Artificial Ionophore Research Articles

Anion‐selective macromolecular artificial ionophores with steroid and fatty acid pendants

AbstractSynthetic anion transporters are potential therapeutics for a plethora of cellular ailments including cystic fibrosis, cancer resistance, epilepsy, etc. In this context, cationic macromolecular amphiphiles are gaining revived interest because of their easy synthesis and ample ion channelization through the membrane barrier. Herein, side chain alanine containing cationic polymer amphiphiles with steroid/fatty acid decoration was established to be an efficient anion‐selective artificial ionophore. The facile amphiphilicity‐assisted assembly makeover of cholic acid containing copolymers channelized the better transmembrane anion transport and efficiency with the maximum selectivity found with NO2− ion.

Recent Advances in Bioactive Artificial Ionophores.

Several life‐threatening diseases, also known as ‘Channelopathies’ are linked to irregularities in ion transport proteins. Significant research efforts have fostered the development of artificial transport systems that facilitates to restore the functions of impaired natural transport proteins. Indeed, a few of these artificial ionophores demonstrate the rare combination of transmembrane ion transport and important biological activity, offering early promises of suitability in ‘channel replacement therapy’. In this review, structural facets and functions of both cationophores and anionophores are discussed. Ionophores that are toxic to various bacteria and yeast, could be exploited as antimicrobial agent. Nevertheless, few non‐toxic ionophores offer the likelihood of treating a wide range of genetic diseases caused by the gene mutations. In addition, their ability to disrupt cellular homeostasis and to alter lysosomal pH endow ionophores as promising candidates for cancer treatment. Overall, critically outlining the advances in artificial ionophores in terms of in vitro ion transport, possible modes of action and biological activities enables us to propose possible future roadmaps in this research area.

Calixarene-based artificial ionophores for chloride transport across natural liposomal bilayer: Synthesis, structure-function relationships, and computational study

An amphiphilic calix[6]arene, alone or complexed with an axle to form a pseudo-rotaxane, has been embedded into liposomes prepared from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the permeability of the membrane-doped liposomes towards Cl− ions has been evaluated by using lucigenin as the fluorescent probe. The pseudo-rotaxane promotes transmembrane transport of Cl− ions more than calix[6]arene does. Surprisingly, the quenching of lucigenin was very fast for liposomes doped with the positively charged axle alone. Molecular dynamics (MD) simulations and quantum-chemical calculations were also carried out for providing a semi-quantitative support to the experimental results.

Cholate Conjugated Polymeric Amphiphiles as Efficient Artificial Ionophores.

A family of amphiphilic copolymers containing hydrophobic cholate pendants has been prepared by copolymerization of cholic acid-based monomer 2-(methacryloxy)-ethyl cholate (MAECA) with polyethylene glycol methyl ether methacrylate (PEGMA). The polymers differ for the content of MAECA that increases from 0 to 35%. The copolymers partition within liposomes and display potent ionophoric activity forming large pores in the membrane and allowing the leakage of small inorganic ions (H+, Na+) and of large polar organic molecules (calcein). Their activity is strictly correlated to the content of cholic acid subunits, increasing as the fraction of cholate moiety increases.

Ionophore constructed from non-covalent assembly of a G-quadruplex and liponucleoside transports K+-ion across biological membranes

The selective transport of ions across cell membranes, controlled by membrane proteins, is critical for a living organism. DNA-based systems have emerged as promising artificial ion transporters. However, the development of stable and selective artificial ion transporters remains a formidable task. We herein delineate the construction of an artificial ionophore using a telomeric DNA G-quadruplex (h-TELO) and a lipophilic guanosine (MG). MG stabilizes h-TELO by non-covalent interactions and, along with the lipophilic side chain, promotes the insertion of h-TELO within the hydrophobic lipid membrane. Fluorescence assays, electrophysiology measurements and molecular dynamics simulations reveal that MG/h-TELO preferentially transports K+-ions in a stimuli-responsive manner. The preferential K+-ion transport is presumably due to conformational changes of the ionophore in response to different ions. Moreover, the ionophore transports K+-ions across CHO and K-562 cell membranes. This study may serve as a design principle to generate selective DNA-based artificial transporters for therapeutic applications.

Carbohydrate-based synthetic ion transporters

In this work, carbohydrate-based systems designed as artificial ion transporters have been surveyed. Despite the large structural diversity and ease of manipulations of carbohydrates, in principle endowed with a variety of desirable properties for ionophoric activity, only few examples of sugar-containing compounds have been reported in the literature for these purposes. The most remarkable example is the family of modified β-cyclodextrins, resulting in active cation and/or anion transporters when long, flexible n-alkyl or oligo-ethylene or butylene glycol chains are appended at the lower rim of the macrocycle. Interesting features have been also found in amphiphilic CyPLOS (Cyclic Phosphate-Linked Oligosaccharide) dimers, that is macrocycles with two phenyl-β-d-glucopyranoside residues, 4,6-linked through phosphodiester bonds, derivatized with tetraethylene glycol tentacles. A wider repertoire of available carbohydrate-based scaffolds is expected to largely stimulate the discovery of novel, efficient artificial ionophores, of great interest for both technological and biomedical applications. [Display omitted]

Steroid/Triterpenoid Functional Molecules based on “Click Chemistry”

This Focus Review highlights the design and synthesis of various functional molecules based on steroid/triterpenoid as building blocks through the copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction, as well as their applications in bioactivity, recognition, and assembly. This method shows great promise to allow us to develop novel molecules with characteristic functions using the CuAAC "click" reaction.

C2-symmetrical sterol–polyether conjugates as highly efficient synthetic ionophores

A new class of artificial ionophores has been rationally designed and synthesized linking to a tetrafunctionalized l-treitol spacer two rigid hydrophobic 3β-hydroxy-5α-23,24-bisnorcholanic units and two flexible hydrophilic oligo(ethylene glycol) chains. Compounds 1a and 1b were incorporated into phospholipid vesicles and shown to facilitate Na +-transport.

An Artificial Ionophore Based on a Polyhydroxylated Steroid Dimer.

The Na+ transporting properties of the first member of a new class of artificial ionophores, based on a C2-symmetric polyhydroxylated steroid dimer, are described.

An artificial ionophore based on a polyhydroxylated steroid dimer.

The Na+ transporting properties of the first member of a new class of artificial ionophores, based on a C2-symmetric polyhydroxylated steroid dimer, are described.

Use of tributyltin to probe contribution of Cl(-)-HCO3- exchange to regulation of steady-state pHi in human neutrophils

Organotin derivatives represent a class of artificial ionophores that mediate Cl(-)-OH- exchange and thereby facilitate the chemical equilibrium distribution of Cl- and H+ across biological membranes. Imposing different pH and Cl- gradients by varying extracellular pH (pHo) and extracellular [Cl-] in the presence of 1 microM tributyltin validated the above assumptions in human neutrophils. Under relatively alkaline conditions [intracellular pH (pHi) greater than or equal to 7.10 and pHo greater than or equal to 7.40], the cell's natural Cl(-)HCO3- exchanger mimicked the actions of the tributyltin compound and was the principal factor controlling steady-state pHi. However, with increasing extracellular acidification, there was a progressive deviation from the predicted equilibrium distribution in the case of the normal Cl(-)-HCO3- transport system, whereas tributyltin-treated cells followed theoretical expectations. Exposure of neutrophils to a number of inhibitors of Cl(-)-HCO3- exchange led to a fall in pHi, apparently confirming the impression that a net HCO3- influx through Cl(-)-HCO3- countertransport was chiefly responsible for maintaining steady-state pHi. However, this intracellular acidification could be satisfactorily ascribed to proton movements through a parallel pathway, namely nonionic diffusion of the free acid form of the drugs. These results imply that Cl(-)-HCO3- exchange is the dominant pH regulatory device only under relatively alkaline conditions and that other mechanisms in addition to Na(+)-H+ exchange are likely to play an important role in recovery from acidification and in maintaining steady-state pHi. The possibility that the lactate carrier may function in this capacity is discussed.