Design, synthesis, and biological evaluation of thiomatrine derivatives as potential anticancer agents

A series of new thiomatrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by 1 H-NMR, 13 C-NMR, and ESI-MS spectral analyses. Single crystals of compound 3k were obtained by recrystallization and the structure was further confirmed by X-ray diffraction determination. All the target compounds were evaluated for their in vitro cytotoxicity against human cancer cell lines A549 and HepG2. Among these compounds, the derivative 3aa displayed the most significant anticancer activity against four cancer cell lines with IC 50 values in range of 7.8–11.4 μM, indicating much better activity than the parent compound (matrine). The cell cycle analysis revealed that compound 3aa could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3aa could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. Western blot analysis revealed that compound 3aa could induce apoptosis by activating caspase-3, increasing expression of cleaved caspase-3 and reducing the ratio of Bcl-2/Bax.