Abstract
Introduction. Licorice or liquorice (Glycyrrhiza glabra, Leguminosae) is a perennial plant naturally occurring or cultivated in Europe and Asia. It was appreciated by many ancient cultures, and was employed within Arabic medicine and (beginning in the Middle Ages) in Europe folk medicine as a remedy for many diseases. Currently, the sweet flavoured root of this plant – Radix Glycyrrhizae (Liquirtiae), is widely taken for the treating of various upper respiratory tract diseases, as well as for gastric ulcer disease. It is also utilized as a sweetening and flavouring agent in the food, tobacco and pharmacy industries. The main active ingredient of liquorice is the triterpenoid saponin, glycyrrhizin, which is a mixture of calcium, magnesium and potassium salts of glycyrrhizic acid (GA). Glycyrrhizic acid is composed of an aglycone, that is 18β-glycyrrhetinic acid (GE), and a D-glucuronic acid dimer. The aim of this review is to discuss some aspects of the activity of glycyrrhetinic acid and its derivatives in infectious diseases.
State of knowledge. The pentacyclic system of glycyrrhetinic acid consists of condensed six-membered rings with a hydroxyl group at C-3, a carboxyl moiety at C-30 and a ketone functional group at C-11. Considering the presence of the above mentioned functional groups, many structural transformations have been proposed, including those by way of esterification, alkylation and reduction reactions. The introduction of various chemical residues into its structure, as well as the modification of the glycyrrhetinic acid in its pentacyclic triterpene skeleton, has led to the generation of compounds with many valuable antimicrobial, anti-parasitic, antiviral properties and modified lipophilic parameters.
Summary. In summary, glycyrrhetinic acid derivatives appear to have promise as active pharmaceutical ingredients that contain a wide range of biological and pharmacological properties.
References
1. Akman T. et al.: The Neuroprotective Effect of Glycyrrhizic Acid on an Experimental Model of Focal Cerebral Ischemia in Rats. Inflammation, 38, 1581, 2015.
2. Aly A.M., Al-Alousi L., Salem H.A.: Licorice: A Possible Anti-inflammatory and Anti-ulcer Drug AAPS PharmSciTech., 6, 74, 2005.
3. Ashfaq U.A. et al: Glycyrrhizin as antiviral agent against Hepatitis C Virus. J. Transl. Med., 9, 1, 2011.
4. Asl M.N., Hosseinzadeh H.: Review of Pharmacological Effects of Glycyrrhiza sp. and its Bioactive Compounds. Phytother. Res., 22, 709, 2008.
5. Baltina L.A. et al.: Search for new drugs prospects for the creation of new antiviral drugs based on glycyrrhizic acid and its derivatives (a review). Pharm. Chem. J., 43, 539, 2009.
6. Bhattacharjee S. et al.: Glycyrrhizic acid suppresses Cox-2-mediated anti-inflammatory responses during Leishmania donovani infection. J. Antimicrob. Chemother., 67, 1905, 2012.
7. Carmines E.L., Lemus R., Gaworski C.L.: Toxicologic evaluation of licorice extract as a cigarette ingredient. Food Chem. Toxicol., 43, 1303, 2005.
8. Fenwick G.R., Lutomski J., Nieman C.: Liquorice, Glycyrrhiza glabra L. Composition, Uses and Analysis. Food Chem., 38, 119, 1990.
9. Fiore C. et al.: A history of the therapeutic use of liquorice in Europe, J. Ethnopharmacol., 99, 317, 2005.
10. Fiore C. et al.: Antiviral Effects of Glycyrrhiza species. Phytother. Res., 22, 141, 2008.
11. Gupta P., Das P.K., Ukil A.: Antileishmanial Effect of 18β-Glycyrrhetinic Acid Is Mediated by Toll-Like Receptor-Dependent Canonical and Noncanonical p38 Activation Antimicrob. Agents Chemother., 59, 2531, 2015.
12. Harada S. et al.: Biochemical characterisation of recombinant HIV-1 reverse transcriptase (rRT) as a glycyrrhizin-binding protein and the CK-II-mediated stimulation of rRT activity potently inhibited by glycyrrhetenic acid derivate. Biol. Pharm. Bull., 21, 1282, 1998.
13. Hardy M.E. et al.: 18β-glycyrrhetinic acid inhibits rotavirus replication in culture. Virol. J., 9, 1, 2012.
14. Hu J., Wu J., Ju Y.: A dual-responsive macrocycle based on glycyrrhetinic acid. Tetrahedron Lett., 53, 6705, 2012.
15. Indena®. Industria Derivati Naturali. www.indena.com/pdf/18beta_18betaPhyto_st_pc.pdf (access: 2016.01.02).
16. Isbrucker R.A., Burdock G.A.: Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul. Toxicol. Pharmacol., 46, 167, 2006.
17. Jeong H.G. et al.: Hepatoprotective effects of 18β-glycyrrhetinic acid on carbontetrachloride-induced liver injury: inhibition of cytochrome p450 2e1 expression. Pharmacol. Res., 46, 221, 2002.
18. Jiang L. et al.: Discovery of glycyrrhetinic acid as an orally active, direct inhibitor of blood coagulation factor xa. Thromb. Res., 133, 501, 2014.
19. Kalani K. et al.: Glycyrrhetinic acid and its analogs: A new class of antifilarial agents. Bioorg. Med. Chem. Lett., 23, 2566, 2013.
20. Kalani K. et al.: In Silico and In Vivo Anti-Malarial Studies of 18β Glycyrrhetinic Acid from Glycyrrhiza glabra. PLoS One, 8, 1, 2013.
21. Kang L. et al.: Research Progress on Structure Modification and Biological Activity of 18β-Glycyrrhetinic Acid, Curr. Opin. Complement. Alternat. Med., 1, 34, 2014.
22. Kao T.C., Wu C.H., Yen G.C.: Bioactivity and Potential Health Benefits of Licorice. J. Agric. Food Chem., 62, 543, 2014.
23. Kayser O., Kiderlen A.F., Croft S.L.: Natural products as antiparasitic drugs, Parasitol. Res., 90, S55, 2003.
24. Kim H.K. et al.: Antimicrobial mechanism of β-glycyrrhetinic acid isolated from licorice, Glycyrrhiza glabra Biotechnol. Lett., 24, 1899, 2002.
25. Krausse R. et al.: In vitro anti-Helicobacter pylori activity of Extractum liquiritiae, glycyrrhizin and its metabolites, J. Antimicrob. Chemother., 54, 243, 2004.
26. Kumada H.: Long-term treatment of chronic hepatitis C with glycyrrhizin [Stronger Neo-Minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma, Oncology, 62, 94, 2002.
27. Lacaille-Dubois M.A., Wagner H.: A review of the biological and pharmacological activities of saponins, Phytomedicine, 2, 363, 1996.
28. Long D.R. et al.: 18β-Glycyrrhetinic Acid Inhibits Methicillin-Resistant Staphylococcus aureus Survival and Attenuates Virulence Gene Expression, Antimicrob. Agents Chemother., 57, 241, 2013.
29. Moon M.H. et al.: 18β-Glycyrrhetinic acid inhibits adipogenic differentiation and stimulates lipolysis, Biochem. Biophys. Res. Commun., 420, 805, 2012.
30. Nascimento G.G.F. et al.: Antibacterial activity of plant extracts and phytochemicals on antibiotic-resistant bacteria. Braz. J. Microbiol., 31, 247, 2000.
31. Nitalikar M.M. et al.: Studies of antibacterial activities of glycyrrhiza glabra root extract. Int. J. Pharm.Tech. Res., 2, 899, 2010.
32. Pellati D. et al.: In vitro Effects of Glycyrrhetinic Acid on the Growth of Clinical Isolates of Candida albicans. Phytother. Res., 23, 572, 2009.
33. Rodrigues I.A. et al.: Natural Products: Insights into Leishmaniasis. Inflammatory Response. Mediators Inflamm., 2015, 1, 2015.
34. Salari M.H., Eshraghi S., Noroozi M.: Antibacterial effects of glycyrrhetinic acid on 55 hospital strains of Staphylococcus aureus and 32 actinobacillus actinomycetemcomitans. DARU, 9, 37, 2001.
35. Salari M.H., Kadkhoda Z.: In vitro antibacterial effects of glycyrrhetinic acid on periodontopathogenic and capnophilic bacteria isolated from adult periodontitis. Clin. Microbiol. Infect., 9, 987, 2003.
36. Semalty A. et al.: Supramolecular phospholipids–polyphenolics interactions: The PHYTOSOME® strategy to improve the bioavailability of phytochemicals. Fitoterapia, 81, 306, 2010.
37. Smolarczyk R. et al.: The Role of Glycyrrhizin, an Inhibitor of HMGB1 Protein, in Anticancer Therapy. Arch. Immunol. Ther. Exp., 60, 391, 2012.
38. Sparg S.G., Light M.E., van Staden J.: Biological activities and distribution of plant saponins. J. Ethnopharmacol., 94, 219, 2004.
39. Stanetty C. et al.: Synthesis and antiviral activities of spacer-linked 1-thioglucuronide analogues of glycyrrhizin. Beilstein J. Org. Chem., 8, 705, 2012.
40. Tolstikov A., Baltina A., Serdyuk N.G.: Search for new drugs: Glycyrrhetic acid (a review). Pharm. Chem. J., 32, 5, 1998.
41. Tykarska E., Czarczyńska-Goslińska B., Lulek J.: Kwas glicyryzynowy i glicyretynowy w nowoczesnej technologii farmaceutycznej. Czas. Aptek., 19, 43, 2012.
42. Ukil A. et al.: Leishmaniasis Associated with the Activation Up-Regulation in Experimental Visceral Th1 Response and Nitric Oxide 18β-Glycyrrhetinic Acid Triggers Curative. J. Immunol., 175, 1161, 2005.
43. Ukil A. et al.: Curative Effect of 18b-Glycyrrhetinic Acid in Experimental Visceral Leishmaniasis Depends on Phosphatase-Dependent Modulation of Cellular MAP Kinases. PLoS One, 6, 1, 2011.
44. Vampa G., Benvenuti S.: Separtion of 18α- and 18β-glycyrrhetinic acid by high-performance thin-layer chromatographic densitometry. J. Chromatogr. A, 543, 479, 1991.
45. Van Rossum T.G. et al.: Glycyrrhizin induced reduction of ALT in Europea n patients with chronic hepatitis C. Am. J. Gastroenterol., 96, 2432, 2001.
46. Wang L.J. et al.: Synthesis, biological evaluation and structure–activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents. Bioorg. Med. Chem. Lett., 22, 3473, 2012.
47. Yamaguchi H. et al.: Novel effects of glycyrrhetinic acid on the central nervous system tumorigenic progenitor cells: Induction of actin disruption and tumor cell-selective toxicity. Eur. J. Med. Chem., 45, 2943, 2010.
48. Yeh C.F. et al.: Water extract of licorice had anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. J. Ethnopharmacol., 148, 466, 2013.
49. Zhao C.H. et al.: Inhibition of human enterovirus 71 replication by pentacyclic triterpenes and their novel synthetic derivatives. Chem. Pharm. Bull., 62, 764, 2014.
50. Zhou J. et al. 18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination. Sci. Rep., 5, 1, 2015.
51. Zhou X. et al.: Antimycobacterial and Synergistic Effects of 18β‐Glycyrrhetinic Acid or Glycyrrhetinic acid‐30‐piperazine in Combination with Isoniazid, Rifampicin or Streptomycin against Mycobacterium bovis. Phytother. Res., 26, 253, 2012.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 Unported License.
Copyright (c) 2016 Authors