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Structural Requirements of 2',4',6'-Tris(methoxymethoxy) chalcone Derivatives for Anti-inflammatory Activity: The Importance of a 2'-Hydroxy Moiety

Jin, Feng    (College of Pharmacy, Wonkwang University   ); Jin, Xing Yu    (College of Pharmacy, Wonkwang University   ); Jin, Ying Lan    (College of Pharmacy, Wonkwang University   ); Sohn, Dae-Won    (College of Pharmacy, Wonkwang University   ); Kim, Soon-Ai    (College of Pharmacy, Wonkwang University   ); Sohn, Dong-Hwan    (College of Pharmacy, Wonkwang University   ); Kim, Youn-Chul    (College of Pharmacy, Wonkwang University   ); Kim, Hak-Sung    (College of Pharmacy, Wonkwang University  );
  • 초록

    Butein, a natural chalcone, has anti-inflammatory and hepatoprotective activity. One synthetic derivative of butein, 2',4',6'-tris(methoxymethoxy)chalcone (TMMC), has potent anti-inflammatory activity via an HO-1 (heme oxygenase 1) dependent pathway. The ${\alpha},{\beta}-unsaturated$ ketone moiety in both TMMC and chalcones could be important in mediating this effect. To investigate the structural requirements of TMMC derivatives for anti-inflammatory effects, we modified the ${\alpha},{\beta}-unsaturated$ ketone moiety through catalytic hydrogenation, hydride reduction, or introduction of a triple bond. In addition, we performed structural modifications such as converting the -OMOM group to an -OMe or -OH group. Generally, modifications in the a,_-unsaturated ketone caused a significant decrease or loss of anti-inflammatory activity, which is consistent with the role of the a,_-unsaturated ketone group acting as a Michael acceptor of nucleophilic species like glutathione or cysteine residues on proteins. Chemically, the electron-donating substituents could make the thiol-adduct more stable by decreasing the acidity of the ${\alpha}-hydrogen$ and slowing the speed of the retro-Michael reaction. Also, like previous studies, the 2'-hydroxy group was crucial in increasing the anti-inflammatory effect. The 2'-hydroxy group produced potent anti-inflammatory effects by increasing the electrophilic properties of ${\alpha},{\beta}-unsaturated$ ketones due to hydrogen bonding between the 2'-hydroxy group and the ketone moiety.


  • 주제어

    Butein .   TMMC .   Chalcone .   Modified synthesis .   Anti-inflammatory .   Cardamonin .   2'-Hydroxy group .   Hydrogen bonding.  

  • 참고문헌 (14)

    1. Lee, S. H., Seo, G S., Kim, J. Y, Jin, X. Y, Kim, H. D., and Sohn, D. H., Heme oxygenase 1 mediates anti-inflammatory effects of 2',4',6'-tris(methoxymethoxy) chalcone, Eur. J. Pharmacol., 532(1-2), 178-186 (2006b) 
    2. Samoszuk, M., Tan, J., and Chorn, G., The chalcone butein from Rhus verniciflua Strokes inhibits clonogenic growth of human breast cancer cells co-cultured with fibroblasts, BMC Complement Altern Med., 5, 5 (2005) 
    3. Israf, D. A, Khaizurin, T. A, Syhida, A, Lajis, N. H., and Khozirah, S., Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-kappaB nuclear translocation and Ikappa-B phosphorylation in RAW 264.7 macrophage cells, Mol. Immunol., 44, 673-679 (2006) 
    4. Lee, S. H., Sohn, D. H., Jin, X. Y, Kim, S. W., Choi, S. C., and Seo, G S., 2',4',6'-Tris(methoxymethoxy) chalcone protects against trinitrobenzene sulfonic acid-induced colitis and blocks tumor mecrosis factor-o-lnduced intestinal epithelial inflammation via heme oxygenase 1-dependent and independent pathways, Biochem. Pharmacol., 74, 870-880 (2007) 
    5. Wang, J., Chan, F. L., Chen, S., and Leung, L. K., The plant ?polyphenol butein inhibits testosterone-induced proliferation in breast cancer cells expressing aromatase, Life Sci., 77(1), 39-51 (2005) 
    6. Khatib, S., Nerya, O., Musa, R., Shmuel, M., Tamir, S., and Vaya, J., Chalcones as potent tyrosinase inhibitors: the importance of a 2,4-substituted resorcinol moiety, Bioorg. Med. Chem., 13(2), 433-441 (2005) 
    7. Selvam, C., Jachak, S. M., and Bhutani, K. K., Cyclooxygenase inhibitory flavonoids from the stem bark of Semecarpus anacardium Linn, Phytother. Res., 18, 582-584 (2004) 
    8. Lee, S. H., Seo, G S., and Sohn, D. H., Inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase by butein in RAW 264.7 cells, Biochem. Biophys. Res. Commun., 323, 125-132 (2004) 
    9. Lee, S. H., Seo, G S., Kim, H. S., Woo, S. w., Ko, G, and Sohn, D. H. 2',4',6'-Tri(methoxymethoxy)chalcone attenuates hepatic stellate cell proliferation by a heme oxygenasedependent pathway, Biochem. Pharmacol., 72(10), 1322-1333 (2006a) 
    10. Tanaka, S., Sakata, Y, Morimoto, K., Tambe, Y, Watanabe, Y, Honda, G, Tabata, M., Oshima, T., Masuda, T., Umezaw, T., Shimada, M., Nagakura, N., Kamisako, W., Kashiwada, Y and Ikeshiro, Y, Influence of natural and synthetic compounds on cell surface expression of cell adhesion molecules. Planta Med., 67, 108-113 (2001 ) 
    11. Ban, H. S., Suzuki, K., Lim, S. S., Jung S. H., Lee, S., Ji, L., Lee, HI, S., Lee, Y S., Shin, K. H., and Ohuchi, K., Inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase and tumor necrosis factor-alpha by 2'hydroxychalcone derivatives in RAW 264.7 cells, Biochem. Pharmacol., 67,1549-1557 (2004) 
    12. Takahashi, T. T., Takasuka, N., Ligo, M., Baba, M., Nishino, H., Tsuda, H., and Ouyama, 1., Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development, Cancer Sci., 95, 448-453 (2004) 
    13. Won, J.-J., Liu, C.-T., Tsao, L.-T., Weng, J.-R., Ko, H.-H., Wang, J.-P., and Lin, C.-N., Synthetic chalcones as potential antiinflammatory and cancer chemopreventive agents. Eur. J. Med. Chem., 40,103-112 (2005) 
    14. Kang, D. G, Kim, Y C., Sohn, E. J., Lee, Y M., Lee, A S., Yin, M. H., and Lee, H. S., Hypotensive effect of butein via the inhibition of angiotensin converting enzyme, BioI. Pharm. Bull., 26(9), 1345-1347 (2003) 
  • 이 논문을 인용한 문헌 (4)

    1. 2008. "" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea, 31(9): 1137~1144     
    2. 2008. "" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea, 31(9): 1145~1152     
    3. Lee, Young-Sook ; Kim, Hak-Sung 2011. "Synthesis of Anti-inflammatory 2'-Hydroxychalcone Derivatives" 약학회지 = Yakhak hoeji, 55(5): 367~373     
    4. Lee, Young-Sook ; Kim, Hak-Sung 2011. "Synthesis of Anti-inflammatory 2'-Hydroxychalcone Derivatives" 약학회지 = Yakhak hoeji, 55(5): 367~373     

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