Bioconjugate Chemistry, volume 32, issue 4, pages 763-781
Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinoma
Yamansarov Emil Yu
1, 2, 3
,
Lopatukhina Elena V.
3
,
Evteev Sergei A
3
,
Skvortsov Dmitry
3
,
Lopukhov Anton V
3
,
Kovalev Sergey
3
,
Vaneev Alexander N.
1, 3
,
Shkil Dmitry O
3
,
Akasov Roman A.
1
,
Naumenko Victor
5
,
Pavlova Ekaterina N
3
,
Ryabaya Oxana O.
6
,
Burenina Olga Y
7
,
Ivanenkov Yan
8, 9
,
Klyachko Natalia L.
3, 7
,
Erofeev Alexander V.
1, 3
,
Gorelkin Peter
1, 3
,
Majouga Alexander G.
1, 3, 10
Publication type: Journal Article
Publication date: 2021-03-11
Journal:
Bioconjugate Chemistry
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 4.7
ISSN: 10431802, 15204812
Organic Chemistry
Pharmacology
Pharmaceutical Science
Biotechnology
Bioengineering
Biomedical Engineering
Abstract
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.
Citations by journals
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1
2
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Molecules
|
Molecules
2 publications, 16.67%
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Pharmaceutics
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2 publications, 16.67%
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1 publication, 8.33%
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1 publication, 8.33%
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1 publication, 8.33%
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1 publication, 8.33%
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SSRN Electronic Journal
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SSRN Electronic Journal
1 publication, 8.33%
|
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European Journal of Medicinal Chemistry
|
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1 publication, 8.33%
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Nanomedicine
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1 publication, 8.33%
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1
2
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Citations by publishers
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1
2
3
4
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Multidisciplinary Digital Publishing Institute (MDPI)
|
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4 publications, 33.33%
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Royal Society of Chemistry (RSC)
|
Royal Society of Chemistry (RSC)
2 publications, 16.67%
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Springer Nature
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Springer Nature
1 publication, 8.33%
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American Chemical Society (ACS)
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American Chemical Society (ACS)
1 publication, 8.33%
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Wiley
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Wiley
1 publication, 8.33%
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Social Science Electronic Publishing
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Social Science Electronic Publishing
1 publication, 8.33%
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Elsevier
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Elsevier
1 publication, 8.33%
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Future Medicine
|
Future Medicine
1 publication, 8.33%
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1
2
3
4
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Yamansarov E. Yu. et al. Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinoma // Bioconjugate Chemistry. 2021. Vol. 32. No. 4. pp. 763-781.
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Yamansarov E. Yu., Lopatukhina E. V., Evteev S. A., Skvortsov D., Lopukhov A. V., Kovalev S., Vaneev A. N., Shkil D. O., Akasov R. A., Lobov A. N., Naumenko V., Pavlova E. N., Ryabaya O. O., Burenina O. Y., Ivanenkov Y., Klyachko N. L., Erofeev A. V., Gorelkin P., Beloglazkina E. K., Majouga A. G. Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinoma // Bioconjugate Chemistry. 2021. Vol. 32. No. 4. pp. 763-781.
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TY - JOUR
DO - 10.1021/acs.bioconjchem.1c00042
UR - https://doi.org/10.1021%2Facs.bioconjchem.1c00042
TI - Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinoma
T2 - Bioconjugate Chemistry
AU - Lopatukhina, Elena V.
AU - Pavlova, Ekaterina N
AU - Evteev, Sergei A
AU - Yamansarov, Emil Yu
AU - Lopukhov, Anton V
AU - Kovalev, Sergey
AU - Vaneev, Alexander N.
AU - Shkil, Dmitry O
AU - Akasov, Roman A.
AU - Lobov, Alexander Nikolaevich
AU - Naumenko, Victor
AU - Ivanenkov, Yan
AU - Klyachko, Natalia L.
AU - Majouga, Alexander G.
AU - Skvortsov, Dmitry
AU - Ryabaya, Oxana O.
AU - Burenina, Olga Y
AU - Erofeev, Alexander V.
AU - Gorelkin, Peter
AU - Beloglazkina, Elena K.
PY - 2021
DA - 2021/03/11 00:00:00
PB - American Chemical Society (ACS)
SP - 763-781
IS - 4
VL - 32
SN - 1043-1802
SN - 1520-4812
ER -
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@article{2021_Yamansarov,
author = {Elena V. Lopatukhina and Ekaterina N Pavlova and Sergei A Evteev and Emil Yu Yamansarov and Anton V Lopukhov and Sergey Kovalev and Alexander N. Vaneev and Dmitry O Shkil and Roman A. Akasov and Alexander Nikolaevich Lobov and Victor Naumenko and Yan Ivanenkov and Natalia L. Klyachko and Alexander G. Majouga and Dmitry Skvortsov and Oxana O. Ryabaya and Olga Y Burenina and Alexander V. Erofeev and Peter Gorelkin and Elena K. Beloglazkina},
title = {Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinoma},
journal = {Bioconjugate Chemistry},
year = {2021},
volume = {32},
publisher = {American Chemical Society (ACS)},
month = {mar},
url = {https://doi.org/10.1021%2Facs.bioconjchem.1c00042},
number = {4},
pages = {763--781},
doi = {10.1021/acs.bioconjchem.1c00042}
}
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Yamansarov, Emil Yu., et al. “Discovery of Bivalent GalNAc-Conjugated Betulin as a Potent ASGPR-Directed Agent against Hepatocellular Carcinoma.” Bioconjugate Chemistry, vol. 32, no. 4, Mar. 2021, pp. 763-781. https://doi.org/10.1021%2Facs.bioconjchem.1c00042.