Supramolecular Ligands Research Articles

Functional Linkers Support Targeting of Multivalent Tweezers to Taspase1.

Taspase 1 is a unique protease not only pivotal for embryonic development but also implicated in leukemias and solid tumors. As such, this enzyme is a promising while still challenging therapeutic target, and with its protein structure featuring a flexible loop preceding the active site a versatile model system for drug development. Supramolecular ligands provide a promising complementary approach to traditional small-molecule inhibitors. Recently, the multivalent arrangement of molecular tweezers allowed the successful targeting of Taspase 1's surface loop. With this study we now want to take the next logic step und utilize functional linker systems that not only allow the implementation of novel properties but also engage in protein surface binding. Consequently, we chose two different linker types differing from the original divalent assembly: a backbone with aggregation-induced emission (AIE) properties to enable monitoring of binding and a calix[4]arene scaffold initially pre-positioning the supramolecular binding units. With a series of four AIE-equipped ligands with stepwise increased valency we demonstrated that the functionalized AIE linkers approach ligand binding affinities in the nanomolar range and allow efficient proteolytic inhibition of Taspase 1. Moreover, implementation of the calix[4]arene backbone further enhanced the ligands' inhibitory potential, pointing to a specific linker contribution.

Thermally Stable P-Chiral Supramolecular Phosphines, their Self-Assembly and Implication in Rh-Catalyzed Asymmetric Hydrogenation.

P-chiral supramolecular phosphine ligands are crucial for asymmetric transformations, but their synthesis is tedious. We report a one-step synthesis of thermally stable P-chiral supramolecular phosphines and their performance in the asymmetric hydrogenation of functionalized alkenes. A rational designing and synthesis of (R, R)-QuinoxP* ligated palladium complex (Pd-2) in excellent yield is reported. This Pd-2 catalyzed a direct P-C coupling of 2,3-dihydro-1-H-phosphindole (A1)/1,2,3,4-tetrahydrophosphindoline (A2) with 1-(3-iodophenyl)urea (B1)/2-iodo /6-hydroxy pyridine (B2) and,produced corresponding ligands L1-L3. The P-C coupling between A1 and B2 produced 6-(2,3-dihydro-1H-phosphindol-1-yl)pyridine-2(1H)-one (L2) with an excellent enantiomeric excess of up to 99 %. L2 was found to be remarkably stable even at 150 °C and did not oxidize/hydrolyze for at least 24 hours in open air. Such thermal stability and an impediment to oxidation are unprecedented. L2 self-assembled and produced L2-C1 (Pt), L2-C2(Pd), and L2-C3(Rh) assemblies. The utility of the self-assembled P-chiral ligand was demonstrated in the Rh-catalyzed asymmetric hydrogenation (AH) of functionalized olefins. The L2-C3 catalyzed AH of functionalized alkenes and delivered chiral products with excellent enantioselectivity of >99 %. A small library of 16 substrates was subjected to AH using L2-C3 to produce chiral compounds with excellent conversion and ee.

Rational correction of pathogenic conformational defects in HTRA1

Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies.

Theoretical Insights on the Complexation of Americium(III) and Europium(III) with Diglycolamide- and Dimethylacetamide-Functionalized Calix[4]arenes

Separation of minor actinides from lanthanides is one of the biggest challenges in spent fuel reprocessing due to the similar physicochemical properties of trivalent lanthanides (Ln(III)) and actinides (An(III)). Therefore, developing ligands with excellent extraction and separation performance is essential at present. As an excellent pre-organization platform, calixarene has received more attention on Ln(III)/An(III) separation. In this work, we systematically explored the complexation behaviors of the diglycolamide (DGA)/dimethylacetamide (DMA)-functionalized calix[4]arene extractants for Eu(III) and Am(III) using relativistic density functional theory (DFT). These calix[4]arene-derived ligands were obtained by functionalization with two or four binding units at the narrow edge of the calix[4]arene platform. All bonding nature analyses suggested that the Eu-L complexes possess stronger interaction compared to Am-L analogues, resulting in the higher extraction capacity of the these calix[4]arene ligands toward Eu(III). Thermodynamic analysis demonstrates that these pre-organized ligands on the calix[4]arene platform with four binding units yield better extraction abilities than the single ligands. Although DMA-functionalized ligands show stronger complexation stability for metal ions, in acidic solutions, the calix[4]arene ligands with DGA binding units have better extraction performance for Eu(III) and Am(III) due to the basicity of the DMA ligand. This work enabled us to gain a deeper understanding of the bonding properties between supramolecular ligands and lanthanides/actinides and afford useful insights into designing efficient supramolecular ligands for separating Ln(III)/An(III).

Pseudorotaxane Ligand‐Induced Formation of Copper(I) Iodide Cluster Based Assembly Materials: From Zero to Three Dimensional

Comprehensive SummaryIn this work, we have successfully obtained a series of novel copper(I)–iodide clusters (CuI NCs) based assembly materials by combining supramolecular pseudorotaxane ligands {[Mebpe+]PF6–@CB[6] (CB[6] = cucurbit[6]uril), L’·PF6} and linkers {BPHF@CB[6], [BPHF = C14H20N4(PF6)2], L·PF6}, including discrete cluster CuI 1 and extended cluster organic frameworks MORF 1 and MORF 2. CuI 1 can be described as a dumbbell‐shaped molecule with its body‐centered site and two vertexes respectively occupied by one [Cu5I6]– cluster and two CB[6] held together by two L’·PF6 ligands. The crystal structures of MORF 1 and MORF 2 are 1D anionic chain and four‐fold interpenetrated 3D cationic diamondoid structure, respectively, which all featured intriguing alternating CB[6] and CuI NCs. Furthermore, CuI 1 exhibits outstanding thermochromic and piezochromic luminescence. MORF 1 and MORF 2 also are detected pressure dependent luminescence properties with an enormous blue‐shift of the near‐infrared (NIR) emission band under high pressure compression. These exciting and smart materials possess great potential in the application field of novel temperature and pressure sensors.

Destabilizing Predictive Copper‐Catalyzed Click Reactions by Remote Interactions with a Zinc‐Porphyrin Backbone

AbstractIn order to obtain new supramolecular ligands that build up around a zinc‐porphyrin scaffold, we envisioned to access sulfonyl triazole intermediates by well‐known copper‐catalyzed click reactions. Unexpectedly, these triazole intermediates do not form due to the presence of the zinc‐porphyrin moiety at close proximity of the active copper species. Indeed, the copper catalyst undergoes a different chemo‐selective reaction pathway reacting with traces of alcohols or water from the media that behave as effective nucleophiles leading to sulfonyl imidates or sulfonyl amides covalently connected to the zinc‐porphyrin. We show that copper‐catalyzed click reactions can follow different reaction mechanisms when the catalytic events occur at close proximity of a zinc‐porphyrin unit which likely acts as a Lewis acid to stabilize otherwise inaccessible reaction intermediates.

NDIPhos as a platform for chiral supramolecular ligands in rhodium-catalyzed enantioselective hydrogenation.

Chiral naphthalene diimide ligands (NDIPhos) were exploited in rhodium-catalyzed enantioselective hydrogenation. The key feature of these ligands is their ability to self-assemble via π-π interactions to mimic bidentate ligands, offering a complementary method to traditional supramolecular strategies. This concept was further substantiated by computations with the composite electronic-structure method r2SCAN-3c.

Superoxide Dismutase 1 Folding Stability as a Target for Molecular Tweezers in SOD1-Related Amyotrophic Lateral Sclerosis.

Protein misfolding and aggregation are hallmarks of many severe neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's disease. As a supramolecular ligand that binds to lysine and arginine residues, the molecular tweezer CLR01 was found to modify the aggregation pathway of disease-relevant proteins in vitro and in vivo with beneficial effects on toxicity. However, the molecular mechanisms of how tweezers exert these effects remain mainly unknown, hampering further drug development. Here, we investigate the modulation mechanism of unfolding and aggregation pathways of SOD1, which are involved in amyotrophic lateral sclerosis (ALS), by CLR01. Using a truncated version of the wildtype SOD1 protein, SOD1bar , we show that CLR01 acts on the first step of the aggregation pathway, the unfolding of the SOD1 monomer. CLR01 increases, by ∼10 °C, the melting temperatures of the A4V and G41D SOD1 mutants, which are commonly observed mutations in familial ALS. Molecular dynamics simulations and binding free energy calculations as well as native mass spectrometry and mutational studies allowed us to identify K61 and K92 as binding sites for the tweezers to mediate the stability increase. The data suggest that the modulation of SOD1 conformational stability is a promising target for future developments of supramolecular ligands against neurodegenerative diseases.

Transition Metal Catalysis Controlled by Hydrogen Bonding in the Second Coordination Sphere.

Transition metal catalysis is of utmost importance for the development of sustainable processes in academia and industry. The activity and selectivity of metal complexes are typically the result of the interplay between ligand and metal properties. As the ligand can be chemically altered, a large research focus has been on ligand development. More recently, it has been recognized that further control over activity and selectivity can be achieved by using the “second coordination sphere”, which can be seen as the region beyond the direct coordination sphere of the metal center. Hydrogen bonds appear to be very useful interactions in this context as they typically have sufficient strength and directionality to exert control of the second coordination sphere, yet hydrogen bonds are typically very dynamic, allowing fast turnover. In this review we have highlighted several key features of hydrogen bonding interactions and have summarized the use of hydrogen bonding to program the second coordination sphere. Such control can be achieved by bridging two ligands that are coordinated to a metal center to effectively lead to supramolecular bidentate ligands. In addition, hydrogen bonding can be used to preorganize a substrate that is coordinated to the metal center. Both strategies lead to catalysts with superior properties in a variety of metal catalyzed transformations, including (asymmetric) hydrogenation, hydroformylation, C–H activation, oxidation, radical-type transformations, and photochemical reactions.

Tetrachromophoric Systems Based On Rigid Tetraphenylmethane (TPM) and Tetraphenylethylene (TPE) Scaffolds.

Tetraphenylmethane (TPM) and tetraphenylethylene (TPE) are among the most common rigid molecular architectures able to spatially arrange four peripheral functional groups. The aim of this Review is to provide a thorough description of the properties that supramolecular systems consisting of four chromophores (common supramolecular motifs, ligands, redox centers and conventional luminophores such as polypyridyl ligands, viologens, and azobenzene units) attached to TPM and TPE cores can show. Specifically, the photophysical properties of these molecules as well as the electronic interactions of the chromophores either in the ground or in the excited states will be highlighted and discussed, outlining the relationship among cores and outer subunits.

Coordination-Adaptive Polydentate Pseudorotaxane Ligand for Capturing Multiple Uranyl Species.

The propensity of uranyl for hydrolysis in aqueous environments prevents precise control of uranyl species in the scenarios of on-demand separation and tailored synthesis. Herein, using cucurbit[7]uril (CB[7]) as the macrocyclic molecule and 4,4'-bipyridine-N,N'-dioxide (DPO) as the string molecule, we propose a new kind of multidentate pseudorotaxane ligand, DPO@CB[7] for capturing uranyl species at different pH's. With the aprotic nature of DPO for metal coordination, the coordination ability of the DPO@CB[7] ligand is less affected by pH and can work in a wide range of pH's. Furthermore, by adaptive uranyl coordination, this aprotic pseudorotaxane ligand achieves effective recognition for different uranyl species ranging from monomeric to tetrameric originating from hydrolysis at varying pH's, and four novel uranyl-rotaxane compounds (URC1-4) are successfully obtained. Single-crystal X-ray diffraction analysis reveals that the DPO@CB[7] ligand coordinates with uranyl centers from monomeric to tetrameric in four different modes, as a result of structural flexibility of the DPO@CB[7] pseudorotaxane ligand. A detailed discussion for conformation flexibility of the DPO@CB[7] ligand has been conducted on the position changes of the DPO ligand trapped in the CB[7], which thus reveals good adaptivity of DPO@CB[7] that is noncovalently bonded as a supramolecular motif. In addition, characterization of the physicochemical properties of URC1 and URC2 with high phase purity, including powder X-ray diffraction (PXRD), infrared spectroscopy (IR), thermogravimetric analysis (TGA), and luminescence properties, are also provided. This work provides a good case of an adaptive pseudorotaxane ligand for the recognition and capture of different uranyl species and will bring valuable hints to the design of multifunctional supramolecular ligands for actinide separation in the future.

Proximity Effect in Uranyl Coordination of the Cucurbit[6]uril-Bipyridinium Pseudorotaxane Ligand for Promoting Host-Guest Synergistic Chelating.

In the present work, we proposed regulating uranyl coordination behavior of cucurbituril-bipyridinium pseudorotaxane ligand by utilizing meta-functionalized bipyridinium dicarboxylate guest. A tailored pseudorotaxane precursor involving 1,1'-(hexane-1,6-diyl)bis(3-cyanopyridin-1-ium) bromide (C6BPCN3) and cucurbit[6]uril (CB[6]) has designed and synthesized. Through in situ hydrolysis of the pseudorotaxane ligands and their coordination assembly with uranyl cations, seven new uranyl-rotaxane coordination polymers URCP1-URCP7 have been obtained under hydrothermal conditions in the presence of different anions. It is demonstrated that the variation of carboxylate groups from para- to meta-position greatly affected the coordination behaviors of the meta-functionalized pseudorotaxane linkers, which are enriched from simple guest-only binding to host-guest simultaneous coordination and synergistic chelating. This effective regulation on uranyl coordination of supramolecular pseudorotaxane can be attributed to the proximity effect, which refers to the meta-position carboxyl group being spatially closer to the portal carbonyl group of CB[6]. Moreover, by combining other regulation methods such as introducing competing counterions and modulating solution acidity, the nuclearity of the uranyl center and the coordination patterns of the pseudorotaxane ligand can be diversely tuned, which subsequently exert great influence on the final dimensionality of resultant uranyl compounds. This work presents a large diversity of uranyl-based coordination polyrotaxane compounds with fascinating mechanically interlocked components and, most importantly, provides a feasible approach to adjust and control the metal coordination behavior of the pseudorotaxane ligand that might expand the scope of application of such supramolecular ligands.

Take your Positions and Shine: Effects of Positioning Aggregation-Induced Emission Luminophores within Sequence-Defined Macromolecules.

A luminophore with aggregation‐induced emission (AIE) is employed for the conjugation onto supramolecular ligands to allow for detection of ligand binding. Supramolecular ligands are based on the combination of sequence‐defined oligo(amidoamine) scaffolds and guanidiniocarbonyl‐pyrrole (GCP) as binding motif. We hypothesize that AIE properties are strongly affected by positioning of the luminophore within the ligand scaffold. Therefore, we systematically investigate the effects placing the AIE luminophore at different positions within the overall construct, for example, in the main or side chain of the olig(amidoamine). Indeed, we can show that the position within the ligand structure strongly affects AIE, both for the ligand itself as well as when applying the ligand for the detection of different biological and synthetic polyanions.

Stabilization and activation of Pd nanoparticles for efficient CO2-reduction: Importance of their generation within supramolecular network of tridentate Schiff-base ligands with N,N coordination sites

Tridentate Schiff base ligand L (L = C14H12N2O3) reacts with palladium(II) chloride, to give a complex of formula [Pd(C14H12N2O3)Cl2]2∙MeOH. The spectroscopic, microanalytical and X-ray crystallographic data are consistent with the view that palladium(II) ion is coordinated by two nitrogen donor atoms, with typical PdII-N distances and two chloride ligands, representing thus N,N instead of possible N,N,O coordination mode. The reduced Pd° catalytic sites are electrochemically generated (by voltammetric potential cycling) within the film of supramolecular network of tridentate Schiff base ligands. The IR and XPS data of the electroreduced material are consistent with the existence of interactions between the palladium catalytic centers and the network of supramolecular ligands with N,N coordination sites. In comparison to conventional Pd nanoparticles, the CO2-reduction current densities, which have been recorded in near-neutral KHCO3 both under voltammetric and chronoamperometric conditions and normalized against electrochemically active surface area of palladium catalyst, are significantly higher at the supramolecular-ligand-supported Pd nanoparticles.

Prospects of ultraviolet resonance Raman spectroscopy in supramolecular chemistry on proteins

Ultraviolet resonance Raman scattering (UVRR) has been frequently used for studying peptide and protein structure and dynamics, while applications in supramolecular chemistry are quite rare. Since UVRR offers the additional advantages of chromophore selectivity and high sensitivity compared with conventional non-resonant Raman scattering, it is ideally suited for label-free probing of relatively small artificial/supramolecular ligands exhibiting electronic resonances in the UV. In this perspective article, we first summarize results of UVRR spectroscopy in supramolecular chemistry in the context of peptide/protein recognition. We focus on selected artificial ligands which were rationally designed as selective carboxylate binders (guanidiniocarbonyl pyrrole, GCP, and guanidiniocarbonyl indole, GCI) and selective lysine binder (molecular tweezer, CLR01), respectively, via a combination of non-covalent interactions involving electrostatics, hydrogen bonding, and hydrophobic effects/van der Waals forces. Current limitations of applying UVRR as a universally applicable method for label-free and site-specific probing of molecular recognition between supramolecular ligands and proteins are highlighted. We then propose solutions to overcome these limitations for transforming UVRR spectroscopy into a generic tool in supramolecular chemistry on proteins, with an emphasis on mono- and multivalent GCP- and GCI-based ligands. Finally, we outline specific cases of supramolecular ligands such as molecular tweezers where alternative approaches such as laser-based mid-IR spectroscopy are required since UVRR can intrinsically not provide the required molecular information.

Ultraviolet resonance Raman spectroscopy with a continuously tunable picosecond laser: Application to the supramolecular ligand guanidiniocarbonyl pyrrole (GCP)

We present a UVRR spectroscopy setup which is equipped with a picosecond pulsed laser excitation source continuously tunable in the 210–2600 nm wavelength range. This laser source is based on a three-stage optical parametric amplifier (OPA) pumped by a bandwidth-compressed second harmonic output of an amplified Yb:KGW laser. It provides <15 cm−1 linewidth pulses below 270 nm, which is sufficient for resolving Raman lines of samples in condensed phase studies. For demonstrating the capability of this tunable setup for UVRR spectroscopy we present its application to the artificial ligand guanidiniocarbonyl pyrrole (GCP), a carboxylate binder used in peptide and protein recognition. A UVRR excitation study in the range 244–310 nm was performed for identifying the optimum laser excitation wavelength for UVRR spectroscopy of this ligand (λmax = 298 nm) at submillimolar concentrations (400 µM) in aqueous solution. The optimum UVRR spectrum is observed for laser excitation with λexc = 266 nm. Only in the relatively narrow range of λexc = 266–275 nm UVRR spectra with a sufficiently high signal-to-noise ratio and without severe interference from autofluorescence (AF) were detectable. At longer excitation wavelengths the UVRR signal is masked by AF. At shorter excitation wavelengths the UVRR spectrum is sufficiently separated from the AF, but the resonance enhancement is not sufficient. The presented tunable UVRR setup provides the flexibility to also identify optimum conditions for other supramolecular ligands for peptide/protein recognition.

UV resonance Raman spectroscopy of the supramolecular ligand guanidiniocarbonyl indole (GCI) with 244 nm laser excitation.

Ultraviolet resonance Raman (UVRR) spectroscopy is a powerful vibrational spectroscopic technique for the label-free monitoring of molecular recognition of peptides or proteins with supramolecular ligands such as guanidiniocarbonyl pyrroles (GCPs). The use of UV laser excitation enables Raman binding studies of this class of supramolecular ligands at submillimolar concentrations in aqueous solution and provides a selective signal enhancement of the carboxylate binding site (CBS). A current limitation for the extension of this promising UVRR approach from peptides to proteins as binding partners for GCPs is the UV-excited autofluorescence from aromatic amino acids observed for laser excitation wavelengths >260 nm. These excitation wavelengths are in the electronic resonance with the GCP for achieving both a signal enhancement and the selectivity for monitoring the CBS, but the resulting UVRR spectrum overlaps with the UV-excited autofluorescence from the aromatic binding partners. This necessitates the use of a laser excitation <260 nm for spectrally separating the UVRR spectrum of the supramolecular ligand from the UV-excited autofluorescence of the peptide or protein. Here, we demonstrate the use of UVRR spectroscopy with 244 nm laser excitation for the characterization of GCP as well as guanidiniocarbonyl indole (GCI), a next generation supramolecular ligand for the recognition of carboxylates. For demonstrating the feasibility of the UVRR binding studies without an interference from the disturbing UV-excited autofluorescence, benzoic acid (BA) was chosen as an aromatic binding partner for GCI. We also present the UVRR results from the binding of GCI to the ubiquitous RGD sequence (arginylglycylaspartic acid) as a biologically relevant peptide. In the case of RGD, the more pronounced differences between the UVRR spectra of the free and complexed GCI (1:1 mixture) clearly indicate a stronger binding of GCI to RGD compared with BA. A tentative assignment of the experimentally observed changes upon molecular recognition is based on the results from density functional theory (DFT) calculations.

Spin-crossover in iron(II)-phenylene ethynylene-2,6-di(pyrazol-1-yl) pyridine hybrids: toward switchable molecular wire-like architectures

Luminescent oligo(p-phenylene ethynylene) (OPE) and spin-crossover (SCO) active Fe(II)-2,6-di(pyrazol-1-yl) pyridine (BPP) systems are prominent examples proposed to develop functional materials such as molecular wires/memories. A marriage between OPE and Fe(II)-BPP systems is a strategy to obtain supramolecular luminescent ligands capable of metal coordination useful to produce novel spin-switchable hybrids with synergistic coupling between spin-state of Fe(II) and a physical property associated with the OPE skeleton, for example, electronic conductivity or luminescence. To begin in this direction, two novel ditopic ligands, namely L1 and L2, featuring OPE-type backbone end-capped with metal coordinating BPP were designed and synthetized. The ligand L2 tailored with 2-ethylhexyloxy chains at the 2 and 5 positions of the OPE skeleton shows modulated optical properties and improved solubility in common organic solvents relative to the parent ligand L1. Solution phase complexation of L1 and L2 with Fe(BF4)2·6H2O resulted in the formation of insoluble materials of the composition [Fe(L1)]n(BF4)2n and [Fe(L2)]n(BF4)2n as inferred from elemental analyses. Complex [Fe(L1)]n(BF4)2n underwent thermal SCO centred at T1/2 = 275 K as well as photoinduced low-spin to high-spin transition with the existence of the metastable high-spin state up to 52 K. On the other hand, complex [Fe(L2)]n(BF4)2n, tethered with 2-ethylhexyloxy groups, showed gradual and half-complete SCO with 50% of the Fe(II)-centres permanently blocked in the high-spin state due to intermolecular steric interactions. The small angle x-ray scattering (SAXS) pattern of the as-prepared solid complex [Fe(L1)]n(BF4)2n revealed the presence of nm-sized crystallites implying a possible methodology towards the template-free synthesis of functional-SCO nanostructures.

Phosphine Oxide Based Supramolecular Ligands in the Rhodium-Catalyzed Asymmetric Hydrogenation

A series of bisphosphine monoxides and a phosphoramidite have been used for the preparation of supramolecular ligands. A structural analysis of the complexes using NMR spectroscopy and DFT calculat...

Origin of the Selectivity and Activity in the Rhodium-Catalyzed Asymmetric Hydrogenation Using Supramolecular Ligands

The reaction mechanism of the asymmetric hydrogenation of functionalized alkenes catalyzed by a supramolecular rhodium complex has been investigated. In-depth NMR analysis combined with X-ray crystal structure determination show that hydrogen bonds are formed between the catalyst and the substrate in the early stages of the mechanism. Detailed kinetic data obtained from UV–vis stopped-flow experiments and gas-uptake experiments confirm that the hydrogen bonds are playing a crucial role in the mechanism. A complete DFT study of the various competitive paths of the reaction mechanism allowed us to identify how these hydrogen bonds are involved in the determining steps of the reaction.