Abstract: OBJECTIVE To investigate the anti-hepatocellular carcinoma efficacy in vitro and mechanism of novel ursolic acid derivatives. METHODS The target compounds were designed according to the “Topliss decision method”, and obtained by substitution reaction between ursolic acid and different substituted diethyl benzyl phosphonic acid, then the anti-hepatocellular activity in vitro of these compounds was studied by MTT. The possible target of the compound was predicted by molecular docking study and verified by Western blotting. RESULTS Target compounds 4a-4e were characterized via ¹H-NMR, ¹³C-NMR, and HRMS. Compound 4b and 4e showed higher antiproliferative activity against the BEL-7402 and HepG2 cell lines compared with the positive-control drug 5-fluorouracil and ursolic acid. All the target compounds exhibited low cytotoxic activities against human normal liver cells(L02). In a concentration-dependent manner, compound 4e decreased p-AKT protein level. CONCLUSION Compound 4e exhibited the most potent antiproliferative activity and commendable selectivity between cancer and normal cells(IC₅₀=2.69 μmol·L^–1 against the HepG2 cell line), and could act as a potential inhibitor of AKT protein.