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We have all either been asked or seen others asked: “So when are you going to have children?” –at family gatherings, as a casual aside by colleagues, or even by complete strangers. There is societal judgement around having children, not having children, when to have children, and how many children to have. Even if we put aside the recent US Supreme Court decision to overturn the 1973 Roe v Wade decision and with it remove long-held rights around access to abortion in the US, there are numerous other ways in which reproductive choices are becoming weaponised, and what may seem to some an innocuous question is racialised, gendered, and loaded.

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.

The rise of antimicrobial resistance remains one of the greatest global health threats facing humanity. Furthermore, the development of novel antibiotics has all but ground to a halt due to a collision of intersectional pressures. Herein we determine the antimicrobial efficacy for 14 structurally related supramolecular self-associating amphiphiles against clinically relevant Gram-positive methicillin resistant Staphylococcus aureus and Gram-negative Escherichia coli. We establish the ability of these agents to selectively target phospholipid membranes of differing compositions, through a combination of computational host:guest complex formation simulations, synthetic vesicle lysis, adhesion and membrane fluidity experiments, alongside our novel 1H NMR CPMG nanodisc coordination assays, to verify a potential mode of action for this class of compounds and enable the production of evermore effective next-generation antimicrobial agents. Finally, we select a 7-compound subset, showing two lead compounds to exhibit ‘druggable’ profiles through completion of a variety of in vivo and in vitro DMPK studies.

A water-soluble self-assembled supramolecular FeII4L4 tetrahedron binds to single stranded DNA, mismatched DNA base pairs, and three-way DNA junctions. Binding of the coordination cage quenches fluorescent labels on the DNA strand, which provides an optical means to detect the interaction and allows the position of the binding site to be gauged with respect to the fluorescent label. Utilizing the quenching and binding properties of the coordination cage, we developed a simple and rapid detection method based on fluorescence quenching to detect unpaired bases in double-stranded DNA.

Since the discovery of the G-quadruplex (G4) structure in telomeres in 1980s, studies have established the role it plays in various biological processes. Here we report binding between DNA G4 and a self-assembled tetrahedral metal-organic cage 1 and consequent formation of aggregates, whereby the cage protects the DNA G4 from cleavage by S1 nuclease. We monitor DNA–cage interaction using fluorescence spectroscopy, firstly by quenching of a fluorescent label appended to the 5′ end of G4. Secondly, we detect the decrease in fluorescence of the G4-selective dyes thioflavin-T and Zn-PPIX bound to various DNA G4 sequences following the addition of cage 1. Our results demonstrate that 1 interacts with a wide range of G4s. Moreover, gel electrophoresis, circular dichroism and dynamic light scattering measurements establish the binding of 1 to G4 and indicate the formation of aggregate structures. Finally, we find that DNA G4 contained in an aggregate of cage 1 is protected from cleavage by S1 nuclease., We find FeII4L4 binds to G-quadruplex and forms aggregates. G-quadruplex in the aggregates is protected from digestion by S1 nuclease.

In recent years, luminescent supramolecular coordination complexes (SCCs), including 2D-metallacycles and 3D-metallacages have been utilised for biomolecular analysis. Unlike small-molecular probes, the dimensions, size, shape, and flexibility of these complexes can easily be tuned by combining ligands designed with particular geometries, symmetries and denticity with metal ions with strong geometrical binding preferences. The well-defined cavities that result, in combination with the other non-covalent interactions that can be programmed into the ligand design, facilitate great selectivity towards guest binding. In this Review we will discuss the application of luminescent metallacycles and cages in the binding and detection of a wide range of biomolecules, such as carbohydrates, proteins, amino acids, and biogenic amines. We aim to explore the effect of the structural diversity of SCCs on the extent of biomolecular sensing, expressed in terms of sensitivity, selectivity and detection range.

Celebrating Supramolecular Chemistry and Mentoring: ChemPlusChem is pleased to publish a Special Collection on Supramolecular Chemistry: Young Talents and their Mentors, guest-edited by Anna McConnell, Cally Haynes, Claudia Caltagirone, and Jennifer Hiscock. The Special Collection features recent developments in supramolecular chemistry and highlights mentoring relationships between emerging investigators and their mentors.

Coordination cages encapsulate a wide variety of guests in the solution state. This ability renders them useful for applications such as catalysis and the sequestration of precious materials. A simple and general method for the immobilization of coordination cages on alumina is reported. Cage loadings are quantified via adsorption isotherms and guest displacement assays demonstrate that the adsorbed cages retain the ability to encapsulate and separate guest and non-guest molecules. Finally, a system of two cages, adsorbed on to different regions of alumina, stabilizes and separates a pair of Diels-Alder reagents. The addition of a single competitive guest results in the controlled release of the reagents, thus triggering their reaction. This method of coordination cage immobilization on solid phases is envisaged to be applicable to the extensive library of reported cages, enabling new applications based upon selective solid-phase molecular encapsulation.

Metal-organic anion channels based on Zn10 L15 pentagonal prisms have been prepared by subcomponent self-assembly. The insertion of these prisms into lipid membranes was investigated by ion-current and fluorescence measurements. The channels were found to mediate the transport of Cl- anions through planar lipid bilayers and into vesicles. Tosylate anions were observed to bind and plug the central channels of the prisms in the solid state and in solution. In membranes, dodecyl sulfate blocked chloride transport through the central channel. Our Zn10 L15 prism thus inserts into lipid bilayers to turn on anion transport, which can then be turned off through addition of the blocker dodecyl sulfate.

A water-soluble self-assembled supramolecular FeII4L4 tetrahedron binds to single stranded DNA, mismatched DNA base pairs, and three-way DNA junctions. Binding of the coordination cage quenches fluorescent labels on the DNA strand, which provides an optical means to detect the interaction and allows the position of the binding site to be gauged with respect to the fluorescent label. Utilizing the quenching and binding properties of the coordination cage, we developed a simple and rapid detection method based on fluorescence quenching to detect unpaired bases in double-stranded DNA.

An unreported d,l‐tripeptide self‐assembled into gels that embedded FeII 4L4 metal–organic cages to form materials that were characterized by TEM, EDX, Raman spectroscopy, rheometry, UV/Vis and NMR spectroscopy, and circular dichroism. The cage type and concentration modulated gel viscoelasticity, and thus the diffusion rate of molecular guests through the nanostructured matrix, as gauged by 19F and 1H NMR spectroscopy. When two different cages were added to spatially separated gel layers, the gel–cage composite material enabled the spatial segregation of a mixture of guests that diffused into the gel. Each cage selectively encapsulated its preferred guest during diffusion. We thus present a new strategy for using nested supramolecular interactions to enable the separation of small molecules.

An unreported d,l-tripeptide self-assembled into gels that embedded FeII4L4 metal–organic cages to form materials that were characterized by TEM, EDX, Raman spectroscopy, rheometry, UV/Vis and NMR spectroscopy, and circular dichroism. The cage type and concentration modulated gel viscoelasticity, and thus the diffusion rate of molecular guests through the nanostructured matrix, as gauged by 19F and 1H NMR spectroscopy. When two different cages were added to spatially separated gel layers, the gel–cage composite material enabled the spatial segregation of a mixture of guests that diffused into the gel. Each cage selectively encapsulated its preferred guest during diffusion. We thus present a new strategy for using nested supramolecular interactions to enable the separation of small molecules., Un tripéptido d,l no informado se autoensambló en geles que incrustaron jaulas metalorgánicas de Fe II 4 L 4 para formar materiales que se caracterizaron por TEM, EDX, espectroscopia Raman, reometría, espectroscopia UV/Vis y NMR, y dicroísmo circular. El tipo de jaula y la concentración modularon la viscoelasticidad del gel y, por lo tanto, la tasa de difusión de los huéspedes moleculares a través de la matriz nanoestructurada, medida por 19 F y 1Espectroscopía de RMN H. Cuando se agregaron dos jaulas diferentes a capas de gel separadas espacialmente, el material compuesto de jaula de gel permitió la segregación espacial de una mezcla de invitados que se difundió en el gel. Cada jaula encapsuló selectivamente a su huésped preferido durante la difusión. Por lo tanto, presentamos una nueva estrategia para utilizar interacciones supramoleculares anidadas para permitir la separación de moléculas pequeñas.

Porous materials are widely used in industry for applications that include chemical separations and gas scrubbing. These materials are typically porous solids, although the liquid state can be easier to manipulate in industrial settings. The idea of combining the size and shape selectivity of porous domains with the fluidity of liquids is a promising one and porous liquids composed of functionalized organic cages have recently attracted attention. Here we describe an ionic-liquid, porous, tetrahedral coordination cage. Complementing the gas binding observed in other porous liquids, this material also encapsulates non-gaseous guests-shape and size selectivity was observed for a series of isomeric alcohols. Three gaseous chlorofluorocarbon guests, trichlorofluoromethane, dichlorodifluoromethane and chlorotrifluoromethane, were also shown to be taken up by the liquid coordination cage with an affinity that increased with their size. We hope that these findings will lead to the synthesis of other porous liquids whose guest-uptake properties may be tailored to fulfil specific functions.

Two differently protected aldehydes, A and B, were demonstrated to deprotect selectively through the application of light and heat, respectively. In the presence of iron(II) and a triamine, two distinct Fe

A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N–H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical monosquaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured. ARC, FCT, CICECO, EPSRC, Royal Society, Wolfson Foundation

An unprecedented Fe

An unprecedented Fe2Pc3 metallo-organic helicate has been assembled using a bidentate phthalocyanine (Pc) ligand, 2-formylpyridine and Fe(OTf)2. This giant helicate has proved itself as a host for large redox-active guests such as fullerene and naphthalenediimide derivatives. Photoactivated electronic interactions between components occur in the host-guest complex, Financial support from Comunidad de Madrid, Spain (S2013/MIT-2841, FOTOCARBON), and MINECO, Spain (CTQ2017-85393-P), and the UK EPSRC (EP/M008258/2) is acknowledged

Metal-organic anion channels based on Zn

A new series of structurally simple compounds containing thiourea groups have been shown by a combination of ion-selective electrode and 13C NMR techniques to be potent chloride-bicarbonate exchange agents that function at low concentration in POPC and POPC/cholesterol membranes.

The transmembrane anion transport activity of 43 synthetic molecules based on the structure of marine alkaloid tambjamine were assessed in model phospholipid (POPC) liposomes. The anionophoric activity of these molecules showed a parabolic dependence with lipophilicity, with an optimum range for transport efficiency. Using a quantitative structure–transport activity (QSAR) approach it was possible to rationalize these results and to quantify the contribution of lipophilicity to the transport activity of these derivatives. While the optimal value of log P and the curvature of the parabolic dependence is a property of the membrane (and so similar for the different series of substituents) we found that for relatively simple substituents in certain locations on the tambjamine core, hydrophobic interactions clearly dominate, but for others, more specific interactions are present that change the position of the membrane hydrophobicity parabolic envelope., RQ acknowledges funding from Consejer´ıa de Educaci´on de la Junta de Castilla y Le´on (Project BU340U13) and Fundaci´o la Marat´o de TV3 (20132730). PAG thanks the EPSRC for funding (EP/J009687/1 and EP/K039466/1). COST CM1005 Supramolecular Chemistry in Water for a STSM (EH). JGF thanks the EPSRC (GR/R67729 & EP/ K003569) for funding

Simple, highly fluorinated receptors are shown to function as effective transmembrane anion transporters with the most active transporters rivalling the transport efficacy of natural anion transporter prodigiosin for chloride/bicarbonate antiport.

This review covers advances in anion complexation in the years 2011 and 2012. The review covers both organic and inorganic systems and also highlights the applications to which anion receptors can be applied such as self-assembly and molecular architecture, sensing, catalysis and anion transport.

Despite extensive interest in transmembrane anion carriers (anionophores), the factors that govern activity are still only partly understood. Herein we report a study which identifies a new principle for anionophore design, that of “lipophilic balance”. A series of simple thioureas with identical molecular formulae has been prepared and assayed for chloride/nitrate transport activity in synthetic vesicles. The molecules differ only in the positioning of the phenylthiourea binding unit within an 11-carbon linear chain. They are shown to possess very similar lipophilicities and anion affinities, while a test for leaching establishes that they locate almost exclusively in the vesicle membranes. Notwithstanding their close similarities, activities across the series show >5-fold variation, peaking when the phenylthiourea group is centrally located. The results suggest that transport is favoured by a balanced array of lipophilic substituents, possibly because this arrangement facilitates transfer of the complexed anion into the apolar membrane interior., info:eu-repo/semantics/published

Small molecule synthetic anion transporters may have potential application as therapeutic agents for the treatment of diseases including cystic fibrosis and cancer. Understanding the factors that can dictate the anion transport activity of such transporters is a crucial step towards their application in biological systems. In this study a series of acylthiourea anion transporters were synthesised and their anion binding and transport properties in POPC bilayers have been investigated. The transport activity of these receptors is dominated by their lipophilicity, which is in turn dependent on both substituent effects and the formation and strength of an intramolecular hydrogen bond as inferred from DFT calculations. This is in contrast to simpler thiourea systems, in which the lipophilicity depends predominantly on substituent effects atone.

Highly potent but structurally simple transmembrane anion transporters are reported that function at receptor to lipid ratios as low as 1 : 1 000 000. The compounds, based on the simple ortho-phenylenediamine-based bisurea scaffold, have been studied for their ability to facilitate chloride/nitrate and chloride/bicarbonate antiport, and HCl symport processes using a combination of ion selective electrode and fluorescence techniques. In addition, the transmembrane transport of dicarboxylate anions (maleate and fumarate) by the compounds was examined. Molecular dynamics simulations showed that these compounds permeate the membrane more easily than other promising receptors corroborating the experimental efflux data. Moreover, cell based assays revealed that the majority of the compounds showed cytotoxicity in cancer cells, which may be linked to their ability to function as ion transporters.

Studies of sulfamide, phosphoric triamide and thiophosphoric triamide-based organocatalysts show that the phosphorus containing systems are effective new hydrogen bonding motifs for the recognition and transport of anions.

A series of neutral thiourea receptors were found to mediate the antiport of chloride with a range of biologically relevant carboxylate anions across phospholipid bilayers. Simple structural modification of the carriers resulted in a change in the lactate/pyruvate transport selectivity.

Heterocyclic groups can play key roles as hydrogen bond donors and charged components in a wide range of anion receptors. This chapter reviews the roles the heterocycles play in anion recognition, covering pyrrole-based systems (both macrocyclic and acyclic, including synthetic systems and natural products such as prodigiosin), indole-based receptors, and foldamers- and charged-imidazolium-based hosts. The chemistry of pyridine- and quinoline-based receptors, including metal-templated systems that employ transition metals to assemble simple organic components, and the role of bipyridinium in anion complexation and sensing are also reviewed. Finally, the chemistry of 1,2,3-triazoles as components of hosts that use CH· · ·anion hydrogen bonds to complex anionic guests is examined. Keywords: anion complexation; hydrogen bonds; heterocycles; molecular recognition; lipid bilayer transport; sensing; prodigiosin; pyrrole; indole; imidazole

This highlight examines recent advances in the development of synthetic membrane transporters for anions, highlighting the underlying principles of transporter design and the promising applications of such transporters to biological systems including potential future treatments for diseases like cystic fibrosis which is caused by dysregulation of chloride transport across epithelial cell membranes.

A ditopic ion-pair receptor (1), which has tunable cation- and anion-binding sites, has been synthesized and characterized. Spectroscopic analyses provide support for the conclusion that receptor 1 binds fluoride and chloride anions strongly and forms stable 1:1 complexes ([1·F](-) and [1·Cl](-)) with appropriately chosen salts of these anions in acetonitrile. When the anion complexes of 1 were treated with alkali metal ions (Li(+), Na(+), K(+), Cs(+), as their perchlorate salts), ion-dependent interactions were observed that were found to depend on both the choice of added cation and the initially complexed anion. In the case of [1·F](-), no appreciable interaction with the K(+) ion was seen. On the other hand, when this complex was treated with Li(+) or Na(+) ions, decomplexation of the bound fluoride anion was observed. In contrast to what was seen with Li(+), Na(+), K(+), treating [1·F](-) with Cs(+) ions gave rise to a stable, host-separated ion-pair complex, [F·1·Cs], which contains the Cs(+) ion bound in the cup-like portion of the calix[4]pyrrole. Different complexation behavior was seen in the case of the chloride complex, [1·Cl](-). Here, no appreciable interaction was observed with Na(+) or K(+). In contrast, treating with Li(+) produces a tight ion-pair complex, [1·Li·Cl], in which the cation is bound to the crown moiety. In analogy to what was seen for [1·F](-), treatment of [1·Cl](-) with Cs(+) ions gives rise to a host-separated ion-pair complex, [Cl·1·Cs], in which the cation is bound to the cup of the calix[4]pyrrole. As inferred from liposomal model membrane transport studies, system 1 can act as an effective carrier for several chloride anion salts of Group 1 cations, operating through both symport (chloride+cation co-transport) and antiport (nitrate-for-chloride exchange) mechanisms. This transport behavior stands in contrast to what is seen for simple octamethylcalix[4]pyrrole, which acts as an effective carrier for cesium chloride but does not operates through a nitrate-for-chloride anion exchange mechanism.

This highlight examines recent advances in the development of synthetic membrane transporters for anions, highlighting the underlying principles of transporter design and the promising applications of such transporters to biological systems including potential future treatments for diseases like cystic fibrosis which is caused by dysregulation of chloride transport across epithelial cell membranes.

The transmembrane transport of anions by small synthetic molecules is a growing field in supramolecular chemistry and has focussed mainly on the transmembrane transport of chloride. On the other hand, the transport of the highly hydrophilic sulfate anion across lipid bilayers is much less developed, even though the inability to transport sulfate across cellular membranes has been linked to a variety of genetic diseases. Tris-thioureas possess high sulfate affinities and have been shown to be excellent chloride and bicarbonate transporters. Herein we report the sulfate transport abilities of a series of tris-ureas and tris-thioureas based on a tris(2-aminoethyl)amine or cyclopeptide scaffold. We have developed a new technique based on 33S NMR that can be used to monitor sulfate transport, using 33S-labelled sulfate and paramagnetic agents such as Mn2+ and Fe3+ to discriminate between intra- and extravesicular sulfate. Reasonable sulfate transport abilities were found for the reported tris-ureas and tris-thioureas, providing a starting point for the development of more powerful synthetic sulfate transporters that can be used in the treatment of certain channelopathies or as a model for biological sulfate transporters.

The transport of anions across biological membranes by small molecules is a growing research field due to the potential therapeutic benefits of these compounds. However, little is known about the exact mechanism by which these drug-like molecules work and which molecular features make a good transporter. An extended series of 1-hexyl-3-phenylthioureas were synthesized, fully characterized (NMR, mass spectrometry, IR and single crystal diffraction) and their anion binding and anion transport properties were assessed using H-1 NMR titration techniques and a variety of vesicle-based experiments. Quantitative structure-activity relationship (QSAR) analysis revealed that the anion binding abilities of the mono-thioureas are dominated by the (hydrogen bond) acidity of the thiourea NH function. Furthermore, mathematical models show that the experimental transmembrane anion transport ability is mainly dependent on the lipophilicity of the transporter (partitioning into the membrane), but smaller contributions of molecular size (diffusion) and hydrogen bond acidity (anion binding) were also present. Finally, we provide the first step towards predictable anion transport by employing the QSAR equations to estimate the transmembrane transport ability of four new compounds.

A series of bis-indolylureas have been found to mediate chloride transport across vesicle bilayers. The anion transport activity of these receptors may be readily modulated by small structural changes to the receptor scaffold as shown by the combination of experimental chloride efflux studies and molecular dynamics simulations in water and POPC bilayers.

Lewis acidic boranes containing the -BMes2 unit (Mes = 2,4,6-Me3C6H2) have been widely exploited in molecular sensors for the fluoride ion reflecting, at least in part, the stability to air and moisture of derivatives of the type ArBMes2. In the current study, the fluoride binding capabilities of the simplest such system, PhBMes2 (1), have been investigated by spectroscopic and crystallographic methods, with a view to experimentally determining the fundamental thermodynamic and structural parameters associated with this host/guest interaction. A binding constant, KF, of 8.9(1.9) × 104 M-1 in dichloromethane solution and a B-F bond length of 1.481(2) for the salt [nBu4N]+[PhMes 2BF]- have thus been elucidated and provide a baseline for the analysis of more complex systems. Competitive binding of the cyanide ion is implied by a similar binding constant, KCN, of 1.9(0.5) × 105 M-1; structurally, similar degrees of pyramidalization of the BC3 framework are observed on coordination of each anion {Σ(C-B-C) = 339.8, 340.1°for [nBu4N] +[PhMes2BF]- and [K(18-crown-6)] +[PhMes2BCN]-, respectively}. Linking of two ArBMes2 units via an alkyne spacer results in a 2,2′- bis(dimesitylboryl)tolan system, which is characterized by independent binding of two equivalents of the CN- anion, rather than cyanide chelation. © 2010 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Easy-to-make tripodal tris-thiourea receptors based upon tris(2-aminoethyl)amine are capable of chloride/bicarbonate transport and as such represent a new class of bicarbonate transport agent.

Two differently protected aldehydes, A and B, were demonstrated to deprotect selectively through the application of light and heat, respectively. In the presence of iron(II) and a triamine, two distinct FeII4L4 cages, 1 and 2, were thus observed to form from the deprotected A and B, respectively. The alkyl tails of B and 2 render them preferentially soluble in cyclopentane, whereas A and 1 remain in acetonitrile. The stimulus applied (either light or heat) thus determines the outcome of self-assembly and dictates whether the cage and its ferrocene cargo remain in acetonitrile, or transport into cyclopentane. Cage self-assembly and cargo transport between phases can in this fashion be programmed using orthogonal stimuli.

Since the discovery of the G-quadruplex (G4) structure in telomeres in 1980s, studies have established the role it plays in various biological processes. Here we report binding between DNA G4 and a self-assembled tetrahedral metal-organic cage 1 and consequent formation of aggregates, whereby the cage protects the DNA G4 from cleavage by S1 nuclease. We monitor DNA-cage interaction using fluorescence spectroscopy, firstly by quenching of a fluorescent label appended to the 5’ end of G4. Secondly, we detect the decrease in fluorescence of the G4-selective dyes Thioflavin-T and Zn-PPIX bound to various DNA G4 sequences following the addtion of cage 1. Our results demonstrate that 1 interacts with a wide range of G4s. Moreover, gel electrophoresis, circular dichroism and dynamic light scattering measurements establish the binding of 1 to G4 and indicate the formation of aggregate structures. Finally, we find that DNA G4 contained in an aggregate of cage 1 is protected from cleavage by S1 nuclease.