Journal of Microbiology and Biotechnology

  • 제29권6호
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  • Pages.856-862
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  • 2019
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  • 1017-7825(pISSN)
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  • 1738-8872(eISSN)
한국미생물·생명공학회 (The Korean Society for Microbiology and Biotechnology)
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Synthesis of Thienopyrimidine Derivatives as Inhibitors of STAT3 Activation Induced by IL-6

  • Jang, Hyun-Jae (Immunoregulatory Materials Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Sung Min (Department of Chemistry, Mokwon University) ;
  • Rho, Mun-Chual (Immunoregulatory Materials Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Lee, Seung Woong (Immunoregulatory Materials Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Song, Yang-Heon (Department of Chemistry, Mokwon University)
  • 투고 : 2018.11.28
  • 심사 : 2019.05.10
  • 발행 : 2019.06.28
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초록

A series of thienopyrimidine compounds (6Aa-g and 6Ba-d) were synthesized and characterized by NMR spectroscopy and mass spectrometry. These compounds (6Aa-g and 6Ba-d) potently inhibited STAT3 expression induced by IL-6 in a dose-dependent manner with $IC_{50}$ values of $5.73-0.32{\mu}M$. Among the prepared thienopyrimidine derivatives, 6Aa, 6Ab, 6Ba and 6Bc significantly suppressed the phosphorylation of STAT3 and ERK1/2 stimulated by IL-6 in Hep3B cells. Furthermore, the synthesized compounds might be useful remedies for the treatment of inflammatory diseases by inhibiting the action of IL-6.

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참고문헌

  1. Feldmann M, Brennan FM, Maini RN. 1996. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14: 397-440. https://doi.org/10.1146/annurev.immunol.14.1.397
  2. F eldmann M, Brennan F M, M aini R N. 1 996. R heumatoid arthritis. Cell 85: 307-310. https://doi.org/10.1016/S0092-8674(00)81109-5
  3. Carson DA1, Chen PP, Kipps TJ. 1991. New roles for rheumatoid factor, J. Clin. Invest. 87: 379-383. https://doi.org/10.1172/JCI115007
  4. Hogg N, Henderson R, Leitinger B, McDowall A, Porter J, Stanley P. 2002. Mechanisms contributing to the activity of integrins on leukocytes. Immunol. Rev. 186: 164-171. https://doi.org/10.1034/j.1600-065X.2002.18614.x
  5. Shimaoka M, Xiao T, Liu JH, Yang Y, Dong Y, Jun CD, et al. 2003. Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 112: 99-111. https://doi.org/10.1016/S0092-8674(02)01257-6
  6. Jones SA, Scheller J, Rose-John S. 2011. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Invest. 121: 3375-3383. https://doi.org/10.1172/JCI57158
  7. Ni CW, Hsieh HJ, Chao YJ, Wang DL. 2004. Interleukin-6- induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow. Am. J. Physiol. Cell Physiol. 287: C771-780. https://doi.org/10.1152/ajpcell.00532.2003
  8. Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R, Walicke PA, Garovoy M. 2002. Psoriasis as a model for T-cellmediated disease: immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-CD11a antibody. Arch. Dermatol. 138: 591-600.
  9. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, et al. 2003. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N. Engl. J. Med. 349: 2004-2013. https://doi.org/10.1056/NEJMoa030002
  10. Sebti S, Der C. 2003. Opinion: Searching for the elusive targets of farnesyltransferase inhibitors. Nat. Rev. Cancer 3: 945-951. https://doi.org/10.1038/nrc1234
  11. Darnell JE Jr. 1997. STATs and gene regulation. Science 277: 1630-1635. https://doi.org/10.1126/science.277.5332.1630
  12. Aaronson D, Horvath C. 2002. A road map for those who don't know JAK-STAT. Science 296: 1653-1655. https://doi.org/10.1126/science.1071545
  13. Oh HM, Lee SW, Yun BR, Hwang BS, Kim SN, Park CS, et al. 2014. Vigna angularis inhibits IL-6-induced cellular signalling and ameliorates collagen-induced arthritis. Rheumatology 53: 56-64. https://doi.org/10.1093/rheumatology/ket302
  14. Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. 2000. IL-6 is required for the development of Th1 cell-mediated murine colitis. J. Immunol. 164: 4878-4882. https://doi.org/10.4049/jimmunol.164.9.4878
  15. Lütticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, et al. 1994. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science 263: 89-92. https://doi.org/10.1126/science.8272872
  16. Prasa MR, Rao AR, Rao PS, Rajan KS, Meena S, Madhavi K. 2008. Synthesis and adenosine receptor binding studies of some novel triazolothienopyrimidines. Eur. J. Med. Chem. 43: 614-620. https://doi.org/10.1016/j.ejmech.2007.05.001
  17. Kortum SW, Lachance RM, Schweitzer BA, Yalamanchili G, Rahman H, Ennis MD, et al. 2009. Thienopyrimidine-based P2Y12 platelet aggregation inhibitors, Bioorg. Med. Chem. Lett. 19: 5919-5923. https://doi.org/10.1016/j.bmcl.2009.08.059
  18. McClellan WJ, Dai Y, Abad-Zapatero C, Albert DH, Bouska JJ, Glaser KB, et al. 2011. Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases. Bioorg. Med. Chem. Lett. 21: 5620-5624. https://doi.org/10.1016/j.bmcl.2011.06.041
  19. El-Sayed WA, Ali OM, Zyada RA, Mohamed AA, Abdel- Rahman AA. 2012. Synthesis and antimicrobial activity of new substituted thienopyrimidines, their tetrazolyl and sugar derivatives. Acta Pol. Pharm. 69: 439-447.
  20. El-Tombary AA, El-Hawash SA, Habib NS, Soliman R, El- Ashmawy IM, Shaaban OG. 2013. Synthesis and biological evaluation of some novel thieno[2,3-d] pyrimidine derivatives as potential anti-inflammatory and analgesic agents. Med. Chem. 9: 1099-1112. https://doi.org/10.2174/1573406411309080012
  21. Bugge S, Kaspersen SJ, Larsen S, Nonstad U, Bjorkoy G, Sundby E, et al. 2014. Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor. Eur. J. Med. Chem. 75: 354-374. https://doi.org/10.1016/j.ejmech.2014.01.042
  22. Wang Y, van Boxel-Dezaire AH, Cheon H, Yang J, Stark GR. 2013. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc. Natl. Acad. Sci. USA 110: 16975-16980. https://doi.org/10.1073/pnas.1315862110
  23. Whang J, Song YH. 2013. Synthesis of thienotriazolopyrimidine derivatives containing triazolothiadiazole moiety. J. Heterocycl. Chem. 50: 603-607. https://doi.org/10.1002/jhet.1574
  24. Whang J, Song YH. 2012. A facile one-pot synthesis of sulfur-linked thieno[1,2,4]-triazolo[4,3-c]pyrimidine derivatives containing phenylpyrazole or thienopyrimidinylpyrazole moiety. Heterocycles 85: 155-164. https://doi.org/10.3987/COM-11-12371
  25. Song YH, Son HY. 2011. Synthesis of new 1-phenylthieno [1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-one derivatives. J. Heterocycl. Chem. 48: 597-603. https://doi.org/10.1002/jhet.549
  26. Song YH, Son HY. 2010. Synthesis of new sulfur-linked 1,2,4-triazolothienopyrimidine and 1,2,4-triazolopyrazolopyrimidine derivatives containing fused heterocyclic pyrimidines. J. Heterocycl. Chem. 47: 1183-1187. https://doi.org/10.1002/jhet.461
  27. Joe BS, Son HY, Song YH. 2008. A mild and efficient synthesis of new 3-phenylthienotriazolopyrimidined derivatives using iodobenzene diacetate. Heterocycles 75: 3091-3097. https://doi.org/10.3987/COM-08-11465
  28. Kim SM, Lee SW, Song YH. 2014. A synthesis of novel pyrazolylthienopyrimidine derivatives as IL-6/STAT3 inhibitors. Bull. Kor. Chem. Soc. 35: 2859-2862. https://doi.org/10.5012/bkcs.2014.35.9.2859
  29. Lee SJ, Jang HJ, Kim Y, Oh HM, Lee S, Jung K, et al. 2016. Inhibitory effects of IL-6-induced STAT3 activation of bioactive compounds derived from Salvia plebeia R. Br. Process Biochem. 51: 2222-2229. https://doi.org/10.1016/j.procbio.2016.09.003
  30. Li HC, Zhang GY. 2003. Inhibitory effect of genistein on activation of STAT3 induced by brain ischemia/reperfusion in rat hippocampus. Acta Pharmacol. Sin. 24: 1131-1136.
  31. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. 2006. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol. 13: 1235-1242. https://doi.org/10.1016/j.chembiol.2006.09.018
  32. Sriuranpong V, Park JI, Amornphimoltham P, Patel V, Nelkin BD, Gutkind JS. 2003. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res. 63: 2948-2956.

피인용 문헌

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  2. Research developments in the syntheses, anti-inflammatory activities and structure-activity relationships of pyrimidines vol.11, pp.11, 2019, https://doi.org/10.1039/d0ra10657g
  3. Synthesis and Some Transformations of 4-Oxo-7-phenyl-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidine-7-carbonitrile vol.57, pp.10, 2019, https://doi.org/10.1134/s1070428021100110