Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinoma

Autor: Dmitry O Shkil, Petr V. Gorelkin, Alexander N. Lobov, V.A. Naumenko, Alexander Erofeev, Olga Y. Burenina, Yan A. Ivanenkov, Emil Yu. Yamansarov, Roman Akasov, Dmitry A. Skvortsov, Natalia L. Klyachko, Elena K. Beloglazkina, Sergey V. Kovalev, Alexander G. Majouga, Oxana Ryabaya, Elena V Lopatukhina, Ekaterina N Pavlova, Alexander Vaneev, Sergei A Evteev, Anton V Lopukhov
Rok vydání: 2021
Předmět:
Acetylgalactosamine
Carcinoma
Hepatocellular
Glycoconjugate
media_common.quotation_subject
Biomedical Engineering
Pharmaceutical Science
Bioengineering
Antineoplastic Agents
02 engineering and technology
Asialoglycoprotein Receptor
01 natural sciences
chemistry.chemical_compound
Drug Delivery Systems
In vivo
Cell Line
Tumor
Drug Discovery
Humans
Cytotoxicity
Internalization
media_common
Fluorescent Dyes
Pharmacology
chemistry.chemical_classification
Betulin
010405 organic chemistry
Organic Chemistry
Liver Neoplasms
Surface Plasmon Resonance
021001 nanoscience & nanotechnology
In vitro
Triterpenes
0104 chemical sciences
Molecular Docking Simulation
Biochemistry
chemistry
Asialoglycoprotein receptor
Drug Screening Assays
Antitumor
0210 nano-technology
Hydrophobic and Hydrophilic Interactions
Biotechnology
Conjugate
Zdroj: Bioconjugate chemistry. 32(4)
ISSN: 1520-4812
Popis: Herein, we describe the design, synthesis, and biological evaluation of novel betulin and N-acetyl-d-galactosamine (GalNAc) glycoconjugates and suggest them as targeted agents against hepatocellular carcinoma. We prepared six conjugates derived via the C-3 and C-28 positions of betulin with one or two saccharide ligands. These molecules demonstrate high affinity to the asialoglycoprotein receptor (ASGPR) of hepatocytes assessed by in silico modeling and surface plasmon resonance tests. Cytotoxicity studies in vitro revealed a bivalent conjugate with moderate activity, selectivity of action, and cytostatic properties against hepatocellular carcinoma cells HepG2. An additional investigation confirmed the specific engagement with HepG2 cells by the enhanced generation of reactive oxygen species. Stability tests demonstrated its lability to acidic media and to intracellular enzymes. Therefore, the selected bivalent conjugate represents a new potential agent targeted against hepatocellular carcinoma. Further extensive studies of the cellular uptake in vitro and the real-time microdistribution in the murine liver in vivo for fluorescent dye-labeled analogue showed its selective internalization into hepatocytes due to the presence of GalNAc ligand in comparison with reference compounds. The betulin and GalNAc glycoconjugates can therefore be considered as a new strategy for developing therapeutic agents based on natural triterpenoids.
Databáze: OpenAIRE
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