Design and synthesis of novel mitochondria-targeted CDDO derivatives as potential anti-cancer agents

A large number of derivatives of natural pentacyclic triterpenoid oleanolic acid (OA) with various activities have been reported, including CDDO derivatives (CDDOs). CDDOs show potent antitumor activity, but they lack selectivity for tumor cells which causes serious side effects. In this study, based on the truth that tumor cells display higher mitochondrial membrane potential, to improve their mitochondrial-targeting ability, triphenyl-phosphine cations (TPP+) or tricyclohexylphosphine cations (TCP+) were linked to CDDO. Among these com-pounds, the TPP+ derivative 5b exhibited greater activity against the tumor cells than CDDO-Me, and the selectivity for the tumor cells was obviously improved. Further investigation revealed that the uptake of 5b in the mitochondria of MCF-7 cells was increased compared to CDDO-Me. In addition, 5b was able to cause mito-chondrial membrane potential decline and cell cycle arrest. Furthermore, 5b caused apoptosis mainly through the mitochondria-mediated intrinsic pathway. Taken together, our study provides a possible solution to the poor selectivity of CDDOs, and regains confidence in the treatment of tumor with CDDOs.

Automated summary

This study improved the mitochondrial-targeting ability and selectivity of CDDO derivatives by linking triphenyl-phosphine cations or tricyclohexylphosphine cations. The new compound 5b showed greater activity against tumor cells than existing CDDO derivatives, causing apoptosis mainly through the mitochondria-mediated intrinsic pathway.