Design,Synthesis And Antitumor Activity Of Mitochondrial-Targeted Oleanolic Acid Derivatives

Oleanolic acid(OA)is a pentacyclic triterpenoid natural product that exists in plants and has a variety of pharmacological activities.In recent years,the antitumor activity of oleanolic acid has been widely studied.Due to the poor water solubility,low bioavailability and poor selectivity of oleanolic acid,its application in anti-tumor is limited.The structural modification of oleanolic acid and its antitumor activity are hot issues in the field of medicinal chemistry.Cancer is one of the diseases with the highest mortality,and the treatment is very difficult.The failure of natural apoptosis of tumor cells is one of the reasons why tumors are difficult to treat.Selective induction of tumor cell apoptosis is an effective treatment.Mitochondria play a key role in programmed cell apoptosis.Compared with normal cells,the structure and function of mitochondria in tumor cells have undergone great changes.According to this change,antitumor drugs that selectively target mitochondria can be designed.Lipophilic cations(DLCs)are a class of common mitochondrial targeting carriers.Covalently connecting DLCs with antitumor drugs can selectively target drugs to tumor cell mitochondria,thereby inducing tumor cell apoptosis.In this paper,43 OA derivatives were designed and synthesized by introducing triphenylphosphine(TPP)and several TPP analogues into the parent skeleton of oleanolic acid.The structures of the target compounds were determined by 1H NMR and 13C NMR.The antitumor activity of OA derivatives against three cancer cells(A549,MCF-7,HepG2)and a normal cell(QSG 7701)was tested and evaluated by in vitro antitumor test.The results of MTT assay showed that compared with the parent compound OA,the antitumor activity of all compounds was significantly improved,and the selectivity was also improved.Among them,compounds WB-22 and WB-30 had the best activity.By exploring the structure-activity relationship of the compounds,it can be seen that the site of the OA skeleton,the length of the linker and the type of DLCs will affect the antitumor activity of OA derivatives.PI3K-Akt signaling pathway is a signal survival pathway closely related to apoptosis and proliferation.Studies have shown that the PI3K-Akt signaling pathway is a potential way for OA derivatives to exert anti-tumor effects.In order to study the interaction between OA derivatives and PI3K,according to the results of in vitro anti-tumor experiments,two compounds with the best activity were selected for virtual molecular docking with PI3K protein and the results were visualized.The results showed that the two compounds could bind and interact with PI3K protein through hydrogen bonds and intermolecular hydrophobic forces.In summary,the novel oleanolic acid derivatives with mitochondrial targeting function synthesized in this study can be further studied as potential anticancer prodrugs.