Design and Synthesis of Novel Oleanolic Acid-Linked Disulfide, Thioether, or Selenium Ether Moieties as Potent Cytotoxic Agents

A series of novel oleanolic acid (OA)-linked disulfide, thioether, or selenium ether derivatives was synthesized, and their antiproliferative activity was evaluated against human liver cancer (BEL-7402 and HepG-2), colon cancer (HCT116), and normal liver (L02) cell lines using methyl thiazolyl tetrazolium assay (MTT). Preliminary bioassay results revealed that OA derivatives modified at the C3-OH position, i. e., compound a4 containing sulfide ether, exhibited the best antiproliferative activity against BEL-7402 cells, with an IC50 value of 5.70 +/- 0.82 mu M. Further flow cytometry assays revealed that compound a4 exerted its antiproliferative effects by inducing cell cycle arrest in the G2/M phase leading to apoptosis. Moreover, compared with the lead compound OA and the positive control drug 5-fluorouracil (5-FU), the OA derivatives demonstrated potent antiproliferative activities against the cancer cell lines.