Stimuli-responsive transmembrane anion transport by AIE-active fluorescent probes.

Anticancer drug resistance implicates multifunctional mechanisms, and hypoxia is one of the key factors in therapeutic resistance. Hypoxia-specific therapy is considered an extremely effective strategy to fight against cancer. The development of small molecule-based synthetic anion transporters has also recently drawn attention for their potential therapeutic applications against several ion-transport-associated diseases, such as cancer and others. Herein, we describe the development of a hypoxia-responsive proanionophore to trigger controlled transport of anions across membranes under pathogenic conditions. Herein, we report the development of tetraphenylethene (TPE)-based anion transporters. The sulfonium-linked p-nitrobenzyl containing TPE-based proanionophore could be converted into a lipophilic fluorescent Cl- ion carrier in a hypoxic or reductive environment. Stimuli such as nitroreductase (NTR) and glutathione (GSH) mediated regeneration of the TPE-based active Cl- ion transporter also showed aggregation-induced emission (AIE) properties. We hypothesize that such hypoxia and reductive stimuli activatable proanionophores have tremendous potential to fight against channelopathies, including cancer.

A comprehensive calibrated phytolith based climatic index from the Himalaya and its application in palaeotemperature reconstruction.

Past climate reconstructions from palaeoecological records require an understanding of relationships between modern vegetation and climate. Phytoliths are being used widely to reconstruct variations in C3/C4 grasses in the past vegetation and corresponding climate. However, little understanding is available on their relationships with the climate driver(s). Even though, the driver(s) regulating C3/C4 grass distributions vary regionally, while reconstructing the past distributions, a grass phytolith-based climatic index (Ic) has often been found to be used globally without assessing its regional consistency. In the Himalaya, the working potential of Ic has proven to be unsatisfactory when compared to other regions of the globe. To improve the efficacy of Ic, we have identified the redundant grass phytolith morphs and revised it by including four exclusive C3-grass indicator morphotypes (bilobate trapezoidal, bilobate scooped, saddle tall and saddle plateaued) to the existing Ic calculation. Thus, a new climatic index, revised Ic (rIc) is proposed in this article. We have compared the rIc with modern climate variables and a relationship with mean annual temperature (MAT) is established with statistical validation. To assess the working potential of the proposed calibration function in the past temperature reconstructions, we have estimated the late Holocene MAT variations in the Himalaya using rIc. We infer that in the mountainous regions like the Himalaya, even with irregular precipitation distribution, variability in C3/C4 grass distributions and their phytolith spectra seem to be a primary function of temperature. Further, we recommend that rIc can be satisfactorily used to reconstruct past temperature variations in the Himalaya and similar mountainous regions where soil water availability is not a limiting factor.

Multi-stimuli controlled release of a transmembrane chloride ion carrier from a sulfonium-linked procarrier.

In recent times, anion transporters have received substantial consideration due to their ability to disrupt the ionic equilibrium across membrane bilayers. While numerous Cl- ion transporters were developed for channelopathies, unfortunately, poor aqueous solubility precluded their bioapplicability. Herein, we demonstrate the development of a multi-stimuli activatable anion transport approach to induce regulated transport of Cl- ions across membranes under specific conditions. The sulfonium-based procarrier was initially inactive, but the transmembrane transport of Cl- ions was activated in the presence of stimuli such as glutathione (GSH), reactive oxygen species (ROS) and light. The release of the hydrophobic anionophore from the aqueous-soluble procarrier under specific conditions leads to the successful transport of Cl- ions. Under physiological conditions, these anion carriers follow an antiport exchange mechanism to transport Cl- ions across lipid bilayers. Such multi-stimuli activatable procarriers have great potential to combat various types of channelopathies, including cancer, cystic fibrosis, kidney stones, myotonia, and others.

Biological applications of synthetic anion transporters.

The use of synthetic ion transporters for alteration of the concentration of ions across cell membranes has drawn attention from scientists over the last two decades. This ion transport property has been sensibly used to reduce the viability of cancer cells mainly due to the disruption of their ion homeostasis, leading to the perturbation of their abnormal pH gradient. The use of the proanionophore strategy has been recently adopted to increase cellular deliverability and reduce unwanted cytotoxicity towards normal cells. Meanwhile, various anionophores exhibiting non-toxic behavior in epithelial cells have shown a great propensity to be used as a putative treatment for channelopathies like cystic fibrosis. Anionophores with Cl- ion transport mediated antibacterial activities have also been successfully used against clinically relevant bacterial strains, many of which are tolerant towards commercial antibiotics. Recent developments in the chloride ion transport mediated biological activities of anionophores have been mainly discussed in this article. It also highlights other aspects, such as design criteria, targeted delivery options, and others, which can be useful for the further development of selective anionophores for specific biological applications.

A stimuli-responsive anticancer drug delivery system with inherent antibacterial activities.

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.

Chloride Ion Transport by PITENINs across the Phospholipid Bilayers of Vesicles and Cells.

Small-molecule-based Cl- ion carriers are gaining revived attention because of their recently discovered role toward anticancer activity. Herein, we showed that the anticancer agents, PITENINs, have an efficient transmembrane Cl- ion transport activity. Theoretical calculations, 1H NMR titration, and spectrophotometric analysis suggest that the PITENINs strongly bind with a Cl- ion. In addition to the lipophilicity, the presence of both acylthiourea and phenolic OH moieties of the compounds plays a crucial role in the transport of Cl- ions. Among the tested compounds, PIT-1 and DM-PIT-1 showed higher Cl- ion selectivity and transport efficiency. Mechanistic studies demonstrated that the potent compounds follow the H+/Cl- transport pathway. Cellular activity studies showed that the disruption of Cl- ion homeostasis by PIT-1 and DM-PIT-1 preferentially promotes apoptotic cell death.

Tuning the solubility of ionophores: glutathione-mediated transport of chloride ions across hydrophobic membranes.

A stimuli-responsive anion transport strategy was successfully employed to regulate the water solubility of ionophores and promote controlled transport of Cl- ions across lipid bilayers. A sulfonium-based proanionophore was efficiently activated by glutathione to regenerate the active anionophore, which allowed controlled transport of Cl- ions in a cellular environment with lower cytotoxicity.

Bis(sulfonamide) transmembrane carriers allow pH-gated inversion of ion selectivity.

Bis(sulfonamide) based synthetic carriers are reported for inversion of ion selectivity upon deviation of pH within a narrow window. A liposomal membrane potential is also generated when potassium ions are passively transported by these carriers.