Abstract
Recent investigations have shown that certain flavonoids, especially flavone derivatives, inhibit nitric oxide (NO) production by inducible NO synthase (iNOS) in macrophages, which contribute their anti-inflammatory action. For the purpose of finding the optimized chemical structures of flavonoids that inhibit NO production, various A- and B-ring substituted flavones were synthesized and evaluated for their inhibitory activity using lipopolysaccharide-treated RAW 264.7 cells. It was found that the optimal chemical structures were A-ring 5,7-dihydroxyflavones having the B-ring 2′,3′-dihydroxy or 3′,4′-dihydroxy or 3′,4′-hydroxy/methoxy (methoxy/hydroxy) groups. These structurally optimized compounds were revealed to be down-regulators of iNOS induction, but not direct iNOS inhibitors. Of these derivatives that were evaluated, 2′,3′,5,7-tet-rahydroxyflavone and 3′,4′,5,7-tetrahydroxyflavone (luteolin) showed the strongest inhibition. The IC50 values for these compounds were 19.7 and 17.1 μM, respectively. Therefore, these compounds may have a potential as new anti-inflammatory agents.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Chen, Y-C., Yang, L-L., and Lee, T. J-F., Oroxylin A inhibition of lipopolysaccharide-induced iNOS and COX-2 gene expressionvia suppression of nuclear factor-KB activation.Biochem. Pharmacol., 59, 1445–1457 (2000).
Cheon, B. S., Kim, Y. H., Son, K. H., Chang, H. W., Kang, S. S., and Kim, H. P., Effects of prenylated flavonoids and biflavonoids on lipopolysaccharide-induced nitric oxide production from the mouse macrophage cell line RAW 264.7.Planta Med., 66, 596–600 (2000).
Chi, Y. S., Cheon, B. S., and Kim, H. P., Effect of wogonin, a plant flavone from Scutellaria radix, on the suppression of cyclooxygenase-2 and induction of inducible nitric oxide synthase in lipopolysaccharide-treated RAW 264.7 cells.Biochem. Pharmacol., 61, 1195–1203 (2001).
Cho, S-Y., Park, S-J., Kwon, M-J., Jeong, T-S., Bak, S-H., Choi, W-Y., Jeong, W-I., Ryu, S-Y., Do, S-H., Lee, C-S., Song, J-C., and Jeong, K-S., Quercetin suppresses proinflammatory cytokines production through MAP kinases andNF-kB pathway in lipopolysaccharide-stimulated macrophage.Mol. Cell Biochem., 243, 153–160 (2003).
Dao, T. T., Chi, Y. S., Kim, J., Kim, H. P., Kim, S. H., and Park, H., Synthesis and PGE2 inhibitory activity of 5,7- dihydroxyflavones and their O-methylated flavone analogs.Arch. Pharm. Res., 26, 345–350 (2003).
Dao, T. T., Chi, Y. S., Kim, J., Kim, H. P., Kim, S. H., and Park, H., Synthesis and inhibitory activity against COX-2 catalyzed prostaglandin production of chrysin derivatives.Bioorg. Med. Chem. Lett., 14, 1165–1167 (2004).
Ferriola, P. C., Cody, V., and Middleton, E., Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationships.Biochem. Pharmacol., 38, 1617–1624 (1989).
Handy, R. L. C. and Moore, P. K., A comparison of the effects of I-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity.Brit. J. Pharmacol., 123, 1119- 1126 (1998).
Kim, H. K., Cheon, B. S., Kim, Y. H., Kim, S. Y., and Kim, H. P., Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structure-activity relationships.Biochem. Pharmacol., 58, 759–765 (1999).
Krol, W., Czuba, Z. P., Threadgill, M. D., Cunningham, B. D., and Pietse, G., Inhibition of nitric oxide production in murine macrophages by flavones.Biochem. Pharmacol., 50, 1031- 1035 (1995).
Liang, Y-C., Huang, Y-T., Tsai, S-H., Shiau, S-Y., Chen, C-F., and Lin, J-K., Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages.Carcinogenesis, 20, 1945–1952 (1999).
Mossmann, T., Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxic assays.J. Immunol. Methods, 65, 55–63 (1983).
Murakami, A., Nakamura, Y., Torikai, K., Tanaka, T., Koshiba, T., Koshimizu, K., Kuwahara, S., Takahashi, Y., Ogawa, K., Yano, M., Tokuda, H., Nishino, H., Mimaki, Y., Sashida, Y., Kitanaka, S., and Oshigashi, H., Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice.Cancer Res., 60, 5059–5066 (2000).
Raso, G. M., Meli, R., Di Carlo, G., Pacilio, M., and Di Carlo, R., Inhibition of inducible nitric oxide synthase and cyclooxygenase- 2 expression by flavonoids in macrophage J774A.1.Life Sci., 68, 921–931 (2001).
Sadowska-Krowicka, H., Mannick, E. E., Oliver, P. D., Sandoval, M., Zhang, X. J., Eloby-Chiless, S., Clark, D. A., and Miller, M. J. S., Genistein and gut inflammation: Role of nitric oxide.Proc. Soc. Exp. Biol. Med., 217, 351–357 (1998).
Soliman, K. F. and Mazzio, E. A.,In vitro attenuation of nitric oxide production in C6 astrocyte cell culture by various dietary compounds.Proc. Soc. Exp. Biol. Med., 218, 390–397 (1998).
Wadsworth, T. and Koop, D. R., Effects of wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages.Biochem. Pharmacol., 57, 941–946 (1999).
Wadsworth, T. L. and Koop, D. R., Effects of Gingko biloba extract (Egb 761) and quercetin on lipopolysaccharide- induced release of nitric oxide.Chem. Biol. Interaction, 137, 43–58 (2001).
Wakabayashi, I., Inhibitory effects of baicalein and wogonin on lipopolysaccharide-induced nitric oxide production in macrophages.Pharmacol. Toxicol., 84, 288–291 (1999).
You, K. M., Jong, H-G., and Kim H. P., Inhibition of cyclooxy- genase/lipoxygenase from human platelets by polyhydroxy- lated/methoxylated flavonoids isolated from medicinal plants.Arch. Pharm. Res., 22, 18–24 (1999).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kim, S.J., Park, H. & Kim, H.P. Inhibition of nitric oxide production from lipopolysaccharide-treated RAW 264.7 cells by synthetic flavones: Structure-activity relationship and action mechanism. Arch Pharm Res 27, 937–943 (2004). https://doi.org/10.1007/BF02975847
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02975847