Synthetic Na+/K+ exchangers promote apoptosis by disturbing cellular cation homeostasis

•Three hemispherand-strapped calix[4]pyrroles NaCl/KCl ion-pair receptors were prepared•These act as efficient Na+ and K+ transporters in the presence of Cl?•The this study promote Na+/K+ exchange cancer cells•Apoptosis is induced without creating osmotic stress or perturbing autophagy The tight regulation intracellular ion concentrations essential for diverse cellular functions eventually sustaining living organisms. Herein, we report a set that liposomal models Cl? anions. These synthetic mediate influx efflux (Na+/K+ exchange) cells. resulting perturbations cation homeostasis induce endoplasmic reticulum (ER) apoptosis. Cell death activity seen artificial across several cell lines. This work highlights new potential approach to drug discovery while providing specific tools can be used modulate concentrations. A number ionophores (or transporters) have been developed basic research biomedical applications. However, their mechanisms action putative correlations between changes remain poorly understood. Here, show three calix[4]pyrrole-based exchangers cells Mechanistic studies reveal these by homeostasis, generation reactive oxygen species, enhance mitochondria-mediated they neither nor affect autophagy. provides support notion receptors, which perturb may provide small molecules with potentially useful apoptotic activity. precise variety natural transporters/channels are responsible maintaining concentration gradients ions membranes. Recently, anion biological activities determined.1Alfonso I. Quesada R. Biological ionophores: prospective drugs?.Chem. Sci. 2013; 4: 3009-3019Google Scholar Additionally, various types molecule-based carriers pore-forming explored applications.1Alfonso For example, polycyclic ether-based products,2Nicolaou K.C. Frederick M.O. Aversa R.J. continuing saga marine polyether biotoxins.Angew. Chem. Int. Ed. 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Moreover, acyclic considerably less calixpyrroles S35). fact, 1, closest analog, 15 times more difference rationalized additional energetic penalty organize unconnected pyrrole rings displayed minimal activity, issues encountered EC50 determined system. trend accord following sequence role coordinating investigated. above-mentioned repeated, time gluconate solutions, 2B). does effectively calixpyrroles. chosen counteranion 1–4 cation-only chloride. promoted slower presence, indicating importance plots). enhanced quantified calculating Fen, apparent 2E), 76 greater; exhibited increase when S36–S40). presumably only increases toward respective effect neutralizing charge will likely penetrate hydrophobic core traverse efficiently. Additional analyzing M+/Cl? symport mechanism M+/H+ antiport class S41–S56; S4 S5). initial effort 1–5 serve ability alter K+, Na+, Ca2+ examined. 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