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Previously we have reported that 25-OCH 3 -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 (IC 50  < 15 µM, 5-fold to 10-fold increases than 25-OCH 3 -PPD). Especially compound 14a displayed the most potent activity against DU145, MCF-7 and HepG2 cells (IC 50  = 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Based on the fact that 25-OCH 3 -PPD, a natural ginsengenin isolated from the leaves of Panax ginseng , is a promising lead compound, novel 25-OCH 3 -PPD derivatives were synthesized to find more potent anti-tumor agents by a simple and facile synthetic method. These derivatives were classified into three types and screened for their cytotoxic activities against seven human cancer cell lines. Compared with 25-OCH 3 -PPD, compounds a5 , a7 , b5 and b7 exhibited higher anti-tumor activities on all tested cell lines with almost 5-fold to 15-fold increases. In particular, compound a7 showed the greatest cytotoxic activity against α-2 cells (IC 50 = 2.4 ± 0.4 μM). The preliminary study on the mechanisms indicated that compound a7 could induce α-2 cell apoptosis. Structure-activity relationships demonstrated that the carbon-carbon double bond at the C-20 position could enhance the antiproliferative activity. In conclusion, the novel derivatives a5 , a7 , b5 and b7 could be further studied as potential candidates for the treatment of cancer. This research provides a theoretical reference for the exploration of new antiproliferative agents.