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.

中文翻译：

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亚细胞靶向阴离子转运蛋白


介导电中性 （H+/Cl−） 转运的合成阴离子转运蛋白因其破坏亚细胞稳态环境的能力而显示出抗癌活性。细胞死亡机制的阐明揭示了转运蛋白中和溶酶体 pH 梯度和抑制自噬的能力。然而，它们对其他亚细胞区室的影响尚不清楚。在此，我们揭示了第一个亚细胞靶向阴离子载体，这些阴离子载体在各种膜结合的细胞器中积累，以偏向它们去极化溶酶体的自然倾向。共聚焦显微镜显示，基于萘苯酰胺的转运蛋白有效地定位于其预期的细胞器内。与非靶向类似物相比，含有内质网 （ER） 和溶酶体靶向基序的类似物显示出增强的 H+/Cl− 转运能力和更大的细胞毒性。此外，溶酶体积累提高了癌细胞选择性，而 ER 和线粒体定位增强了癌细胞的凋亡。我们的工作为设计以治疗为重点的合成阴离子转运蛋白提供了一种替代方法，并深入了解可能的亚细胞区室特异性对体内平衡的影响。