Development of Asialoglycoprotein-Mediated Hepatocyte-Targeting Antitumor Prodrugs Triggered by Glutathione

作者：Mian Wang, Zhenjie Li, Feiyang Liu, Qingyuan Yi, Chunxiao Pu, Yajie Li, Tingrong Luo, Jian Liang, Jianyi Wang · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c01365 · 被引用次数：37 · 研究领域：Drug Transport and Resistance Mechanisms、Nanoparticle-Based Drug Delivery、Synthesis and Characterization of Heterocyclic Compounds

One antitumor β-elemene derivative W-105 and three novel hepatocyte-targeting prodrugs ( W-1-5, W-2-9, and W-3-8 ) were designed and synthesized. W-105 (IC 50 6.107 μM) could cause cell apoptosis through upregulating the activity of caspase-3. The hepatocyte-targeting capacities of the aimed compounds followed the W-105 (parent compound) < W-1-5 (monodentate-galactose) < W-2-9 (bidentate-galactose) < W-3-8 (tridentate-galactose) order, which is attributed to the excellent affinity of the galactose ligand to ASGPR and the galactose-cluster recognition effect. Furthermore, prodrugs W-3-8 exhibited good antitumor activity and low toxic side effects. The liquid chromatography-mass spectrometry (LC-MS) assays revealed that prodrugs ( W-1-5, W-2-9, and W-3-8 ) could release the antitumor pharmacophore in the presence of GSH (mimic the condition of the tumor cell) and maintain the low-toxic structures in the absence of GSH (mimic the condition of the normal cell). The release mechanisms of prodrugs were also proposed. Overall, these prodrugs developed in this study had potential in the treatment of liver cancer.