Uril Host Research Articles

Supramolecular Immobilization of Adamantyl and Carboxylate Modified N-Heterocyclic Carbene Ligand on Cucurbituril Substrates.

Herein, the design, synthesis, supramolecular interactions and structural analysis of a novel bidentate carboxylate chelating N-heterocylic carbene (NHC) ligand is presented. The NHC structure was modified to strategically incorporate adamantyl moiety for the formation of a supramolecular complex with host molecules such as cucurbiturils. The adamantyl modified NHC ligand could potentially be used in recoverable homogeneous catalysts when Immobilized on a solid support via host–guest chemistry. As a versatile precursor, NHC ligand (8) was synthesized and characterized by 1H-NMR, 13C-NMR, FTIR, single crystal x-ray crystallography and elemental analysis. A proof-of-principle non-covalent immobilization of the NHC ligand (8) with a Cucurbit[7]uril (CB7) host was demonstrated using 1H-NMR titration.

“Click” Cucurbit[7]uril Hosts on Self-Assembled Monolayers: Quantitative Supramolecular Complexation with Ferrocene Guests

“Click” Cucurbit[7]uril Hosts on Self-Assembled Monolayers: Quantitative Supramolecular Complexation with Ferrocene Guests

Back electron transfer rates determine the photoreactivity of donor-acceptor stilbene complexes in a macrocyclic host.

Host-guest 2 : 1 complexation of photoreactive alkene guests improves the selectivity of [2 + 2] photodimerizations by templating alkene orientation prior to irradiation. Host-guest chemistry can also provide 1 : 1 : 1 complexes through the inclusion of electronically complementary donor and acceptor guests, but the photoreactivity of such complexes has not been investigated. We imagined that such complexes could enable selective cross-[2 + 2] photocycloadditions between donor and acceptor stilbenes. In pursuit of this strategy, we investigated a series of stilbenes and found 1 : 1 : 1 complexes with cucurbit[8]uril that exhibited charge-transfer (CT) absorption bands in the visible and near-IR regions. Irradiation of the CT band of an azastilbene, 4,4'-stilbenedicarboxylate, and cucurbit[8]uril ternary complex led to a selective cross-[2 + 2] photocycloaddition, while other substrate pairs exhibited no productive chemistry upon CT excitation. Using transient absorption spectroscopy, we were able to understand the variable photoreactivity of different stilbene donor-acceptor complexes. We found that back electron transfer following CT excitation of the photoreactive complex is positioned deep in the Marcus inverted region due to electrostatic stabilization of the ground state, allowing [2 + 2] to effectively compete with this relaxation pathway. Control reactions revealed that the cucurbit[8]uril host not only serves to template the reaction from the ground state, but also protects the long-lived radical ions formed by CT from side reactions. This protective role of the host suggests that donor-acceptor host-guest ternary complexes could be used to improve existing CT-initiated photochemistry or access new reactivity.

A General Picture of Cucurbit[8]uril Host-Guest Binding.

Describing, understanding, and designing complex interaction networks within macromolecular systems remain challenging in modern chemical research. Host-guest systems, despite their relative simplicity in both the structural feature and interaction patterns, still pose problems in theoretical modeling. The barrel-shaped supramolecular container cucurbit[8]uril (CB8) shows promising functionalities in various areas, e.g., catalysis and molecular recognition. It can stably coordinate a series of structurally diverse guests with high affinities. In this work, we examine the binding of seven commonly abused drugs to the CB8 host, aiming at providing a general picture of CB8-guest binding. Extensive sampling of the configurational space of these host-guest systems is performed, and the binding pathway and interaction patterns of CB8-guest complexes are investigated. A thorough comparison of widely used fixed-charge models for drug-like molecules is presented. Iterative refitting of the atomic charges suggests significant conformation dependence of charge generation. The initial model generated at the original conformation could be inaccurate for new conformations explored during conformational search, and the newly fitted charge set improves the prediction-experiment correlation significantly. Our investigations of the configurational space of CB8-drug complexes suggest that the host-guest interactions are more complex than expected. Despite the structural simplicities of these molecules, the conformational fluctuations of the host and the guest molecules and orientations of functional groups lead to the existence of an ensemble of binding modes. The insights of the binding thermodynamics, performance of fixed-charge models, and binding patterns of the CB8-guest systems are useful for studying and elucidating the binding mechanism of other host-guest complexes.

Cucurbiturils as Effectors on the Self-Assembly of Pd(II) and Pt(II) Metallacycles.

Four bidentate, dicationic ligands (L12+-L42+) were prepared and investigated as guests for binding by the cucurbit[7]uril (CB[7]) host and structural components for metal (Pd and Pt)-coordinated self-assembly into metallacycles. In aqueous solutions, all the ligands were found to form stable complexes of variable stoichiometries with CB[7], and only one (L22+) failed to self-assemble, induced by the presence of suitable Pd or Pt complexes, into metallacycles. Exposure of the Pd-based metallacycles to CB[7] led to their disassembly at room temperature, while the Pt-based metallacycles remained stable under these conditions. However, heating of the Pt metallacycles in the presence of CB[7] also led to their disassembly. This interplay between the interactions in aqueous media of the L12+, L32+, and L42+ ligands with the CB[7] host and Pd (or Pt) complexes suggests the possibility of using these or related systems for controlled drug delivery applications.

Host-guest interaction between cucurbit[6]uril and chain amino acids

The interaction between cucurbit[6]uril and chain amino acids was studied via fluorescence probe method, molecular simulation, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy. The experimental results of this work show that the cucurbit[6]uril host possesses a strong binding force with the chain amino acids leucine and methionine, and can form a host–guest inclusion complex. At the same time, the side chain alkyl moieties of the guests leucine, methionine and valine are contained in the hydrophobic cavity of cucurbit[6]uril, but the host–guest interaction between cucurbit[6]uril and valine molecule is weak.

Tunable White-Light Emissions of Azapyrene Derivatives with Cucurbit[n]uril Hosts in Aqueous Solution.

Cucurbit[n]uril (CB[n])-mediated assembly of π-conjugated azapyrene derivatives with rigid aromatic rings as bridging units into optically tunable complexes is reported. Due to the hindrance of rotation of diazapyrene moieties and the enhancement of intramolecular charge transfer of chromophore guests within the cavity of the CB[8] host, color tuning including white-light emission was easily achieved by introducing CB[8] into the guest aqueous solution, therefore suggesting a feasible strategy for the creation of tunable white-light emission materials through CB[n]-based host-guest interactions.

Photooxidation-Driven Purely Organic Room-Temperature Phosphorescent Lysosome-Targeted Imaging.

The construction of host-guest-binding-induced phosphorescent supramolecular assemblies has become one of increasingly significant topics in biomaterial research. Herein, we demonstrate that the cucurbit[8]uril host can induce the anthracene-conjugated bromophenylpyridinium guest to form a linear supramolecular assembly, thus facilitating the enhancement of red fluorescence emission by the host-stabilized charge-transfer interactions. When the anthryl group is photo-oxidized to anthraquinone, the obtained linear nanoconstructs can be readily converted into the homoternary inclusion complex, accompanied by the emergence of strong green phosphorescence in aqueous solution. More intriguingly, dual organelle-targeted imaging abilities have been also distinctively achieved in nuclei and lysosomes after undergoing photochemical reaction upon UV irradiation. This photooxidation-driven purely organic room-temperature phosphorescence provides a convenient and feasible strategy for supramolecular organelle identification to track specific biospecies and physiological events in the living cells.

Cucurbituril-Ferrocene: Host-Guest Based Pretargeted Positron Emission Tomography in a Xenograft Model.

Pretargeted positron emission tomography is a macromolecule-driven nuclear medicine technique that involves targeting a preadministered antigen target-bound macromolecule with a radioligand in vivo, aiming to minimize the overall radiation dose. This study investigates the use of antibody based host-guest chemistry methodology for pretargeted positron emission tomography. We hypothesize that the novel pretargeting approach reported here overcomes the challenges the current pretargeting platforms have with the in vivo stability and modularity of the pretargeting components. A cucurbit[7]uril host molecule modified, anti-carcinoembryonic antigen antibody (M5A; CB7-M5A) and a 68Ga-radiolabeled ferrocene guest radioligand ([68Ga]Ga-NOTA-PEG3-NMe2-Fc) were studied as potential host-guest chemistry pretargeting agents for positron emission tomography in BxPC3 xenografted nude mice. The viability of the platform was studied via in vivo biodistribution and positron emission tomography. Tumor uptake of [68Ga]Ga-NOTA-PEG3-NMe2-Fc was significantly higher in mice which received CB7-M5A prior to the radioligand injection (pretargeted) (3.3 ± 0.7%ID/g) compared to mice which only received the radioligand (nonpretargeted) (0.2 ± 0.1%ID/g).

A computational study on the complexation of bisbenzimidazolyl derivatives with cucurbituril and cyclohexylcucurbituril

The binding properties of 1,ω-bisbenzimidazolyl derivatives with cucurbit[6]uril (Q[6]) and cyclohexanocucurbit[6]uril (Cy6Q[6]) host, for 1:1 stoichiometry, have been studied using density functional theory. The distance between the two benimidazole acidic hydrogen’s along with the flexible butyl spacer group play a vital role in the complexation with host. The energetic analysis exhibits strong complexation ability of guests with Q[6] than Cy6Q[6] host. The computed enthalpy and free energy change were negative indicating the encapsulation process to be spontaneous and thermodynamically favorable and enthalpy driven. The global reactivity descriptors based charge transfer calculations show that charge transfer occurs from the guest to host molecule which was supported by the electron density difference map. The main factors for the higher stability of stable complex was the presence of C–H····O=C hydrogen bonding interactions in addition to the weak C···O, C···N, N···O, C···H, H···N type of interactions. AIM topological parameters and NCI analysis reveals the existence of weak interaction, mainly of electrostatic in nature and more number of hydrogen bonds are present in stable complexes. EDA analysis demonstrates the presence of noncovalent and electrostatic interaction with partial covalent character in the encapsulated complexes. The lower stability of Cy6Q[6] complexes compare to Q[6] are due to the presence of positive Vs,max values of cyclohexanone methylene hydrogen’s on Cy6Q[6] host.Graphic abstract

Supramolecular properties of amphiphilic adamantylated azo dyes

Despite environmental and health risks, azo dyes are still very popular colourising agents; therefore, methods for removing the dyes and/or related pollutants from wastewater have been developed. We have incorporated a lipophilic adamantane cage into two polar disulphonatonaphthalene-1-azobenzene dyes to prove the concept that modified dyes can be treated via host–guest supramolecular interactions using suitable cyclodextrin (CD) and cucurbit[n]uril (CBn) hosts. We conducted 1H NMR experiments to demonstrate that both dyes form specific inclusion complexes with an adamantane cage buried inside the CB7 or β-CD cavity. Using isothermal titration calorimetry, we determined association constants with β-CD and CB7 in the range of (0.7–1.3) × 106 and (1.4–3.4) × 108, respectively. As the dye@CB7 complexes were sparingly soluble in water, the dye can be efficiently removed from water by precipitation, even in the presence of β-CD.

Halide anion solvation and recognition by bambusurils: A DFT study

The phenomenon of ion solvation in water has received considerable attention in recent years as the most common species used in the study of aqueous ionic solvation are halide anions and alkali cations. The solvation of the halide ions appears to have great impact on the complex formation processes with the neutral macrocyclic dodecamethylbambus[6]uril host system. Bambusuril host system binds halide ions, preferably in the order I > Br > Cl > F. Various theoretical approaches (different DFT functionals, quite large basis sets, implicit/explicit consideration of the solvent) were employed unsuccessfully in an attempt to overcome the discrepancy between DFT predicted affinities and those experimentally observed in solution (reversed ordering for all or for some of the halide anions). A strategy for calculating the thermodynamic parameters by taking into account two sequential reactions of the guest anion (1) desolvation and (2) inclusion inside the cavity of the host system is applied in our computational study of the dodecamethylbambus[6]uril – halide ions complex formation process. DFT predicted affinities for solvated halide anions are fully in line with available experimental results in solution.

Host-Guest Complexation of Cucurbit[7]Uril and Cucurbit[8]Uril with the Antineoplastic and Multiple Sclerosis Agent Mitoxantrone (Novantrone).

The nature of interactions between the neutral/protonated mitoxantrone and the cucurbit[n]uril (n = 7, 8) host system was analyzed by employing density functional theory calculations. A comparison between the inclusion complexes of CB[7] and CB[8] shows various subtle differences in the complexation thermodynamics, given as changes in the Gibbs energy. Doubly and quadruply charged mitoxantrone (MX) molecules spontaneously form complexes in a water solvent, which are modeled using the polarizable continuum model approach. Both CB[7] and CB[8] complexes are stable as the geometry of the cavity allows for electrostatic interactions between the charged MX arms and the rim of the CB cavity. CB[8] also forms a stable complex with two mitoxantrone molecules with their aromatic rings stacked inside the cavity. Both CB[7] and CB[8] show properties that can be utilized in drug delivery.

Host–guest interaction-directed strategy for managing mechanochromic luminescence behavior by modulating molecular packing and conformation

A simple strategy was developed to modulate mechanochromic luminescence (MCL) behavior of NBDP (1-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)pyridin-4-one) molecules using cucurbit[8]uril (CB[8]) host as a carrier to change the molecular packing.

Inclusion and Charge Transfer Interaction of a Multi-Redox Active 1,3,5-Triazine Derivative by Cucurbit[7,8]urils

The redox active 1,3,5-triazine derivative (MPT) was used as a guest to study host-guest, charge transfer interaction with CB[7,8] in water. The multi-redox active MPT undergoes four chemically and electrochemically reversible one electron redox states in organic media, but in water, the fourth redox state shows an unstable nature. As a guest, the host-guest interaction of MPT was studied with two macrocyclic cucurbit[7,8]uril (CB[7,8]) hosts in water; resulting supramolecular complexes were characterized by NMR, ESI-MS, UV-vis, ITC, and cyclic voltammetric studies.

Kinetics and Thermodynamics of Binding between Zwitterionic Viologen Guests and the Cucurbit[7]uril Host.

The host-guest binding interactions between a series of zwitterionic, symmetric viologens, and the cucurbit[7]uril host were investigated using NMR and UV-vis spectroscopic techniques. The nature of the viologen side arms had strong effects on the kinetics of association and dissociation and weaker, more uniform influence on the thermodynamic stability of the final 1:1 inclusion complexes, which can also be characterized as pseudorotaxanes.

Zwitterionic Ru(III) Complexes: Stability of Metal-Ligand Bond and Host-Guest Binding with Cucurbit[7]uril.

A wide range of ruthenium-based coordination compounds have been reported to possess potential as metallodrugs with anticancer or antimetastatic activity. In this work, we synthesized a set of new zwitterionic Ru(III) compounds bearing ligands derived from N-alkyl (R) systems based on pyridine, 4,4'-bipyridine, or 1,4-diazabicyclo[2.2.2]octane (DABCO). The effects of the ligand(s) and their environment on the coordination stability have been investigated. Whereas the [DABCO-R]+ ligand is shown to be easily split out of a negative [RuCl4]- core, positively charged R-pyridine and R-bipyridine ligands form somewhat more stable Ru(III) complexes and can be used as supramolecular anchors for binding with macrocycles. Therefore, supramolecular host-guest assemblies between the stable zwitterionic Ru(III) guests and the cucurbit[7]uril host were investigated and characterized in detail by using NMR spectroscopy and single-crystal X-ray diffraction. Paramagnetic 1H NMR experiments supplemented by relativistic DFT calculations of the structure and hyperfine NMR shifts were performed to determine the host-guest binding modes in solution. In contrast to the intramolecular hyperfine shifts, dominated by the through-bond Fermi-contact mechanism, supramolecular hyperfine shifts were shown to depend on the "through-space" spin-dipole contributions with structural trends being satisfactorily reproduced by a simple point-dipole approximation.

Physicochemical and in vitro cytotoxicity studies of inclusion complex between gemcitabine and cucurbit[7]uril host.

Gemcitabine, a cytostatic drug from the pyrimidine antimetabolite group, exhibits limited storage stability and numerous side effects during therapy. One of the strategies to improve the effectiveness of therapy with such drugs is the use of supramolecular nano-containers, including dendrimers and macrocyclic compounds. The ability of gemcitabine to attach a proton in an aqueous environment necessitates the search for a carrier that is well-tolerated by an organism and capable of supramolecular binding of a ligand (drug) in a cationic form. In the current study a promising strategy was tested for using cucurbituril Q7 to bind gemcitabine cations for its efficient intracellular delivery on three selected cancer cell lines (MOLT4, THP-1 and U937). Based on physicochemical studies (equilibrium dialysis, UV and 1H NMR titrations, DOSY 1H NMR measurements, DSC calorimetry) and cytotoxicity tests on cells with a free and blocked hENT1 transporter, the conclusion was drawn about the binding and penetration of the cucurbituril-drug complex into cancer cells.

Shape-Induced Selective Separation of Ortho-substituted Benzene Isomers Enabled by Cucurbit[7]uril Host Macrocycles

Summary The separation of benzene derivatives is energy intensive and laborious as a result of the overlapping physicochemical properties of these isomers. Here, we report on the separation of ortho-disubstituted benzene isomers using cucurbit[7]uril (CB7) aqueous solution with more than 92% selectivity. Thermodynamic and kinetic analysis proves that the ortho-isomer has stronger binding ability and slower decomplexation rate constant than the para- and meta-isomers when hosted by CB7. Optimized host-guest models indicate that the ortho-isomer with the smallest aspect ratio well matches the spherical interior cavity of CB7, resulting in highly stable complexes. Furthermore, laboratory scale-up experiments using commercial xylenes and C8 aromatic fraction of pyrolysis gasoline proved that CB7 is able to separate ortho-xylene (OX) with a remarkable selectivity of up to 83%. We believe that this work accentuates the role of molecular recognition studies using macrocyclic hosts to improve the quality and energy bill of critical industrial separations. Video Abstract Download : Download video (27MB)

Emission enhancement of cationic tetraphenylethylene derivatives by encapsulation in a cucurbit[10]uril host in water

Encapsulation of cationic tetraphenylethylene guests in a cucurbit[10]uril host in water results in strong emission enhancement of these guests since the host–guest interaction caused restriction of intramolecular rotation.