Macrocyclic Transmembrane Anion Transporters via a One-Pot Condensation Reaction

Abstract

Synthetic chloride transporters are potential therapeutic agents for cystic fibrosis and cancer. Reported herein are macrocyclic transmembrane chloride transporters prepared by a onepot condensation reaction. The most efficient macrocycle possesses a fine balance of hydrophobicity for membrane permeation and hydrophilicity for ion recognition. The macrocycle transports chloride ions by forming channels in the membrane. Hydrogen bonds and anion−π interactions assist chloride transport. Letter pubs.acs.org/OrgLett

One-Pot Synthesis of Diverse Anion-Binding Macrocycles

“…Anion receptors 1 are used in applications ranging from bioimaging, 2 membrane transport, 3,4 and therapeutics 4,5 to catalysis, 6 and sensing. 7 They typically possess hydrogen bond donors or electron deficient rings to enhance anionaffinity via hydrogen-bonding or anion-pi interactions.…”

An Amphiphilic Peptide Carrier for HCl Transport

“…Ion‐binding domains for chloride transporters include NH groups as hydrogen bond donors for halide binding or electron‐deficient aromatic units for anion‐π interactions [1e,7] . Small molecules, peptides, and macrocycles decorated with suitable ion‐binding motifs have been employed as chloride transporters [1e,7f,g,8] . To facilitate HCl co‐transport, calix[4]arene tetrabutylamide [9] or heterocyclic analogs of prodigiosin are reported [5a,10] .…”

“…Lipid‐like molecules containing hydrophobic cholesterol units or long alkyl chains have often been employed as the hydrophobic membrane permeable domain [7f,g,15] . Fatty acids such as oleic acid are reported to transport H + across the membrane.…”

Molecular clips with spatially proximal urea residues for efficient transmembrane co-transport of H+/Cl− ions

“…[19][20][21] For instance, Gale and co-workers have recently reported a coumarin-based fluorescent transporter consisting of a bis(urea) moiety that allows for the co-transport of H + /Cl − across lipid bilayer membranes, resulting in organelle deacidification and apoptosis in cancer cells. 22 Amongst the series of macrocyclic chloride ion channels developed by Madhavan and co-workers, 23 the one with optimal lipophilicity (clog P = 11.7) showed the highest Cl − transport efficiency in lipid vesicles.…”