Synthesis and discovery of mitochondria-targeting oleanolic acid derivatives for potential PI3K inhibition

Oleanolic acid and its derivatives have been widely reported for their antitumor activities. Recently, the introduction of a triphenylphosphonium cation moiety has been described to improve the selectivity and cytotoxicity of pentacyclic triterpenoids by targeting the mitochondria of human cancer cells. In this work, a series of novel mitochondria-targeting oleanolic acid derivatives were synthesized and their antitumor activities assessed. The majority of the compounds are more cytotoxicity to cancer cells than normal cells, especially for 6c with IC50 of 0.81 μM in A549 cells, which showed a slight increase compared to doxorubicin (0.97 μM). Mechanism studies demonstrated that 6c induced apoptosis of A549 cells in a dose-dependent manner, and reactive oxygen species production, mitochondrial membrane potential depolarization, and particularly pro-apoptotic proteins upregulated by western blotting experiment may be responsible for the results. Moreover, 6c arrested the cell cycle at G2/M phase and cell migration in A549 cells. Compound 6c had a comparable or somewhat improved activity to the positive control LY294002 in molecular docking studies and in vitro testing, demonstrating that the apoptosis mechanism may involve inhibition of the PI3K-Akt pathway. These results augur well for the use of 6c as a novel triphenylphosphonium-conjugated anticancer agent.