RESUMO
Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta-substituent containing derivatives 1-3 and 1-6, in which γ-butyrolactam replaced α,ß-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta-substituted derivative, compared with the corresponding ortho- or para-substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1-3 and 1-6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1-3 or 1-6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta-substituted derivatives 1-3 and 1-6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.
