Synthesis of a new betulinic acid glycoconjugate with N-acetyl-d-galactosamine for the targeted delivery to hepatocellular carcinoma cells

A new promising conjugate of betulinic acid with N -acetyl- d -galactosamine was synthesized by the simple reaction sequence: esterification and copper-catalyzed azide-alkyne cycloaddition. The obtained glycoderivative exhibited high activity against hepatocarcinoma cell lines in vitro , selectivity of cytotoxic action, and excellent binding to the asialoglycoprotein receptor (ASGPR) of hepatocytes. Its affinity to the ASGPR was established by surface plasmon resonance spectroscopy and confirmed by molecular docking in silico . An original approach was proposed to enhance the cytotoxic properties of C-28 betulinic esters by introducing a hemioxalate fragment bearing free carboxyl group into the C(3) position of ring A.