Potent anti‐inflammatory effects of two quinolinedione compounds, OQ1 and OQ21, mediated by dual inhibition of inducible NO synthase and cyclooxygenase‐2

Abstract

Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been suggested as key components in various inflammatory diseases. Here we examined the effects of new quinolinedione derivatives, 6-(4-fluorophenyl)-amino-5,8-quinolinedione (OQ1) and 6-(2,3,4-trifluorophenyl)-amino-5,8-quinolinedione (OQ21) on activity and expression of iNOS and COX-2 to explore their anti-inflammatory properties. The effects of OQ1 and OQ21 were assessed on lipopolysaccharide (LPS)-induced iNOS and COX-2 in murine macrophage cell line (RAW264.7), along with isolated enzyme assays to measure enzyme inhibition. Nuclear factor-kappaB (NFkappaB) activation pathways were investigated to elucidate mechanisms underlying OQ-mediated suppression of the expression of iNOS and COX-2. In vivo anti-inflammatory activities of OQ compounds were evaluated in mouse ear oedema, induced by topical 12-O-tetradecanoylphorbol-13-acetate (TPA). LPS-induced NO production in RAW264.7 cells was inhibited by OQ1 and OQ21 through the attenuation of iNOS expression as well as iNOS activity. Down-regulation of iNOS followed blocking of NFkappaB activation, as assessed by inhibitory kappaB degradation and electrophoretic mobility shift assay for NFkappaB. Synthesis and accumulation of prostaglandin E(2) were also suppressed by OQ1 and OQ21. LPS-induced COX-2 expression and cellular COX-2 activities were attenuated by OQ1 and OQ21. Consistent with these results, OQ1 showed potent anti-inflammatory effects in mouse ear oedema induced by TPA. The novel quinolinedione derivatives, OQ1 and OQ21, showed potent anti-inflammatory activity through dual inhibitory effects on iNOS and COX-2, suggesting that OQ derivatives might provide a new therapeutic modality for chronic inflammatory diseases, refractory to conventional drug therapies.