Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

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)
  • Received : 2018.11.28
  • Accepted : 2019.05.10
  • Published : 2019.06.28
Download PDF
⟨ Previous Next ⟩

Abstract

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.

Keywords

References

  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.

Cited by

  1. 4-(3-Phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)thieno[3,2-d]pyrimidine vol.2020, pp.2, 2020, https://doi.org/10.3390/m1136
  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