Subcellular targeted anionophores

Synthetic anion transporters that mediate electroneutral (H+/Cl-) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostasis. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralise 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 depolarise lysosomes. The series of naphthalimide-based transporters were studied by confocal microscopy, and were found to accumulate in different subcellular organelles. The analogues that contained endoplasmic reticulum (ER)- and lysosomal targeting motifs showed enhanced the H+/Cl- transport ability compared to their non-targeted analogues. Moreover, ER and lysosomal localisation was found to enhance the cytotoxic effect of the transporters on cancerous cells. Our work provides an alternative approach in the design of therapeutically focused synthetic anion transporters and an insight into possible subcellular compartment-specific effects on homeostasis.