ИСТИНА

The development of new, effective drugs for the treatment of liver diseases is an important task in modern society. Diseases such as hepatocellular carcinoma, hepatitis B and C, and malaria are directly associated in the human body with the liver and hepatocytes, which represent the major group of cells in the liver. The above diseases affect a large part of the human population and, in many cases, lead to serious consequences and lethal effects. For example, the viruses that cause hepatitis B and C may lead to chronic hepatitis, which can cause cirrhosis and liver cancer. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and accounts for 90% of all liver cancers (782,000 deaths were associated with HCC in the year 2018). To date, there is no universal pill that guarantees a complete cure in each case. Additionally, the need for timely diagnosis remains relevant, which is especially important for the detection of HCC at an early stage. Pentacyclic triterpenoids are a class of natural compounds widely represented in plant sources. It is known, that triterpenoids are characterized by diverse biological activity, especially antiviral and antitumor. However, most terpenoid structures are characterized by common drawbacks – low solubility and bioavailability, weak pharmacological effects at low concentrations. At present work, a new series of triterpenoid based glycoconjugates were synthesized and characterized. Initially, the primary alkyne derivatives of betulinic, oleanolic, ursolic, and glycyrrhetinic acids were obtained using different esterification reactions. Subsequent CuAAC-conjugation with azido-derivatives of N-acetyl-D-galactosamine (GalNAc) led to selective formation of new triterpenoid based glycoconjugates. Generally, 24 new compounds were synthesized during the study. Residues of GalNAc are known to provide selective binding of conjugates with ASGP-receptor on the surface of hepatocytes and thus to facilitate targeted delivery of drugs to the liver. All compounds were screened for cytotoxicity in vitro against the HepG2, Huh7, and several control cell lines. SPR-spectroscopy studies of Kd values for conjugate-ASGPR complex showed the binding affinity, comparable to the conventional branched ASGPR-ligands. Chemical and enzymatic stability studies showed the ability of presented compounds to degrade under physiological conditions. Results of subsequent biological evaluation of the obtained glycoconjugates will be published separately during the current investigations.