Coupling Photoresponsive Transmembrane Ion Transport with Transition Metal Catalysis.

Artificial ion transporters have been explored both as tools for studying fundamental ion transport processes and as potential therapeutics for cancer and channelopathies. Here we demonstrate that synthetic transporters may also be used to regulate the transport of catalytic metal ions across lipid membranes and thus control chemical reactivity inside lipid-bound compartments. We show that acyclic lipophilic pyridyltriazoles enable Pd(II) cations to be transported from the external aqueous phase across the lipid bilayer and into the interior of large unilamellar vesicles. In situ reduction generates Pd(0) species, which catalyze the generation of a fluorescent product. Photocaging the Pd(II) transporter allows for photoactivation of the transport process and hence photocontrol over the internal catalysis process. This work demonstrates that artificial transporters enable control over catalysis inside artificial cell-like systems, which could form the basis of biocompatible nanoreactors for applications such as drug synthesis and delivery or to mediate phototargeted catalyst delivery into cells.

Transient Photoactivation of Anionophores by Using Redshifted Fast-Relaxing Azobenzenes.

Photo-regulated transmembrane ionophores enable spatial and temporal control over activity, offering promise as targeted therapeutics. Key to such applications is control using bio-compatible visible light. Herein, we report red-shifted azobenzene-derived synthetic anionophores that use amber or red light to trigger (E)-(Z) photoisomerisation and activation of transmembrane chloride transport. We demonstrate that by tuning the thermal half-life of the more active, but thermodynamically unstable, Z isomer to relax on the timescale of minutes, transient activation of ion transport can be achieved by activating with solely with visible light and deactivating by thermal relaxation.

Photoswitchable luminescent lanthanide complexes controlled and interrogated by four orthogonal wavelengths of light.

Optical information storage requires careful control of excitation and emission wavelengths in a reversible and orthogonal manner to enable efficient reading, writing, and erasing of information. Photochromic systems, in which a photoswitch is typcially coupled to an emissive organic fluorophore, have much promise in this regard. However, these suffer from considerable spectral overlap between the switch and fluorophore, such that their emissive and photoswitchable properties are not orthogonal. Here, we overcome this limitation by coupling visible/NIR emissive lanthanide complexes with molecular photoswitches, enabling reversible and orthogonal photoswitching with visible light. Crucially, photoswitching does not lead to sensitised emission from the lanthanide, while excitation of the lanthanide does not induce photoswitching, enabling the state of the system to be probed without perturbation of the switch. This opens up the possibility of developing multi-colour read-write methods for information storage using emissive photoswitches.

Responsive Anionophores with AND Logic Multi-Stimuli Activation.

Artificial ion transport systems have emerged as an important class of compounds that promise applications in chemotherapeutics as anticancer agents or to treat channelopathies. Stimulus-responsive systems that offer spatiotemporally controlled activity for targeted applications remain rare. Here we utilize dynamic hydrogen bonding interactions of a 4,6-dihydroxy-isophthalamide core to generate a modular platform enabling access to stimuli-responsive ion transporters that can be activated in response to a wide variety of external stimuli, including light, redox, and enzymes, with excellent OFF-ON activation profiles. Alkylation of the two free hydroxyl groups with stimulus-responsive moieties locks the amide bonds through intramolecular hydrogen bonding and hence makes them unavailable for anion binding and transport. Triggering using a particular stimulus to cleave both cages reverses the hydrogen bonding arrangement, to generate a highly preorganized anion binding cavity for efficient transmembrane transport. Integration of two cages that are responsive to orthogonal stimuli enables multi-stimuli activation, where both stimuli are required to trigger transport in an AND logic process. Importantly, the strategy provides a facile method to post-functionalize the highly active transporter core with a variety of stimulus-responsive moieties for targeted activation with multiple triggers.

Molecular Machines For The Control Of Transmembrane Transport.

Nature embeds some of its molecular machinery, including ion pumps, within lipid bilayer membranes. This has inspired chemists to attempt to develop synthetic analogues to exploit membrane confinement and transmembrane potential gradients, much like their biological cousins. In this perspective, we outline the various strategies by which molecular machines─molecular systems in which a nanomechanical motion is exploited for function─have been designed to be incorporated within lipid membranes and utilized to mediate transmembrane ion transport. We survey molecular machines spanning both switches and motors, those that act as mobile carriers or that are anchored within the membrane, mechanically interlocked molecules, and examples that are activated in response to external stimuli.

Multistate Redox-Switchable Ion Transport Using Chalcogen-Bonding Anionophores.

Synthetic supramolecular transmembrane anionophores have emerged as promising anticancer chemotherapeutics. However, key to their targeted application is achieving spatiotemporally controlled activity. Herein, we report a series of chalcogen-bonding diaryl tellurium-based transporters in which their anion binding potency and anionophoric activity are controlled through reversible redox cycling between Te oxidation states. This unprecedented in situ reversible multistate switching allows for switching between ON and OFF anion transport and is crucially achieved with biomimetic chemical redox couples.

Photo- and Redox-Regulated Transmembrane Ion Transporters.

Synthetic supramolecular ion transporters find applications as potential therapeutics and as tools for engineering functional membranes. Stimuli-responsive systems enable external control over transport, which is necessary for targeted activation. The Minireview provides an overview of current approaches to developing stimuli-responsive ion transport systems, including channels and mobile carriers, that can be controlled using photo or redox inputs.

Inter-Vesicle Signal Transduction Using a Photo-Responsive Zinc Ionophore.

Transmission of chemical information between cells and across lipid bilayer membranes is of profound significance in many biological processes. The design of synthetic signalling systems is a critical step towards preparing artificial cells with collective behaviour. Here, we report the first example of a synthetic inter-vesicle signalling system, in which diffusible chemical signals trigger transmembrane ion transport in a manner reminiscent of signalling pathways in biology. The system is derived from novel ortho-nitrobenzyl and BODIPY photo-caged ZnII transporters, in which cation transport is triggered by photo-decaging with UV or red light, respectively. This decaging reaction can be used to trigger the release of the cationophores from a small population of sender vesicles. This in turn triggers the transport of ions across the membrane of a larger population of receiver vesicles, but not across the sender vesicle membrane, leading to overall inter-vesicle signal transduction and amplification.

Exploiting the Catenane Mechanical Bond Effect for Selective Halide Anion Transmembrane Transport.

The first examples of [2]catenanes capable of selective anion transport across a lipid bilayer are reported. The neutral halogen bonding (XB) [2]catenanes were prepared via a chloride template-directed strategy in an unprecedented demonstration of using XB⋅⋅⋅anion interactions to direct catenane assembly from all-neutral components. Anion binding experiments in aqueous-organic solvent media revealed strong halide over oxoanion selectivity, and a marked enhancement in the chloride and bromide affinities of the catenanes relative to their constituent macrocycles. The catenanes additionally displayed an anti-Hofmeister binding preference for bromide over the larger iodide anion, illustrating the efficacy of employing sigma-hole interactions in conjunction with the mechanical bond effect to tune receptor selectivity. Transmembrane anion transport studies conducted in POPC LUVs revealed that the catenanes were more effective anion transporters than the constituent macrocycles, with high chloride over hydroxide selectivity, which is critical to potential therapeutic applications of anionophores. Remarkably these outperform existing acyclic halogen bonding anionophores with regards to this selectivity. Record chloride over nitrate anion transport selectivity was also observed. This represents a rare example of the direct translation of intrinsic anion binding affinities to anion transport behaviour, and demonstrates the key role of the catenane mechanical bond effect for enhanced anion transport selectivity.

A Photo-responsive Transmembrane Anion Transporter Relay.

Ion transport across lipid membranes in biology is controlled by stimuli-responsive membrane channels and molecular machine ion pumps such as ATPases. Here, we report a synthetic molecular machine-like ion transport relay, in which transporters on opposite sides of a lipid bilayer membrane facilitate transport by passing ions between them. By incorporating a photo-responsive telescopic arm into the relay design, this process is reversibly controlled in response to irradiation with blue and green light. Transport occurs only in the extended state when the length of the arm is sufficient to pass the anion between transporters located on opposite sides of the membrane. In contrast, the contracted state of the telescopic arm is too short to mediate effective transport. The system acts as a stimuli-responsive ensemble of machine-like components, reminiscent of robotic arms in a factory assembly line, working cooperatively to mediate ion transport. This work points to new prospects for using lipid bilayer membranes as scaffolds for confining, orientating, and controlling the relative positions of molecular machines, thus enabling multiple components to work in concert and opening up new applications in biological contexts.

Highly Active Halogen Bonding and Chalcogen Bonding Chloride Transporters with Non-Protonophoric Activity.

Synthetic anion transporters show much promise as potential anti-cancer agents and therapeutics for diseases associated with mis-regulation of protein anion channels. In such applications high activity and anion selectivity are crucial to overcome competing proton or hydroxide transport which dissipates cellular pH gradients. Here, highly active bidentate halogen bonding and chalcogen bonding anion carriers based on electron deficient iodo- and telluromethyl-triazole derivatives are reported. Anion transport experiments in lipid bilayer vesicles reveal record nanomolar chloride transport activity for the bidentate halogen bonding anion carrier, and remarkably high chloride over proton/hydroxide selectivity for the chalcogen bonding anionophore. Computational studies provide further insight into the role of sigma-hole mediated anion recognition and desolvation at the membrane interface. Comparison with hydrogen bonding analogues demonstrates the importance of employing sigma-hole donor motifs in synthetic anionophores for achieving both high transport activity and selectivity.

Red-shifted tetra-ortho-halo-azobenzenes for photo-regulated transmembrane anion transport.

Photo-responsive synthetic ion transporters are of interest as tools for studying transmembrane transport processes and have potential applications as targeted therapeutics, due to the possibility of spatiotemporal control and wavelength-dependent function. Here we report the synthesis of novel symmetric and non-symmetric red-shifted tetra-ortho-chloro- and tetra-ortho-fluoro azobenzenes, bearing pendant amine functionality. Functionalisation of the photo-switchable scaffolds with squaramide hydrogen bond donors enabled the preparation of a family of anion receptors, which act as photo-regulated transmembrane chloride transporters in response to green or red light. The subtle effects of chlorine/fluorine substitution, meta/para positioning of the anion receptors, and the use of more flexible linkers are explored. NMR titration experiments on the structurally diverse photo-switchable receptors reveal cooperative binding of chloride in the Z, but not E isomer, by the two squaramide binding sites. These results are supported by molecular dynamics simulations in explicit solvent and model membranes. We show that this intramolecular anion recognition leads to effective switching of transport activity in lipid bilayer membranes, in which optimal Z isomer activity is achieved using a combination of fluorine substitution and para-methylene spacer units.

Halogen Bonding Tetraphenylethene Anion Receptors: Anion-Induced Emissive Aggregates and Photoswitchable Recognition.

A series of tetraphenylethene (TPE) derivatives functionalized with highly potent electron-deficient perfluoroaryl iodo-triazole halogen bond (XB) donors for anion recognition are reported. 1 H NMR titration experiments, fluorescence spectroscopy, dynamic light scattering measurements, TEM imaging and X-ray crystal structure analysis reveal that the tetra-substituted halogen bonding receptor forms luminescent nanoscale aggregates, the formation of which is driven by XB-mediated anion coordination. This anion-coordination-induced aggregation effect serves as a powerful sensory mechanism, capable of luminescence chloride sensing at parts per billion concentration. Furthermore, the doubly substituted geometric isomers act as unprecedented photoswitchable XB donor anion receptors, where the composition of the photostationary state can be modulated by the presence of a coordinating halide anion.

Recognition-Controlled Membrane Translocation for Signal Transduction across Lipid Bilayers.

Membrane signaling proteins transduce information across lipid bilayer membranes in response to extra-cellular binding of chemical messengers. The design of chemical systems that initiate transmembrane signal transduction through molecular binding events is a critical step toward preparing responsive synthetic vesicles. Here we report a vesicle-based signaling system controlled by a metal cation binding event. Competition between binding of copper ions to a membrane-embedded synthetic transducer and to an extra-vesicle messenger (EDTA) is used to control translocation of the transducer across the lipid bilayer. The translocation process is coupled to activation of a catalyst that turns over encapsulated substrates on the inside of the vesicle to generate an amplified fluorescence output signal. External EDTA and copper ions can be used to reversibly switch catalysis inside the vesicles on and off in a controlled manner.

Triggered Release from Lipid Bilayer Vesicles by an Artificial Transmembrane Signal Transduction System.

The on-demand delivery of drug molecules from nanoscale carriers with spatiotemporal control is a key challenge in modern medicine. Here we show that lipid bilayer vesicles (liposomes) can be triggered to release an encapsulated molecular cargo in response to an external control signal by employing an artificial transmembrane signal transduction mechanism. A synthetic signal transducer embedded in the lipid bilayer membrane acts as a switchable catalyst, catalyzing the formation of surfactant molecules inside the vesicle in response to a change in external pH. The surfactant permeabilizes the lipid bilayer membrane to facilitate release of an encapsulated hydrophilic cargo. In the absence of the pH control signal, the catalyst is inactive, and the cargo remains encapsulated within the vesicle.

Iodide Recognition and Sensing in Water by a Halogen-Bonding Ruthenium(II)-Based Rotaxane.

The synthesis and anion-recognition properties of the first halogen-bonding rotaxane host to sense anions in water is described. The rotaxane features a halogen-bonding axle component, which is stoppered with water-solubilizing permethylated ß-cyclodextrin motifs, and a luminescent tris(bipyridine)ruthenium(II)-based macrocycle component. (1) H NMR anion-binding titrations in D2 O reveal the halogen-bonding rotaxane to bind iodide with high affinity and with selectively over the smaller halide anions and sulfate. The binding affinity trend was explained through molecular dynamics simulations and free-energy calculations. Photo-physical investigations demonstrate the ability of the interlocked halogen-bonding host to sense iodide in water, through enhancement of the macrocycle component's Ru(II) metal-ligand charge transfer (MLCT) emission.

Anion Recognition in Water: Recent Advances from a Supramolecular and Macromolecular Perspective.

The recognition of anions in water remains a key challenge in modern supramolecular chemistry, and is essential if proposed applications in biological, medical, and environmental arenas that typically require aqueous conditions are to be achieved. However, synthetic anion receptors that operate in water have, in general, been the exception rather than the norm to date. Nevertheless, a significant step change towards routinely conducting anion recognition in water has been achieved in the past few years, and this Review highlights these approaches, with particular focus on controlling and using the hydrophobic effect, as well as more exotic interactions such as C-H hydrogen bonding and halogen bonding. We also look beyond the field of small-molecule recognition into the macromolecular domain, covering recent advances in anion recognition based on biomolecules, polymers, and nanoparticles.

Rotaxane and catenane host structures for sensing charged guest species.

CONSPECTUS: The promise of mechanically interlocked architectures, such as rotaxanes and catenanes, as prototypical molecular switches and shuttles for nanotechnological applications, has stimulated an ever increasing interest in their synthesis and function. The elaborate host cavities of interlocked structures, however, can also offer a novel approach toward molecular recognition: this Account describes the use of rotaxane and catenane host systems for binding charged guest species, and for providing sensing capability through an integrated optical or electrochemical reporter group. Particular attention is drawn to the exploitation of the unusual dynamic properties of interlocked molecules, such as guest-induced shuttling or conformational switching, as a sophisticated means of achieving a selective and functional sensor response. We initially survey interlocked host systems capable of sensing cationic guests, before focusing on our accomplishments in synthesizing rotaxanes and catenanes designed for the more challenging task of selective anion sensing. In our group, we have developed the use of discrete anionic templation to prepare mechanically interlocked structures for anion recognition applications. Removal of the anion template reveals an interlocked host system, possessing a unique three-dimensional geometrically restrained binding cavity formed between the interlocked components, which exhibits impressive selectivity toward complementary anionic guest species. By incorporating reporter groups within such systems, we have developed both electrochemical and optical anion sensors which can achieve highly selective sensing of anionic guests. Transition metals, lanthanides, and organic fluorophores integrated within the mechanically bonded structural framework of the receptor are perturbed by the binding of the guest, with a concomitant change in the emission profile. We have also exploited the unique dynamics of interlocked hosts by demonstrating that an anion-induced conformational change can be used as a means of signal transduction. Electrochemical sensing has been realized by integration of the redox-active ferrocene functionality within a range of rotaxane and catenanes; binding of an anion perturbs the metallocene, leading to a cathodic shift in the ferrocene/ferrocenium redox couple. In order to obtain practical sensors for target charged guest species, confinement of receptors at a surface is necessary in order to develop robust, reuseable devices. Surface confinement also offers advantages over solution based receptors, including amplification of signal, enhanced guest binding thermodynamics and the negation of solubility problems. We have fabricated anion-templated rotaxanes and catenanes on gold electrode surfaces and demonstrated that the resulting mechanically bonded self-assembled monolayers are electrochemically responsive to the binding of anions, a crucial first step toward the advancement of sophisticated, highly selective, anion sensory devices. Rotaxane and catenane host molecules may be engineered to offer a superior level of molecular recognition, and the incorporation of optical or electrochemical reporter groups within these interlocked frameworks can allow for guest sensing. Advances in synthetic templation strategies has facilitated the synthesis of interlocked architectures and widened their interest as prototype molecular machines. However, their unique host-guest properties are only now beginning to be exploited as a sophisticated approach to chemical sensing. The development of functional host-guest sensory systems such as these is of great interest to the interdisciplinary field of supramolecular chemistry.

Active-Metal Template Synthesis of a Halogen-Bonding Rotaxane for Anion Recognition.

The synthesis of an all-halogen-bonding rotaxane for anion recognition is achieved by using active-metal templation. A flexible bis-iodotriazole-containing macrocycle is exploited for the metal-directed rotaxane synthesis. Endotopic binding of a Cu(I) template facilitates an active-metal CuAAC iodotriazole axle formation reaction that captures the interlocked rotaxane product. Following copper-template removal, exotopic coordination of a more sterically demanding rhenium(I) complex induces an inversion in the conformation of the macrocycle component, directing the iodotriazole halogen-bond donors into the rotaxane's interlocked binding cavity to facilitate anion recognition.

Chloride-Anion-Templated Synthesis of a Strapped-Porphyrin-Containing Catenane Host System.

The synthesis, structure and anion-recognition properties of a new strapped-porphyrin-containing [2]catenane anion host system are described. The assembly of the catenane is directed by discrete chloride anion templation acting in synergy with secondary aromatic donor-acceptor and coordinative pyridine-zinc interactions. The [2]catenane incorporates a three-dimensional, hydrogen-bond-donating anion-binding pocket; solid-state structural analysis of the catenane⋅chloride complex reveals that the chloride anion is encapsulated within the catenane's interlocked binding cavity through six convergent CH⋅⋅⋅⋅Cl and NH⋅⋅⋅Cl hydrogen-bonding interactions and solution-phase (1) H NMR titration experiments demonstrate that this complementary hydrogen-bonding arrangement facilitates the selective recognition of chloride over larger halide anions in DMSO solution.