New anti-inflammatory synthetic biflavonoid with C-C (6-6") linkage: differential effects on cyclooxygenase-2 and inducible nitric oxide synthase.
Previously, a synthetic biflavone having a C-C (6-6") linkage ([6,6"]biflavone, BF6-6) was shown to possess considerable anti-inflammatory activity. The present investigation was conducted to develop more active anti-inflammatory biflavonoids having unique mechanisms of action based on the BF6-6 molecule. For this purpose, 5,7-dihydroxy[6,6"]biflavone (G168) was synthesized using Suzuki-Miyaura C-C cross coupling reaction. The anti-inflammatory activities of G168 were then examined on lipopolysaccharide-treated RAW 264.7 cells, carrageenan-induced paw edema and acetic acid-induced writhing in mice. It was found that G168 showed much stronger inhibition against cyclooxygenase-2-mediated PGE2 production than the original molecule, BF6-6. It also demonstrated inhibitory activity against inducible nitric oxide synthase (iNOS)-mediated NO production at least partly by the down-regulation of iNOS. Furthermore, G168, administered intraperitoneally at a dosage of 1-5 mg/kg, showed a potent in vivo anti-inflammatory activity on carrageenan-induced paw edema and analgesic activity on acetic acid-induced writhing in mice. Therefore, the newly synthesized biflavonoid, G168, may be used as a synthetic lead for new anti-inflammatory drug development.
Lim
Hyun
H
College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea.
Kim
Soo Bae
SB
Park
Haeil
H
Chang
Hyeun Wook
HW
Kim
Hyun Pyo
HP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D044946:Biflavonoids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; C547233:BF6-6 biflavone; D044946:Biflavonoids; D052246:Cyclooxygenase 2 Inhibitors; C547234:G168 biflavone; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone