Anti-inflammatory activity of the synthetic chalcone derivatives: inhibition of inducible nitric oxide synthase-catalyzed nitric oxide production from lipopolysaccharide-treated RAW 264.7 cells.
Chalcones belong to the flavonoid family from plant origin and some of them possess anti-inflammatory activity. Recently, several natural and synthetic chalcone derivatives were reported to inhibit inducible nitric oxide synthase (iNOS)-catalyzed NO production in cell cultures. In the present study, to find the optimal chemical structures and to elucidate their action mechanisms, 41 synthetic chalcones having the substituent(s) on A- and B-rings were prepared and their effects on iNOS-catalyzed NO production were evaluated using lipopolysaccharide (LPS)-treated RAW 264.7 cells. When simultaneously added with LPS, 2'-methoxy-3,4-dichlorochalcone (Ch15), 2'-hydroxy-6'-methoxychalcone (Ch29), 2'-hydroxy-3-bromo-6'-methoxychalcone (Ch31) and 2'-hydroxy-4',6'-dimethoxychalcone (Ch35) among the tested compounds potently inhibited NO production (IC(50)s, 7.1-9.6 muM). The favorable chemical structures were found to be a methoxyl substitution in A-ring at an adjacent position (2' or 6') to carbonyl moiety with/without 2'-(or 6'-)hydroxyl group and 3-halogen substitution in B-ring. When the cellular action mechanisms of Ch15, Ch31 and Ch35 were further examined using Western blotting and electrophoretic mobility shift assay, it was revealed that Ch15 and Ch31 clearly down-regulated iNOS expression while Ch35 did not. Moreover, Ch15 and Ch31 were proved to suppress the nuclear transcription factor-kappaB activation. From the results, it is suggested that certain chalcone derivatives potently inhibit iNOS-catalyzed NO production by the different cellular mechanisms, iNOS down-regulation and/or iNOS inhibition, depending on their chemical structures. These chalcone derivatives may possibly be used as lead compounds for developing new anti-inflammatory agents.
College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea.
Young Hoon
YH
Kim
Jeongsoo
J
Kim
Haeil
H
Park
Hyun Pyo
HP
Kim
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D047188:Chalcones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II