The molecular confinement within rigid macrocyclic receptors can trigger catalytic activity and steer the selectivity of organic reactions. In this work, the dimerization of methylcyclopentadiene (MCPD) isomers in the presence of cucurbit[7]uril (CB7) was found to display, besides a large rate acceleration, a striking regioselectivity in aqueous solution at pH 3, different from the thermodynamic products predominating in the absence of the supramolecular catalyst. Among the different possible regioisomers and diastereomers, the endo-3,7-dimethyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene adduct was selectively formed, which is otherwise found only as a minor product in the dimerization of neat MCPD or in commercial dimeric mixtures.
View Article and Find Full Text PDFA novel cell-penetrating peptide (CPP) called -YR, with as a fluorescent probe, was developed. Initially, we aimed to use Y as a supramolecular host for water-insoluble drugs, with R driving the complex into cells. However, an unexpected hurdle was discovered; the peptide self-assembled into amorphous aggregates, rendering it ineffective for our intended purpose.
View Article and Find Full Text PDFBoron clusters are applied in medicinal chemistry because of their high stability in biological environments and intrinsic ability to capture neutrons. However, their intermolecular interactions with lipid membranes, which are critical for their cellular delivery and biocompatibility, have not been comprehensively investigated. In this study, we combine different experimental methods - Langmuir monolayer isotherms at the air-water interface, calorimetry (DSC, ITC), and scattering techniques (DLS, SAXS) - with MD simulations to evaluate the impact of closo-dodecaborate clusters on model membranes of different lipid composition.
View Article and Find Full Text PDFPerhalogenated closo-borates represent a new class of membrane carriers. They owe this activity to their chaotropicity, which enables the transport of hydrophilic molecules across model membranes and into living cells. The transport efficiency of this new class of cluster carriers depends on a careful balance between their affinity to membranes and cargo, which varies with chaotropicity.
View Article and Find Full Text PDFThe non-canonical amino acid adamantylglycine (Ada) is introduced into peptides to allow high-affinity binding to cucurbit[7]uril (CB7). Introduction of Ada into a cell-penetrating peptide (CPP) sequence had minimal influence on the membrane transport, yet enabled up- and down-regulation of the membrane transport activity.
View Article and Find Full Text PDFWe report the synthesis of a series of amphiphilic p-sulfonatocalix[4]arenes with varying alkyl chain lengths (CX4-Cn) and their application as efficient counterion activators for membrane transport of cell-penetrating peptides (CPPs). The enhanced membrane activity is confirmed with the carboxyfluorescein (CF) assay in vesicles and by the direct cytosolic delivery of CPPs into CHO-K1, HCT 116, and KTC-1 cells enabling excellent cellular uptake of the CPPs into two cancer cell lines. Intracellular delivery was confirmed by fluorescence microscopy after CPP entry into live cells mediated by CX4-Cn, which was also quantified after cell lysis by fluorescence spectroscopy.
View Article and Find Full Text PDFAcc Chem Res
December 2023
ConspectusThe past decade has seen significant progress in the understanding and appreciation of the importance of London dispersion interactions (LDIs) in supramolecular systems and solutions. The Slater-Kirkwood formula relates LDIs to the molecular polarizabilities of the two interacting molecular species (α) and their interaction distance (a dependence of ). When advancing arguments related to intermolecular interactions, it is frequently assumed that molecules with larger molecular polarizabilities are more amenable to larger LDIs.
View Article and Find Full Text PDFPolyoxometalates (POMs) are known antitumoral, antibacterial, antiviral, and anticancer agents and considered as next-generation metallodrugs. Herein, a new biological functionality in neutral physiological media, where selected mixed-metal POMs are sufficiently stable and able to affect membrane transport of impermeable, hydrophilic, and cationic peptides (heptaarginine, heptalysine, protamine, and polyarginine) is reported. The uptake is observed in both, model membranes as well as cells, and attributed to the superchaotropic properties of the polyoxoanions.
View Article and Find Full Text PDFCucurbiturils (CBs), barrel-shaped macrocyclic molecules, are capable of self-assembling at the surface of nanomaterials in their native state, via their carbonyl-ringed portals. However, the symmetrical two-portal structure typically leads to aggregated nanomaterials. We demonstrate that fluorescent quantum dot (QD) aggregates linked with CBs can be broken-up, retaining CBs adsorbed at their surface, via inclusion of guests in the CB cavity.
View Article and Find Full Text PDFDocking of alkali metal ions to water-soluble macrocyclic receptors generally reduces the affinity of guest molecules due to competitive binding. The idea that solvation water molecules could display a larger steric hindrance towards guest binding than cations has not been considered to date. We show that the docking of large cations to cucurbit[5]uril (CB5) unexpectedly increases (by a factor of 5-8) the binding of hydrophobic guests, methane and ethane.
View Article and Find Full Text PDFThe design of synthetic systems with interrelated reaction sequences that model incipient biological complexity is limited by physicochemical tools that allow the direct monitoring of the individual processes in real-time. To mimic a simple digestion-resorption sequence, the authors have designed compartmentalized liposomal systems that incorporate extra- and intravesicular chemosensing ensembles. The extravesicular reporter pair consists of cucurbit[7]uril and methylene blue to monitor the enzymatic cleavage of short enkephalin-related peptides by thermolysin through a switch-off fluorescence response ("digestion").
View Article and Find Full Text PDFLarge water-soluble anions with chaotropic character display surprisingly strong supramolecular interactions in water, for example, with macrocyclic receptors, polymers, biomembranes, and other hydrophobic cavities and interfaces. The high affinity is traced back to a hitherto underestimated driving force, the , which is orthogonal to the common hydrophobic effect. This review focuses on the binding of large anions with water-soluble macrocyclic hosts, including cyclodextrins, cucurbiturils, bambusurils, biotinurils, and other organic receptors.
View Article and Find Full Text PDFCobalt bisdicarbollides (COSANs) are inorganic boron-based anions that have been previously reported to permeate by themselves through lipid bilayer membranes, a propensity that is related to their superchaotropic character. We now introduce their use as selective and efficient molecular carriers of otherwise impermeable hydrophilic oligopeptides through both artificial and cellular membranes, without causing membrane lysis or poration at low micromolar carrier concentrations. COSANs transport not only arginine-rich but also lysine-rich peptides, whereas low-molecular-weight analytes such as amino acids as well as neutral and anionic cargos (phalloidin and BSA) are not transported.
View Article and Find Full Text PDFIn the gas phase, thermal activation of supramolecular assemblies such as host-guest complexes leads commonly to noncovalent dissociation into the individual components. Chemical reactions, for example of encapsulated guest molecules, are only found in exceptional cases. As observed by mass spectrometry, when 1-amino-methyl-2,3-diazabicyclo[2.
View Article and Find Full Text PDFIn the huge field of polymer structure and dynamics, including intrinsically disordered peptides, protein folding, and enzyme activity, many questions remain that cannot be answered by methodology based on artificial intelligence, X-ray, or NMR spectroscopy but maybe by fluorescence spectroscopy. The theory of Förster resonance energy transfer (FRET) describes how an optically excited fluorophore transfers its excitation energy through space to an acceptor moiety-with a rate that depends on the distance between donor and acceptor. When the donor and acceptor moiety are conjugated to different sites of a flexible peptide chain or any other linear polymer, the pair could in principle report on chain structure and dynamics, on the site-to-site distance distribution, and on the diffusion coefficient of mutual site-to-site motion of the peptide chain.
View Article and Find Full Text PDFAlthough ensemble experiments have suggested that mitotic arrest deficient protein 2 (Mad2), a metamorphic protein, has folding intermediates, direct evidence and characterization are not available. It remains an outstanding challenge to capture the folding intermediates in real time, which is crucial to elucidate the folding mechanism, but the folding intermediates are normally unstable and only exist transiently. By combining confocal-microscopy-based and total internal reflection fluorescence (TIRF)-microscopy-based single-molecule Förster resonance energy transfer (sm-FRET) techniques, we have investigated the folding/unfolding process of Mad2 and captured its folding intermediate at the single-molecule level.
View Article and Find Full Text PDFAqueous solubility and stability often limit the application of aminophenoxazinones and their sulfur mimics as promising agrochemicals in a sustainable agriculture inspired by allelopathy. This paper presents a solution to the problem using host-guest complexation with cucurbiturils (). Computational studies show that is the most suitably sized homologue due to its strong affinity for guest molecules and its high water solubility.
View Article and Find Full Text PDFPerhalogenated boron clusters derived from BBr, a superchaotropic dianion with a globular icosahedral shape, serve as inorganic cavity binders for cyclodextrins (CDs), in particular for large CDs (γ-CD and δ-CD), with high binding affinity ( > 10 M) in aqueous solution. This opens the door for applications of this anchoring moiety by linking it to organic residues, prominently fluorescent dyes. We report here the synthesis of a novel fluorescein-substituted perbrominated dodecaborate cluster by a copper(I)-catalyzed azide-alkyne click reaction.
View Article and Find Full Text PDFGram-negative porins are the main entry for small hydrophilic molecules. We studied translocation of structurally related cephalosporins, ceftazidime (CAZ), cefotaxime (CTX) and cefepime (FEP). CAZ is highly active on E.
View Article and Find Full Text PDFAn overarching challenge in the development of supramolecular sensor systems is to enhance their sensitivity, which commonly involves the synthesis of refined receptors with increased affinity to the analyte. We show that a dramatic sensitivity increase by 1-2 orders of magnitude can be achieved by encapsulating supramolecular chemosensors inside liposomes and exposing them to a pH gradient across the lipid bilayer membrane. This causes an imbalance of the influx and efflux rates of basic and acidic analytes leading to a significantly increased concentration of the analyte in the liposome interior.
View Article and Find Full Text PDFWe introduce a versatile recognition tunneling technique using doubly cucurbit[7]uril-functionalized electrodes to form supramolecular junctions that capture analytes dynamically by host-guest complexation. This results in characteristic changes in their single-molecule conductance. For structurally related drug molecules (camptothecin, sanguinarine, chelerythrine, and berberine) and mixtures thereof, we observed distinct current switching signals related to their intrinsic conductance properties as well as pH-dependent effects which can be traced back to their different states (protonated versus neutral).
View Article and Find Full Text PDFWe report on the discovery of the first two examples of cationic palladium(II)-oxo clusters (POCs) containing f-metal ions, [Pd O M {(CH ) AsO } (H O) ] (M=Ce , Th ), and their physicochemical characterization in the solid state, in solution and in the gas phase. The molecular structure of the two novel POCs comprises an octahedral {Pd O } core that is capped by eight M ions, resulting in a cationic, cubic assembly {Pd O M } , which is coordinated by a total of 16 terminal dimethylarsinate and eight water ligands, resulting in the mixed Pd -Ce /Th oxo-clusters [Pd O M {(CH ) AsO } (H O) ] (M=Ce, Pd Ce ; Th, Pd Th ). We have also studied the formation of host-guest inclusion complexes of Pd Ce and Pd Th with anionic 4-sulfocalix[n]arenes (n=4, 6, 8), resulting in the first examples of discrete, enthalpically-driven supramolecular assemblies between large metal-oxo clusters and calixarene-based macrocycles.
View Article and Find Full Text PDFThe membrane translocation of hydrophilic substances constitutes a challenge for their application as therapeutic compounds and labelling probes. To remedy this, charged amphiphilic molecules have been classically used as carriers. However, such amphiphilic carriers may cause aggregation and non-specific membrane lysis.
View Article and Find Full Text PDFA new set of hybrid guest molecules bearing organic and inorganic residues have been studied for their recognition by cyclodextrins in aqueous solution. The guest molecules consist of nitroanilines linked through their amino group to the dodecahydrido--dodecaborate cluster BH, which serves as an anchor group. They show sizable affinity to cyclodextrins, and unexpected photophysical properties, with a very strong and low-energy charge-transfer band.
View Article and Find Full Text PDF