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

Kyung Min Lim, Joo Young Lee, Song Mi Lee, Ok Nam Bae, Ji Yoon Noh, Eun Jin Kim, Seung Min Chung, Jin Ho Chung

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Background and purpose: 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. Experimental approach: 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-κB (NFκB) 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). Key results: 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 NFκB activation, as assessed by inhibitory κB degradation and electrophoretic mobility shift assay for NFκB. 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. Conclusions and implications: 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. Mandarin translation of abstract.

Original languageEnglish
Pages (from-to)328-337
Number of pages10
JournalBritish Journal of Pharmacology
Volume156
Issue number2
DOIs
StatePublished - Jan 2009

Keywords

  • Anti-inflammatory agent
  • Cyclooxygenase-2
  • Inflammation
  • INOS
  • Quinolinedione
  • TPA-induced mouse ear oedema

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