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

초록

To identify anti-inflammatory flavonoid derivatives with optimal chemical structures, various 8-heterocyclic-substituted chrysin derivatives were previously synthesized and their effects on prostaglandin E-2 (PGE(2)) 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 PGE(2) and NO production by LPS-treated RAW cells. The IC50 values of C-721 were 6.2 and 22.6 mu M, respectively, for cyclooxygenase-2 (COX-2) mediated PGE(2) and inducible nitric oxide (iNOS)-mediated NO production. Western blotting and reverse transcriptase-polymerase chain reaction analysis demonstrated that this compound inhibited PGE(2) 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 INF-alpha and IL-6 production at 10-50 mu M. An in vivo study revealed that oral and intraperitoneal administration of C-721 showed 25.2%-44.3% inhibition against lambda-carrageenan-induced paw edema in mice at 10-100 mg/kg. Furthermore, this compound significantly inhibited collagen-induced arthritis in mice when administered by intraperitoneal injection at 50 mg/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. (C) 2011 Elsevier B.V. All rights reserved.

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