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The Pharmaceutical Society of Korea (대한약학회)
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The Role of the Hydrophobic Group on Ring A of Chalcones in the Inhibition of Interleukin-5

  • Yang, Hyun-Mo (College of Pharmacy, Chungnam National University) ;
  • Shin, Hye-Rim (College of Pharmacy, Chungnam National University) ;
  • Cho, Soo-Hyun (College of Pharmacy, Chungnam National University) ;
  • Song, Gyu-Yong (College of Pharmacy, Chungnam National University) ;
  • Lee, In-Jeong (College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University) ;
  • Kim, Mi-Kyeong (College of Medicine, Chungbuk National University) ;
  • Lee, Seung-Ho (College of Pharmacy, Yeungnam University) ;
  • Ryu, Jae-Chun (Toxicology Laboratory, Korea Institute of Science and Technology) ;
  • Kim, Young-Soo (College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University) ;
  • Jung, Sang-Hun (College of Pharmacy, Chungnam National University)
  • Published : 2006.11.30
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Abstract

Novel chalcones were found as potent inhibitors of interleukin-5 (II-5). 1-(6-Benzyloxy-2-hydroxyphenyl)-3-(4-hydroxyphenyl)propenone (2a, 78.8% inhibition at $50\;{\mu}M,\;IC_{50}=25.3\;{\mu}M$) was initially identified as a potent inhibitor of IL-5. This activity is comparable to that of budesonide or sophoricoside (1a). The benzyloxy group appears to be critical for the enhancement of the IL-5 inhibitory activity. To identify the role of this hydrophobic moiety, cyclohexyloxy (2d), cyclohexylmethoxy (2c), cyclohexylethoxy (2e), cyclohexylpropoxy (2f), 2-methylpropoxy (2g), 3-methylbutoxy (2h), 4-methylpentoxy (2i), and 2-ethylbutoxy (2j) analogs were prepared and tested for their effects on IL-5 bioactivity. Compounds 2c ($IC_{50}=12.6\;{\mu}M$), 2d ($IC_{50}=12.2\;{\mu}M$), and 2i ($IC_{50}=12.3\;{\mu}M$) exhibited the most potent activity. Considering the cLog P values of 2, the alkoxy group contributes to the cell permeability of 2 for the enhancement of activity, rather than playing a role in ligand motif binding to the receptor. The optimum alkoxy group in ring A of 2 should be one that provides the cLog P of 2 in the range of 4.22 to 4.67.

Keywords

References

  1. Allakhverdi, Z., Allam, M., and Renzi, P. M., Inhibition of antigeninduced eosinophilia and airway hyperresponsiveness by antisense oligonucleotides directed against the common beta chain of IL-3, IL-5, GM-CSF receptors in a rat model of allergic asthma. Am. J. Respir. Crit. Care Med., 165, 1015- 1021 (2002) https://doi.org/10.1164/ajrccm.165.7.2109095
  2. Bagley, C. J., Woodcock, J. M., Guthridge, M. A., Stomski, F. C., and Lopez. A. F., Structural and functional hot spots in cytokine receptors. Int. J. Hematol., 73, 299-307 (2001) https://doi.org/10.1007/BF02981954
  3. Devos, R., Guisez. Y., Plaetinck, G., Cornelis, S., Traverier, J., Van der Heyden, J., Florey, C. H., and Scheffler, J. E., Covalent modification of the interleukin-5 receptor by isothiazolones leads to inhibition of the binding of interleukin- 5. Eur. J. Biochem., 225, 635-640 (1994) https://doi.org/10.1111/j.1432-1033.1994.00635.x
  4. Djukanovic, R., Asthma: A disease of inflammation and repair. J. Allergy Clin. Immunol., 105, 522-526 (2000) https://doi.org/10.1067/mai.2000.104251
  5. Foster, P. S., Hogan, S. P., Ramsay, A. J., Matthaei, K. I., and Young. I. G., Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med., 183, 195-201 (1996) https://doi.org/10.1084/jem.183.1.195
  6. Gelfand, E. W., Essential role of T lymphocytes in the development of allergen-driven airway hyperresponsiveness. Allergy Asthma Proc., 19, 365-369 (1998)
  7. Ghose, A. K. and Crippen, G. M., Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions. J. Chem. Inform. Comp. Sci., 27, 21-35 (1987) https://doi.org/10.1021/ci00053a005
  8. Hamelmann, E. and Gelfand, E. W., Role of IL-5 in the development of allergen-induced airway hyperresponsiveness. Int. Arch. Allergy Immunol., 120, 8-16 (1999) https://doi.org/10.1159/000024215
  9. Hogan, S. P., Matthaei, K. I., Young, J. M., Koskinen, A., Young, I. G., and Foster. P. S., A novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5. J. Immunol., 161, 1501-1509 (1998)
  10. Jung, S. H., Cho, S. H., Dang, T. H., Lee, J. H., Ju, J. H., Kim, M. K., Lee, S. H., Ryu, J. C., and Kim, Y., Structural requirement of isoflavonones for the inhibitory activity of interleukin-5. Eur. J. Med. Chem., 38, 537 (2003) https://doi.org/10.1016/S0223-5234(03)00064-3
  11. Kraneveld, A. D., Folkerts, G.., Van Oosterhout, A. J., and Nijkamp, F. P., Airway hyperresponsiveness: first eosinophils and then neuropeptides. Int. J. Immunopharmacol., 19, 517- 527 (1997) https://doi.org/10.1016/S0192-0561(97)00085-4
  12. Lee, J. J., McGarry, M. P., Farmer, S. C., Denzler, K. L., Larson, K. A., Carrigan, P. E., Brenneise, I. E., Horton, M. A., Haczku, A., Gelfand, E. W., Leikauf, G. D., and Lee. N. A., Interleukin- 5 expression in the epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J. Exp. Med., 185, 2143-2156 (1997) https://doi.org/10.1084/jem.185.12.2143
  13. Min, B., Oh, S. H., Lee, H.-K., Takatsu, K., Chang, I.-M., Min, K. R., and Kim. Y., Sophoricoside analogs as the IL-5 inhibitors from Sophora japonica. Planta Med., 65, 408-412 (1999) https://doi.org/10.1055/s-1999-14016
  14. Mishra, A., Hogan, S. P., Brandt, E. B., and Rothenberg, M. E., IL-5 promotes eosinophil trafficking to the esophagus. J. Immunol., 168, 2464-2469 (2002) https://doi.org/10.4049/jimmunol.168.5.2464
  15. Mita, S., Takaki, S., Tominaga, A., and Takatsu, K., Comparative analysis of the kinetics of binding and internalization of IL-5 in murine IL-5 receptors of high and low affinity. J. Immunol., 151, 6924-6932 (1993)
  16. Murata, Y., Takaki, S., Migita, M., Kikuchi, Y., Tominaga, A., and Takatsu,K., Molecular cloning and expression of the human interleukin 5 receptor. J. Exp. Med., 175, 341-351 (1992) https://doi.org/10.1084/jem.175.2.341
  17. Perrin, D. D., Armarego, W. L. F., and Perrin, D. R., Purification of laboratory chemicals, 2nd edition. Pergamon Press, Oxford, England, (1982)
  18. Riffo-Vasquez, Y., and Spina, D., Role of cytokines and chemokines in bronchial hyperresponsiveness and airway inflammation. Pharmacol. Ther., 94,185-211 (2002) https://doi.org/10.1016/S0163-7258(02)00217-6
  19. Takaki, S., Tominaga, A., Hitoshi, Y., Mita, S., Sonoda, E., Yamaguchi, N., and Takatsu. K., Molecular cloning and expression of the murine interleukin-5 receptor. EMBO J., 9, 4367-4374 (1990)
  20. Tomaki, M, Zhao, L. L., Sjostrand, M., Linden, A., Ichinose, M., and Lotvall, J., Comparison of Effects of Anti-IL-3, IL-5 and GM-CSF Treatments on Eosinophilopoiesis and Airway Eosinophilia Induced by Allergen. Pulm. Pharmacol. Ther., 15, 161-168 (2002) https://doi.org/10.1006/pupt.2001.0333
  21. Webb, D. C., McKenzie, A. N., Koskinen, A. M., Yang, M., Mattes, J., and Foster, P. S., Integrated signals between IL- 13, IL-14, and IL-5 regulate airways hyperreactivity. J. Immunol., 165, 108-113 (2000) https://doi.org/10.4049/jimmunol.165.1.108
  22. Yun, J., Lee, C.-K., Chang, I.-M., Takatsu, K., Hirano, T., Min, K. R., Lee, M. K., and Kim. Y., Differential inhibitory effects of sophoricoside analogs on bioactivity of several cytokines. Life Sci., 67, 2855-2863 (2000) https://doi.org/10.1016/S0024-3205(00)00873-0