Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Design, Synthesis, and Molecular Docking Study of Flavonol Derivatives as Selective JAK1 Inhibitors

  • Kim, Mi Kyoung (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Bae, Onnuri (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Chong, Youhoon (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University)
  • Received : 2014.04.24
  • Accepted : 2014.04.28
  • Published : 2014.08.20
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Abstract

Keywords

Experimental Section

Preparation of the Title Compound 2b. To a stirred suspension of 2′-hydroxyacetophenone (4) (1 g, 2.3 mmol) in dichloromethane (10 mL) was added EDC (881 mg, 4.6 mmol) followed by DMAP (562 mg, 4.6 mmol). Upon complete dissolution, benzoic acid 6b (2.3 mmol) was added. The mixture was stirred at rt for 4 h and concentrated under reduced pressure. The ester (7) (2.3 mmol) thus obtained was dissolved in toluene (10 mL), and the resulting solution was treated with K2CO3 (636 mg, 4.6 mmol) and tetra-n-butylammonium bromide (741 mg, 2.3 mmol). After stirring for 3 h at 90 ℃, solid materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude compound obtained above was dissolved in MeOH (5 mL), and the resulting solution was treated with p-TsOH (10 mmol) at 0 ℃. The reaction mixture was stirred for 4 h at room temperature, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2:1 = Hex:Acetone) to give 2-(2-(3-hydroxyprop-1-yn-1-yl)-5-(3,5,7-trihydroxy-4-oxo-4Hchromen-2-yl)phenyl) acetonitrile (2b) as yellow powder: 1H NMR (400 MHz, Acetone-d6) δ 12.8 (s, OH), 7.42 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 2.1, 8.4 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 4.42 (s, 2H), 4.12 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 176.1, 166.7, 161.8, 160.3, 147.2, 136.6, 133.5, 130.2, 128.1, 126.9, 125.9, 122.3, 117.8, 104.8, 99.5, 95.1, 98.6, 88.4, 52.6, 23.5.

References

  1. (a) O'Shea, J. J. Immunity 1997, 7, 1. https://doi.org/10.1016/S1074-7613(00)80505-1
  2. (b) Pesu, M.; Laurence, A.; Kishore, N.; Wzillich, S. H.; Chan, G.; O'Shea, J. J. Immunol. Rev. 2008, 223, 132. https://doi.org/10.1111/j.1600-065X.2008.00644.x
  3. O'Shea, J. J.; Pesu, M.; Borie, D. C.; Changelian, P. S. Nat. Rev. Drug Discovery 2004, 3, 555. https://doi.org/10.1038/nrd1441
  4. (a) Clark, S. C.; Kamen, R. Science 1987, 236, 1229. https://doi.org/10.1126/science.3296190
  5. (b) Metcalf, D. Nature 1989, 339, 27. https://doi.org/10.1038/339027a0
  6. Rodig, S. J.; Meraz, M. A.; White, J. M.; Lampe, P. A.; Riley, J. K.; Arthur, C. D.; King, K. L.; Sheehan, K. C.; Yin, L.; Pennica, D.; Johnson, E. M., Jr.; Schreiber, R. D. Cell 1998, 93, 373. https://doi.org/10.1016/S0092-8674(00)81166-6
  7. Shimoda, K.; Kouji, K.; Aoki, K.; Matsuda, T.; Miyamoto, A.; Shibamori, M.; Yamashita, M.; Numata, A.; Takase, K.; Kobayashi, S.; Shibata, S.; Asano, Y.; Gondo, H.; Sekiguchi, K.; Nakayama, K.; Nakayama, T.; Okamura, T.; Okamura, S.; Niho, Y.; Nakayama, K. Immunity 2000, 13, 561. https://doi.org/10.1016/S1074-7613(00)00055-8
  8. Parganas, E.; Wang, D.; Stravopodis, D.; Topham, D. J.; Marine, J. C.; Teglund, S.; Vanin, E. F.; Bodner, S.; Colamonici, O. R.; van Deursen, J. M.; Grosveld, G.; Ihle, J. N. Cell 1998, 93, 385. https://doi.org/10.1016/S0092-8674(00)81167-8
  9. Smolen, J. S.; Beaulieu, A.; Rubbert-Roth, A.; Ramos-Remus, C.; Rovensky, J.; Alecock, E.; Woodworth, T.; Alten, R. Lancet 2008, 371, 987. https://doi.org/10.1016/S0140-6736(08)60453-5
  10. Haan, C.; Rolvering, C.; Raulf, F.; Kapp, M.; Druckes, P.; Thoma, G.; Behrmann, I.; Zerwes, H. G. Chem. Biol. 2011, 18, 314. https://doi.org/10.1016/j.chembiol.2011.01.012
  11. Kulagowski, J. J.; Blair, W.; Bull, R. J.; Chang, C.; Deshmukh, G.; Dyke, H. J.; Eigenbrot, C.; Ghilardi, N.; Gibbons, P.; Harrison, T. K.; Hewitt, P. R.; Liimatta, M.; Hurley, C. A.; Johnson, A.; Johnson, T.; Kenny, J. R.; Kohli, P. B.; Maxey, R. J.; Mendonca, R.; Mortara, K.; Murray, J.; Narukulla, R.; Shia, S.; Steffek, M.; Ubhayakar, S.; Ultsch, M.; van Abbema, A.; Ward, S. I.; Waszkowycz, B.; Zak, M. J. Med. Chem. 2012, 55, 5901. https://doi.org/10.1021/jm300438j
  12. Zak, M.; Mendonca, R.; Balazs, M.; Barrett, K.; Bergeron, P.; Blair, W. S.; Chang, C.; Deshmukh, G.; DeVoss, J.; Dragovich, P. S.; Eigenbrot, C.; Ghilardi, N.; Gibbons, P.; Gradl, S.; Hamman, C.; Hanan, E. J.; Harstad, E.; Hewitt, P. R.; Hurley, C. A.; Jin, T.; Johnson, A.; Johnson, T.; Kenny, J. R.; Koehler, M. F. T.; Kohli, P. B.; Kulagowski, J. J.; Labadie, S.; Liao, J.; Liimatta, M.; Lin, J.; Lupardus, P. J.; Maxey, R. J.; Murray, J. M.; Pulk, R.; Rodriguez, M.; Savage, S.; Shia, S.; Steffek, M.; Ubhayakar, S.; Ultsch, M.; van Abbema, A.; Ward, S. I.; Xiao, L.; Xiao, Y. J. Med. Chem. 2012, 55, 6176. https://doi.org/10.1021/jm300628c
  13. Vardiman, J. W.; Harris, N. L.; Brunning, R. D. Blood. 2002, 100, 2292. https://doi.org/10.1182/blood-2002-04-1199
  14. Wilks, A. F. Semin. Cell Dev. Biol. 2008, 19, 319. https://doi.org/10.1016/j.semcdb.2008.07.020
  15. Williams, N. K.; Bamert, R. S.; Patel, O.; Wang, C.; Walden, P. M.; Wilks, A. F.; Fantino, E.; Rossjohn, J.; Lucet, I. S. J. Mol. Biol. 2009, 387, 219. https://doi.org/10.1016/j.jmb.2009.01.041
  16. Agullo, G.; Gamet-Payrastre, L.; Manenti, S.; Viala, C.; Remesy, C.; Chap, H.; Payrastre, B. Biochem. Pharmacol. 1997, 53, 1649. https://doi.org/10.1016/S0006-2952(97)82453-7
  17. Hou, D. X.; Kumamoto, T. Antioxid. Redox Signal 2010, 13, 691. https://doi.org/10.1089/ars.2009.2816
  18. Caldwell, S. T.; Crozier, A.; Hartley, R. C. Tetrahedron 2000, 56, 4101. https://doi.org/10.1016/S0040-4020(00)00325-2
  19. Han, B. H.; Boudjouk, P. Tetrahedron Lett. 1982, 23, 1643. https://doi.org/10.1016/S0040-4039(00)87179-8
  20. Sonogashira, K. Organomet. Chem. 2002, 653, 46. https://doi.org/10.1016/S0022-328X(02)01158-0
  21. Thompson, J. E.; Cubbon, R. M.; Cummings, R. T.; Wicker, L. S.; Frankshun, R.; Cunningham, B. R.; Cameron, P. M.; Meinke, P. T.; Liverton, N.; Weng, Y.; DeMartino, J. A. Bioorg. Med. Chem. Lett. 2002, 12, 1219. https://doi.org/10.1016/S0960-894X(02)00106-3
  22. Lucet, I. S.; Fantino, E.; Styles, M.; Bamert, R.; Patel, O.; Broughton, S. E.; Walter, M.; Burns, C. J.; Treutlein, H.; Wilks, A. F.; Rossjohn, J. Blood 2006, 107, 176. https://doi.org/10.1182/blood-2005-06-2413
  23. Chrencik, J. E.; Patny, A.; Leung, I. K.; Korniski, B.; Emmons, T. L.; Hall, T.; Weinberg, R. A.; Gormley, J. A.; Williams, J. M.; Day, J. E.; Hirsch, J. L.; Kiefer, J. R.; Leone, J. W.; Fischer, H. D.; Sommers, C. D.; Huang, H. C.; Jacobsen, E. J.; Tenbrink, R. E.; Tomasselli, A. G.; Benson, T. E. J. Mol. Biol. 2010, 400, 413. https://doi.org/10.1016/j.jmb.2010.05.020

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