8-(Tosylamino)quinoline inhibits macrophage-mediated inflammation by suppressing NF-B signaling

Aim:The macrophage-mediated inflammatory response may contribute to the development of cancer, diabetes, atherosclerosis and septic shock. This study was to characterize several new compounds to suppress macrophage-mediated inflammation.Methods:Peritoneal macrophages from C57BL/6 male mice and RAW264.7 cells were examined. Anti-inflammatory activity was evaluated in the cells exposed to lipopolysaccharide (LPS). The mechanisms of the anti-inflammatory activity were investigated via measuring transcription factor activation in response to specific signals and via assaying the activities of the target kinases.Results:Of 7 candidate compounds tested, 8-(tosylamino)quinoline (8-TQ, compound 7) exhibited the strongest activities in suppressing the production of NO, TNF-α, and PGE₂ in LPS-activated RAW264.7 cells and peritoneal macrophages (the IC₅₀ values=15 mol/L). This compound (1.2520 mol/L) dose-dependently suppressed the expression of the pro-inflammatory genes for iNOS, COX-2, TNF-α, and the cytokines IL-1Β and IL-6 at the level of transcription in LPS-activated RAW264.7 cells. 8-TQ (20 mol/L) significantly suppressed the activation of NF-B and its upstream signaling elements, including inhibitor of B (IBα), IBα kinase (IKK) and Akt in LPS-activated RAW264.7 cells. In in vivo experiments, oral administration of 20 and 40 mg/kg 8-TQ for 3 d significantly alleviated the signs of LPS-induced hepatitis and HCl/EtOH-induced gastritis, respectively, in ICR mice.Conclusion:8-TQ (compound 7) exerts significant anti-inflammatory activity through the inhibition of the Akt/NF-B pathway, thus may be developed as a novel anti-inflammatory drug.