Glycyrrhetinic acid: a promising scaffold for the discovery of anticancer agents

References

• Thomford NE, Senthebane DA, Rowe A, et al. Natural products for drug discovery in the 21st century: innovations for novel drug discovery. Int J Mol Sci. 2018;19:1578.
   PubMed Web of Science ®Google Scholar
• Ashrafizadeh M, Zarrabi A, Orouei S, et al. Recent advances and future directions in anti-tumor activity of cryptotanshinone: a mechanistic review. Phytother Res. 2021;35:155–179.
   PubMed Web of Science ®Google Scholar
• Ashrafizadeh M, Najafi M, Makvandi P, et al. Versatile role of curcumin and its derivatives in lung cancer therapy. J Cell Physiol. 2020;235:9241–9268.
   PubMed Web of Science ®Google Scholar
• Sultani HN, Morgan I, Hussain H, et al. Access to new cytotoxic triterpene and steroidal acid-TEMPO conjugates by Ugi multicomponent-reactions. Int J Mol Sci. 2021;22:7125.
   Google Scholar
• Salminen A, Lehtonen M, Suuronen T, et al. Terpenoids: natural inhibitors of NF-kappaB signaling with anti-inflammatory and anticancer potential. Cell Mol Life Sci. 2008;65(19):2979–2999.
   PubMed Web of Science ®Google Scholar
• Lee KH. Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J Nat Prod. 2010;73:500–516.
   PubMed Web of Science ®Google Scholar
• Nobili S, Lippi D, Witort E, et al. Natural compounds for cancer treatment and prevention. Pharmacol Res. 2009;59:365–378.
   PubMed Web of Science ®Google Scholar
• Rao GV, Kumar S, Islam M, et al. Folk medicines for anticancer therapy-a current status. Cancer Ther. 2008;6:913–922.
   Google Scholar
• Hussain H, Green IR, Ali I, et al. Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016). Expert Opin Ther Pat. 2017;27(9):1061–1072.
   PubMed Web of Science ®Google Scholar
• Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol. 1995;49:57–68.
   PubMed Web of Science ®Google Scholar
• Kuo RY, Qian K, Morris-Natschke SL, et al. Plant-derived triterpenoids and analogues as antitumor and anti-HIV agents. Nat Prod Rep. 2009;26:1321–1344.
   PubMed Web of Science ®Google Scholar
• Bahmani M, Rafieian-Kopaei M, Jeloudari M, et al. A review of the health effects and uses of drugs of plant licorice (Glycyrrhiza glabra L.) in Iran. Asian Pac J Trop Dis. 2014;4:S847–S849.
   Google Scholar
• Zargaran A, Zarshenas MM, Mehdizadeh A, et al. Management of tremor in medieval Persia. J Hist Neurosci. 2013;22:53–61.
   PubMed Web of Science ®Google Scholar
• Hort A. Theophrastus: enquiry into plants and minor works on odours and weather signs. London: Harvard University Press; 1961. p. 13 (Chapter IX).
   Google Scholar
• Fiore C, Eisenhut M, Ragazzi E, et al. A history of the therapeutic use of liquorice in Europe. J Ethnopharmacol. 2005;99:317–324.
   PubMed Web of Science ®Google Scholar
• Marcellus. Marcelli De medicamentis. Lipsiae, liber: Teubneri; 1889. p. XIV, 7; XVI, 103; XX, 108; XXVI, 63; XXIX, 11; XXX, 24.
   Google Scholar
• Toletanum G. Abub. Rhazae lib. De pestilentia ad Mansorem finis. Cremona: Librum Divisionium; 1544. p. 371–374.
   Google Scholar
• Von Sontheimer J. Grosse Zusammenstellung ueber die Kraefte der bekannten einfachen Heil-und Nahrungsmittel von Abu Mohammed Abdallah Ben Ahmed aus Malaga bekannt unter dem Namen Ebn Baithar. Stuttgart: Aus dem Arabischen uebersetzt. Hallberger’sche Verlagshandlung; 1842.
   Google Scholar
• Scribonius. Scribonii largi compositiones. Leipzig: Teubner; 1983. p. LXXV, LXXXVI.
   Google Scholar
• Plinius, 1875 and 1897. C. Plini Secundi Naturalis historiae. Lipsiae, libri: Teubneri; XXXVII, XI, 119; XXII, 11; XXV, 43.II, IV.
   Google Scholar
• Celsus. A. Cornelii Celsi De medicina libri octo. Lipsiae: Teubneri; 1859. p. 20, 6.
   Google Scholar
• Avicenna. Liber canonis De Medicinis cordialibus Cantica De Removendis nocumentis in regimine sanitatis De syrupo acetoso. Iuntas, Venetiis. 1562;II(2):437.
   Google Scholar
• Hussain H, Green IR, Shamra U, et al. Therapeutic potential of glycyrrhetinic acids: a patent review (2010-2017). Expert Opin Ther Pat. 2018;28(5):383–398.
   PubMed Web of Science ®Google Scholar
• Huang W, Chen X, Li Q, et al. Inhibition of intercellular adhesion in herpex simplex virus infection by glycyrrhizin. Cell Biochem Biophys. 2012;62:137–140.
   PubMed Web of Science ®Google Scholar
• Cinatl J, Morgenstern B, Bauer G, et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361:2045–2046.
   PubMed Web of Science ®Google Scholar
• Van De Sand L, Bormann M, Alt M, et al. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses. 2021;13:609.
   PubMed Web of Science ®Google Scholar
• Pompei R, Flore O, Marccialis MA, et al. Glycyrrhizic acid inhibits virus growth and inactivates virus particles. Nature. 1979;281:689–690.
   PubMed Web of Science ®Google Scholar
• Fiore C, Eisenhut M, Krausse R, et al. Antiviral effects of Glycyrrhiza species. Phytother Res. 2008;22:141–148.
   PubMed Web of Science ®Google Scholar
• Murck H. Symptomatic protective action of glycyrrhizin (Licorice) in COVID-19 Infection? Front Immunol. 2020;11:1239.
   PubMed Web of Science ®Google Scholar
• Armanini D, Lewicka S, Pratesi C, et al. Further studies on the mechanism of the mineralocorticoid action of licorice in humans. J Endocrinol Invest. 1996;19:624–629.
   PubMed Web of Science ®Google Scholar
• Armanini D, Karbowiak I, Funder JW. Affinity of liquorice derivatives for mineralocorticoid and glucocorticoid receptors. Clin Endocrinol. 1983;19:609–612.
   PubMed Web of Science ®Google Scholar
• Ding H, Deng W, Ding L, et al. Glycyrrhetinic acid and its derivatives as potential alternative medicine to relieve symptoms in nonhospitalized COVID-19 patients. J Med Virol. 2020;2200–2204. DOI:https://doi.org/10.1002/jmv.26064
   Google Scholar
• Sontia B, Mooney J, Gaudet L, et al. Pseudohyperaldosteronism, liquorice, and hypertension. J Clin Hypertens. 2008;10:153–157.
   Web of Science ®Google Scholar
• Wang CY, Kao TC, Lo WH, et al. Glycyrrhizic acid and 18-glycyrrhetinic acid modulate lipopolysaccharide-induced inflammatory response by suppression of NF-B through PI3K p110 and p110 inhibitions. J Agric Food Chem. 2011;59:7726–7733.
   PubMed Web of Science ®Google Scholar
• Kao TC, Shyu MH, Yen GC. Glycyrrhizic acid and 18-glycyrrhetinic acid inhibit inflammation via PI3K/Akt/GSK3 signaling and glucocorticoid receptor activation. J Agric Food Chem. 2010;58:8623–8629.
   PubMed Web of Science ®Google Scholar
• Chen S, Zou L, Li L, et al. The protective effect of glycyrrhetinic acid on carbon tetrachloride-induced chronic liver fibrosis in mice via upregulation of Nrf2. PLoS One. 2013;8:e53662.
   PubMed Web of Science ®Google Scholar
• Jeong HG, You HJ, Park SJ, et al. Hepatoprotective effects of 18-glycyrrhetinic acid on carbon tetrachloride-induced liver injury: inhibition of cytochrome P450 2E1 expression. Pharmacol Res. 2002;46:221–227.
   PubMed Web of Science ®Google Scholar
• Hardy ME, Hendricks JM, Paulson JM, et al. 18β-glycyrrhetinic acid inhibits rotavirus replication in culture. Virol J. 2012;9:96.
   PubMed Web of Science ®Google Scholar
• Wang LJ, Geng CA, Ma YB, et al. Synthesis, biological evaluation and structure-activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents. Bioorg Med Chem Lett. 2012;22:3473–3479.
   PubMedGoogle Scholar
• Huang YC, Kuo CL, Lu KW, et al. 18-glycyrrhetinic acid induces apoptosis of HL-60 human leukemia cells through caspases-and mitochondria-dependent signaling pathways. Molecules. 2016;21:872.
   Web of Science ®Google Scholar
• Huang RY, Chu YL, Huang QC, et al. 18β-Glycyrrhetinic acid suppresses cell proliferation through inhibiting thromboxane synthase in non-small cell lung cancer. PLoS One. 2014;9:e93690.
   PubMed Web of Science ®Google Scholar
• Wu SY, Wang WJ, Dou JH, et al. Research progress on the protective effects of licorice-derived 18β-glycyrrhetinic acid against liver injury. Acta Pharmacol Sin. 2021;42:18–26.
   PubMed Web of Science ®Google Scholar
• Li ZY, Tung YT, Chen SY, et al. Novel findings of 18β‐glycyrrhetinic acid on sRAGE secretion through inhibition of transient receptor potential canonical channels in high‐glucose environment. Biofactors. 2019;45:607–615.
   PubMed Web of Science ®Google Scholar
• Wang K, Zhang Y, Cao Y, et al. Glycyrrhetinic acid alleviates acute lung injury by PI3K/AKT suppressing macrophagic Nlrp3 inflammasome activation. Biochem Biophys Res Commun. 2020;532:555–562.
   PubMed Web of Science ®Google Scholar
• Zhang KX, Wang PR, Chen F, et al. Synthesis and Anti-HCV Activities of 18β-Glycyrrhetinic Acid Derivatives and Their In-silico ADMET analysis. Curr Comput Aided Drug Des. 2021;(in print): DOI:https://doi.org/10.2174/1573409916666200827104008
   Google Scholar
• Shen P, Zhang J, Zhu Y, et al. Microbial transformation of glycyrrhetinic acid derivatives by Bacillus subtilis ATCC 6633 and Bacillus megaterium CGMCC 1.1741 P. Bioorg Med Chem. 2020;28:115465.
   PubMed Web of Science ®Google Scholar
• Satomi Y, Nishino H, Shibata S. Glycyrrhetinic acid and related compounds induce G1 arrest and apoptosis in human hepatocellular carcinoma HepG2. Anticancer Res. 2005;25:4043–4047.
   PubMed Web of Science ®Google Scholar
• Wang D, Wong HK, Feng YB, et al. 18beta-Glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway. J Neurooncol. 2014;116:221–230.
   PubMed Web of Science ®Google Scholar
• Li S, Zhu JH, Cao LP, et al. Growth inhibitory in vitro effects of glycyrrhizic acid in U251 glioblastoma cell line. Neurol Sci. 2014;35:1115–1120.
   PubMed Web of Science ®Google Scholar
• Shetty AV, Thirugnanam S, Dakshinamoorthy G, et al. 18-glycyrrhetinic acid targets prostate cancer cells by down-regulating inflammation-related genes. Int J Oncol. 2011;39:635–640.
   PubMed Web of Science ®Google Scholar
• Lee CS, Kim YJ, Lee MS, et al. 18-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. Life Sci. 2008;83:481–489.
   PubMed Web of Science ®Google Scholar
• Hibasami H, Iwase H, Yoshioka K, et al. Glycyrrhetic acid (a metabolic substance and aglycon of glycyrrhizin) induces apoptosis in human hepatoma, promyelotic leukemia and stomach cancer cells. Int J Mol Med. 2006;17:215–219.
   PubMed Web of Science ®Google Scholar
• Yang JC, Myung SC, Kim W, et al. 18-Glycyrrhetinic acid potentiates Hsp90 inhibition-induced apoptosis in human epithelial ovarian carcinoma cells via activation of death receptor and mitochondrial pathway. Mol Cell Biochem. 2012;370:209–219.
   PubMed Web of Science ®Google Scholar
• Gao Z, Kang X, Ju Y, et al. Induction of apoptosis with mitochondrial membrane depolarization by a glycyrrhetinic acid derivative in human leukemia K562 cells. Cytotechnology. 2012;64:421–428.
   PubMed Web of Science ®Google Scholar
• Bing X, Gao-Rong W, Xin-Yu Z, et al. An overview of structurally modified glycyrrhetinic acid derivatives as antitumor agents. Molecules. 2017;22:924.
   Web of Science ®Google Scholar
• Csuk R. Recent developments in the synthesis of antitumor-active glycyrrhetinic acid derivatives. Mini-Rev Org Chem. 2014;11:253–261.
   Web of Science ®Google Scholar
• Serbian I, Wolfram RK, Fischer L, et al. Hydroxylated boswellic and glycyrrhetinic acid derivatives: synthesis and cytotoxicity. Mediterr J Chem. 2018;7(4):286–293.
   Google Scholar
• Jun H, Yang W, Chang-Qi Z. Synthesis and anti-tumor activity of opened A-ring modified 18 beta-glycyrrhetinic acid derivatives. Chem J Chin Univ. 2010;31:1762–1768.
   Web of Science ®Google Scholar
• Gao Y, Guo X, Li X, et al. The synthesis of glycyrrhetinic acid derivatives containing a nitrogen heterocycle and their antiproliferative effects in human leukemia cells. Molecules. 2010;15:4439–4449.
   PubMed Web of Science ®Google Scholar
• Alho DPS, Salvador JAR, Cascante M, et al. Synthesis and antiproliferative activity of novel heterocyclic glycyrrhetinic acid derivatives. Molecules. 2019;24(766):1–21.
   Google Scholar
• Huang M, Gong P, Wang Y, et al. Synthesis and antitumor effects of novel 18β-glycyrrhetinic acid derivatives featuring an exocyclic α,β-unsaturated carbonyl moiety in ring A. Bioorg Chem. 2020;103:104187.
   PubMed Web of Science ®Google Scholar
• Chadalapaka G, Jutooru I, McAlees A, et al. Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives. Bioorg Med Chem Lett. 2008;18:2633–2639.
   PubMed Web of Science ®Google Scholar
• Yang LF, Xing Y, Xiao JX, et al. Synthesis of cyanoenone-modified diterpenoid analogs as novel bmi-1-mediated antitumor agents. ACS Med Chem Lett. 2018;9(11):1105–1110.
   PubMed Web of Science ®Google Scholar
• Salomatina OV, Markov AV, Logashenko EB, et al. Synthesis of novel 2-cyano substituted glycyrrhetinic acid derivatives as inhibitors of cancer cells growth and NO production in LPS-activated J-774 cells. Bioorg Med Chem. 2014;22:585–593.
   PubMed Web of Science ®Google Scholar
• Logashenko EB, Salomatina OV, Markov AV, et al. Synthesis and pro-apoptotic activity of novel glycyrrhetinic acid derivatives. ChemBioChem. 2011;12:784–794.
   PubMed Web of Science ®Google Scholar
• Lin K-W, Huang A-M, Hour T-C, et al. 18β-Glycyrrhetinic acid derivatives induced mitochondrial-mediated apoptosis through reactive oxygen species-mediated p53 activation in NTUB1 cells. Bioorg Med Chem. 2011;19:4274–4285.
   PubMed Web of Science ®Google Scholar
• Alho DPS, Salvador JAR, Cascante M, et al. Synthesis and antiproliferative activity of novel A-ring cleaved glycyrrhetinic acid. Molecules. 2019;24:2938.
   Google Scholar
• Csuk R, Schwarz S, Siewert B, et al. Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives. Eur J Med Chem. 2011;46:5356–5369.
   PubMed Web of Science ®Google Scholar
• Jin L, Zhang B, Hua S, et al. Glycyrrhetinic acid derivatives containing aminophosphonate ester species as multidrug resistance reversers that block the NF-κB pathway and cell proliferation. Bioorg Med Chem Lett. 2018;28:3700–3707.
   PubMed Web of Science ®Google Scholar
• Lallemand B, Chaix F, Bury M. N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b): a novel anticancer glycyrrhetinic acid derivative that targets the proteasome and displays anti-kinase activity. J Med Chem. 2011;54:6501–6513.
   PubMed Web of Science ®Google Scholar
• Zheng Q-X, Wang R, Xu Y, et al. Design, preparation and studies regarding cytotoxic properties of glycyrrhetinic acid derivatives. Biol Pharm Bull. 2020;43:102–109.
   PubMed Web of Science ®Google Scholar
• Schwarz S, Csuk R. Synthesis and antitumor activity of glycyrrhetinic acid derivatives. Bioorg Med Chem. 2010;18:7458–7474.
   PubMedGoogle Scholar
• Csuk R, Schwarz S, Kluge R. Improvement of the cytotoxicity and tumor selectivity of glycyrrhetinic acid by derivatization with bifunctional amino acids. Arch Pharm. 2011;344:505–513.
   PubMed Web of Science ®Google Scholar
• Csuk R, Schwarz S, Siewert B, et al. Synthesis and cytotoxic activity of methyl glycyrrhetinate esterified with amino acids. Z Naturforsch B. 2012;67:731–746.
   Google Scholar
• Li Y, Feng L, Song ZF. Synthesis and anticancer activities of glycyrrhetinic acid derivatives. Molecules. 2016;21(199):1–20.
   Google Scholar
• Tatsuzaki J, Taniguchi M, Bastow KF. Anti-tumor agents 255: novel glycyrrhetinic acid-dehydrozingerone conjugates as cytotoxic agents. Bioorg Med Chem. 2007;15:6193–6199.
   PubMed Web of Science ®Google Scholar
• Aminin DL, Menchinskaya ES, Pisliagin EA, et al. Anticancer activity of sea cucumber triterpene gycosides. Mar Drugs. 2015;13:1202–1223.
   PubMed Web of Science ®Google Scholar
• Dai L, Li J, Yang J, et al. Enzymatic synthesis of novel glycyrrhizic acid glucosides using a Promiscuous bacillus glycosyltransferase. Catalysts. 2018;8(615):1–11.
   Google Scholar
• Schwarz S, Siewert B, Xavier NM, et al. A “natural” approach: synthesis and cytoxicity of monodesmosidic glycyrrhetinic acid glycosides. Eur J Med Chem. 2014;72:78–83.
   PubMed Web of Science ®Google Scholar
• Csuk R, Schwarz S, Kluge R, et al. Synthesis and biological activity of some antitumor active derivatives from glycyrrhetinic acid. Eur J Med Chem. 2010;45:5718–5723.
   PubMed Web of Science ®Google Scholar
• Wang R, Li Y, Huai X-D, et al. Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties. Drug Des Dev Ther. 2018;12:1321–1336.
   PubMed Web of Science ®Google Scholar
• Yadav DK, Kalani K, Khan F, et al. QSAR and docking based semi-synthesis and in vitro evaluation of 18-glycyrrhetinic acid derivatives against human lung cancer cell line A-549. Med Chem. 2013;9:1073–1084.
   PubMed Web of Science ®Google Scholar
• Lai Y, Shen L, Zhang Z, et al. Synthesis and biological evaluation of furoxan-based nitric oxide-releasing derivatives of glycyrrhetinic acid as anti-hepatocellular carcinoma agents. Bioorg Med Chem Lett. 2010;20:6416–6620.
   PubMed Web of Science ®Google Scholar
• Csuk R, Schwarz S, Siewert B. Conversions at C-30 of glycyrrhetinic acid and their impact on antitumor activity. Arch Pharm. 2012;345:223–230.
   PubMed Web of Science ®Google Scholar
• Li K, Ma T, Cai J, et al. Conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid as Pin1 inhibitors displaying anti-prostate cancer ability. Bioorg Med Chem. 2017;25:5441–5451.
   PubMed Web of Science ®Google Scholar
• Hostetler BJ, Uchakina ON, Ban H, et al. Treatment of hematological malignancies with glycyrrhizic acid. Anticancer Res. 2017;37(3):997–1004.
   PubMed Web of Science ®Google Scholar
• Su X, Wu L, Hu M, et al. Glycyrrhizic acid: a promising carrier material for anticancer therapy. Biomed Pharmacother. 2017;95:670–678.
   PubMed Web of Science ®Google Scholar
• Smolarczyk R, Cichon T, Matuszczak S, et al. The role of glycyrrhizin, an inhibitor of HMGB1 protein, in anticancer therapy. Arch Immunol Ther Exp. 2012;60(5):391–399.
   PubMed Web of Science ®Google Scholar
• Kohlschütter J, Michelfelder S, Trepel M. Drug delivery in acute myeloid leukemia. Expert Opin Drug Deliv. 2008;5(6):653–663.
   PubMed Web of Science ®Google Scholar
• Pan X, Liu H, Jia G, et al. Microwave-assisted extraction of glycyrrhizic acid from licorice root. Biochem Eng J. 2000;5(3):173–177.
   PubMed Web of Science ®Google Scholar
• Tian M, Yan H, Row KH, et al. Extraction of glycyrrhizic acid and glabridin from Licorice. Int J Mol Sci. 2008;9:571–577.
   PubMed Web of Science ®Google Scholar
• Charpe TW, Rathod VK. Extraction of glycyrrhizic acid from licorice root using ultrasound: process intensification studies. Chem Eng Process. 2012;54:37–41.
   Web of Science ®Google Scholar
• Cirillo G, Curcio M, Parisi OI, et al. Molecularly imprinted polymers for the selective extraction of glycyrrhizic acid from liquorice roots. Food Chem. 2011;125(3):1058–1063.
   Web of Science ®Google Scholar
• Jang S, Lee AY, Lee AR, et al. Optimization of ultrasound-assisted extraction of glycyrrhizic acid from licorice using response surface methodology. Integr Med Res. 2017;6(4):388–394.
   PubMed Web of Science ®Google Scholar
• Shabkhiz MA, Eikani MH, Sadr ZB, et al. Superheated water extraction of glycyrrhizic acid from licorice root. Food Chem. 2016;210:396–401.
   PubMed Web of Science ®Google Scholar
• Hedayati A, Ghoreishi SM. Supercritical carbon dioxide extraction of glycyrrhizic acid from licorice plant root using binary entrainer: experimental optimization via response surface methodology. J Supercrit Fluid. 2015;100:209–217.
   Web of Science ®Google Scholar
• Wang Q, Fu SMB. Development of multi-stage countercurrent extraction technology for the extraction of glycyrrhizic acid (GA) from licorice (Glycyrrhiza uralensis Fisch). Biochem Eng J. 2004;21(3):285–292.
   Web of Science ®Google Scholar
• Edelman ER, Butala NM, Avery LL, et al. Case 30-2020: a 54-year-old man with sudden cardiac arrest. N Engl J Med. 2020;83:1263–1275.
   Google Scholar
• Sabbadin C, Bordin L, Donà G, et al. Licorice: from Pseudohyperaldosteronism to Therapeutic Uses. Front Endocrinol. 2019;10:484.
   PubMed Web of Science ®Google Scholar
• Wang X, Tan Y, Zhang Y, et al. The novel glycyrrhetinic acid–tetramethylpyrazine conjugate TOGA induces anti-hepatocarcinogenesis by inhibiting the effects of tumor-associated macrophages on tumor cells. Pharmacol Res. 2020;161:105233.
   PubMed Web of Science ®Google Scholar