Selective Anion Binding Research Articles

Oxoanion binding: a change of selectivity for porphyrin–alkaloid conjugates as a result of substitution pattern

The selective interaction of two porphyrin–brucine quaternary salts with oxoanions in a methanol/aqueous environment is described. The influence of both meta and para substitution of the tetraphenylporphyrin core with four brucine units on anion binding selectivity is discussed. The interaction of cationic porphyrin–brucine conjugates with anions are based not only on an anion-exchange mechanism; differences between the porphyrins tested also revealed the influence of peripheral substitution on the final selectivity.

Novel Residues Lining the CFTR Chloride Channel Pore Identified by Functional Modification of Introduced Cysteines

Substituted cysteine accessibility mutagenesis (SCAM) has been used widely to identify pore-lining amino acid side chains in ion channel proteins. However, functional effects on permeation and gating can be difficult to separate, leading to uncertainty concerning the location of reactive cysteine side chains. We have combined SCAM with investigation of the charge-dependent effects of methanethiosulfonate (MTS) reagents on the functional permeation properties of cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels. We find that cysteines substituted for seven out of 21 continuous amino acids in the eleventh and twelfth transmembrane (TM) regions can be modified by external application of positively charged [2-(trimethylammonium)ethyl] MTS bromide (MTSET) and negatively charged sodium [2-sulfonatoethyl] MTS (MTSES). Modification of these cysteines leads to changes in the open channel current-voltage relationship at both the macroscopic and single-channel current levels that reflect specific, charge-dependent effects on the rate of Cl(-) permeation through the channel from the external solution. This approach therefore identifies amino acid side chains that lie within the permeation pathway. Cysteine mutagenesis of pore-lining residues also affects intrapore anion binding and anion selectivity, giving more information regarding the roles of these residues. Our results demonstrate a straightforward method of screening for pore-lining amino acids in ion channels. We suggest that TM11 contributes to the CFTR pore and that the extracellular loop between TMs 11 and 12 lies close to the outer mouth of the pore.

Selective Anion Binding in Water with Use of a Zinc(II) Dipicolylamino Functionalized Diketopiperazine Scaffold

The design and synthesis of a diketopiperazine based anion receptor bearing two dipicolylamino arms complexed to zinc(II) ions is described. This receptor is readily prepared from the dipeptide precursor by a microwave-assisted intramolecular cyclization reaction. Upon addition of zinc(II), the receptor binds di- and triphosphate ions with high affinity and selectivity in aqueous solution, as determined by using a fluorescent indicator displacement assay.

A unique type of a dicobalt cage templated by a weakly coordinated hexafluorophosphate anion: design, structure and solid-state NMR investigations

A dinuclear cobalt capsule [PF(6) subset(CH(3)CN)(2)(Co(2)L(4))][PF(6)](3) (2), (L = bis-benzimidazole-1,3-phenylene) has been prepared using a self-assembly approach. This unique class of cage is perfectly designed to encapsulate weakly coordinated anions, i.e. BF(4)(-) and PF(6)(-)via an Manion weak interaction as illustrated by X-ray and solid-state NMR investigations. Selective anion binding for BF(4)(-) over PF(6)(-) is also observed.

Interlocked hostrotaxane and catenane structures for sensing charged guest species via optical and electrochemical methodologies

The potential of interlocked host rotaxane and catenane structures as innovative optical and electrochemical sensors is highlighted. Interlocked structures can be engineered to bind specific guests within the topologically constrained three dimensional cavities created during their template-driven syntheses. This binding ability, when coupled to the signal transduction capabilities associated with appended reporter groups and their dynamic structures, make catenanes and rotaxanes highly promising candidates for the development of molecular sensors. With the ultimate challenge of fabricating highly selective anion sensing configurations, a three-staged strategy has been followed. First, we developed a general anion templation methodology for the construction of a variety of interpenetrated and interlocked molecular structures. [2]Rotaxanes and [2]catenanes synthesised using this novel protocol show, after template removal, favourable selective anion binding characteristics distinct from their separate components. At the second stage, the incorporation of redox- and photo-active groups into these interlocked frameworks converts them into electrochemical/optical molecular sensors. In the final third stage, the confinement of interlocked anion receptors at surfaces results in the fabrication of devices exhibiting highly selective binding and electrochemical and/or optical sensing behaviour.

The Recognition and Sensing of Anions through “Positive Allosteric Effects” Using Simple Urea−Amide Receptors

The design, synthesis, and X-ray crystallographic analysis of three simple diaryl-urea based anion receptors possessing an amide moiety on one of the aryl groups, and an electron withdrawing CF(3) group on the other, is described. The three receptors differ only in the position of the amide functionality relative to the hydrogen bonding urea moiety (being para, meta, and ortho for 1, 2, and 3, respectively). This simple modification was shown to have a significant effect on the anion recognition ability, the strength of the recognition process, and the stoichiometry (host/guest) for these sensors. We demonstrate, by using both UV-vis absorption and (1)H NMR spectroscopy, that these factors are caused by the ability of the amide moiety to both modulate the anion binding selectivity and the sensitivity of the urea moiety. We also demonstrate that, in the case of 1 and 2, this anion recognition at the urea moiety leads to concomitant activation (through enhanced inductive effect) in the amide functionality toward anions, which leads to the formation of an overall 1:2 (sensor/anion) binding stoichiometry for these receptors. This "activation" we describe as being an example of a "positive allosteric activation" by the urea site, caused directly by the first anion binding interaction, which to the best of our knowledge, has not been previously demonstrated for anion recognition and sensing.

A new FeII quaterpyridyl M4L6 tetrahedron exhibiting selective anion binding

A rigid linear bis-bidentate quaterpyridine undergoes metal directed self-assembly with iron(ii) salts yielding M(4)L(6) host-guest complexes; selective anion binding for PF(6)(-) over BF(4)(-) is observed.

Anion binding properties of indolylmethanes

The anion binding properties of the indolylmethanes (1) were investigated by 1H-NMR spectroscopy in CDCl3. Tris(3-methylindol-2-yl)methane (1a) selectively bound a chloride anion the over other tested anions (Br−, I−, HSO4−, and NO3−). In contrast, analogous compounds, phenyl bis(3-methylindol-2-yl)methane (1b), 2-hydroxyphenyl bis(3-methylindol-2-yl)methane (1c), tri(indol-3-yl)methane (1d), and phenyl di(indol-2-yl)methane (1e), showed a low anion binding ability and selectivity. These results indicate that the number and a position of the binding sites (indole NH protons) of the indolylmethanes are important factors for the formation of the complex with an anion. The high binding ability and selectivity of 1a toward a chloride anion is attributed to the proper size of the binding pocket for a chloride anion and the formation of multiple hydrogen bonds between the three indole NH protons and a chloride anion. The anion affinity of 1a was significantly affected by the cation component of quaternary ammonium salts, indicating that it is ion pair binding and not solely anion binding.

Structural Variation Governs Substrate Specificity for Organic Anion Transporter (OAT) Homologs: POTENTIAL REMOTE SENSING BY OAT FAMILY MEMBERS

Organic anion transporters (OATs, SLC22) interact with a remarkably diverse array of endogenous and exogenous organic anions. However, little is known about the structural features that determine their substrate selectivity. We examined the substrate binding preferences and transport function of olfactory organic anion transporter, Oat6, in comparison with the more broadly expressed transporter, Oat1 (first identified as NKT). In analyzing interactions of both transporters with over 40 structurally diverse organic anions, we find a correlation between organic anion potency (pKi) and hydrophobicity (logP) suggesting a hydrophobicity-driven association with transporter-binding sites, which appears particularly prominent for Oat6. On the other hand, organic anion binding selectivity between Oat6 and Oat1 is influenced by the anion mass and net charge. Smaller mono-anions manifest greater potency for Oat6 and di-anions for Oat1. Comparative molecular field analysis confirms these mechanistic insights and provides a model for predicting new OAT substrates. By comparative molecular field analysis, both hydrophobic and charged interactions contribute to Oat1 binding, although it is predominantly the former that contributes to Oat6 binding. Together, the data suggest that, although the three-dimensional structures of these two transporters may be very similar, the binding pockets exhibit crucial differences. Furthermore, for six radiolabeled substrates, we assessed transport efficacy (Vmax) for Oat6 and Oat1. Binding potency and transport efficacy had little correlation, suggesting that different molecular interactions are involved in substrate binding to the transporter and translocation across the membrane. Substrate specificity for a particular transporter may enable design of drugs for targeting to specific tissues (e.g. olfactory mucosa). We also discuss how these data suggest a possible mechanism for remote sensing between OATs in different tissue compartments (e.g. kidney, olfactory mucosa) via organic anions.

Pyrazole Complexes as Anion Receptors: Effects of Changing the Metal, the Pyrazole Substitution Pattern, and the Number of Pyrazole Ligands

Compound cis,fac-[Mo(eta3-allyl)(CO)2(Hdmpz)3]BAr'4 (1) (Hdmpz = 3,5-dimethylpyrazole, Ar' = 3,5-bis(trifluoromethyl)phenyl) undergoes rapid substitution of one of the pyrazole ligands by anions, including the low nucleophilic ReO4-, a reaction that afforded [Mo(OReO3)(eta3-allyl)(CO)2(Hdmpz)2] (2), structurally characterized by X-ray diffraction. The new compounds fac-[Mn(CO)3(Hdmpz)3]BAr'4 (4a) and fac-[Mn(CO)3(HtBupz)3]BAr'4 (4b) (HtBupz = 3(5)-tert-butylpyrazole) also undergo pyrazole substitution with most anions, and the product from the reaction with nitrate was crystallographically characterized. Compounds 4a,b were found to be substitutionally stable toward perrhenate, and the adducts [Mn(CO)3(Hdmpz)3].[ReO4] (7a) and [Mn(CO)3(HtBupz)3].[ReO4].[Bu4N].[BAr'4] (7b), crystallographically characterized, display hydrogen bonds between one of the perrhenate oxygens and the N-H groups of two of the pyrazole ligands. The structurally similar adduct [Re(CO)3(Hdmpz)3].[ReO4] (8) was found to result from the interaction of [Re(CO)3(Hdmpz)3]BAr'4 with perrhenate. The reaction of [Re(OTf)(CO)5] with 3,5-dimethylpyrazole (Hdmpz) afforded [Re(CO)5(Hdmpz)]OTf (9). The reaction of 9 with Hdmpz and NaBAr'4 yielded [Re(CO)4(Hdmpz)2]BAr'4 (10), which was found to be unstable toward chloride anion. In contrast, the new compound fac,cis-[Re(CO)3(CNtBu)(Hdmpz)2]BAr'4 (11) is stable in solution in the presence of different anions. Binding constants for 11 with chloride, bromide, and nitrate are 1-2 orders of magnitude lower than those found for these anions and rhenium tris(pyrazole) hosts, indicating that the presence of the third pyrazole ligand is crucial. Compounds fac-[Re(CO)3(HPhpz)3]BAr'4 (14) (HPhpz = 3(5)-phenylpyrazole) and fac-[Re(CO)3(HIndz)3]BAr'4 (15) (HIndz = indazole) are, in terms of anion binding strength and selectivity, inferior to those with dimethylpyrazole or tert-butylpyrazole ligands.

Sulfoniumcalixpyrrole: the decoration of a calix[4]pyrrole host with positive charges boosts affinity and selectivity of anion binding in DMSO solvent

With the goal to improve host–guest binding affinity, while retaining guest selectivity, the parent calixpyrrole artificial receptor unit was decorated with four sulfonium moieties (e.g.3b) placed rigidly in symmetrical fashion remote from the core binding site. The determination of binding constants using isothermal titration calorimetry (ITC), in conjunction with trend analyses in a series of related anions, reveals the occurrence of several specific and unspecific binding steps. The former predominate in affinity by 20–1000 fold depending on guest charge and structure. The dissection of the free energy of association into its enthalpic and entropic parts, in combination with structural variation in the guest anion, offers insight into the nature and diversity of the guest binding modes. On these grounds, the supplementation of parent host scaffolds with rigidly positioned positive charge centers, holds promise as a general concept for anion binding in competitive media.

Synthesis, Structure, Anion Binding, and Sensing by Calix[4]pyrrole Isomers

The synthesis, structure, and anion binding properties of chromogenic octamethylcalix[4]pyrroles (OMCPs) and their N-confused octamethylcalix[4]pyrrole isomers (NC-OMCPs) containing an inverted pyrrole ring connected via alpha'- and beta-positions are described. X-ray diffraction analyses proved the structures of two synthesized isomeric pairs of OMCPs and NC-OMCPs. The addition of anions to solutions of chromogenic OMCPs and NC-OMCPs resulted in different colors suggesting different anion-binding behaviors. The chromogenic NC-OMCPs showed significantly stronger anion-induced color changes compared to the corresponding chromogenic OMCP, and the absorption spectroscopy titrations indicated that chromogenic OMCPs and NC-OMCPs also possess different anion binding selectivity. Detailed NMR studies revealed that this rather unusual feature stems from a different anion-binding mode in OMCPs and NC-OMCPs, one where the beta-pyrrole C-H of the inverted pyrrole moiety participates in the hydrogen-bonded anion-NC-OMCP complex. Preliminary colorimetric microassays using synthesized chromogenic calixpyrroles embedded in partially hydrophilic polyurethane matrices allow for observation of analyte-specific changes in color when the anions are administered in the form of their aqueous solutions and in the presence of weakly competing anions.

Metal salen complexes incorporating triphenoxymethanes: efficient, size selective anion binding by phenolic donors with a visual report

A metal salen complex has been designed to orientate four phenol groups into a tetrahedral array that tightly binds fluoride ion though four OH...F hydrogen bonding interactions.

Halide anion solvation and recognition by a macrotricyclic tetraammonium host in an ionic liquid: a molecular dynamics study

We report a molecular dynamics study of halide anions X− and their inclusion complexes X− ⊂ L4+ with a macrotricyclic tetrahedral host L4+ built from four quaternary ammonium sites, in an ionic liquid (IL) based on the 1-butyl-3-methylimidazolium (BMI+) cation and the PF6− anion. The “dry” and “humid” forms of the [BMI][PF6] IL are compared, showing the importance of IL ions in the “dry” IL and, in some cases, of water molecules in the “humid” IL. In the “dry” IL the F−, Cl−, Br− and I− uncomplexed halides are surrounded by 4–5 BMI+ cations whose binding mode evolves from hydrogen bonding to facial coordination along this series. Solvent humidity has the largest impact on the solvation of F− whose first shell BMI+ cations are all displaced by H2O molecules, while the first solvation shell of Cl−, Br− and I− comprises 3–4 BMI+ cations plus ca. 4 H2O molecules. The solvation of the L4+ host and of its X− ⊂ L4+ complex mainly involves PF6− anions in the “dry” IL, and additional H2O molecules in the “humid” IL. The question of anion binding selectivity is addressed by free energy perturbation calculations which predict that, in the “dry” liquid, F− is preferred over Cl−, Br− and I−, which contrasts with the aqueous solution where L4+ is selective for Cl−. In the “humid” liquid however, there is no F−/Cl− discrimination, showing the importance of “small amounts” of water on the complexation selectivity.

Anion Recognition by Neutral Macrocyclic Amides

Although amides often serve as anchoring groups in natural and synthetic anion receptors, the structure-affinity relationship studies of amide-based macrocyclic receptors are still very limited. Therefore, we decided to investigate the influence of the size of the macroring on the strength and selectivity of anion binding by uncharged, amide-based receptors. With this aim, we synthesized a series of macrocyclic tetraamides derived from 2,6-pyridinedicarboxylic acid and aliphatic alpha,omega-diamines of different lengths. X-ray analysis shows that all ligands studied adopt expanded conformations in the solid state with the convergent arrangement of all four hydrogen-bond donors. 1H NMR titrations in DMSO solution revealed a significant effect of the ring size on the stability constants of anion complexes; the 20-membered macrocyclic tetraamide 2 is a better anion receptor than its both 18- and 24-membered analogues. This effect cannot be interpreted exclusively in terms of matching between anion diameter and the size of macrocyclic cavity, because 2 forms the most stable complexes with all anions studied, irrespective of their sizes. However, geometric complementarity manifests in extraordinarily high affinity of 2 towards the chloride anion. The results obtained for solutions were interpreted in the light of solid-state structural studies. Taken together, these data suggest that anion binding by this family of macrocycles is governed by competitive interplay between their ability to adjust to a guest, requiring longer aliphatic spacers, and preorganization, calling for shorter spacers. The 20-membered receptor 2 is a good compromise between these factors and, therefore, it was selected as a promising leading structure for further development of anion receptors. Furthermore, the study of an open chain analogue of 2 revealed a substantial macrocyclic effect. X-ray structure of the acyclic model 14 suggests that this may be due to its ill-preorganized conformation, stabilized by two intramolecular hydrogen bonds.

Buried Solvent Determines Both Anion-Binding Selectivity and Binding Stoichiometry with Hydrogen-Bonding Receptors

[reaction: see text] The crystal structure of a tetraurea picket porphyrin-chloride anion complex has previously shown the anion to be situated between two adjacent ureas and hydrogen bonded via four NH protons (J. Am. Chem. Soc. 1998, 120, 11684-11692). The porphyrin receptor also binds a DMSO molecule and utilizes it as a participant in its anion recognition unit, in a manner similar to enzymes that bind water for use as part of their substrate recognition unit. The bound solvent molecule determines the anion-binding affinity, selectivity, and stoichiometry of binding. With a bound DMSO molecule, the tetraurea picket porphyrin is a highly selective receptor for chloride anion and binds all anions with a 1:1 binding stoichiometry. Absent the buried DMSO molecule, the receptor is selective for phosphate anion and binds chloride and phosphate anions with both 1:1 and 1:2 receptor-anion stoichiometries. Additionally, a remarkable reversal in the selectivity of anion complexation between various picket porphyrin receptors is observed, wherein the binding constant ratios change over 3 orders of magnitude as the receptor's number of urea pickets change from four to two. The latter receptor has no urea pickets available to bind to solvent after complexation with an anion. The results demonstrate that anion complexation with hydrogen-bonding receptors in a competitive solvent is enhanced when a ubiquitous solvent molecule is incorporated into the binding motif. In this way, competitive solvent adds to the overall complexation energy and thereby strengthens binding rather than weakens it, as commonly believed. The results are pertinent to drug design, for they suggest that pharmaceuticals need not be completely desolvated to selectively bind to their biological target when water can be included in the binding motif.

Direct Comparison of the Functional Roles Played by Different Transmembrane Regions in the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel contains 12 transmembrane (TM) regions that are presumed to form the channel pore. However, little is known about the relative functional contribution of different TM regions to the pore. We have used patch clamp recording to investigate the functional consequences of point mutations throughout the six transmembrane regions in the N-terminal part of the CFTR protein (TM1-TM6). A range of specific functional assays compared the single channel conductance, anion binding, and anion selectivity properties of different channel variants. Overall, our results suggest that TM1 and -6 play dominant roles in forming the channel pore and determining its functional properties, with TM5 perhaps playing a lesser role. In contrast, TM2, -3, and -4 appear to play only minor supporting roles. These results define transmembrane regions 1 and 6 as major contributors to the CFTR channel pore and have strong implications for emerging structural models of CFTR and related ATP-binding cassette proteins.

The Selective Binding of Anions to Gemini and Trimeric Surfactants at Air/Solution Interfaces

The selective binding of Br–, Cl–, I–, NO3–, and salicylate anions to quaternary ammonium gemini and trimer surfactant solution/air interfaces has been studied by ion flotation, examining the effect of the degree of oligomerization and polymethylene spacer length between the quaternary nitrogen atoms. The binding of the halides and nitrate showed no significant change with degree of oligomerization. However, salicylate showed a marked decrease in selective uptake with increasing degree of oligomerization, and increased with increasing spacer length.

A novel ditopic receptor and reversal of anion binding selectivity in the presence and absence of bound cation.

A calix[4]arene-derived ditopic receptor 1 has been synthesized. In the absence of Na+, the receptor binds acetate in preference to diphenyl phosphate (as the tetrabutylammonium salts), but in the presence of Na+, the selectivity is reversed and the receptor, instead, binds diphenyl phosphate, and not acetate, which preferentially forms a salt ion-pair in free solution. [structure: see text]

CFTR: what's it like inside the pore?

The Cystic Fibrosis Conductance Regulator (CFTR) functions as a cAMP-activated, anion-selective channel, but the structural basis for anion permeation is not well understood. Here we summarize recent studies aimed at understanding how anions move through the CFTR channel, and the nature of the environment anions experience inside the pore. From these studies it is apparent that anion permeability selectivity and anion binding selectivity of the pore are consistent with a model based on a "dielectric tunnel." The selectivity pattern for halides and pseudohalides can be predicted if it is assumed that permeant anions partition between bulk water and a polarizable space that is characterized by an effective dielectric constant of about 19. Covalent labeling of engineered cysteines and pH titration of engineered cysteines and histidines lead to the conclusion that the CFTR anion conduction path includes a positively charged outer vestibule. A residue in transmembrane segment 6 (TM6) (R334) appears to reside in the outer vestibule of the CFTR pore where it creates a positive electrostatic potential that enhances anion conduction.