Dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones as anti-hepatoma agents by inhibiting NF-κB pathway activation.

Abstract To get new anti-hepatoma agents with anti-inflammatory activity and hypotoxicity, a series of dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones (BAPs, 25 – 82) were designed and synthesized. Many of them exhibited potential anti-hepatoma properties against human hepatocellular carcinoma cell lines (HepG2, QGY-7703, SMMC-7721) and hypotoxicity for human normal heptical cell line (HHL-5, LO2), and prominently inhibited lipopolysaccharides (LPS) induced IL-6, TNF-α secretion to exert its anti-inflammatory effect. Combining the data of cytotoxicity, cytocompatibility and anti-inflammatory activity, 3-pyridyl and -CF 3 substituted 67 may be the potential anti-hepatoma agent. 67 effectively promoted cell apoptosis through up-regulating cleaved caspase-3 and Bax expression and down-regulating Bcl-2 expression. Furthermore, 67 prominently inhibited NF-κB pathway activation by blocking the phosphorylation of IκBα, p65 and the nuclear translocation of NF-κB induced by TNF-α and LPS. In addition, 67 could reasonably bind to the active site of Bcl-2 and NF- κ B/p65 protein proved by Molecular docking analyses. Moreover, 67 significantly suppressed the growth and inflammatory response of HepG2 xenografts in nude mice and was relatively nontoxic to mice. These results suggest that 67 may be effective and hypotoxicity anti-hepatoma agent for the clinical treatment of liver cancers. Graphical abstract Fifty-eight dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) were synthesized and evaluated for their cytotoxicity and anti-inflammatory activity. 3-Pyridyl and -CF 3 substituted 67 could be the most potential anti-hepatoma agents by inhibiting NF-κB pathway activation. In vivo , 67 suppressed the growth and inflammatory response of HepG2 xenografts and was relatively nontoxic to mice. Image 1 Highlights • Fifty-eight dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) were synthesized. • 3-Pyridyl and -CF 3 substituted 67 could be the most potential anti-hepatoma agents by inhibiting NF-κB pathway activation. • 67 showed good anti-inflammatory activity by inhibiting nuclear translocation of NF-κB and phosphorylation of IκBα and p65. • 67 could reasonably bind to the active site of Bcl-2 and NF-κB/p65 protein proved by Molecular docking analyses. • In vivo , 67 suppressed the growth and inflammatory response of HepG2 xenografts and was relatively nontoxic to mice. [ABSTRACT FROM AUTHOR]