N-phenylsulfonyl-3,5-bis(arylidene)-4-piperidone derivatives as activation NF-κB inhibitors in hepatic carcinoma cell lines.

Ten novel symmetric 3,5-bis(arylidene)-4-piperidone derivatives (BAPs, 1-10) and fourteen dissymmetric BAPs (11-24) were synthesized and evaluated the cytotoxicity. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibitory effects on LPS-induced IL-6, TNF-α secretion. Among them, BAP 23 exhibits both the highest anti-inflammatory and anti-cancer properties. Western blot analysis showed that BAP 23 markedly reduced the levels of Bcl-2 but increased the levels of cleaved caspase-3and Bax. Moreover, BAP 23 prominently inhibited LPS-induced activation of NF-κB in RAW264.7 cells as well as TNF-α-induced activation of NF-κB in HepG2 cells by blocking phosphorylation of inhibitor IκBα and p65. Consistent with these results, we found that BAP 23 prevented the nuclear translocation of NF-κB induced by LPS or TNF-α. BAP 23 could reasonably bind to the active site of Bcl-2 protein and p65 which is proved by molecular docking modes. These data indicate that BAP 23 is a more potent inhibitor of NF-κB activity which exhibites both anti-inflammatory and anticancer activities.