Quaternary ammonium‐based mitochondria targeting anticancer agents with high water solubility

Abstract Triphenylphosphonium derivatives induce mitochondrial dysfunction by inhibiting the respiratory chain, membrane depolarization, and generation of reactive oxygen species. However, the clinical application has been limited due to low aqueous solubility. In this regard, a series of novel mitochondria targeting agents were designed by introducing quaternary ammonium that increases aqueous solubility. Among them, diquaternary ammonium containing triphenylphosphonium molecules specifically inhibited mitochondrial respiratory chain, disrupted mitochondrial proteostasis, and intra‐mitochondrial protein in cancer cells, resulting in apoptosis induction. Overall, the high water‐soluble mitochondria targeting agents would be a potential anticancer drug.