文献类型：期刊文献

英文题名：Design, synthesis and mechanism study of fluorine-containing bulbocapnine derivatives inducing ferroptosis for anti-colon Cancer therapy

作者：Duan, Guojian[1,2,3];Wang, Taotao[1,2,3];Qiu, Guoliang[1,2,3];Shi, Jiankun[1,2,3];Xu, Yaxing[1,2,3];Chen, Hui[1,4];Ma, Yongfei[1,2,3];Xie, Yongqiang[1,4];Li, Shuo[1,2,3]

第一作者：段国建

通信作者：Duan, GJ[1];Li, S[1]

机构：[1]Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Gansu, Peoples R China;[2]Gansu Univ Chinese Med, Northwest Collaborat Innovat Ctr Tradit Chinese Me, Lanzhou 730000, Peoples R China;[3]Gansu Univ Chinese Med, Coll Pharm, MOE PRC, Lanzhou 730000, Peoples R China;[4]Gansu Univ Chinese Med, Expt & Training Teaching Ctr, Lanzhou 730000, Gansu, Peoples R China

第一机构：甘肃中医药大学药学院（西北中藏药协同创新中心办公室）

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Gansu, Peoples R China.|[1073501e14fb35863569f]甘肃中医药大学药学院（西北中藏药协同创新中心办公室）;[10735]甘肃中医药大学;

年份：2026

卷号：189

外文期刊名：INTERNATIONAL IMMUNOPHARMACOLOGY

收录：;Scopus(收录号：2-s2.0-105050395664);WOS:【SCI-EXPANDED(收录号:WOS:001879671600001)】；

基金：This work was supported by the Key Laboratory of Traditional Chi-nese Medicine Quality and Standard, Gansu Province (Gansu University of Chinese Medicine) (grant number ZYZL2025-13); Department of Education of Gansu Province, Industry Support Project (grant number 2025CYZC-050); Science and Technology Program Funding of Gansu Province (grant number 24JRRA883; 25JRRA1179) .

语种：英文

外文关键词：Corydalis dasyptera maxim .; Bulbocapnine derivatives; Ferroptosis; GPX4; Colon cancer

摘要：In this study, using repeated silica gel column chromatography with gradient elution, we isolated seven natural alkaloids from Corydalis dasyptera Maxim. Among them, bulbocapnine has a significant inhibitory effect on colon cancer cells. We chemically modified bulbocapnine by esterifying its phenolic hydroxyl group with various aromatic acyl chlorides, including fluorinated benzoyl, fluorinated phenylacetyl, and fluorinated nicotinoyl moieties, to systematically study the effects of different substituents on its anti-cancer activity. Among them, the two fluorinated derivatives: B1 (4-fluorobenzoate) and B6 (4-fluorophenylacetate) exhibited IC50 values of 13.92 and 11.00 mu M against HT-29 cells, outperforming 5-FU. Molecular docking revealed that B1 and B6 anchor to GPX4 via synergistic salt-bridge and hydrogen-bond interactions. This binding suppresses the enzymatic activity of GPX4, thereby disrupting the glutathione (GSH)-dependent antioxidant defense system. Consequently, the detoxification of lipid peroxides is impaired, which, together with the concomitant accumulation of ferrous ions (Fe2+), triggers a massive burst of lipid reactive oxygen species (ROS). Ultimately, this cascade of oxidative damage executes ferroptosis and effectively inhibits HT-29 colorectal cancer cell proliferation. Ferrostatin-1 (Fer1) and Deferoxamine (DFO) could antagonize this process by inhibiting oxidative stress and iron homeostasis imbalance. Molecular dynamics simulation results show that GPX4-B1 and GPX4-B6 can bind to form a stable complex. The computational models offer a plausible explanation for the observed activity difference: the fluorine atom may influence the overall dipole moment, potentially facilitating interactions with the GPX4 binding pocket. However, this hypothesis requires direct experimental validation through techniques such as isothermal titration calorimetry (ITC) or surface plasmon resonance (SPR) in future studies. They also further elucidate the mechanism by which the drug molecule inhibits colorectal cancer through ferrocide. Taken together, the novel drug based on bulbocapnine exhibited potent inhibitory effects on colon cancer cells, which may provide a proof-of-concept basis for B1 and B6 as ferroptosis inducers specifically in the HT-29 colorectal cancer model, warranting further evaluation in broader preclinical models to assess their translational potential.