Synthesis and Evaluation of Glycyrrhetic Acid-aromatic Hybrids as Anti-inflammatory Agents

Author(s): Zhi Chen, Shi-Chao Chen, Bo Li, Yong-An Yang, Jing Zhang*

Journal Name: Medicinal Chemistry

Volume 16 , Issue 6 , 2020


DOI : 10.2174/1573406415666190603095502

  Journal Home
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Inflammation is a biological response of body tissues to harmful stimuli, so it is desirable to search for novel anti-inflammatory agents with improved pharmaceutical profiles and reduced adverse effects.

Objective: This study was to explore natural anti-inflammatory agents and improve therapeutic application of glycyrrhetic acid (GA) through molecular hybridization with active aromatics.

Methods: Fourteen novel GA-aromatic hybrids were synthesized and evaluated for their antiinflammatory activities by inhibiting LPS-induced nitric oxide (NO) release in RAW264.7 cells. The synthesized compounds were characterized by single-crystal X-ray diffraction, 1H NMR, 13C NMR and HRMS.

Results: The structure-activity relationship (SAR) study indicated that compounds with styryl displayed better NO inhibitory activity. Among them, compounds 2a and 3c exhibited the most promising activity with IC50 values of 9.93 μM and 12.25 μM, respectively. In addition, X-ray singlecrystal diffraction data for compounds 2e and 3c showed that the absolute configuration of GA skeleton was consistent with that of natural 18 β-glycyrrhetic acid.

Conclusion: The results showed that GA-aromatic hybrids were a new class of anti-inflammatory agents and this study provided useful information on further optimization.

Keywords: Glycyrrhetic acid, natural product, anti-inflammatory activity, structure-activity relationship, molecular hybridization, X-ray crystallography.

[1]
Medzhitov, R. Origin and physiological roles of inflammation. Nature, 2008, 454(7203), 428-435.
[http://dx.doi.org/10.1038/nature07201] [PMID: 18650913]
[2]
Merry, A.F.; Gibbs, R.D.; Edwards, J.; Ting, G.S.; Frampton, C.; Davies, E.; Anderson, B.J. Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial. Br. J. Anaesth., 2010, 104(1), 80-88.
[http://dx.doi.org/10.1093/bja/aep338] [PMID: 20007794]
[3]
Pereira-Leite, C.; Nunes, C.; Jamal, S.K.; Cuccovia, I.M.; Reis, S. Nonsteroidal anti-inflammatory therapy: a journey toward safety. Med. Res. Rev., 2017, 37(4), 802-859.
[http://dx.doi.org/10.1002/med.21424] [PMID: 28005273]
[4]
Patridge, E.; Gareiss, P.; Kinch, M.S.; Hoyer, D. An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discov. Today, 2016, 21(2), 204-207.
[http://dx.doi.org/10.1016/j.drudis.2015.01.009] [PMID: 25617672]
[5]
Kao, T-C.; Wu, C-H.; Yen, G-C. Bioactivity and potential health benefits of licorice. J. Agric. Food Chem., 2014, 62(3), 542-553.
[http://dx.doi.org/10.1021/jf404939f] [PMID: 24377378]
[6]
Pastorino, G.; Cornara, L.; Soares, S.; Rodrigues, F.; Oliveira, M.B.P.P. Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review. Phytother. Res., 2018, 32(12), 2323-2339.
[http://dx.doi.org/10.1002/ptr.6178] [PMID: 30117204]
[7]
Kao, T-C.; Shyu, M-H.; Yen, G-C. Glycyrrhizic acid and 18beta glycyrrhetinic acid inhibit inflammation via PI3K/Akt/GSK3beta signaling and glucocorticoid receptor activation. J. Agric. Food Chem., 2010, 58(15), 8623-8629.
[http://dx.doi.org/10.1021/jf101841r] [PMID: 20681651]
[8]
Kao, T-C.; Wu, C-H.; Yen, G-C. Glycyrrhizic acid and 18β-glycyrrhetinic acid recover glucocorticoid resistance via PI3K induced AP1, CRE and NFAT activation. Phytomedicine, 2013, 20(3-4), 295-302.
[http://dx.doi.org/10.1016/j.phymed.2012.10.013] [PMID: 23218403]
[9]
Oztanir, M.N.; Ciftci, O.; Cetin, A.; Durak, M.A.; Basak, N.; Akyuva, Y. The beneficial effects of 18β-glycyrrhetinic acid following oxidative and neuronal damage in brain tissue caused by global cerebral ischemia/reperfusion in a C57BL/J6 mouse model. Neurol. Sci., 2014, 35(8), 1221-1228.
[http://dx.doi.org/10.1007/s10072-014-1685-9] [PMID: 24554419]
[10]
Wang, C-Y.; Kao, T-C.; Lo, W-H.; Yen, G-C. Glycyrrhizic acid and 18β-glycyrrhetinic acid modulate lipopolysaccharide-induced inflammatory response by suppression of NF-κB through PI3K p110δ and p110γ inhibitions. J. Agric. Food Chem., 2011, 59(14), 7726-7733.
[http://dx.doi.org/10.1021/jf2013265] [PMID: 21644799]
[11]
Li, B.; Cai, S.; Yang, Y.A.; Chen, S.C.; Chen, R.; Shi, J.B.; Liu, X.H.; Tang, W.J. Novel unsaturated glycyrrhetic acids derivatives: Design, synthesis and anti-inflammatory activity. Eur. J. Med. Chem., 2017, 139, 337-348.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.002] [PMID: 28803048]
[12]
Yang, G.; Zhang, L.; Ma, L.; Jiang, R.; Kuang, G.; Li, K.; Tie, H.; Wang, B.; Chen, X.; Xie, T.; Gong, X.; Wan, J. Glycyrrhetinic acid prevents acetaminophen-induced acute liver injury via the inhibition of CYP2E1 expression and HMGB1-TLR4 signal activation in mice. Int. Immunopharmacol., 2017, 50, 186-193.
[http://dx.doi.org/10.1016/j.intimp.2017.06.027] [PMID: 28668488]
[13]
Li, B.; Yang, Y.; Chen, L.; Chen, S.; Zhang, J.; Tang, W. 18α-Glycyrrhetinic acid monoglucuronide as an anti-inflammatory agent through suppression of the NF-κB and MAPK signaling pathway. MedChemComm, 2017, 8(7), 1498-1504.
[http://dx.doi.org/10.1039/C7MD00210F] [PMID: 30108861]
[14]
Chen, J.; Li, W.; Yao, H.; Xu, J. Insights into drug discovery from natural products through structural modification. Fitoterapia, 2015, 103, 231-241.
[http://dx.doi.org/10.1016/j.fitote.2015.04.012] [PMID: 25917513]
[15]
Pan, S.; Zhang, H.; Wang, C.; Yao, S.C.L.; Yao, S.Q. Target identification of natural products and bioactive compounds using affinity-based probes. Nat. Prod. Rep., 2016, 33(5), 612-620.
[http://dx.doi.org/10.1039/C5NP00101C] [PMID: 26580476]
[16]
Csuk, R.; Schwarz, S.; Kluge, R.; Ströhl, D. Synthesis and biological activity of some antitumor active derivatives from glycyrrhetinic acid. Eur. J. Med. Chem., 2010, 45(12), 5718-5723.
[http://dx.doi.org/10.1016/j.ejmech.2010.09.028] [PMID: 20884085]
[17]
Csuk, R.; Schwarz, S.; Siewert, B.; Kluge, R.; Ströhl, D. Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives. Eur. J. Med. Chem., 2011, 46(11), 5356-5369.
[http://dx.doi.org/10.1016/j.ejmech.2011.08.038] [PMID: 21959232]
[18]
Roohbakhsh, A.; Iranshahy, M.; Iranshahi, M. Glycyrrhetinic acid and its derivatives: anti-cancer and cancer chemopreventive properties, mechanisms of action and structure- cytotoxic activity relationship. Curr. Med. Chem., 2016, 23(5), 498-517.
[http://dx.doi.org/10.2174/0929867323666160112122256] [PMID: 26758798]
[19]
Maitraie, D.; Hung, C-F.; Tu, H-Y.; Liou, Y-T.; Wei, B-L.; Yang, S-C.; Wang, J-P.; Lin, C-N. Synthesis, anti-inflammatory, and antioxidant activities of 18beta-glycyrrhetinic acid derivatives as chemical mediators and xanthine oxidase inhibitors. Bioorg. Med. Chem., 2009, 17(7), 2785-2792.
[http://dx.doi.org/10.1016/j.bmc.2009.02.025] [PMID: 19278854]
[20]
Salomatina, O.V.; Markov, A.V.; Logashenko, E.B.; Korchagina, D.V.; Zenkova, M.A.; Salakhutdinov, N.F.; Vlassov, V.V.; Tolstikov, G.A. 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(1), 585-593.
[http://dx.doi.org/10.1016/j.bmc.2013.10.049] [PMID: 24268542]
[21]
Bérubé, G. An overview of molecular hybrids in drug discovery. Expert Opin. Drug Discov., 2016, 11(3), 281-305.
[http://dx.doi.org/10.1517/17460441.2016.1135125] [PMID: 26727036]
[22]
Matias, M.; Silvestre, S.; Falcao, A.; Alves, G. Recent highlights on molecular hybrids potentially useful in central nervous system disorders. Mini Rev. Med. Chem., 2017, 17(6), 486-517.
[http://dx.doi.org/10.2174/1389557517666161111110121] [PMID: 27834131]
[23]
Choudhary, S.; Singh, P.K.; Verma, H.; Singh, H.; Silakari, O. Success stories of natural product-based hybrid molecules for multi-factorial diseases. Eur. J. Med. Chem., 2018, 151, 62-97.
[http://dx.doi.org/10.1016/j.ejmech.2018.03.057] [PMID: 29605809]
[24]
Lai, Y.; Shen, L.; Zhang, Z.; Liu, W.; Zhang, Y.; Ji, H.; Tian, J. 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(22), 6416-6420.
[http://dx.doi.org/10.1016/j.bmcl.2010.09.070] [PMID: 20932754]
[25]
Li, K.; Ma, T.; Cai, J.; Huang, M.; Guo, H.; Zhou, D.; Luan, S.; Yang, J.; Liu, D.; Jing, Y.; Zhao, L. 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(20), 5441-5451.
[http://dx.doi.org/10.1016/j.bmc.2017.08.002] [PMID: 28838831]
[26]
Jin, L.; Huang, R.; Huang, X.; Zhang, B.; Ji, M.; Wang, H. Discovery of 18β-glycyrrhetinic acid conjugated aminobenzothiazole derivatives as Hsp90-Cdc37 interaction disruptors that inhibit cell migration and reverse drug resistance. Bioorg. Med. Chem., 2018, 26(8), 1759-1775.
[http://dx.doi.org/10.1016/j.bmc.2018.02.021] [PMID: 29486954]
[27]
Laszczyk, M.N. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med., 2009, 75(15), 1549-1560.
[http://dx.doi.org/10.1055/s-0029-1186102] [PMID: 19742422]
[28]
Sheldrick, G.M. SHELXTL-97, Program for crystal structure solution and refinement; University of Göttingen: Göttingen, Germany, 1997.
[29]
Aktan, F. iNOS-mediated nitric oxide production and its regulation. Life Sci., 2004, 75(6), 639-653.
[http://dx.doi.org/10.1016/j.lfs.2003.10.042] [PMID: 15172174]
[30]
Chen, L.Z.; Sun, W.W.; Bo, L.; Wang, J.Q.; Xiu, C.; Tang, W.J.; Shi, J.B.; Zhou, H.P.; Liu, X.H. New arylpyrazoline-coumarins: Synthesis and anti-inflammatory activity. Eur. J. Med. Chem., 2017, 138, 170-181.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.044] [PMID: 28667873]
[31]
Baltina, L.A. Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine. Curr. Med. Chem., 2003, 10(2), 155-171.
[http://dx.doi.org/10.2174/0929867033368538] [PMID: 12570715]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 6
Year: 2020
Published on: 02 June, 2019
Page: [715 - 723]
Pages: 9
DOI: 10.2174/1573406415666190603095502
Price: $65

Article Metrics

PDF: 42
HTML: 3
EPUB: 1
PRC: 1



Related Article(s)