1.D.336.  The TrtraBenzylPhosphonium Mitochondrial-targeting Artificial Anion Channel       (TBP-AAC) Family

Artificial ion channels with specific organelle-targeting capabilities were not known, but Gou et al. 2025 reported the first-in-class mitochondria-targeting anion channels derived from a structurally simple tetrabenzylphosphonium framework. This is in contrast to its phenyl-based counterpart, which lacks anion transport activity. Structural and computational analyses underscored the critical role of the methylene (CH₂) linkers in the benzyl groups. These CH₂ units reduce positive charge delocalization to enhance σ-hole-anion interactions, while also enabling H-atoms from both the CH₂ linkers and aromatic rings to cooperatively form multiple C─H⋯anion H─bonds. In further conjunction with the rigid benzene rings, they help create sufficient spatial voids to accommodate anion translocation, collectively facilitating and energizing the anion transport process. Among the series studied, those bearing methyl and tert-butyl substituents exhibit the highest transport activity via a channel mechanism, with a conductance value as high as 26.5 ± 0.8 pS. Furthermore, leveraging the cationic nature of the quaternary phosphonium center, this family of anion channels readily achieves targeted mitochondrial localization, demonstrating potent anticancer activity, with IC₅₀ values ranging from 1.42 to 3.04 µM across three cancer cell lines (Gou et al. 2025).