Structural modification was performed at the C-3 and C-28 positions of ursolic acid (UA). Ten UA derivatives with distinct electrical property were synthesized. They could be divided into two groups according to their charge under physiological conditions: (1) Group I negatively charged and (2) Group II positively charged. The anti-proliferative capability of the derivatives was evaluated against HepG2, AGS, HT-29 and PC-3 cells by the MTT assay. Flow cytometry and Annexin V/PI dual staining assay were carried out to explore the antitumor mechanism. The results showed the cytotoxic capacity of the compounds was: Group I<UA<Group II. The UA derivatives in Group II exhibited potent cytotoxicity and the enhancement of the lipophilicity could further strengthen the cytotoxicity. Triggering apoptosis and causing cell cycle arrest contributed to the anticancer mechanism. The UA derivative UA-7 had the therapeutic potential in the treatment of gastric carcinoma since it showed potent cytotoxicity, reasonable oil/water partition, enhanced water solubility, and the ability to induce the apoptosis of AGS cells.
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