Subcellular targeted anion transporters

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 effect on other subcellular compartments is 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 the ability of the naphthalimide-based transporters to localize within their intended membrane-bound organelles. Analogues that contained endoplasmic reticulum (ER) and lysosomal targeting motifs showed an enhanced H+/Cl– transport ability and cytotoxicity compared to non-targeted analogues. Moreover, ER and mitochondrial localization was found to enhance apoptosis in cancerous 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.