This article describes the syntheses and biological activity of five 3-arylisoquinoline natural products corydamine (1), N-formyl Corydamine (2), hypecumine (3), Decumbenine B (XW) and 2-(1,3-dioxolo [4,5-h]isoquinolin-7-yl)-4,5-dimethoxy-N-methyl-Benzeneethanamine (A), and twelve analogues. Among them, 1, 2, and A were synthesized for the first time. In vitro screening for anti-proliferative activity showed that derivative 1a could significantly inhibit the proliferation of HCC cells (IC<sub>50</sub> = 9.82 μM on Huh7 cells and 6.83 μM on LM9 cells), and arrest cell cycle at G<sub>2</sub>/M phase. The mechanistic studies further suggested compound 1a was a dual inhibitor of Topo I and Topo II, and Topo II inhibitory activity was superior to etoposide. In addition, 1a could significantly inhibit the invasion and migration of cancer cells by inhibiting the expression of MMP-9, and induce apoptosis through inhibiting the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, in vivo studies demonstrated 1a could obviously reduce the growth of xenograft tumor and possessed good pharmacokinetic parameters, which indicated the potential value of 1a in treating liver cancer.