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

Abstract

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 10-50 μM. 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.

• Authors: Hyun Lim, Jeong Ho Jin, Haeil Park, Hyun Pyo Kim
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 670 Issue 2-3 Pg. 617-22 (Nov 30 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21946106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• 5,7-dihydroxy-8-(pyridine-4-yl)flavone
• Anti-Inflammatory Agents
• Flavones
• Flavonoids
• Pyridines
• chrysin
• Carrageenan

Topics

• Animals
• Anti-Inflammatory Agents (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Carrageenan (pharmacology)
• Edema (chemically induced, drug therapy)
• Flavones (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Flavonoids (chemistry)
• Male
• Mice
• Mice, Inbred ICR
• Pyridines (chemical synthesis, chemistry, pharmacology, therapeutic use)