Synthetic Ionophores Research Articles

Transmembrane Delivery of an Aryl Azopyrazole Photo‐switchable Ion Transporter Relay

Stimuli‐responsive synthetic ionophores allow for spatial and temporal control over ion transport, with promise for applications in targeted therapy. Relay transporters have emerged as a new class of ion transporters ‐ these are anchored carriers that sit in both leaflets of the bilayer and mediate transport across the membrane by passing ions between them. The relays are themselves membrane impermeable, and so must be incorporated into the membrane during vesicle preparation. Here we show that relay transporters can be delivered to both sides of the membrane of vesicles using a synthetic flippase. By incorporating an aryl azopyrazole photo‐switch into the movable arm of the relay transporters the ion transport activity can be very efficiently and reversibly switched between off and on states. This control is achieved by extension and contraction of their movable arms via photo‐isomerization of the central aryl azopyrazole moiety, hence modulating the ability of the relays to pass ions across the membrane.

Limitations of non-polarizable force fields in describing anion binding poses in non-polar synthetic hosts.

Transmembrane anion transport by synthetic ionophores has received increasing interest not only because of its relevance for understanding endogenous anion transport, but also because of potential implications for therapeutic routes in disease states where chloride transport is impaired. Computational studies can shed light on the binding recognition process and can deepen our mechanistic understanding of them. However, the ability of molecular mechanics methods to properly capture solvation and binding properties of anions is known to be challenging. Consequently, polarizable models have been suggested to improve the accuracy of such calculations. In this study, we calculate binding free energies for different anions to the synthetic ionophore, biotin[6]uril hexamethyl ester in acetonitrile and to biotin[6]uril hexaacid in water by employing non-polarizable and polarizable force fields. Anion binding shows strong solvent dependency consistent with experimental studies. In water, the binding strengths are iodide > bromide > chloride, and reversed in acetonitrile. These trends are well captured by both classes of force fields. However, the free energy profiles obtained from potential of mean force calculations and preferred binding positions of anions depend on the treatment of electrostatics. Results from simulations using the AMOEBA force-field, which recapitulate the observed binding positions, suggest strong effects from multipoles dominate with a smaller contribution from polarization. The oxidation status of the macrocycle was also found to influence anion recognition in water. Overall, these results have implications for the understanding of anion host interactions not just in synthetic ionophores, but also in narrow cavities of biological ion channels.

Interaction of crown ethers with the ABCG2 transporter and their implication for multidrug resistance reversal.

Overexpression of ABC transporters, such as ABCB1 and ABCG2, plays an important role in mediating multidrug resistance (MDR) in cancer. This feature is also attributed to a subpopulation of cancer stem cells (CSCs), having enhanced tumourigenic potential. ABCG2 is specifically associated with the CSC phenotype, making it a valuable target for eliminating aggressive and resistant cells. Several natural and synthetic ionophores have been discovered as CSC-selective drugs that may also have MDR-reversing ability, whereas their interaction with ABCG2 has not yet been explored. We previously reported the biological activities, including ABCB1 inhibition, of a group of adamantane-substituted diaza-18-crown-6 (DAC) compounds that possess ionophore capabilities. In this study, we investigated the mechanism of ABCG2-inhibitory activity of DAC compounds and the natural ionophores salinomycin, monensin and nigericin. We used a series of functional assays, including real-time microscopic analysis of ABCG2-mediated fluorescent substrate transport in cells, and docking studies to provide comparative aspects for the transporter-compound interactions and their role in restoring chemosensitivity. We found that natural ionophores did not inhibit ABCG2, suggesting that their CSC selectivity is likely mediated by other mechanisms. In contrast, DACs with amide linkage in the side arms demonstrated noteworthy ABCG2-inhibitory activity, with DAC-3Amide proving to be the most potent. This compound induced conformational changes of the transporter and likely binds to both Cavity 1 and the NBD-TMD interface. DAC-3Amide reversed ABCG2-mediated MDR in model cells, without affecting ABCG2 expression or localization. These results pave the way for the development of new crown ether compounds with improved ABCG2-inhibitory properties.

Synthetic Receptors Based on Abiotic Cyclo(pseudo)peptides.

Work on the use of cyclic peptides or pseudopeptides as synthetic receptors started even before the field of supramolecular chemistry was firmly established. Research initially focused on the development of synthetic ionophores and involved the use of macrocycles with a repeating sequence of subunits along the ring to facilitate the correlation between structure, conformation, and binding properties. Later, nonnatural amino acids as building blocks were also considered. With growing research in this area, cyclopeptides and related macrocycles developed into an important and structurally diverse receptor family. This review provides an overview of these developments, starting from the early years. The presented systems are classified according to characteristic structural elements present along the ring. Wherever possible, structural aspects are correlated with binding properties to illustrate how natural or nonnatural amino acids affect binding properties.

A water-soluble membrane transporter for biologically relevant cations.

Synthetic ionophores are promising therapeutic targets, yet poor water solubility limits their potential for translation into the clinic. Here we report a water-soluble, supramolecular self-associating amphiphile that functions as a cation uniporter in synthetic vesicle systems, deriving mechanistic insight through planar bilayer patch clamp experiments.

An Ionophore for High Lithium Loading and Selective Capture from Brine.

The continuous demand and uneven dispersal of natural mineral resources of lithium with a low recycling rate of lithium commodities have forced researchers to look for alternative resources like geothermal brine, brackish brines, and sea brines. But selective lithium-ion extraction and even lithium-ion binding from these aqueous systems is a recognized challenge due to very high hydration energy and the coexistence of other like metal ions but appealing due to economic benefits. Therefore, the designed synthesis of synthetic ionophores with high lithium selectivity is crucial as they can work on dilute conditions without removal of interfering metal ions. However, most of the lithium selective ionophores known in the literature are mononucleated, and no emphasis is given on designing multinucleating ionophore systems to improve the lithium loading capacity which will open up unexplored paths toward the development of a more sustainable and economical extraction process. Herein, we describe a rare fluorogenic macrocyclic ionophore with two binding pockets for selective lithium recognition and extraction among various major alkali and alkaline earth metal ions of oceanic presence through both solid-state and solution studies. Under solid-liquid extraction conditions, this receptor shows a high lithium loading capacity of 135% with LiClO4 and 69.16% with LiCl salt with exclusive selectivity. Under liquid-liquid extraction conditions, this ionophore shows a loading capacity of 27% with 1 M LiCl and 48.57% with 1 M LiClO4 source phase concentration. This new ionophore, therefore, inspiring further to modify and develop a better multinucleating extractant with high lithium loading capacity which is rare in the literature.

Synthetic ionophores as non-resistant antibiotic adjuvants.

Antimicrobial resistance is a world-wide health care crisis. New antimicrobials must both exhibit potency and thwart the ability of bacteria to develop resistance to them. We report the use of synthetic ionophores as a new approach to developing non-resistant antimicrobials and adjuvants. Most studies involving amphiphilic antimicrobials have focused on either developing synthetic amphiphiles that show ion transport, or developing non-cytotoxic analogs of such peptidic amphiphiles as colistin. We have rationally designed, prepared, and evaluated crown ether-based synthetic ionophores (‘hydraphiles’) that show selective ion transport through bilayer membranes and are toxic to bacteria. We report here that hydraphiles exhibit a broad range of antimicrobial properties and that they function as adjuvants in concert with FDA-approved antibiotics against multi-drug resistant (MDR) bacteria. Studies described herein demonstrate that benzyl C14 hydraphile (BC14H) shows high efficacy as an antimicrobial. BC14H, at sub-MIC concentrations, forms aggregates of ∼200 nm that interact with the surface of bacteria. Surface-active BC14H then localizes in the bacterial membranes, which increases their permeability. As a result, antibiotic influx into the bacterial cytosol increases in the presence of BCnHs. Efflux pump inhibition and accumulation of substrate was also observed, likely due to disruption of the cation gradient. As a result, BC14H recovers the activity of norfloxacin by 128-fold against resistant Staphylococcus aureus. BC14H shows extremely low resistance development and is less cytotoxic than colistin. Overall, synthetic ionophores represent a new scaffold for developing efficient and non-resistant antimicrobial-adjuvants.

Helical peptide–polyamine and –polyether conjugates as synthetic ionophores

Two new synthetic ionophores in which the hydrophobic portion is represented by a short helical Aib-peptide (Aib=α-amino-isobutyric acid) and the hydrophilic one is a poly-amino (1a) or a polyether (1b) chain have been prepared. The two conjugates show a high ionophoric activity in phospholipid membranes being able to efficiently dissipate a pH gradient and, in the case of 1b, to transport Na+ across the membrane. Bioactivity evaluation of the two conjugates shows that 1a has a moderate antimicrobial activity against a broad spectrum of microorganisms and it is able to permeabilize the inner and the outer membrane of Escherichia coli cells.

ChemInform Abstract: Biological Activity of Synthetic Ionophores: Ion transporters as Prospective Drugs?

AbstractReview: 111 refs.

Ion Transport through Lipid Bilayers by Synthetic Ionophores: Modulation of Activity and Selectivity

The ion-coupled processes that occur in the plasma membrane regulate the cell machineries in all the living organisms. The details of the chemical events that allow ion transport in biological systems remain elusive. However, investigations of the structure and function of natural and artificial transporters has led to increasing insights about the conductance mechanisms. Since the publication of the first successful artificial system by Tabushi and co-workers in 1982, synthetic chemists have designed and constructed a variety of chemically diverse and effective low molecular weight ionophores. Despite their relative structural simplicity, ionophores must satisfy several requirements. They must partition in the membrane, interact specifically with ions, shield them from the hydrocarbon core of the phospholipid bilayer, and transport ions from one side of the membrane to the other. All these attributes require amphipathic molecules in which the polar donor set used for ion recognition (usually oxygens for cations and hydrogen bond donors for anions) is arranged on a lipophilic organic scaffold. Playing with these two structural motifs, donor atoms and scaffolds, researchers have constructed a variety of different ionophores, and we describe a subset of interesting examples in this Account. Despite the ample structural diversity, structure/activity relationships studies reveal common features. Even when they include different hydrophilic moieties (oxyethylene chains, free hydroxyl, etc.) and scaffolds (steroid derivatives, neutral or polar macrocycles, etc.), amphipathic molecules, that cannot span the entire phospholipid bilayer, generate defects in the contact zone between the ionophore and the lipids and increase the permeability in the bulk membrane. Therefore, topologically complex structures that span the entire membrane are needed to elicit channel-like and ion selective behaviors. In particular the alternate-calix[4]arene macrocycle proved to be a versatile platform to obtain 3D-structures that can form unimolecular channels in membranes. In these systems, the selection of proper donor groups allows us to control the ion selectivity of the process. We can switch from cation to anion transport by substituting protonated amines for the oxygen donors. Large and stable tubular structures with nanometric sized transmembrane nanopores that provide ample internal space represent a different approach for the preparation of synthetic ion channels. We used the metal-mediated self-assembly of porphyrin ligands with Re(I) corners as a new method for producing to robust channel-like structures. Such structures can survive in the complex membrane environment and show interesting ionophoric behavior. In addition to the development of new design principles, the selective modification of the biological membrane permeability could lead to important developments in medicine and technology.

Biological activity of synthetic ionophores: ion transporters as prospective drugs?

The control of ion transport and homeostasis is a critical function of living organisms. In this perspective, an overview of different synthetic systems capable of facilitating the transmembrane transport of ions along with the biological activity exerted by these compounds is presented. Examples of both cation selective and anion selective transporters are highlighted. The potential future applications of these systems in the treatment of conditions derived from the dysregulation of natural ion transport mechanisms and the development of new antimicrobials and anticancer drugs are discussed.

Calcium Selectivity in Liquid Membrane Transport using Anthraquinone Derived Redox Switched Synthetic Ionophores

Selective recognition of alkali and alkaline earth metal ion pairs viz.Li+, Na+, K+, Mg2+ and Ca2+ is of great biological importance. Design and synthesis of ionophores and receptor molecules capable of selectively binding and transporting substrates (neutral and ionic) are based on molecular recognition and used to develop membrane separation systems. This has potential applications in analytical, environmental, and biomimetic chemistry. We have designed and synthesized new series of anthraquinone derived single and double armed ionophores. Supermolecules have been isolated with these synthetic podands as host and metal ions as guest. Interaction has been confirmed by melting point (m.p.), infrared red (IR), and proton nuclear magnetic resonance (1H NMR) spectral analysis and cyclic voltammetric studies. Further, the liquid liquid extraction, bulk liquid membrane (BLM) transport, and supported liquid membrane (SLM) transport studies using polytetrafloroethylene membrane, cellulose nitrate membrane, onion membrane and egg shell membrane, have been done to find out the selectivity of these ionophores for various metal ions. Among the two liquid membrane systems used SLMs is more efficient than BLMs. It is found that double armed and bridged ionophores (A3 to A8) show better extraction ability than single armed ionophores (A1, A2) and ionophore A3 is calcium selective.

Crown Ether Host-Rotaxanes as Cytotoxic Agents

Highly toxic bacterial ionophores are commonly used in veterinary medicine, but their therapeutic index is too narrow for human usage. With the goal of developing ionophores with a broader therapeutic index, we constructed highly derivatized synthetic ionophores. The toxicities of crown ether host-rotaxanes (CEHR's) against the SKOV-3 cell line were measured. The effect of Mg2+ or Ca2+ on toxicity was explored because changes in the intracellular concentration of these cations can cause cell death through apoptosis. We found Boc-CEHR is highly toxic and Arg-CEHR is slightly less toxic with IC50 values of 0.5 μM and 6 μM, respectively, in standard growth medium. Increasing the concentration of Ca2+ resulted in greater toxicity of the CEHRs, whereas increasing the concentration of Mg2+ was less effective on reducing IC50. Cell death occurs mainly through apoptosis. Although preliminary, these results suggest that the CEHRs deliver Ca2+ and perhaps Mg2+ into cells inducing apoptosis.

Selective transport of zinc and copper ions by synthetic ionophores using liquid membrane technology

This work highlights the role of synthetic carrier (ionophore) in the separation of heavy metal ions. A new series of ionophores; 4,4′-nitrophenyl-azo-O,O′-phenyl-3,6,9-trioxaundecane-1,10-dioate (R1), bis[4,4′nitro-phenylazo-naphthyl-(2,2-dioxydiethylether)] (R2) 1,8-bis-(2-naphthyloxy)-3,6-dioxaoctane (R3), 1,11-bis-(2-naphthyloxy)-3,6,9-trioxaunde-cane (R4), 1,5-bis-(2-naphthyloxy)-3-oxa-pentane (R5) have been synthesized and used as extractant as well as carrier for the transport of various metal ions (Na+, K+, Mg2+, Ni2+, Cu2+ and Zn2+) through liquid membranes. Effect of various parameters such as metal ion concentration, ionophore concentration, liquid–liquid extraction, back extraction, comparison of transport efficiency of BLM and SLM and different membrane support (hen’s egg shell and PTFE) have been studied. In BLM ionophores (R2–R5) transport Zn+ at greater extent and the observed trend for the transport of Zn2+ is R2 > R4 > R3 > R5 respectively. Further transport efficiency is increased in SLM. In egg shell membrane ionophores (R2–R5) transport Zn+ due to their non-cyclic structure and pseudo cavity formation while ionophore R1 transports Cu2+ ions at greater extent due to its cyclic structure and cavity size. Among the membrane support used egg shell membrane is found best for the transport of zinc ions because of its hydrophobic nature and exhibits electrostatic interactions between positively charged zinc ions and –COOH group of egg shell membrane. Thus structure of ionophores, hydrophobicity and porosity of the membrane support plays important role in separation of metal ions.

Characterization of Anthraquinone-DerivedRedox Switchable Ionophores and Their Complexes with Li+, Na+, K+, Ca+, and Mg+Metal Ions

Anthraquinone derived redox switchable ionophores 1,5 bis (2-(2-(2-ethoxy) ethoxy) ethoxy)anthracene-9,10-dione (V1) and 1,8-bis(2-(2-(2-ethoxy)ethoxy)ethoxy) anthracene—9,10-dione (V2) have been used for isolation, extraction and liquid membrane transport studies of Li+, Na+, K+, Ca2+and Mg2+metal ions. These isolated complexes were characterized by melting point determination, CV and IR,1H NMR spectral analysis. Ionophore V2shows maximum shift in reduction potential(ΔE)with Ca(Pic)2. The observed sequence for the shifting in reduction potential(ΔE)between V2and their complexes is V2calcium picrate (42 mV) > V2potassium picrate (33 mV) > V2lithium picrate (25 mV) > V2sodium picrate (18 mV) > V2magnesium picrate (15 mV). These findings are also supported by results of extraction, back extraction and transport studies. Ionophore V2complexed with KPic and showed much higher extractability and selectivity towards K+than V1. These synthetic ionophores show positive and negative cooperativity towards alkali and alkaline earth metal ions in reduced and oxidized state. Hence, this property can be used in selective separation and enrichment of metal ions using electrochemically driven ion transport.

Design, Synthesis and Characterisation of a Fluorescently Labelled CyPLOS Ionophore

A novel fluorescently labelled synthetic ionophore, based on a cyclic phosphate-linked disaccharide (CyPLOS) backbone and decorated with four tetraethylene glycol tails carrying dansyl units, has been synthesised in 12 steps in 26% overall yield. The key intermediate in the synthetic strategy is a novel glucoside building block, serving through its 2- and 3-hydroxy groups as the anchor point for flexible tetraethylene glycol tentacles with reactive azido moieties at their ends. To test the versatility of this glucoside scaffold, it was preliminarily functionalised with a set of diverse probes--as fluorescent, redox-active or hydrophobic tags--either by reduction of the azides followed by condensation with activated carboxylic acid derivatives, or by a direct coupling with a terminal alkyne in a Cu(I)-promoted 1,3-dipolar cycloaddition. Tagging of the monomeric building block with dansyl residues allowed us to prepare a fluorescent, amphiphilic macrocycle, which was investigated for its propensity to self-aggregate in CDCl(3)--studied by means of concentration-dependent (31)P NMR spectroscopy experiments--and in aqueous solution, in which combined dynamic light scattering (DLS) and small-angle neutron scattering (SANS) measurements provided a detailed physico-chemical analysis of the self-assembled systems, mainly organised in the form of large vesicles. Its ion-transport properties through phospholipid bilayers, determined by HPTS fluorescence assays, showed this compound to be more active than the previously synthesised CyPLOS congeners. Solvent-dependent fluorescence changes for the labelled ionophore in liposome suspension established that the dansyl moieties are dispersed in environments with polarity intermediate between those of CH(2)Cl(2) and propan-2-ol, suggesting that the CyPLOS tentacles infiltrate the mid-polar region of the membranes.

ChemInform Abstract: Synthetic Ionophores. Part 7. Synthesis and Ionophore Character of Uracil-Based Podands.

6-Methyl-1,3-oxazine-2,4(3H)-dione reacts with α,ω-dihalides under PTC conditions to give the 3,3′-(α,ω-dialkylene)bis[6-methyl-1,3-oxazine-2,4(3H)-diones]3, 11, 17. Further reactions of the latter with amines provide the bis(uracil) podands 5–10, 12–14, 18, 19 with different spacers between N-3 and functionalized alkyl appendages at N-1. The podands 5–10, 14, 18 and 19 are effective ionophores and 18 selectively extracts and transports Tl+ picrate, over Li+, Na+, K+ and NH4 picrates, across a chloroform membrane.

Fabrication of a novel iron(III)–PVC membrane sensor based on a new 1,1′-(iminobis(methan-1-yl-1-ylidene))dinaphthalen-2-ol synthetic ionophore for direct and indirect determination of free iron species in some biological and non-biological samples

In this novel, the iron(III)–PVC membrane sensor was investigated based on a new 1,1′-(iminobis(methan-1-yl-1-ylidene))dinaphthalen-2-ol (IBMYD) synthetic ionophore as a suitable carrier. The best performance was observed for the membrane composition including 33.0% PVC, 65.0% TEHP, 1.0% NaTPB and 1.0% ionophore. The electrode displayed a linear potential response over a wide concentration range from 1.0 × 10 −7 to 1.0 × 10 −1 mol L −1, with a detection limit of 5.0 × 10 −8 mol L −1 and a good Nernstian slope of 19.9 ± 0.3 mV decade −1. The sensor possessed some advantages such as short conditioning time, very fast response time (<12 s) and especially good discriminating ability towards Fe(III) ions over a wide variety of alkali, alkaline earth, transition, and heavy metal ions. The potential response of the proposed sensor was independent of the pH of the test solution, in the pH working range from 3.0 to 6.3. The fabricated electrode was applied for at least 2 months, without any measurable divergence in the potential characteristics. The optimized sensor was used successfully for direct and indirect determination of free iron species in some different synthetic and real samples with satisfactory results.

ChemInform Abstract: Transport of Chloride Ion Through Phospholipid Bilayers Mediated by Synthetic Ionophores.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Liquid Membrane Extraction &amp; Transport Studies of Some Divalent Metal Ions (Cu2+, Zn2+ and Ni2+) by Synthetic Ionophores

Liquid Membrane Extraction &amp; Transport Studies of Some Divalent Metal Ions (Cu2+, Zn2+ and Ni2+) by Synthetic Ionophores