Design and synthesis of novel tetrandrine derivatives as potential anti-tumor agents against human hepatocellular carcinoma

Tetrandrine, a lead anti-tumor compound with a bis-benzyltetrahydroisoquinoline skeleton isolated from medicinal plant Stephania tetrandra. In order to obtain active anti-tumor agents and evaluate their structure-activity relationships, a series of novel tetrandrine derivatives were designed and synthesized in this study. Their anti-tumor activities against human hepatocellular carcinoma cell lines (HMCC97L and PLC/PRF/5) were also evaluated. The bioassay results showed that the derivatives exhibited moderate to strong inhibition against the two cell lines. Among them, compound 31 showed prominent cytotoxicity with IC50 = 1.06 μM (15.8 folds than that of tetrandrine, and 30.3 folds than that of Sorafenib). Further studies on the mechanisms demonstrated that the in vitro anti-tumor activity of compound 31 was predominantly due to the inducement of apoptosis of HCC cells. Compound 31 was capable of initiating endoplasmic reticulum stress-associated apoptotic cell death, and the activation of JNK as well as caspase pathways were probably involved. Our results suggest that compound 31, a new 14-position substituted amide tetrandrine derivative, might be a potential candidate for developing novel anti-HCC drugs in the coming future.