Rutaecarpine analogues with potent anti-inflammation to alleviate acute ulcerative colitis via regulating TLR4/MAPK/NF-κB pathway

Abstract

Natural products are a rich resource in drug discovery. In the report, series novel rutaecarpine-derived compounds with potent anti-inflammatory activity and therapeutic efficacy against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) were designed and synthesized. Thirty-two target compounds inhibiting on LPS-induced NO production in RAW264.7 cells were screened. Compound 7mA with the most potent inhibitory activity and low cytotoxicity was selected as representative compound for further studies on the anti-inflammatory efficacy and mechanism. The results indicated that 7mA could significantly inhibit the transcription or expression of iNOS, IL-6 and IL-1β via regulating the TLR4/MAPK/NF-κB signal pathway. What's more, 7mA also could alleviate UC in DSS-induced mice, and down-regulated the release of IL-6, IL-1β, inhibited activation of TLR4/MAPK/NF-κB pathway in mice model as well, suggesting that this new rutaecarpine-derived scaffold might serve as therapeutic candidate for further development to anti-inflammatory agent.

Keywords

• Rutaecarpine analogues
• Anti-inflammation
• Ulcerative colitis
• TLR4/MAPK/NF-κB pathway
• Structural modification