Design, synthesis and in vitro anticancer research of novel tetrandrine and fangchinoline derivatives.

[Display omitted] • 10 of the 20 synthetic derivatives exhibited significant antitumor activity. • Compound 4g shows the most potent against A549 cells (14.34-fold of d- Tet). • Compound 4g inhibits A549 proliferation, migration, invasion and arrest G2/M cycle. • Compound 4g can induce apoptosis by inactivating the PI3K/Akt/mTOR pathway. Cancer treatment is one of the major public health issues in the world. Tetrandrine (Tet) and fangchinoline (d -Tet) are two bis -benzyl isoquinoline alkaloids extracted from Stephania tetrandra S. Moore, and their antitumor activities have been confirmed. However, the effective dose of Tet and d -Tet were much higher than that of the positive control and failed to meet clinical standards. Therefore, in this study, as a continuation of our previous work to study and develop high-efficiency and low-toxic anti-tumor lead compounds, twenty new Tet and d -Tet derivatives were designed, synthesized and evaluated as antitumor agents against six cancer cell lines (H460, H520, HeLa, HepG-2, MCF-7, SW480 cell lines) and BEAS-2B normal cells by CCK-8 analysis. Ten derivatives showed better cytotoxic effects than the parent fangchinoline, of which 4g showed the strongest cell growth inhibitory activity with an IC 50 value of 0.59 μM against A549 cells. Subsequently, the antitumor mechanism of 4g was studied by flow cytometry, Hoechst 33258, JC-1 staining, cell scratch, transwell migration, and Western blotting assays. These results showed that compound 4g could inhibit A549 cell proliferation by arresting the G2/M cell cycle and inhibiting cell migration and invasion by reducing MMP-2 and MMP-9 expression. Meanwhile, 4g could induce apoptosis of A549 cells through the intrinsic pathway regulated by mitochondria. In addition, compound 4g inhibited the phosphorylation of PI3K, Akt and mTOR, suggesting a correlation between blocking the PI3K/Akt/mTOR pathway and the above antitumor activities. These results suggest that compound 4g may be a future drug for the development of new potential drug candidates against lung cancer. [ABSTRACT FROM AUTHOR]