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KMID : 0043320080310091145
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Archives of Pharmacal Research
2008 Volume.31 No. 9 p.1145 ~ p.1152
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Structure Activity Relationship Studies of Anti-inflammatory TMMC Derivatives: 4-Dimethylamino Group on the B Ring Responsible for Lowering the Potency
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Jin Ying-Lan
Kim Hak-Sung
Sohn Dong-Hwan
Jin Feng
Jin Xing-Yu
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Abstract
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We previously synthesized 2’,4’,6’-tris(methoxymethoxy)chalcone (TMMC) derivatives with various substituents on the A ring that showed potent anti-inflammatory effects by inhibiting NO production in RAW 264.7 cells. The 2’-hydroxy group on the A ring could elevate the electrophilicity of Michael addition of GSH and electron donating groups on the A ring could stabilize the GSH adduct by decreasing the acidity of the α-hydrogen. Using this interpretation, we tested various substituents on the B ring and established a proper balance between biological activity and the position of the electron donating or electron withdrawing groups on the B ring. In this case, the 2’-hydroxy group was excluded because it could cause the formation of GSSG through a phenoxy radical and can confuse the interpretation of the biological results. Chalcone derivatives without 2’-hydroxy are likely to deplete cellular GSH levels by a Michael addition process. Strong electron donating groups on the B ring, such as 4-dimethylamino group, gave the weakest inhibition of NO production. A 4-dimethyamino group on the B ring could decrease the stability of the GSH adduct by weakening the C-S bond strength through movement of an electron pair on nitrogen via an aromatic ring.
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KEYWORD
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B Ring, Butein, TMMC, Chalcone, GSH addcut, Anti-inflammatory, GSSG, GSH oxidation, Michael addition
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