Jin Feng, Jin Xing Yu, Jin Ying Lan, Sohn Dae Won, Kim Soon-Ai, Sohn Dong Hwan, Kim Youn Chul, Kim Hak Sung
College of Pharmacy, Wonkwang University, Iksan 570-749, Korea.
Arch Pharm Res. 2007 Nov;30(11):1359-67. doi: 10.1007/BF02977357.
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.
白杨素是一种天然查尔酮，具有抗炎和保肝活性。白杨素的一种合成衍生物2',4',6'-三(甲氧基甲氧基)查尔酮(TMMC)通过一条HO-1（血红素加氧酶1）依赖性途径具有强大的抗炎活性。TMMC和查尔酮中的α,β-不饱和酮部分在介导这种效应中可能很重要。为了研究TMMC衍生物抗炎作用的结构要求，我们通过催化氢化、氢化物还原或引入三键对α,β-不饱和酮部分进行了修饰。此外，我们还进行了结构修饰，如将-OMOM基团转化为-OMe或-OH基团。一般来说，α,β-不饱和酮的修饰导致抗炎活性显著降低或丧失，这与α,β-不饱和酮基团作为蛋白质上谷胱甘肽或半胱氨酸残基等亲核物质的迈克尔受体的作用一致。从化学角度来看，供电子取代基可以通过降低α-氢的酸度和减缓逆迈克尔反应的速度使硫醇加合物更稳定。同样，与之前的研究一样，2'-羟基在增强抗炎作用方面至关重要。2'-羟基通过2'-羟基与酮部分之间的氢键增加α,β-不饱和酮的亲电性质而产生强大的抗炎作用。
