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

Abstract 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 IC 50 value of 5.70±0.82 μM. 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.