ИСТИНА

Synthesis of glycoconjugated molecules take important place in the chemistry of triterpenoids, which are characterized by low bioavailability. Pharmacological profile of the original terpenes could be improved using saccharides and it’s a well-known method in laboratory practice. Moreover, the presence of specific monosaccharides residues provide the therapeutic agents with the properties of targeted delivery to different biological targets. For example, N-acetyl-D-galactosamine (GalNAc) is responsible for the selective interaction with the asialoglycoprotein receptor (ASGP-R), which is expressed in large quantities on the surface of hepatocytes. In the present work, 29 new covalent conjugates of N-acetyl-D-galactosamine with betulin, betulinic, oleanolic, ursolic and glycyrrhetinic acids, were synthesized and characterized. Molecular docking showed their ability to interact with ASGP-R, scoring values were predicted for all structures with similar binding affinities. Evaluation of the thermodynamic constants of complexes "conjugate-receptor" using surface plasmon resonance spectroscopy showed high affinity of synthesized conjugates to ASGP-R. Cell viability assay allowed to identify the lead compounds with the highest cytotoxic activity. Extended studies of the several compounds for stability under physiological conditions, receptor-mediated cellular uptake and mechanism of antitumor action have been carried out. Summary, our studies showed the conjugates of natural triterpenoids and GalNAc are promising agents for the treatment of liver diseases, including the targeted therapy of hepatocellular carcinoma.