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KMID : 0043320070300111359
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Archives of Pharmacal Research
2007 Volume.30 No. 11 p.1359 ~ p.1366
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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
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Jin Feng
Jin Xing-Yu
Jin Lan Ying
Sohn Dae-Won
Kim Soon-Ai
Sohn Dong-Hwan
Kim Youn-Chul
Kim Hak-Sung
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Abstract
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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 α,β-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 α,β-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 α,β-unsaturated ketone caused a significant decrease or loss of anti-inflammatory activity, which is consistent with the role of the α,β-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 α-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 α,β-unsaturated ketones due to hydrogen bonding between the 2’-hydroxy group and the ketone moiety
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KEYWORD
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Butein, TMMC, Chalcone, Modified synthesis, Anti-inflammatory, Cardamonin, 2’- Hydroxy group, Hydrogen bonding
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