Synthesis and Structure-activity Relationship Studies of Water-soluble β-cyclodextrin-glycyrrhetinic Acid Conjugates As Potential Anti-influenza Virus Agents

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2019 Feb 8

PMID 30731401

Citations 21

Authors

Shuobin Liang

Man Li

Xiaojuan Yu

Hongwei Jin

Yongmin Zhang

Lihe Zhang

Demin Zhou

Sulong Xiao

Affiliations

Soon will be listed here.

Abstract

Glycyrrhetinic acid (GA) is a major constituent of the herb Glycyrrhiza glabra, and many of its derivatives demonstrate a broad spectrum of antiviral activities. In the current study, 18 water-soluble β-cyclodextrin (CD)-GA conjugates, in which GA was covalently coupled to the primary face of β-CD using 1,2,3-triazole moiety along with varying lengths of linker, were synthesized via copper-catalyzed azide-alkyl cycloaddition reaction. Benefited from the attached β-CD moiety, all these conjugates showed lower hydrophobicity (AlogP) compared with their parent compound GA. With the exception of per-O-methylated β-CD-GA conjugate (35), all other conjugates showed no significant cytotoxicity to MDCK cells, and these conjugates were then screened against A/WSN/33 (H1N1) virus using the cytopathic effect assay. The preliminary results indicated that six conjugates showed promising antiviral activity, and the C-3 and C-30 of GA could tolerate some modifications. Our findings suggested that GA could be used as a lead compound for the development of potential anti-influenza virus agents.

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References

Yu M, Si L, Wang Y, Wu Y, Yu F, Jiao P . Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses. J Med Chem. 2014; 57(23):10058-71. DOI: 10.1021/jm5014067. View

Lovering F, Bikker J, Humblet C . Escape from flatland: increasing saturation as an approach to improving clinical success. J Med Chem. 2009; 52(21):6752-6. DOI: 10.1021/jm901241e. View

Csuk R, Schwarz S, Siewert B, Kluge R, Strohl D . Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives. Eur J Med Chem. 2011; 46(11):5356-69. DOI: 10.1016/j.ejmech.2011.08.038. View

Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr H . Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003; 361(9374):2045-6. PMC: 7112442. DOI: 10.1016/s0140-6736(03)13615-x. View

Onodera R, Motoyama K, Okamatsu A, Higashi T, Arima H . Potential use of folate-appended methyl-β-cyclodextrin as an anticancer agent. Sci Rep. 2013; 3:1104. PMC: 3551233. DOI: 10.1038/srep01104. View

Paolino D, Lucania G, Mardente D, Alhaique F, Fresta M . Ethosomes for skin delivery of ammonium glycyrrhizinate: in vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers. J Control Release. 2005; 106(1-2):99-110. DOI: 10.1016/j.jconrel.2005.04.007. View

Yu F, Wang Q, Zhang Z, Peng Y, Qiu Y, Shi Y . Development of oleanane-type triterpenes as a new class of HCV entry inhibitors. J Med Chem. 2013; 56(11):4300-19. DOI: 10.1021/jm301910a. View

Lopez-Miranda S, Guardiola L, Hernandez-Sanchez P, Nunez-Delicado E . Complexation between oleanolic and maslinic acids with native and modified cyclodextrins. Food Chem. 2017; 240:139-146. DOI: 10.1016/j.foodchem.2017.07.092. View

Hardy M, Hendricks J, Paulson J, Faunce N . 18β-glycyrrhetinic acid inhibits rotavirus replication in culture. Virol J. 2012; 9:96. PMC: 3478227. DOI: 10.1186/1743-422X-9-96. View

10.

Udo K, Hokonohara K, Motoyama K, Arima H, Hirayama F, Uekama K . 5-Fluorouracil acetic acid/beta-cyclodextrin conjugates: drug release behavior in enzymatic and rat cecal media. Int J Pharm. 2009; 388(1-2):95-100. DOI: 10.1016/j.ijpharm.2009.12.039. View

11.

Sabbioni C, Mandrioli R, Ferranti A, Bugamelli F, Saracino M, Cantelli Forti G . Separation and analysis of glycyrrhizin, 18beta-glycyrrhetic acid and 18alpha-glycyrrhetic acid in liquorice roots by means of capillary zone electrophoresis. J Chromatogr A. 2005; 1081(1):65-71. PMC: 7125616. DOI: 10.1016/j.chroma.2005.03.044. View

12.

Xiao S, Tian Z, Wang Y, Si L, Zhang L, Zhou D . Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives. Med Res Rev. 2018; 38(3):951-976. PMC: 7168445. DOI: 10.1002/med.21484. View

13.

Beseda I, Czollner L, Shah P, Khunt R, Gaware R, Kosma P . Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases. Bioorg Med Chem. 2009; 18(1):433-54. DOI: 10.1016/j.bmc.2009.10.036. View

14.

Hao J, Sun Y, Wang Q, Tong X, Zhang H, Zhang Q . Effect and mechanism of penetration enhancement of organic base and alcohol on glycyrrhetinic acid in vitro. Int J Pharm. 2010; 399(1-2):102-8. DOI: 10.1016/j.ijpharm.2010.08.009. View

15.

Jambhekar S, Breen P . Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, and complexation efficiency. Drug Discov Today. 2015; 21(2):363-8. DOI: 10.1016/j.drudis.2015.11.016. View

16.

Wang H, Soica C, Wenz G . A comparison investigation on the solubilization of betulin and betulinic acid in cyclodextrin derivatives. Nat Prod Commun. 2012; 7(3):289-91. View

17.

Baltina L, Zarubaev V, Baltina L, Orshanskaya I, Fairushina A, Kiselev O . Glycyrrhizic acid derivatives as influenza A/H1N1 virus inhibitors. Bioorg Med Chem Lett. 2015; 25(8):1742-1746. PMC: 7127794. DOI: 10.1016/j.bmcl.2015.02.074. View

18.

Xiao S, Si L, Tian Z, Jiao P, Fan Z, Meng K . Pentacyclic triterpenes grafted on CD cores to interfere with influenza virus entry: A dramatic multivalent effect. Biomaterials. 2015; 78:74-85. DOI: 10.1016/j.biomaterials.2015.11.034. View

19.

Takeda S, Ishthara K, Wakui Y, Amagaya S, Maruno M, Akao T . Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysis. J Pharm Pharmacol. 1996; 48(9):902-5. DOI: 10.1111/j.2042-7158.1996.tb05998.x. View

20.

Tetko I, Tanchuk V, Villa A . Prediction of n-octanol/water partition coefficients from PHYSPROP database using artificial neural networks and E-state indices. J Chem Inf Comput Sci. 2001; 41(5):1407-21. DOI: 10.1021/ci010368v. View