Structural requirements of 2',4',6'-tris(methoxymethoxy) chalcone derivatives for anti-inflammatory activity: the importance of a 2'-hydroxy moiety.
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 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 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.
Jin
Feng
F
College of Pharmacy, Wonkwang University, Iksan 570-749, Korea.
Jin
Xing Yu
XY
Jin
Ying Lan
YL
Sohn
Dae Won
DW
Kim
Soon-Ai
SA
Sohn
Dong Hwan
DH
Kim
Youn Chul
YC
Kim
Hak Sung
HS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology*; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D006860:Hydrogen Bonding; D051379:Mice; D013329:Structure-Activity Relationship
C510589:2',4',6'-tris(methoxymethoxy) chalcone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D047188:Chalcones