Synthesis and anti-cancer activity studies of dammarane-type triterpenoid derivatives

Abstract Two series of novel derivatives of AD-2, an active ginsenoside derived from ginseng were designed and synthesized. Five human cancer cell lines (MGC-803, SGC-7901, A549, MCF-7, PC-3 cells) and one normal ovarian cell IOSE144 were employed to evaluate the anti-proliferative activity. Most of derivatives possessed obvious enhanced activity compared with AD-2. Among them, compound 4c displayed the most excellent activity in all tested cancer cell lines, especially A549 cells with an IC50 value of 1.07 ± 0.05 μM. The underlying mechanism study suggested that 4c induced S-phase arrest and apoptosis in A549 cells. Increasing the level of ROS and inducing collapse of MMP in cells treated with 4c were also proved. Moreover, Western blot analysis showed that the expression level of p53 and p21 were obviously increased. 4c could remarkably up-regulate the expression of cyt c in cytosol, the ratio of Bax to Bcl-2 and activate caspase-3/9/PARP. Besides, the expression level of MDM2 was remarkably decreased. The results indicated that 4c caused apoptosis through the mitochondrial pathway, which ROS generation was probably involved in, and had the potent to serve as anti-proliferative agent.