Mitochondria-Targeted Ergosterol Peroxide Derivatives: Synthesis, Anticancer Properties and Their Preliminary Mechanism of Inhibiting MCF-7 Cell Proliferation

Ergosterol peroxide (EP) has been extensively studied for its antitumor activities. However, its further development has been restricted due to its limited intracellular accumulation and poor aqueous solubility. In this study, a novel triphenylphosphonium cation (TPP+) moiety was coupled to ergosterol peroxide to precisely target it at tumor cell mitochondria. The synthesized Mito-EP derivatives Mito-EP-3a-3d displayed stronger cytotoxicity than the EP parent and exhibited selectively cytotoxic effects between cancer cells and normal gastric epithelial (GES-1) cells. The most potent compound, Mito-EP-3b, was 9.7-fold more efficacious than ergosterol peroxide in the MCF-7 (breast cancer) cell line and showed good selectivity (SI = IC50GES-1/IC50MCF-7 = 4.04, IC50: concentrations to inhibit 50% of cell growth). Furthermore, Mito-EP-3b was able to decrease the mitochondrial membrane potential and induced reactive oxygen species production, accompanied by activating the expression of cytochrome c and Bax, while Bcl-2 expression was suppressed. The molecular mechanism may refer to the mitochondrial apoptotic pathway. Overall, the above results incentivize the further study of Mito-EP-3b derivatives as potent anticancer agents.