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This brief review highlights recent advances in the transport of oxoanions using synthetic carriers, focusing on both progress and ongoing challenges in the field. The difficulty of transporting these oxoanions increases with their hydration enthalpies, with less hydrated nitrate and perchlorate being relatively easy to transport. Recent progress has focused on the transport of moderately hydrated anions such as bicarbonate and carboxylates, where studies are influenced by the free diffusion of neutral species obtained by (de)protonation equilibria. Despite significant innovations in the design of synthetic carriers, the transport of the highly hydrated oxoanions sulfate and phosphate remains a major challenge. Progress on sulfate transport has stalled, while the first example of phosphate transport was reported only last year. [Display omitted] [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is the main cause of cancer-related deaths worldwide, mainly due to treatment resistance. For that reason, it is necessary to develop novel therapeutic strategies to overcome this phenomenon. The aim of our study was to design and characterize a synthetic anionophore, LAI-1, that would be able to efficiently disrupt lysosomal activity, leading to autophagy blockage, one of the most important resistance mechanisms in cancer cells. We confirmed that LAI-1 selectively localized in lysosomes, deacidifying them. This effect produced a blockage of autophagy, characterized by an abrogation of autophagosomes and lysosomes fusion. Moreover, LAI-1 produced cell death in lung cancer cells from different histological subtypes, inducing cytotoxicity more efficiently than other known autophagy inhibitors. Finally, LAI-1 was evaluated in combination therapy, showing sensitization to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a novel late-stage autophagy inhibitor with potential therapeutic applications in tumors with cytoprotective autophagy. Overcoming resistance is one of the most challenging features in current anticancer therapy. Autophagy is a cellular process that confers resistance in some advanced tumors, since it enables cancer cells to adapt to stressful situations, such as anticancer treatments. Hence, the inhibition of this cytoprotective autophagy leads to tumor cells sensitization and death. In this regard, we designed a novel potent anionophore compound that specifically targets lysosomes, called LAI-1 (late-stage autophagy inhibitor-1), and evaluated its role in blocking autophagy and its potential anticancer effects in three lung cancer cell lines from different histological subtypes. Compared to other autophagy inhibitors, such as chloroquine and 3-Methyladenine, the LAI-1 treatment induced more potent anticancer effects in all tested cancer cells. LAI-1 was able to efficiently target and deacidify lysosomes, while acidifying cytoplasmic pH. Consequently, LAI-1 efficiently blocked autophagy, indicated by the increased LC3-II/I ratio and p62/SQSTM1 levels. Moreover, no colocalization was observed between autophagosomes, marked with LC3 or p62/SQSTM1, and lysosomes, stained with LAMP-1, after the LAI-1 treatment, indicating the blockage of autophagolysosome formation. Furthermore, LAI-1 induced cell death by activating apoptosis (enhancing the cleavage of caspase-3 and PARP) or necrosis, depending on the cancer cell line. Finally, LAI-1 sensitized cancer cells to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a new late-stage autophagy inhibitor that causes lysosomal dysfunction and the blockage of autophagolysosome formation, as well as potently induces cancer cell death and sensitization to conventional treatments at lower concentrations than other known autophagy inhibitors, appearing as a potential new therapeutic approach to overcome cancer resistance. [ABSTRACT FROM AUTHOR]

There has been a tremendous evolution for artificial ion transport systems, especially gated synthetic systems, which closely mimic their natural congeners. Herein, we demonstrate a trans‐azobenzene‐based photoregulatory anionophoric system that transports chloride by forming a sandwich dimeric complex. Further studies confirmed a carrier‐mediated chloride‐anion antiport mechanism, and the supramolecular interactions involved in chloride recognition within the sandwich complex were revealed from theoretical studies. Reversible trans–cis photoisomerization of the azobenzene was achieved without any significant contribution from the thermal cis→trans isomerization at room temperature. Photoregulatory transport activity across the lipid bilayer membrane inferred an outstanding off‐on response of the azobenzene photoswitch. [ABSTRACT FROM AUTHOR]

Acidic microenvironments in solid tumors are a hallmark of cancer. Inspired by that, we designed a family of pseudopeptidic cage‐like anionophores displaying pH‐dependent activity. When protonated, they efficiently bind chloride anions. They also transport chloride through lipid bilayers, with their anionophoric properties improving at acidic pH, suggesting an H+/Cl− symport mechanism. NMR studies in DPC micelles demonstrate that the cages bind chloride within the lipid phase. The chloride affinity and the chloride‐exchange rate with the aqueous bulk solution are improved when the pH is lowered. This increases cytotoxicity towards lung adenocarcinoma cells at the pH of the microenvironment of a solid tumor. These properties depend on the nature of the amino‐acid side chains of the cages, which modulate their lipophilicity and interactions with the cell membrane. This paves the way towards using pH as a parameter to control the selectivity of cytotoxic ionophores as anticancer drugs. [ABSTRACT FROM AUTHOR]

Bicarbonate plays a central role in human physiology from cellular respiration to pH homeostasis. However, so far, the measurement of bicarbonate concentration changes in living cells has only been possible by measuring intracellular pH changes. In this article, we report the development of a genetically encoded pH-independent fluorescence-based single-use sensory cellular test system for monitoring intracellular bicarbonate concentration changes in living cells. We describe the usefulness of the developed biosensor in characterizing the bicarbonate transport activities of anionophores—small molecules capable of facilitating the membrane permeation of this anion. We also demonstrate the ability of the bicarbonate sensory cellular test system to measure intracellular bicarbonate concentration changes in response to activation and specific inhibition of wild-type human CFTR protein when co-expressed with the bicarbonate sensing and reporting units in living cells. A valuable benefit of the bicarbonate sensory cellular test system could be the screening of novel anionophore library compounds for bicarbonate transport activity with efficiencies close to the natural anion channel CFTR, which is not functional in the respiratory epithelia of cystic fibrosis patients.

Two tripodal squaramide conjugates having 4-(trifluoromethyl)phenyl and 3,5-bis(trifluoromethyl)phenyl substituents were synthesized and found to exhibit highly efficient transmembrane anion transport with the EC 50 values being 0.14 and 0.75 mol%, respectively. Though one of them has been reported to act as a strong anion receptor, in particular for sulfate anions, these two compounds exhibit no significant selectivity with respect to the tested monovalent anions and a very low level of activity in the presence of sulfate anions. [ABSTRACT FROM AUTHOR]

2,6-Bis(benzimidazol-2-yl)pyridine was shown to exhibit potent anionophoric activity via a process of both Cl − /NO 3 − antiport and H + /Cl − symport. This is in sharp contrast to the finding that its corresponding N -methylated analog exhibited negligible activity and reveals the importance of the imidazolyl-N H fragments in the anion-transport process. [ABSTRACT FROM AUTHOR]

A rigid bis(choloyl) conjugate functionalized with guanidino groups was synthesized and fully characterized on the basis of NMR ( 1 H and 13 C) and ESI MS (LR and HR) data. Its transmembrane ionophoric activity across egg-yolk l -α-phosphatidylcholine-based liposomal membranes was investigated by means of chloride ion selective electrode technique and pH discharge assay. The data indicate that under the assay conditions, this conjugate was capable of promoting the transport of anions, presumably via a cation/anion symport process. A Hill analysis reveals that two molecules of this compound are assembled into the transport-active species. [ABSTRACT FROM AUTHOR]

We describe application of theory and kinetic modeling to study transport of basic anions by the small synthetic molecules. The findings should equip researchers in the particular field with a tool necessary to address an essential question: whether a given anion transporter facilitates permeation of F, CHCOO, N, and SCN across biological membrane or it does not. The basic anions undergo hydrolysis and conjugate acids (HAnion) are permeant species. However, because methods to quantitatively account for HAnion transport do not exist, traditionally, the phenomenon is also treated as non-existing. When the relative activities and selectivity of the synthetic anionophores are evaluated, basic and non-basic anions are regarded in the same exact way. Here, we show that HAnion and H/OH transport proceed on the same time scale as the anion exchange, nevertheless, comprehensive kinetic study could provide solution to the problems at hands, such as selective transport of HCO or F anions. We also use theory and modeling to study other questions of particular concern: transport of OH and H ions, facilitated by the small synthetic anionophore, origin of modified anti-Hofmeister selectivity, multi-ion hopping, and anomalous mole-fraction effect in the synthetic ion channels. We do not need to model kinetics in a synthetic channel with multiple ion binding sites. Instead, we 'test' the most simple anionophore, a lipophilic electroneutral carrier with Hofmeister-like selectivity, in the classical assays as 'presumably, Cl/OH antiporter.' The implications of findings to the particular field and beyond are discussed. Graphical Abstract: [Figure not available: see fulltext.]. [ABSTRACT FROM AUTHOR]

We describe an application of the Goldman–Hodgkin–Katz (GHK) theory and kinetic modelling to study the function of the anion transporters in liposomes. The study is based on a concept, which has not yet been comprehensively explored within the field, that the low-turnover anion transporters initiate electrogenic exchange across biomembrane. We have devised an analytical description for two compounds, cationic and electroneutral, constructed flowchart-based kinetic models and solved the transport equations numerically. To our knowledge, the function of the small molecules, which selectively increases the anion permeability of a bilayer, has never been examined using this technique. The findings illustrate that the GHK-based kinetic modelling, easily available in organic laboratory by means of commercially available differential equation solvers, is an essential tool, which aims to complement the experiential studies. The application of theory affects fundamental understanding of the phenomena, providing an alternative way to address questions about mechanism and selectivity of the small molecules, which have been raised in the field. In particular, it aims to facilitate the search for anionophores that are selective for a specific inorganic anion. ‘Valinomycin for anions’ will find numerous applications, ranging from carrier-based ion-selective electrodes to a new tool for transport studied in the living cells and a potential treatment for the anion transport disorders such as cystic fibrosis. [ABSTRACT FROM AUTHOR]

Prodiginines and tambjamines are anion-selective ionophores capable of facilitating the transport of anions across the plasma membrane in mammalian cells. One of the potential applications of these anionophores is the possibility of employing them as a substitutive therapy for pathologies involving anion channels, as in cystic fibrosis. We have studied the interaction of a large anion as gluconate with three prodiginine- and two tambjamine-like compounds. Apparent dissociation constants for the chloride, iodide and gluconate complexes were estimated from iodide influx experiments in mammalian cells exposed to different extracellular anion combinations. Our experiments indicate that gluconate is not transported by the prodiginines, leaving the anionophores free to transport chloride and iodide. Conversely, gluconate would be transported to some extent by the tambjamines, competing with halides for the anionophores, and consequently reducing their flux. This might be related to the different structural features of both families of compounds. These data have important implications for the selection of impermeable anions in the analysis of the anionophore mechanism. [ABSTRACT FROM AUTHOR]

Bicarbonate plays a central role in human physiology from cellular respiration to pH homeostasis. However, so far, the measurement of bicarbonate concentration changes in living cells has only been possible by measuring intracellular pH changes. In this article, we report the development of a genetically encoded pH-independent fluorescence-based single-use sensory cellular test system for monitoring intracellular bicarbonate concentration changes in living cells. We describe the usefulness of the developed biosensor in characterizing the bicarbonate transport activities of anionophores—small molecules capable of facilitating the membrane permeation of this anion. We also demonstrate the ability of the bicarbonate sensory cellular test system to measure intracellular bicarbonate concentration changes in response to activation and specific inhibition of wild-type human CFTR protein when co-expressed with the bicarbonate sensing and reporting units in living cells. A valuable benefit of the bicarbonate sensory cellular test system could be the screening of novel anionophore library compounds for bicarbonate transport activity with efficiencies close to the natural anion channel CFTR, which is not functional in the respiratory epithelia of cystic fibrosis patients. [ABSTRACT FROM AUTHOR]