Previously we have reported that 25-OCH3-PPD could suppress the reproduction of cancer cells and cause apoptosis without obvious toxicity. Herein, we aimed to enhance its bioactivity by introducing aromatic groups to its dammarane-type skeleton. These synthesized derivatives were tested for their inhibitory activities against five cancer cell lines. Of them, compounds 3a, 14a and 18a had the strongest antiproliferative activities against tumor cells (IC50 < 15 µM, 5-fold to 10-fold increases than 25-OCH3-PPD). Especially compound 14a displayed the most potent activity against DU145, MCF-7 and HepG2 cells (IC50 = 6.7 ± 0.8, 4.3 ± 0.8 and 5.8 ± 0.6 µM, respectively). Structure-activity relationships demonstrated that having aromatic ester at the C3 position could improve the bioactivity. The data provided new insights into exploring novel antiproliferative lead compounds.