New synthetic anti-inflammatory chrysin analog, 5,7-dihydroxy-8-(pyridine-4yl)flavone

• Published in: European journal of pharmacology Vol. 670; no. 2-3; pp. 617 - 622
• Main Authors: Lim, Hyun, Jin, Jeong Ho, Park, Haeil, Kim, Hyun Pyo
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 30-11-2011; Elsevier
• Subjects: 5,7-Dihydroxy-8-(pyridine-4yl)flavone; Animals; Anti-inflammation; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Biological and medical sciences; Carrageenan - pharmacology; Cyclooxygenase; Edema - chemically induced; Edema - drug therapy; Flavones - chemical synthesis; Flavones - chemistry; Flavones - pharmacology; Flavones - therapeutic use; Flavonoid; Flavonoids - chemistry; Male; Medical sciences; Mice; Mice, Inbred ICR; Nitric oxide synthase; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyridines - therapeutic use; Nitric oxide synthase; Cyclooxygenase; 5,7-Dihydroxy-8-(pyridine-4yl)flavone; Flavonoid; Anti-inflammation; Prostaglandin-endoperoxide synthase; Flavones; Enzyme; Antiinflammatory agent; Inflammation; Nitric-oxide synthase; Polyphenol; Pyridine; Analog; Phenols; Flavone derivatives; Oxidoreductases
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.09.010

To identify anti-inflammatory flavonoid derivatives with optimal chemical structures, various 8-heterocyclic-substituted chrysin derivatives were previously synthesized and their effects on prostaglandin E2 (PGE2) production from the lipopolysaccharide (LPS)-treated mouse macrophage cell line, RAW 264.7, were evaluated. Through this screening procedure, 5,7-dihydroxy-8-(pyridine-4yl)flavone (C-721) among the derivatives was selected for further pharmacological study. Contrary to the parent molecule, chrysin, C-721 was found to potently inhibit PGE2 and NO production by LPS-treated RAW cells. The IC50 values of C-721 were 6.2 and 22.6μM, respectively, for cyclooxygenase-2 (COX-2) mediated PGE2 and inducible nitric oxide (iNOS)-mediated NO production. Western blotting and reverse transcriptase-polymerase chain reaction analysis demonstrated that this compound inhibited PGE2 production, at least in part, via COX-2 down-regulation and COX-2 inhibition, while C-721 primarily inhibited NO via down-regulation of iNOS expression. In addition, C-721 inhibited TNF-α and IL-6 production at 10–50μM. An in vivo study revealed that oral and intraperitoneal administration of C-721 showed 25.2%–44.3% inhibition against λ-carrageenan-induced paw edema in mice at 10–100mg/kg. Furthermore, this compound significantly inhibited collagen-induced arthritis in mice when administered by intraperitoneal injection at 50mg/kg three times/week. Taken together, these results suggest that C-721 has the potential for use as a synthetic lead compound for development of a new anti-inflammatory agent.