The role of the hydrophobic group on ring A of chalcones in the inhibition of interleukin-5
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 μM, IC50=25.3 μM) 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. Compounds2c (IC50=12.6 μM),2d (IC50=12.2 μM), and2i (IC50=12.3 μM) exhibited the most potent activity. Considering the cLog P values of2, the alkoxy group contributes to the cell permeability of2 for the enhancement of activity, rather than playing a role in ligand motif binding to the receptor. The optimum alkoxy group in ring A of2 should be one that provides the cLog P of2 in the range of 4.22 to 4.67.
Key wordsChalcones Inhibitor Interleukin-5
- Allakhverdi, Z., Allam, M., and Renzi, P. M., Inhibition of antigen-induced 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).PubMedGoogle Scholar
- 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).PubMedCrossRefGoogle Scholar
- 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).Google Scholar
- 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., 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).PubMedCrossRefGoogle Scholar
- Perrin, D. D., Armarego, W. L. F., and Perrin, D. R.,Purification of laboratory chemicals, 2nd edition. Pergamon Press, Oxford, England, (1982).Google Scholar