DHN 28

Hepatocellular carcinoma (HCC) ranks sixth amongst frequent malignant tumors worldwide. Activation of NF-κB and MAPK pathways promoted occurrence and development of HCC. Herein, thirty-five piperazine-substituted 3,4-dihydronaphthalen-1(2H)-one derivatives (DHNs, 1-35) were synthesized and characterized by Nuclear Magnetic Resonance (NMR) and High-resolution mass spectrometry (HRMS). The 2,3,4-fluoro-substituted DHN 28 was chosen as the lead compound, showing better anti-cancer effects than previous compounds, because of its lower cytotoxicity to THLE-3 and higher anti-HCC activity against HepG2 cells. At the genetic level, 28 promoted apoptosis by down-regulating the expression of B-cell lymphoma 2 (Bcl-2), up-regulating the expression of Bcl-2-associated X protein (BAX) and Cleaved caspase-3 (C-caspase-3). In addition, 28 blocked off the HepG2 cells in G₂ phase and inhibited the migration of HepG2 cells. More importantly, treatment with 28 significantly reduced the phosphorylation levels of the nuclear factor-κB p65 subunit (p65), nuclear factor-κB inhibitor α (IκB-α), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase (ERK) phosphorylation levels, exerting its anti-hepatocellular carcinoma (HCC) effects by inhibiting the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, 28 is predicted as a potential NF-κB and MAPK inhibitor for excellent therapeutic prospects.