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

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 H-1 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.