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Synthesis of Heterocycle-linked Thioureas and Their Inhibitory Activities of NO Production in LPS Activated Macrophages

  • Cheon, Ye-Jin (College of Pharmacy, Sookmyung Women's University) ;
  • Gim, Hyo-Jin (College of Pharmacy, Sookmyung Women's University) ;
  • Jang, Hee-Ryun (College of Pharmacy, Sookmyung Women's University) ;
  • Ryu, Jae-Ha (College of Pharmacy, Sookmyung Women's University) ;
  • Jeon, Raok (College of Pharmacy, Sookmyung Women's University)
  • Published : 2010.01.20

Abstract

A series of thioureas were synthesized as inhibitors of NO production in lipopolysaccharide-activated macrophages. We investigated the effect of lipophilic moiety and N-substituents of the thioureas on the activity. Phenoxazine and carbazole-containing derivatives revealed higher activity than indole-containing thioureas. The appropriate spacer between lipophilic tail and thiourea head and methyl substituent at N3 position of thiourea brought beneficial effect on the inhibition of NO production. Among prepared compounds, phenoxazine-containing derivative 2a was the most potent with $2.32 {\mu}M$ of $IC_{50}$ value. RT-PCR analysis suggested that the prepared thioureas inhibited NO production through the suppression of iNOS mRNA expression.

Keywords

References

  1. Forstermann, U.; Schmidt, H. H.; Pollock, J. S.; Sheng, H.; Mitchell, J. A.; Warner, T. D.; Nakane, M.; Murad, F. Biochem. Pharmacol. 1991, 42, 1849. https://doi.org/10.1016/0006-2952(91)90581-O
  2. Bredt, D. S.; Snyder, S. H. Proc. Natl. Acad. Sci. USA 1990, 87, 682. https://doi.org/10.1073/pnas.87.2.682
  3. Lowenstein, C. J.; Glatt, C. S.; Bredt, D. S.; Snyder, S. H. Proc. Natl. Acad. Sci. USA 1992, 89, 6711. https://doi.org/10.1073/pnas.89.15.6711
  4. Cook, H. T.; Cattell, V. Clin. Sci. 1996, 91, 375.
  5. Mocellin, S.; Bronte, V.; Nitti, D. Med. Res. Rev. 2007, 27, 317. https://doi.org/10.1002/med.20092
  6. Squadrito, G. L.; Pryor, W. A. Free Radic. Biol. Med. 1998, 25, 392. https://doi.org/10.1016/S0891-5849(98)00095-1
  7. Ricciardolo, F. L.; Nijkamp, F. P.; Folkerts, G. Current Drug Targets 2006, 7, 721. https://doi.org/10.2174/138945006777435290
  8. Fitzpatrick, B.; Mehibel, M.; Cowen, R. L.; Stratford, I. J. Nitric Oxide 2008, 19, 217. https://doi.org/10.1016/j.niox.2008.05.001
  9. Olken, N. M.; Marletta, M. A. Biochemistry 1993, 32, 9677. https://doi.org/10.1021/bi00088a020
  10. Furfine, E. S.; Harmon, M. F.; Paith, J. E.; Garvey, E. P. Biochemistry 1993, 32, 8512. https://doi.org/10.1021/bi00084a017
  11. Moore, W. M.; Webber, R. K.; Fok, K. F.; Jerome, G. M.; Kornmeier, C. M.; Tjoeng, F. S.; Currie, M. G. Bioorg. Med. Chem. 1996, 4, 1559. https://doi.org/10.1016/0968-0896(96)00148-4
  12. Beaton, H.; Hamley, P.; Nicholls, D. J.; Tinker, A. C.; Wallace, A. V. Bioorg. Med. Chem. Lett. 2001, 11, 1023. https://doi.org/10.1016/S0960-894X(01)00119-6
  13. Paesano, N.; Marzocco, S.; Vicidomini, C.; Saturnino, C.; Autore, G.; De Martino, G.; Sbardella, G. Bioorg. Med. Chem. Lett. 2005, 15, 539. https://doi.org/10.1016/j.bmcl.2004.11.047
  14. Raman, C. S.; Li, H.; Martasek, P.; Babu, B. R.; Griffith, O. W.; Masters, B. S.; Poulos, T. L. J. Biol. Chem. 2001, 276, 26486. https://doi.org/10.1074/jbc.M102255200
  15. Prabhakar, S. S.; Zeballos, G. A.; Montoya-Zavala, M.; Leonard, C. Am. J. Physiol. 1997, 273, C1882.
  16. Goodyer, C. L. M.; Chinje, E. C.; Jaffar, M.; Stratford, I. J.; Threadgill, M. D. Bioorg. Med. Chem. 2003, 11, 4189. https://doi.org/10.1016/S0968-0896(03)00451-6
  17. Shearer, B. G.; Lee, S.; Oplinger, J. A.; Frick, L. W.; Garvey, E. P.; Furfine, E. S. J. Med. Chem. 1997, 40, 1901. https://doi.org/10.1021/jm960785c
  18. Kim, Y. J.; Ryu, J. H.; Cheon, Y. J.; Lim, H. J.; Jeon, R. Bioorg. Med. Chem. Lett. 2007, 17, 3317. https://doi.org/10.1016/j.bmcl.2007.04.005
  19. Jin, G. H.; Lee, D. Y.; Cheon, Y. J.; Gim, H. J.; Kim, D. H.; Kim, H. D.; Ryu, J. H.; Jeon, R. Bioorg. Med. Chem. Lett. 2009, 19, 3088. https://doi.org/10.1016/j.bmcl.2009.04.001
  20. Green, L. C.; Wagner, D. A.; Glogowski, J.; Skipper, P. L.; Wishnok, J. S.; Tannenbaum, S. R. Anal. Biochem. 1982, 126, 131. https://doi.org/10.1016/0003-2697(82)90118-X

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