Structure activity relationship studies of anti-inflammatory TMMC derivatives: 4-dimethylamino group on the B ring responsible for lowering the potency.
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 alpha-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.
Jin
Ying Lan
YL
College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, 570-749, Korea.
Jin
Xing Yu
XY
Jin
Feng
F
Sohn
Dong Hwan
DH
Kim
Hak Sung
HS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D047188:Chalcones / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
C510589:2',4',6'-tris(methoxymethoxy) chalcone; D000893:Anti-Inflammatory Agents; D047188:Chalcones; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; D009569:Nitric Oxide