Subcellular targeted anion transporters

Abstract

Synthetic anion transporters that mediate electroneutral (H⁺/Cl⁻) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostatic environments. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralize lysosomal pH gradients and inhibit autophagy. However, their effects on other subcellular compartments are unknown. Herein, we disclose the first subcellular targeted anionophores that accumulate in various membrane-bound organelles to bias their natural propensity to depolarize lysosomes. Confocal microscopy revealed that the naphthalimide-based transporters effectively localized within their intended organelles. Analogs containing endoplasmic reticulum (ER) and lysosomal targeting motifs showed an enhanced H⁺/Cl⁻ transport ability and greater cytotoxicity compared with non-targeted analogs. Moreover, lysosomal accumulation improved cancer cell selectivity, while ER and mitochondrial localization enhanced apoptosis in cancer cells. Our work provides an alternative approach to the design of therapeutically focused synthetic anion transporters and an insight into possible subcellular compartment-specific effects on homeostasis.