Anti-inflammatory activity of the synthetic C-C biflavonoids.
To find anti-inflammatory agents based on plant constituents, the effects of six synthetic C-C biflavonoids connecting with different positions of C-C bond between flavone monomers (a: 4'-4', b: 4'-3', c: 4'-6, d: 3'-6, e: 6-6, f: 4'-3) were examined on PGE(2) and nitric oxide (NO) production from lipopolysaccharide (LPS)-treated macrophages, RAW 264.7. Among the compounds tested, the biflavonoids d, e, and f showed a considerable inhibition of cyclooxygenase-2 (COX-2)-mediated PGE(2) production at concentrations up to 50 microM, while the derivative c exerted cytotoxic effects on RAW cells. Especially, the biflavonoid e possessed the most potent inhibitory activity of PGE(2) production with an IC50 of 3.7 microM, compared with an IC50 of 8.2-20.7 microM by ginkgetin (natural biflavonoid). Western blot and reverse transcriptase-polymerase chain reaction analyses have shown that the inhibition of PGE(2) production by these synthetic derivatives was mediated at least in part by COX-2 inhibition, but not by COX-2 down-regulation. Meanwhile, these synthetic biflavonoids did not considerably inhibit inducible nitric oxide synthase-mediated NO production at concentrations up to 50 microM. When intraperitoneally administered, the biflavonoid e showed a significant anti-inflammatory activity (22.2% inhibition) against rat carrageenan-induced paw oedema at 5 mg kg(-1). The biflavonoid e may be used as a synthetic lead for developing new anti-inflammatory agents.
Park
Haeil
H
College of Pharmacy, Kangwon National University, Chunchon, Korea.
Kim
Young Hoon
YH
Chang
Hyeun Wook
HW
Kim
Hyun Pyo
HP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044946:Biflavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D044946:Biflavonoids; D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009569:Nitric Oxide; D002351:Carrageenan; D011239:Prednisolone; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone