Chloride-Mediated Apoptosis-Inducing Activity of Bis(sulfonamide) Anionophores

Abstract

Transmembrane anion transport modality is enjoying a renewed interest because of recent advances toward anticancer therapy. Here we show bis(sulfonamides) as efficient receptors for selective Cl– ion binding and transport across lipid bilayer membranes. Anion-binding studies by 1H NMR indicate a logical correlation between the acidity of sulfonamide N–H proton and binding strength. Such recognition is influenced further by the lipophilicity of a receptor during the ion-transport process. The anion-binding and transport activity of a bis(sulfonamide) system are far superior compared to those of the corresponding bis(carboxylic amide) derivative. Fluorescent-based assays confirm the Cl–/anion antiport as the operational mechanism of the ion transport by bis(sulfonamides). Disruption of ionic homeostasis by the transported Cl– ion, via bis(sulfonamide), is found to impose cell death. Induction of a caspase-dependent intrinsic pathway of apoptosis is confirmed by monitoring the changes in mitrochondrial membrane potential, cytochrome c leakage, activation of family of caspases, and nuclear fragmentation studies