期刊
ARCHIVES OF PHARMACAL RESEARCH
卷 30, 期 11, 页码 1359-1367出版社
PHARMACEUTICAL SOC KOREA
DOI: 10.1007/BF02977357
关键词
butein; TMMC; chalcone; modified synthesis; anti-inflammatory; cardamonin; 2'-hydroxy group; hydrogen bonding
Butein, a natural chalcone, has anti-inflammatory and hepatoprotective activity. One synthetic derivative of butein, 2', 4', 6'-tris(meth oxymethoxy)chalcone (TMMC), has potent anti-inflammatory activity via an HO-1 (heme oxygenase 1) dependent pathway. The U,P-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 alpha,beta-unsaturated ketone caused a significant decrease or loss of anti-inflammatory activity, which is consistent with the role of the alpha, beta-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 gioup 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.
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