New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids

Yamansarov, Emil Yu.; Skvortsov, Dmitry A.; Lopukhov, Anton V; Ковалев, С. В.; Evteev, Sergei A; Petrov, Rostislav A.; Klyachko, Natalia L.; Зык, Н. В.; Белоглазкина, Е. К.; Ivanenkov, Ya. A.; Majouga, Alexander G.

doi:10.1007/s11172-019-2707-9

Cited by 7 publications

(8 citation statements)

References 33 publications

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“…38 corresponded to the binding potency of the multivalent synthetic ligand. 39 As previously found, 31 we speculate that the SPR assay results also showed an additional effect between the N-acetyl-Dgalactosamine moiety and the triterpenoid skeleton of betulin, thus increasing the binding with ASGPR. The multivalency of the ligand (from 3 to 4 GalNAc residues) is regarded as a minimum requirement in designing the final conjugate for optimal accumulation into the hepatocytes via ASGPR endocytosis.…”

Section: ■ Results and Discussionsupporting

confidence: 79%

“…Azido sugars 1 and 2 (and also 3) were obtained according to the published literature. 30,31 The spectroscopic characteristics of 3 corresponded to the published data. 54 Compound 13 was synthesized as previously described.…”

Section: ■ Conclusionsupporting

confidence: 63%

“…Despite the observed high affinity, we concluded the loss of cytotoxicity by glycoconjugated betulin during the modification with the hydrophilic moiety in the isopropenyl group via the C-30 position. 31 Moreover, the described derivative possessed an undegradable link between the triterpenoid and the sugar residue. In the course of our research, we try to synthesize mono-and bivalent conjugates of betulin and GalNAc via a linker anchored to the terpenoidal carbon skeleton through the C-3 and C-20 positions.…”

Section: ■ Results and Discussionmentioning

confidence: 92%

“…We chose betulin, a lupane-type pentacyclic triterpenoid with a significant cytotoxic effect against hepatocarcinoma cells (HepG2), as a template platform for the present study. We recently published several articles on the synthesis of glycoconjugated triterpenoids with N -acetyl- d -galactosamine. , The obtained derivatives of allobetulin, betulinic acid, and betulin turned out to be nontoxic and had high affinity to ASGPR. Despite the observed high affinity, we concluded the loss of cytotoxicity by glycoconjugated betulin during the modification with the hydrophilic moiety in the isopropenyl group via the C-30 position .…”

Section: Results and Discussionmentioning

confidence: 99%

“…We recently published several articles on the synthesis of glycoconjugated triterpenoids with N -acetyl- d -galactosamine. , The obtained derivatives of allobetulin, betulinic acid, and betulin turned out to be nontoxic and had high affinity to ASGPR. Despite the observed high affinity, we concluded the loss of cytotoxicity by glycoconjugated betulin during the modification with the hydrophilic moiety in the isopropenyl group via the C-30 position . Moreover, the described derivative possessed an undegradable link between the triterpenoid and the sugar residue.…”

Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: ■ Results and Discussionsupporting

confidence: 79%