant activity with IC50 values of 1.6, 1.3, and 0.7 μmol·L−1, which were 13.1, 14.2, and 34.9-fold greater than those of costunolide. Compound 19 showed favorable selectivity against human normal liver cells (THLE-2) and markedly inhibited colony formation. Through a combination of bioinformatics, docking, and molecular dynamics (MD) simulations, glucose-6-phosphate dehydrogenase (G6PD) was identified as a target of compound 19, which was subsequently validated by DARTS and SPR assays. Functional studies revealed that compound 19 arrested the HCC cell cycle at the G2/M phase, suppressed migration and invasion by inhibiting epithelial-mesenchymal transition, and triggered both apoptosis and ferroptosis. These findings establish triazole-linked costunolide dimer 19 as a promising lead candidate for the development of novel anti-HCC therapies.}
}