Generic placeholder image

Current Bioactive Compounds

Author(s): Leonid A. Yakovishin*

DOI: 10.2174/1573407215666191007111603

DownloadDownload PDF Flyer Cite As
Molecular Complex of Glycyrrhizic Acid Monoammonium Salt with Cholesterol

Page: [1042 - 1048] Pages: 7

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: Glycyrrhizic Acid (GA) is the major triterpene saponin of licorice roots. The most important derivative of GA is its monoammonium salt (glycyram, GC). Some pharmacological properties of triterpene saponins explain their molecular complexation with Cholesterol (Chol). However, the molecular complexation of GC with Chol has not been proven. The functional groups of GA and GC involved in the interactions with Chol were not identified.

Methods: The complexation has been investigated by the method of isomolar series in the spectrophotometric version, IR, and 13C NMR spectroscopy. The constant is calculated on the basis of isomolar curves.

Results: The molecular complex of GC with Chol has been prepared for the first time. It has been shown that GC forms a 1 : 1 complex with Chol having a stability constant Ks of (3.3 ± 0.2)×105 (mol/L)-1 (in 70% aqueous EtOH at 18 °С).

Conclusion: Intermolecular interaction in the complex is carried out by hydrogen bond formation between C=O group of GC (in carboxyl group of the terminal residue of glucuronic acid in the carbohydrate part) and 3β-hydroxyl group of Chol: -С=О⋅⋅⋅Н-О-. Hydrophobic contacts of the aglycone part of GC with a lipophilic Chol molecule are possible.

Keywords: Molecular complex, glycyrrhizic acid, monoammonium glycyrrhizinate, cholesterol, licorice, saponins.

Graphical Abstract

[1]
Hostettmann, K.; Marston, A. Saponins; Cambrige University Press: Cambrige, 1995.
[http://dx.doi.org/10.1017/CBO9780511565113]
[2]
Tolstikov, G.A.; Baltina, L.A.; Grankina, V.P.; Kondratenko, R.M.; Tolstikova, T.G. Licorice: Biodiversity, chemistry, and application in medicine In: Geo: Novosibirsk; , 2007.
[3]
Asl, M.N.; Hosseinzadeh, H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother. Res., 2008, 22(6), 709-724.
[http://dx.doi.org/10.1002/ptr.2362] [PMID: 18446848]
[4]
Pavlova, S.I.; Uteshev, B.S.; Sergeev, A.V. Licorice root: Possible mechanisms of antitoxicant, anticarcinogen, and antitumor properties (a review). Pharm. Chem. J., 2003, 37(6), 314-317.
[http://dx.doi.org/10.1023/A:1026005931751]
[5]
Niu, T.; Yang, J.; Zhang, L.; Cheng, X.; Li, K.; Zhou, G. Research advances on anticancer effect of licorice. Curr. Bioact. Compd., 2009, 5(3), 234-242.
[http://dx.doi.org/10.2174/157340709789054803]
[6]
Gol’dberg, E.D.; Amosova, E.N.; Zueva, E.P.; Razina, T.G.; Krylova, S.G.; Zorikov, P.S. Licorice preparations improve efficiency of chemotherapy and surgical treatment of transplanted tumors. Bull. Exp. Biol. Med., 2008, 145(2), 252-255.
[http://dx.doi.org/10.1007/s10517-008-0063-0] [PMID: 19023982]
[7]
Razina, T.G.; Zueva, E.P.; Amosova, E.N.; Zhdanov, V.V. Glyciram as an enhancer of the effectiveness of chemotherapy and surgery in the treatment of experimental neoplasms. Vopr. Onkol., 1999, 45(5), 554-556.
[PMID: 10629717]
[8]
Hayashi, H.; Sudo, H. Economic importance of licorice. Plant Biotechnol., 2009, 26(1), 101-104.
[http://dx.doi.org/10.5511/plantbiotechnology.26.101]
[9]
Salnitskaya, M.A.; Pasiuga, V.N.; Magda, I.Y.; Yakovishin, L.A.; Grishkovets, V.I.; Shckorbatov, Y.G. Effect of some triterpene glycosides applied in vitro on chromatin state in human cells. Curr. Bioact. Compd., 2014, 10(1), 37-43.
[http://dx.doi.org/10.2174/157340721001140725000118]
[10]
Tolstikova, T.G.; Khvostov, M.V.; Bryzgalov, A.O. The complexes of drugs with carbohydrate-containing plant metabolites as pharmacologically promising agents. Mini Rev. Med. Chem., 2009, 9(11), 1317-1328.
[http://dx.doi.org/10.2174/138955709789878123 ] [PMID: 19929808]
[11]
Kondratenko, R.M.; Baltina, L.A.; Mustafina, S.R.; Ismagilova, A.F.; Zarudii, F.S.; Davydova, V.A.; Bazekin, G.V.; Suleimanova, G.F.; Tolstikov, G.A. Complex compounds of glycyrrhizic acid with antimicrobial drugs. Pharm. Chem. J., 2003, 37(9), 485-488.
[http://dx.doi.org/10.1023/B:PHAC.0000008250.02124.d6]
[12]
Dalimov, D.N.; Isaev, Y.T.; Saiitkulov, A.M. Molecular complexes of ammonium glycyrrhizate with certain medicinal agents and their interferon-inducing activity. Chem. Nat. Compd., 2001, 37(2), 151-153.
[http://dx.doi.org/10.1023/A:1012382904059]
[13]
Yakovishin, L.A.; Grishkovets, V.I. Ivy and Licorice Triterpene Glycosides: Promising Molecular Containers for Some Drugs and Biomolecules. Studies in Natural Products Chemistry; Atta-ur-Rahman; Elsevier, B.V., Ed.; Amsterdam, 2018, Vol. 55, pp. 351-383.
[14]
Polyakov, N.E.; Leshina, T.V. Glycyrrhizic acid as a novel drug delivery vector: Synergy of drug transport and efficacy. Open Conf. Proc. J., 2011, 2, 64-72.
[http://dx.doi.org/10.2174/2210289201102010064]
[15]
Yakovishin, L.A.; Korzh, E.N. Molecular complex of quercetin with glycyram.In: AIP Conf. Proc 2019.2063, pp. 040066.
[http://dx.doi.org/10.1063/1.5087398]
[16]
Paolino, D.; Cosco, D.; Cilurzo, F.; Fresta, M. Innovative drug delivery systems for the administration of natural compounds. Curr. Bioact. Compd., 2007, 3(4), 262-277.
[http://dx.doi.org/10.2174/157340707783220301]
[17]
Tschesche, R.; Wulff, G. Konstitution und eigenschaften der saponine. Planta Med., 1964, 12(3), 272-292.
[http://dx.doi.org/10.1055/s-0028-1100180]
[18]
Yakovishin, L.A.; Borisenko, N.I.; Rudnev, M.I.; Vetrova, E.V.; Grishkovets, V.I. Self-association and complexation of triterpene glycosides and cholesterol. Chem. Nat. Compd., 2010, 46(1), 49-52.
[http://dx.doi.org/10.1007/s10600-010-9522-8]
[19]
Yakovishin, L.A.; Grishkovets, V.I. Molecular complexes of ivy triterpene glycosides with cholesterol. Khimiya Rastitel’nogo Syr’ya, 2018, 4, 133-140.
[20]
Francis, G.; Kerem, Z.; Makkar, H.P.S.; Becker, K. The biological action of saponins in animal systems: A review. Br. J. Nutr., 2002, 88(6), 587-605.
[http://dx.doi.org/10.1079/BJN2002725] [PMID: 12493081]
[21]
Augustin, J.M.; Kuzina, V.; Andersen, S.B.; Bak, S. Molecular activities, biosynthesis and evolution of triterpenoid saponins. Phytochemistry, 2011, 72(6), 435-457.
[http://dx.doi.org/10.1016/j.phytochem.2011.01.015] [PMID: 21333312]
[22]
Lorent, J.H.; Quetin-Leclercq, J.; Mingeot-Leclercq, M.P. The amphiphilic nature of saponins and their effects on artificial and biological membranes and potential consequences for red blood and cancer cells. Org. Biomol. Chem., 2014, 12(44), 8803-8822.
[http://dx.doi.org/10.1039/C4OB01652A] [PMID: 25295776]
[23]
Selyutina, O.Yu.; Apanasenko, I.E.; Kim, A.V.; Shelepova, E.A.; Khalikov, S.S.; Polyakov, N.E. Spectroscopic and molecular dynamics characterization of glycyrrhizin membrane-modifying activity. Colloids Surf. B Biointerfaces, 2016, 147, 459-466.
[http://dx.doi.org/10.1016/j.colsurfb.2016.08.037] [PMID: 27580071]
[24]
Selyutina, O.Yu.; Polyakov, N.E.; Korneev, D.V.; Zaitsev, B.N. Effect of glycyrrhizic acid on hemolysis of red blood cells and properties of cell membranes. Russ. Chem. Bull., 2014, 63(5), 1201-1204.
[http://dx.doi.org/10.1007/s11172-014-0573-z]
[25]
Selyutina, O.Yu.; Apanasenko, I.E.; Polyakov, N.E. Membrane-modifying activity of glycyrrhizic acid. Russ. Chem. Bull., 2015, 64(7), 1555-1559.
[http://dx.doi.org/10.1007/s11172-015-1040-1]
[26]
Selyutina, O.Yu.; Polyakov, N.E.; Korneev, D.V.; Zaitsev, B.N. Influence of glycyrrhizin on permeability and elasticity of cell membrane: Perspectives for drugs delivery. Drug Deliv., 2016, 23(3), 858-865.
[http://dx.doi.org/10.3109/10717544.2014.919544 ] [PMID: 24870200]
[27]
Selyutina, O.Yu.; Apanasenko, I.E.; Shilov, A.G.; Khalikov, S.S.; Polyakov, N.E. Effect of natural polysaccharides and oligosaccharides on the permeability of cell membranes. Russ. Chem. Bull., 2017, 66(1), 129-135.
[http://dx.doi.org/10.1007/s11172-017-1710-2]
[28]
Visavadiya, N.P.; Narasimhacharya, A.V. Hypocholesterolaemic and antioxidant effects of Glycyrrhiza glabra (Linn) in rats. Mol. Nutr. Food Res., 2006, 50(11), 1080-1086.
[http://dx.doi.org/10.1002/mnfr.200600063] [PMID: 17054099]
[29]
Moghimipour, E.; Kooshapour, H.; Rezaee, S.; Khalili, S.; Handali, S. In vitro cholesterol binding affinity of total saponin extracted from Glycyrrhiza glabra. Asian J. Pharm. Clin. Res., 2014, 7(1), 170-173.
[30]
Sidhu, G.S.; Oakenfull, D.G. A mechanism for the hypocholesterolaemic activity of saponins. Br. J. Nutr., 1986, 55(3), 643-649.
[http://dx.doi.org/10.1079/BJN19860070 ] [PMID: 3676181]
[31]
Polyakov, N.E.; Leshina, T.V. NMR relaxation study of cholesterol binding with plant metabolites. Appl. Magn. Reson., 2011, 41(2), 283-294.
[32]
Gluschenko, O.Yu.; Polyakov, N.E.; Leshina, T.V. NMR study of cholesterol complexes with glycyrrhizic acid. Magn. Reson. Solids, 2011, 13(2), 5-9.
[33]
Zelikman, M.V.; Kim, A.V.; Medvedev, N.N.; Selyutina, O.Yu.; Polyakov, N.E. Structure of dimers of glycyrrhizic acid in water and their complexes with cholesterol: Molecular dynamics simulation. J. Struct. Chem., 2015, 56(1), 67-76.
[http://dx.doi.org/10.1134/S0022476615010102]
[34]
Wojciechowski, K.; Orczyk, M.; Gutberlet, T.; Geue, T. Complexation of phospholipids and cholesterol by triterpenic saponins in bulk and in monolayers. Biochim. Biophys. Acta, 2016, 1858(2), 363-373.
[http://dx.doi.org/10.1016/j.bbamem.2015.12.001] [PMID: 26654784]
[35]
Babko, A.K. Physico-chemical analysis of complex compounds in the solutions; Izd-vo AN USSR: Kiev, 1955.
[36]
Yakovishin, L.A.; Grishkovets, V.I.; Korzh, E.N. Molecular complexes of monoammonium glycyrrhizinate with alpha-hederin and hederasaponin C. Lett. Org. Chem., 2015, 12(2), 109-114.
[http://dx.doi.org/10.2174/1570178612666141230234729]
[37]
Yakovishin, L.A.; Grishkovets, V.I.; Klimenko, A.V.; Degtyar, A.D.; Kuchmenko, O.B. Molecular complexes of ivy and licorice triterpene glycosides with doxorubicin. Pharm. Chem. J., 2014, 48(6), 391-394.
[http://dx.doi.org/10.1007/s11094-014-1117-4]
[38]
Yakovishin, L.A.; Grishkovets, V.I.; Korzh, E.N.; Vetrova, E.V.; Borisenko, N.I. Physico-chemical characteristic and biological activity of the supramolecular complex of glycyram with β-cyclodextrin. Macroheterocycles, 2015, 8(1), 94-98.
[http://dx.doi.org/10.6060/mhc141139y]
[39]
Hobza, P.; Zagradnik, R. Intermolecular complexes; Academia: Prague, 1989.
[40]
Kalinin, V.I.; Levin, V.S.; Stonik, V.A. The chemical morphology: triterpene glycosides of sea cucumbers (Holothurioidea, Echinodermata); Dalnauka: Vladivostok, 1994.
[41]
Ioffe, D.V. Sterols as complex-forming species. Russ. Chem. Rev., 1986, 55(2), 143-152.
[http://dx.doi.org/10.1070/RC1986v055n02ABEH003177]
[42]
Konkina, I.G.; Shitikova, O.V.; Lobov, A.N.; Murinov, Yu.I.; Bachurin, S.O. Host-guest complexation in the β-glycyrrhizic acid-2,8-dimethyl-5-[2′-(6′′-methylpyridin-3′′-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole system. Russ. Chem. Bull., 2015, 64(6), 1385-1393.
[http://dx.doi.org/10.1007/s11172-015-1021-4]