Mitochondria-Targeted Lupane Triterpenoid Derivatives And Their Selective Anticancer Mechanisms

Betulin(BN)and Betulinic acid(BA)are naturally occurring triterpenes.It has been demonstrated that BA and BN lower the survival rates of many types of malignant tumor cells.To strengthen their antitumor activities,pharmaceutical scientists have modified their structures to enhance their bioavailability and solubility.However,the antitumor activities of such triterpenes are still not very satisfactory for clinic use.As tumor cells are well known to be resistant to apoptosis,whereas mitochondria are deeply associated with both intrinsic and extrinsic apoptosis,a new area of research in pharmacology is focused on purposefully targeting drugs to the mitochondria of cancer cells to induce apoptosis but not harm normal cells.In addition,comprehensive research on the mitochondrial membrane potential(??m)differences between normal and cancer cells has provided a solid basis for mitochondrial targeting studies.Among the considerable number of studies in this area,studies on delocalized lipophilic cations(DLCs)have capitalized on ??m.The most extensively used DLC is the triphenylphosphonium cation(TPP+),which has been conjugated to many small molecular drugs to target mitochondria.In the present study,we attempted to transport BA and BN to mitochondria by conjugating them to TPP+ to improve their selectivity for cancer cells.For this purpose,we designed and synthesized a series of mitochondria-targeted derivatives of BA and BN.The results demonstrated that three times more mitochondria-targeted BN(Mito-BN-1)than BN accumulated in the mitochondria and that the mitochondria-targeted derivatives of BN and BA showed stronger cytotoxicities to cancer cells than to normal cells.The mechanisms may involve the production of reactive oxygen species,reducing the mitochondrial membrane potential and triggering the mitochondrial apoptosis pathway.In addition,Mito-BN-1 inhibited cancer cell proliferation and migration in a zebrafish xenograft model involving human chronic myeloid leukemia cells.In conclusion,the mitochondrial targeting effect was accomplished in a certain degree by conjugating BA and BN to TPP+ according to our studies both in vitro and in vivo.The synthesis procedures are simple and the agents are relatively cheap.Therefore,a class of natural pentacyclic triterpene compounds with useful properties can now be targeted to mitochondria,where they can fulfill their biomedical potential.