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The Pharmaceutical Society of Korea (대한약학회)
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Anti-Inflammatory Effects of N1-Benzyl-4-Methylbenzene-1,2-Diamine (JSH-21) Analogs on Nitric Oxide Production and Nuclear Factor-kappa B Transcriptional Activity in Lipopolysaccharide-Stimulated Macrophages RAW 264.7

  • Min, Kyung-Rak (College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University) ;
  • Shin, Hyun-Mo (College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University) ;
  • Lee, Jee-Hyun (College of Pharmacy, Chungnam National University) ;
  • Kim, Byung-Hak (College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University) ;
  • Chung, Eun-Yong (College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University) ;
  • Jung, Sang-Hun (College of Pharmacy, Chungnam National University) ;
  • Kim , Young-Soo (College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University)
  • Published : 2004.01.01
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Abstract

$N^1$-Benzyl-4-methylbenzene-1,2-diamine (JSH-21) and its analogs were chemically synthesized and their anti-inflammatory potentials investigated. JSH-21 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7 in a dose-dependent manner, with an $IC_{50}$ value of 9.2 ${\mu}M$, where pyrrolidine dithiocarbamate and parthenolide as positive controls exhibited $IC_{50}$ values of 29.3 and 3.6 ${\mu}M$, respectively. The inhibitory effect of JSH-21 on the NO production was attributable to its down-regulatory action on LPS-inducible NO synthase (iNOS), which was documented by iNOS promoter activity. In the mechanism of the anti-inflammatory action, JSH-21 exhibited inhibitory effects on LPS-induced DNA binding activity and transcriptional activity of nuclear factor-kappa B (NF-$_KB$). Structural analogs of JSH-21 also inhibited both the LPS-induced NO production and NF-$_KB$). transcriptional activity, where diamine substitution at positions 1 and 2 of JSH-21 seems to play an important role in the anti-inflammatory activity.

Keywords

References

  1. Archer, S., Measurement of nitric oxide in biological models. FASEB J., 7, 349-360 (1993) https://doi.org/10.1096/fasebj.7.2.8440411
  2. Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A., and Karin, M., Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science, 270, 286-290 (1995) https://doi.org/10.1126/science.270.5234.286
  3. Baeuerle, P. A. and Baltimore, D., NF-kappa B: ten years after. Cell, 87,13-20 (1996) https://doi.org/10.1016/S0092-8674(00)81318-5
  4. Beg, A. A., Ruben, S. M., Scheinman, R. I., Haskill, S., Rosen, C. A., and Baldwin, A. S. Jr., I kappa B interacts with the nuclear localization sequences of the subunits of NF-kappa B: a mechanism for cytoplasmic retention. Genes Dev., 6, 1899-1913 (1992) https://doi.org/10.1101/gad.6.10.1899
  5. Blantz, R. C. and Munger, K., Role of nitric oxide in inflammatory conditions. Nephron, 90, 373-378 (2002) https://doi.org/10.1159/000054723
  6. Bogdan, C., Nitric oxide and the immune response. Nat. Immunol., 2, 907-916 (2001) https://doi.org/10.1038/ni1001-907
  7. Brown, S. A. and Rizzo, C. J., A 'one-pot' phase transfer alkylation/hydrolysis of o-nitrotrifluoroacetanilides. a convenient route to N-alkyl o-phenylenediamines. Synthet. Commun., 26, 4065-4080 (1996) https://doi.org/10.1080/00397919608003827
  8. Cavaillon, J. M., Adib-Conquy, M., Fitting, C., Adrie, C., and Payen, D., Cytokine cascade in sepsis. Scand. J. Infect. Dis., 35, 535-544 (2003) https://doi.org/10.1080/00365540310015935
  9. Collins, T., Read, M. A., Neish, A. S., Whitley, M. Z., Thanos, D., and Maniatis, T., Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J., 9, 899-909 (1995) https://doi.org/10.1096/fasebj.9.10.7542214
  10. Dick, L. R., Cruikshank, A. A., Destree, A. T., Grenier, L., McCormack, T. A., Melandri, F. D., Nunes, S. L., Palombella, V. J., Parent, L. A., Plamondon, L., and Stein, R. L., Mechanistic studies on the inactivation of the proteasome by lactacystin in cultured cells. J. Biol. Chem., 272, 182-188 (1997) https://doi.org/10.1074/jbc.272.1.182
  11. Hehner, S. P., Hofmann, T. G., Droge, W., and Schmitz, M. L., The anti-inflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. J. Immunol., 163,5617-5623 (1999)
  12. Ignarro, L. J., Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J. Physiol. Pharmacal., 53,503-514 (2002)
  13. Jones, B. W., Means, T. K., Heldwein, K. A., Keen, M. A., Hill, P. J., Belisle, J. T., and Fenton, M. J., Different Toll-like receptor agonists induce distinct macrophage responses. J. Leukoc. Biol., 69,1036-1044 (2001)
  14. Liaudet, L., Soriano, F. G., and Szabo, C., Biology of nitric oxide signaling. Crit. Care Med., 28, N37-N52 (2000) https://doi.org/10.1097/00003246-200004001-00005
  15. Lowenstein, C. J., Alley, E. W., Raval, P., Snowman, A. M., Snyder, S. H., Russell, S. W., and Murphy, W. J., Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl. Acad. Sci. U.S.A., 90, 9730-9734 (1993) https://doi.org/10.1073/pnas.90.20.9730
  16. MacMicking, J., Xie, Q. W., and Nathan, C., Nitric oxide and macrophage function. Annu. Rev. Immunol., 15, 323-350 (1997) https://doi.org/10.1146/annurev.immunol.15.1.323
  17. Manna, S. K., Bueso-Ramos, C., Alvarado, F., and Aggarwal, B. B., Calagualine inhibits nuclear transcription factors-kappaB activated by various inflammatory and tumor promoting agents. Cancer Lett., 190, 171-182 (2003) https://doi.org/10.1016/S0304-3835(02)00618-3
  18. Moon, K. Y., Hahn, B. S., Lee, J., and Kim, Y. S., A cell-based assay system for monitoring NF-kappaB activity in human HaCat transfectant cells. Anal. Biochem., 292, 17-21 (2001) https://doi.org/10.1006/abio.2001.5059
  19. Moreland, L. W., Drugs that block tumor necrosis factor: experience in patients with rheumatoid arthritis. Pharmacoeconomics, 22,39-53 (2004) https://doi.org/10.2165/00019053-200422001-00005
  20. Palmer, R. M., Ashton, D. S., and Moncada, S., Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature, 333, 664-666 (1988) https://doi.org/10.1038/333664a0
  21. Paramore, A. and Frantz, S., Bortezomib. Nat. Rev. Drug Discov., 2, 611-612 (2003) https://doi.org/10.1038/nrd1159
  22. Perrin, D. D., Armarego, W. L. F., and Perrin, D. R., Purification of Laboratory Chemicals, 2nd ed. Pergamon Press, Oxford (1982)
  23. Prast, H. and Philippu, A., Nitric oxide as modulator of neuronal function. Prog. Neurobiol., 64, 51-68 (2001) https://doi.org/10.1016/S0301-0082(00)00044-7
  24. Sherman, M. P., Aeberhard, E. E., Wong, V. Z., Griscavage, J. M., and Ignarro, L. J., Pyrrolidine dithiocarbamate inhibits induction of nitric oxide synthase activity in rat alveolar macrophages. Biochem. Biophys. Res. Commun., 191, 1301-1308 (1993) https://doi.org/10.1006/bbrc.1993.1359
  25. Tlan, B. and Brasier, A. R., Identification of a nuclear factor kappa B-dependent gene network. Recent Prog. Horm. Res., 58, 95-130 (2003) https://doi.org/10.1210/rp.58.1.95
  26. Verma, I. M., Stevenson, J. K., Schwarz, E. M., Van Antwerp, D., and Miyamoto, S., Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev., 9, 2723-2735 (1995) https://doi.org/10.1101/gad.9.22.2723
  27. Xie, Q. W., Whisnant, R., and Nathan, C., Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J. Exp. Med., 177, 1779-1784 (1993) https://doi.org/10.1084/jem.177.6.1779
  28. Yuste, F., Saldana, M., and Walls, F., Selective reduction of aromatic nitrounds containing O- and N-benzyl groups with hydrazine and Raney nickel. Tetrahedron Lett., 23, 147-148 (1982) https://doi.org/10.1016/S0040-4039(00)86770-2
  29. Zafarullah, M., Li, W. Q., Sylvester, J., and Ahmad, M., Molecular mechanisms of N-acetylcysteine actions. Cell Mol. Life Sci., 60, 6-20 (2003) https://doi.org/10.1007/s000180300001