Structural requirements of 2′,4′,6′-tris(methoxymethoxy) chalcone derivatives for anti-inflammatory activity: The importance of a 2′-hydroxy moiety

Abstract

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.