We report two pyridyl-linked benzimidazolyl hydrazones as HCl cotransporters that are 5 and 2 times superior to prodigiosin, a natural product whose transport efficiency has never been routed by synthetic molecules. These hydrazones provide a suitable HCl binding site through a cooperative protonation and chloride ion recognition. HCl transport by the most active compound induces lysosome deacidification. Viability assays confirmed that the compounds induce cytotoxicity toward human breast cancer MCF-7 cells but are relatively nontoxic toward noncancerous HEK293T cells.

Achieving superfast water transport by synthetically designed molecular artifacts, which exclude salts and protons, is a challenging task in separation science today, as it requires the concomitant presence of a...

The majority of cellular physiological processes depend on natural ion channels, which are pore-forming membrane-embedded proteins that let ions flow across the cell membranes selectively. This selective movement of ions...

Stimulus-responsive reversible transformation between two structural conformers is an essential process in many biological systems. An example of such a process is the conversion of amyloid-β peptide into β-sheet-rich oligomers, which leads to the accumulation of insoluble amyloid in the brain, in Alzheimer’s disease. To reverse this unique structural shift and prevent amyloid accumulation, β-sheet breakers are used. Herein, we report a series of bis(indole)-based biofunctional molecules, which form a stable double helix structure in the solid and solution state. In presence of chloride anion, the double helical structure unwinds to form an anion-coordinated supramolecular polymeric channel, which in turn rewinds upon the addition of Ag+ salts. Moreover, the formation of the anion-induced supramolecular ion channel results in efficient ion transport across lipid bilayer membranes with excellent chloride selectivity. This work demonstrates anion-cation-assisted stimulus-responsive unwinding and rewinding of artificial double-helix systems, paving way for smart materials with better biomedical applications.

Synthetic anion transmembrane transporters are adding new aspirations for treating channelopathies by replacing defective ion channels. The availability of such suitable candidates is still infrequent due to the associated toxicity. Here, we report 3-(1H-1,2,3-triazol-1-yl)­benzamides as transmembrane anion carriers, nontoxic to cells. The selective and electrogenic chloride transport activity was established by fluorescence and ion selective electrode-based assays. MQAE assay confirmed the chloride uptake into the cells by the nontoxic compounds.

Fluctuations in the intracellular chloride ion concentration, mediated by synthetic ion transporters, have been known to induce cytotoxicity in cells by disrupting ionic homeostasis. However, the activity of these transporters in modulating autophagy remains largely unexplored. Here, we report a benzoylbenzohydrazide (1c) that self-assembles to form a supramolecular nanochannel lumen that allows selective and efficient transport of chloride ions across the cell membranes, disrupts ion homeostasis, and thus leads to the induction of apoptosis in cancer cells. It is important to note that the transporter was relatively nontoxic to cells of noncancerous origin. 1c was also shown to induce the deacidification of lysosomes, thereby disrupting autophagy in cancer cells. Taken together, these findings provide a rare example of an artificial ion channel that specifically targets cancer cells by induction of apoptosis via disruption of autophagy.

Artificial channels capable of facilitating the transport of Cl À ions across cell membranes while being nontoxic to the cells are rare. Such synthetic ion channels can mimic the functions of membrane transport proteins and, therefore, have the potential to treat channelopathies by replacing defective ion channels. Here we report isophthalic acid-based structurally simple molecules 1 a and 2 a, which self-assemble to render supramolecular nanochannels that allow selective transport of Cl À ions. As evident from the single-crystal X-ray diffraction analysis, the self-assembly is governed by intermolecular hydrogen bonding and π-π stacking interactions. The MD simulation studies for both 1 a and 2 a confirmed the formation of stable Cl À channel assembly in the lipid membrane and Cl À transport through them. The MQAE assay showed the efficacy of the compounds in delivering Cl À ions into cells, and the MTT assays proved that the compounds are nontoxic to cells even at a concentration of 100 μM.

Artificial biomimetic chloride anionophores have shown promising applications as anticancer scaffolds. Importantly, stimuli-responsive chloride transporters that can be selectively activated inside the cancer cells to avoid undesired toxicity to normal,...