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 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 <i>c</i> leakage, activation of family of caspases, and nuclear fragmentation studies

Chloride Transport through Supramolecular Barrel-Rosette Ion Channels: Lipophilic Control and Apoptosis-Inducing Activity

Despite the great interest in artificial ion channel design, only a small number of channel-forming molecules are currently available for addressing challenging problems, particularly in the biological systems. Recent advances in chloride-mediated cell death, aided by synthetic ion carriers, encouraged us to develop chloride selective supramolecular ion channels. The present work describes vicinal diols, tethered to a rigid 1,3-diethynylbenzene core, as pivotal moieties for the barrel-rosette ion channel formation, and the activity of such channels was tuned by controlling the lipophilicity of designed monomers. Selective transport of chloride ions via an antiport mechanism and channel formation in the lipid bilayer membranes were confirmed for the most active molecule. A theoretical model of the supramolecular barrel-rosette, favored by a network of intermolecular hydrogen bonding, has been proposed. The artificial ion-channel-mediated transport of chloride into cells and subsequent disruption of cellular ionic homeostasis were evident. Perturbation of chloride homeostasis in cells instigates cell death by inducing the caspase-mediated intrinsic pathway of apoptosis

Hopping-Mediated Anion Transport through a Mannitol-Based Rosette Ion Channel

Artificial anion selective ion channels with single-file multiple anion-recognition sites are rare. Here, we have designed, by hypothesis, a small molecule that self-organizes to form a barrel rosette ion channel in the lipid membrane environment. Being amphiphilic in nature, this molecule forms nanotubes through intermolecular hydrogen bond formation, while its hydrophobic counterpart is stabilized by hydrophobic interactions in the membrane. The anion selectivity of the channel was investigated by fluorescence-based vesicle assay and planar bilayer conductance measurements. The ion transport by a modified hopping mechanism was demonstrated by molecular dynamics simulation studies

Self-Assembly of Fluorinated Sugar Amino Acid Derived α,γ-Cyclic Peptides into Transmembrane Anion Transport

Syntheses of fluorinated sugar amino acid derived <i>α</i>,<i>γ</i>-cyclic tetra- and hexapeptides are reported. The IR, NMR, ESI-MS, CD, and molecular modeling studies of cyclic tetra- and hexapeptides showed <i>C</i>₂ and <i>C</i>₃ symmetric flat oval- and triangular-ring shaped β-strand conformations, respectively, which appear to self-assemble into nanotubes. The <i>α,γ</i>-cyclic hexapeptide (<i>EC</i>₅₀ = 2.14 μM) is found to be a more efficient ion transporter than <i>α</i>,<i>γ</i>-cyclic tetrapeptide (<i>EC</i>₅₀ = 14.75 μM). The anion selectivity and recognition of <i>α</i>,<i>γ</i>-cyclic hexapeptide with NO₃^– ion is investigated

Self-Assembly of Fluorinated Sugar Amino Acid Derived α,γ-Cyclic Peptides into Transmembrane Anion Transport

Syntheses of fluorinated sugar amino acid derived <i>α</i>,<i>γ</i>-cyclic tetra- and hexapeptides are reported. The IR, NMR, ESI-MS, CD, and molecular modeling studies of cyclic tetra- and hexapeptides showed <i>C</i>₂ and <i>C</i>₃ symmetric flat oval- and triangular-ring shaped β-strand conformations, respectively, which appear to self-assemble into nanotubes. The <i>α,γ</i>-cyclic hexapeptide (<i>EC</i>₅₀ = 2.14 μM) is found to be a more efficient ion transporter than <i>α</i>,<i>γ</i>-cyclic tetrapeptide (<i>EC</i>₅₀ = 14.75 μM). The anion selectivity and recognition of <i>α</i>,<i>γ</i>-cyclic hexapeptide with NO₃^– ion is investigated