Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinomaстатья
Статья опубликована в высокорейтинговом журнале
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Дата последнего поиска статьи во внешних источниках: 4 июня 2021 г.
Аннотация:Herein, we describe the design, synthesis, andbiological evaluation of novel betulin and N-acetyl-D-galactosamine(GalNAc) glycoconjugates and suggest them as targeted agentsagainst hepatocellular carcinoma. We prepared six conjugatesderived via the C-3 and C-28 positions of betulin with one or twosaccharide ligands. These molecules demonstrate high affinity tothe asialoglycoprotein receptor (ASGPR) of hepatocytes assessedby in silico modeling and surface plasmon resonance tests.Cytotoxicity studies in vitro revealed a bivalent conjugate withmoderate activity, selectivity of action, and cytostatic propertiesagainst hepatocellular carcinoma cells HepG2. An additionalinvestigation confirmed the specific engagement with HepG2cells by the enhanced generation of reactive oxygen species.Stability tests demonstrated its lability to acidic media and tointracellular enzymes. Therefore, the selected bivalent conjugate represents a new potential agent targeted against hepatocellularcarcinoma. Further extensive studies of the cellular uptake in vitro and the real-time microdistribution in the murine liver in vivo forfluorescent dye-labeled analogue showed its selective internalization into hepatocytes due to the presence of GalNAc ligand incomparison with reference compounds. The betulin and GalNAc glycoconjugates can therefore be considered as a new strategy fordeveloping therapeutic agents based on natural triterpenoids.