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

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 (IC50 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.