Recent Progress in Gas Phase Cucurbit[n]uril Chemistry

Cucurbit[n]urils (CB[n]s) are of great significance due to their unique molecular recognition properties and their potential applications in areas such as drug delivery or analytical assays. Gas phase studies, without interference from solvents or counterions, provide fundamental insights into the mechanism of CB[n] complex formation and binding. In this paper, we review the progress in gas phase CB[n] chemistry, mainly based on mass spectrometry, since 2011, including important discoveries in structural studies, mechanistic studies, and gas phase studies related to analytical or clinical applications of CB[n]s. We expect the use of gas phase methods to continue to expand and diversify.     

Portal Effects on the Stability of Cucurbituril Complexes

This work is concerned with the properties of cucurbit[n]uril (CBn) host portals. The carbonyl oxygens lining each of the cavity openings on these hosts give rise to a rim of negative charge density, which often has strong effects on guest binding processes. The negative effect that carboxylates exert on guest binding to cucurbit[7]uril (CB7) is described in detail, as well as the fact that the protonation state of terminal −COO⁻/COOH groups can be utilized to control CB7 shuttling on suitably designed pseudorotaxanes. Carboxylates can also slow down the kinetics of CB7 complex formation and dissociation. Finally, the electrostatic properties of the portals are useful -with suitable molecular design- to develop strong cooperativity effects, resulting from attractive side-by-side interactions, on the assembly of multi-component supramolecular complexes.     

Ultrastable Host–Guest Complexes and Their Applications

This review describes monovalent synthetic receptor–ligand (or host–guest) pairs with extremely high binding affinity, comparable to that of the biotin–avidin pair, and their applications. Cucurbit[7]uril (CB[7]), a member of the host family cucurbit[n]uril (CB[n], n=5–8, 10), forms ultrastable host–guest complexes with ferrocene-, adamantane- or bicyclo[2.2.2]octane-based molecules having ammonium groups properly positioned to interact with the carbonyl oxygens at the portals of CB[7]. The extremely high affinity is achieved by a large enthalpic gain arising from the near perfect size/shape complementarity between the rigid CB cavity and the rigid core of the guest molecules, with the critical assistance of the positive entropy change due to the extensive dehydration of the host and guest. The high stability of the complexes allowed us and others to explore several biological applications such as immobilization of biomolecules on a solid surface, protein isolation, triggering intracellular events, and regulating enzymatic activities. These complexes with their exceptional affinity, chemical robustness, simple preparation, biocompatibility, and easy handling may replace the biotin–(strept)avidin system in diverse areas of research, including affinity chromatography, high throughput biochemical assays, imaging, and sensor technologies.     

Cucurbit[n]uril Host-Guest Complexes of Acids,Photoacids, and Super Photoacids

The supramolecular chemistry of host-guest complexes of cucurbit[n]urils (CB[n]) with acidic guests in the ground (HG⁺) and excited states (HG⁺*) are reviewed. The effects of CB[n] complexation on the guests’ pK_a and/or pK_a* values are related to relative binding constants and host-guest structures of the acid form of the guest and its conjugate base. Included are carbon acids, guests of biological and medicinal interest, dyes and related polyaromatic guests, and other organic and organometallic guests. The applications of the pK_a shifts to the solubility, stability, and bioavailabilty of drug molecules, the stability and enhanced spectral properties of dyes, and in pH-induced self-sorting, micelle formation, host-guest shuttling, and controlled guest release, are discussed.     

The Mechanism of Cucurbituril Formation

This article begins by describing the synthesis and recognition properties of the cucurbit[n]uril homologues CB[5], CB[6], CB[7], CB[8], and CB[10]. Subsequently, we describe the state-of-the-art in understanding the mechanism of CB[n] formation. We describe the experiments that establish that glycoluril ( 1 _H) undergoes condensation with formaldehyde by a combination of chain-growth and step-growth polymerization processes. Chain-growth processes deliver methylene bridged glycoluril oligomers 2 C – 8 C as intermediates that may undergo macrocyclization to nor-seco-CB[n] when the oligomer is long enough ( 5 C – 8 C) and subsequently form CB[n]. Step-growth processes allow oligomers to condense to give longer oligomers connected by a single CH₂-bridge that undergo macrocyclization to deliver (±)-bis-nor-seco-CB[6] and bis-nor-seco-CB[10]. Lastly, we describe some of the exciting new recognition processes of the newly formed members of the CB[n] family. For example, bis-nor-seco-CB[10] undergoes homotropic allostery during ternary complex formation, (±)-bis-nor-seco-CB[6] exhibits moderately diastereoselective recognition processes (d.r. up to 88 : 12) with chiral ammonium ions in water, and nor-seco-CB[6] functions as an aldehyde reactive CB[n] synthon that can control the folding of alkanediammonium ions into a backfolded conformation in water.     

Acyclic Cucurbit[n]uril-type Receptors: Preparation,Molecular Recognition Properties and Biological Applications

This article traces the development of acyclic cucurbit[n]uril-type receptors with a focus on work from the Isaacs group. First, we describe the synthesis of methylene bridged glycoluril dimers capped with aromatic sidewalls which allowed us to probe the interconversion of the S- and C-shaped dimers which is a fundamental step in CB[n] formation. The C-shaped compounds were found to undergo discrete self-assembly (dimerization) in both water and organic solvents which lead us to investigate multicomponent self-sorting systems. We supressed the self-association of 8 by electrostatic repulsion in the putative dimer which allowed expression of its innate molecular recognition properties toward methylene blue and related planar cationic dyes. Longer glycoluril oligomers (trimer-hexamer, acyclic decamer) were prepared by starving the CB[n]-forming reaction of formaldehyde. The longer oligomers (e. g. 15 and 16 ) bind to alkylammonium ions in water ≈100-fold weaker than macrocyclic CB[n] highlighting the high preorganization of the acyclic but polycyclic framework. We prepared a wide variety of acyclic CB[n] compounds (wall variants, solubilizing group variants, linker variants) based on glycoluril trimer and tetramer. In particular, 26 and 27 have been shown to possess a wide variety of chemically and biologically interesting functions. For example, 26 was used to formulate the insoluble drug Albendazole and treat mice bearing SK-OV-3 xenograft tumors. Compound 27 binds tightly to the neuromuscular blocking agents rocuronium, vecuronium, and cisatracurium and acts as an in vivo reversal agent for these compounds in anesthetized rats. Container 27 was also found to modulate the hyperlocomotive effect of rats that had been treated with methamphetamine. Finally, 38 has been used as a cross reactive component of sensor arrays that are capable of classifying and quantifying cancer related nitroamine and a range of over the counter drugs. Overall, the work demonstrates that acyclic CB[n]-type compounds are nicely pre-organized and therefore retain the essential aspects of the recognition properties of macrocyclic CB[n] but allow for more straightforward tailoring of structure and solubility that enables a variety of chemically and biologically important applications.     

Guest-responsive,Non-proteolytic Harvest of a Cell-sheet using Controllable Host-guest Chemistry

A new non-proteolytic method to harvest a cell-sheet was demonstrated using controllable host-guest interactions which can be dissociated by treating a strong guest on demand. Fibroblast cells (NIH3T3) were grown to confluence on a 1,6-diammoniumhexane conjugated hyaluronic acid (DAH-HA) polymer which was anchored to a cucurbit[7]uril (CB[7]) surface using the host-guest interaction between DAH and CB[7]. Treating with a strong guest allowed the cultured cells to be detached from the surface as a free standing sheet. This approach demonstrated the great potential of controllable host-guest chemistry as a novel tool for non-proteolytic harvesting of cell-sheets useful for regenerative therapy.     

The Effect of Cucurbit[7]uril on the Antitumor and Immunomodulating Properties of Oxaliplatin and Carboplatin

Cucurbit[7]uril (CB[7]) is a molecular container that may form host–guest complexes with platinum(II) anticancer drugs and modulate their efficacy and safety. In this paper, we report our studies of the effect of CB[7]–oxaliplatin complex and the mixture of CB[7] and carboplatin (1:1) on viability and proliferation of a primary cell culture (peripheral blood mononuclear cells), two tumor cell lines (B16 and K562) and their activity in the animal model of melanoma. At the same time, we studied the impact of platinum (II) drugs with CB[7] on T cells and B cells in vitro. Although the stable CB[7]–carboplatin complex was not formed, the presence of cucurbit[7]uril affected the biological properties of carboplatin. In vivo, CB[7] increased the antitumor effect of carboplatin, but, at the same time, increased its acute toxicity. Compared to free oxaliplatin, its complex with CB[7] shows a greater cytotoxic effect on tumor cell lines B16 and K562, while in vivo, the effects of the free drug and encapsulated drug were comparable. However, in vivo studies also demonstrated that the encapsulation of oxaliplatin in CB[7] lowered the toxicity of the drug.     

Cucurbituril As A Versatile Tool to Tune the Functions of Proteins

Tuning the functions of proteins is a key issue in chemistry and biochemistry. The modification of proteins by chemical or biological methods is proven to be a classical method that allows proteins to achieve multiple functions. Compared with traditional methods, cucurbiturils as a new series of macrocyclic supramolecular hosts have been explored to modify and control protein functions because they could recognize and bind to short aromatic peptide sequences specifically. After guest molecules are incorporated into proteins by chemical and biological methods, CB[n]-induced supramolecular protein assemblies show distinct functions in catalysis, biosensor and drug delivery. Herein we review the recent progress in the field of functional regulation of proteins with cucurbiturils.     

The encouraging improvement of polyamide nanofiltration membrane by cucurbituril-based host–guest chemistry

The considerable performance enhancement of small molecule-sieving nanofiltration membrane has been achieved by the functional combination between host–guest chemistry and interfacial polymerization (IP) for the first time in this work. First, the water-insolubility of cucurbit[6]uril (CB6) was ameliorated by constructing host–guest complex (CB6-PIP) with piperazine. Second, the incorporation of water-soluble CB6-PIP in the selective layer via IP leads to the generation of not only the enlarged conventional polyamide network tunnels but also rotaxane tunnels. Such enrichment of solvent transport tunnels contributes to an amazing pure water permeability of 15.5–25.4 Lm⁻²bar⁻¹h⁻¹, three times higher than that of traditional polyamide membranes, with a high R/MgSO₄ of 99.5–92.5%, perfect SO₄²⁻/Cl⁻ selectivity due to the electronegative contribution of CB6, as well as untapped potential in organic solvent nanofiltration. This work not only provides a fire-new strategy to design new type of NF materials but also promotes the application of CBs in many other fields.     

Applications of Cucurbit[n]urils (n=7 or 8) in Pharmaceutical Sciences and Complexation of Biomolecules

Cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) are two key members of the cucurbit[n]uril (CB[n]) family of macrocycles. Because of the good water solubility of CB[7] and the unique ternary binding properties of CB[8], these two macrocycles have attracted increasing attentions in recent years. In particular, many promising reports of exciting applications regarding CB[7] and CB[8] have emerged in the pharmaceutical sciences and complexations of biomolecules, which has become one of the most important areas of potential applications of CB[n]s. This review summarizes the applications of macrocyclic CB[7], CB[8] and their derivatives as supramolecular platforms that have been developed in recent years within the field of pharmaceutical sciences and biomolecular sciences, and discusses the current challenges and future prospects of this area.     

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[¹⁸F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([¹⁸F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [¹⁸F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.     

氨基甲酸酯和脲生成反应的机理与动力学

综述了氨基甲酸酯（ＵＴ）和脲（ＵＡ）的自发反应和叔胺催化、有机锡催化、锡－胺协同催化反应的机理与动力学,以及反应介质、有机酸、水解氯、活泼氢组分分子结构及反应体系相态对反应的影响。ＵＴ和ＵＡ的生成反应存在产物催化现象。反应机理不仅与催化剂的性质有关,而且与反应物的结构和溶剂的性质有关。近期对反应注射成型体系的研究表明,相分离在聚合过程的早期发生,此后反应转为扩散控制。ＵＡ生成反应的动力学行为受相态     

Pillar[n]arenes for Construction of Artificial Transmembrane Channels

Pillar[n]arenes have been intensively used during the last decade in supramolecular chemistry as host systems for guest recognition and self-assembly, toward functional materials and devices. They present electron-rich and tuneable size cavities, as well as reactive rims for further functionalization. Their unique pillar shape promotes pillar[n]arenes as molecular analogues of carbon nanotubes. For this reasons pillar[n]arenes have been embedded into membranes and used to construct artificial water, proton, ions and molecular channels. This review discusses the incipient developments of the first artificial channels based on pillar[n]arenes. We include also systems that integrate pillar[n]arenes as synthetic elements for the construction of selective pores of nanodevices for ion rectification.     

Cucurbiturils as Versatile Receptors for Redox Active Substrates

Research on the chemistry of cucurbit[n]uril (CBn) hosts has picked up and maintained an impressive pace in the last decade, primarily due to the isolation of hosts with relatively larger cavity sizes, such as CB7 and CB8. This review article summarizes our involvement in this research effort, with particular emphasis on the binding of redox active guests by the CB7 and CB8 hosts. The binding of 4,4′-bipyridinium (viologen) derivatives was the starting point of our CB research. While methylviologen is encapsulated by CB7, forming a highly symmetric inclusion complex, more hydrophobic viologens are bound by inclusion of one of the terminal N-substituents inside the host cavity. Cationic ferrocene derivatives reach extremely high binding affinities with CB7. Binding by CB8 offers additional possibilities, since this host may accommodate two aromatic units inside its cavity, which can be utilized to exert redox control on the assembly of suitably dendronized guests. From a purely electrochemical standpoint, CB7-included viologens maintain their voltammetric reversibility, but CB7-included ferrocene residues experience a pronounced attenuation of their electron transfer kinetics. We have also applied these binding and electrochemical properties to the design and preparation of switchable, CB-based pseudorotaxanes.     

Aggregation behavior of poly(methacrylic acid) with cucurbit[7]uril and the effect of ammonia ions on aggregation

The interaction between poly(methacrylic acid) (PMAA) and cucurbit[7]uril (CB[7]) in aqueous solution were investigated by dynamic light scattering (DLS), fluorescence techniques, UV-spectrophotometer, and resonance light scattering (RLS). The experimental results show that the aggregates were formed between CB[7] and H⁺ of PMAA by the hydrogen bonding interaction that increases with increasing the concentration of CB[7], which leads to the formation of the larger aggregates. Interestingly, PMAA has temperature sensitivity with the addition of CB[7] by UV-spectrophotometer and DLS. The pH of the solution of PMAA appears a inflection point with increasing the concentration of CB[7] comparing with the increase of the electrical conductivity all the time with the addition of CB[7]. In addition, in order to investigate the effect of cation on the size of the aggregates and avoid the effect of other anions at the same time, the dilute ammonia was added into the solution of PMAA. The experimental data show that the size of the aggregates increases with adding CB[7] because CB[7] could combine with both NH₄⁺ by the electrostatic and iondipole interactions and H⁺ by the hydrogen bonding interaction, and a possible model is proposed to explain the host-guest interactions between PMAA and CB[7].     

四氮杂杯[2]芳烃[2]三嗪叠氮化衍生物的合成及其与RDX的配合研究

文合成了氮原子桥连杯[2]芳烃[2]三嗪化合物。室温下,以碳酸钾为缚酸剂,利用三聚氯氰和间苯二胺的亲核取代反应合成主体,并将其叠氮化,反应温度为40％。产物通过元素分析,红外光谱和氢谱对其结构进行了表征,并采用XRD对氮杂杯[4]芳烃及其衍生物与黑索今的配合性能进行了表征分析,结果表明主客体之间发生了相互作用。     

Cucurbituril homologues and derivatives: new opportunities in supramolecular chemistry

The supramolecular chemistry of cucurbituril, a synthetic receptor, is fascinating because of the remarkable guest binding behavior of the host. Studies in the field, however, have met with limitations, since the only species known was the hexameric macrocyclic compound, cucurbit[6]uril. Recently we synthesized its homologues, cucurbit[n]uril (n = 5, 7, 8), and derivatives. These new members of the cucurbituril family have expanded the scope further, and interest in them has grown enormously. This Account is a compilation of recent literature covering the syntheses of the homologues and derivatives, and their supramolecular chemistry.     

香菇多糖微波降解反应动力学研究

文中建立了微波降解后香菇多糖特性黏度[η]变化的反应动力学方程。通过测定微波功率对[η]的影响,可得到不同功率下[η]t-1/α-[η]0-1/α随微波处理时间t的变化关系及降解速率常数kn随[η]n的变化关系。结果表明:香菇多糖微波降解速率常数随反应时间发生变化;在微波功率为195,385,575 W时,降解速率常数kn与特性黏度[η]n之间呈正相关性,表明kn和[η]n的线性关系服从一级动力学;微波功率上升至765 W时,kn和[η]n之间呈负相关性,表明kn和[η]n的线性关系偏离了一级动力学。     

Side-chain pseudopolyrotaxanes by threading cucurbituril[6] onto quaternized poly-4-vinylpyridine derivative: Synthesis and properties

A novel side-chain pseudopolyrotaxanes 4 is synthesized from cucurbituril (CB[6]) and quaternized poly-4-vinylpyridine derivative 3 in water by simple stirring at room temperature. CB[6] beads are localized on hexamethylene units in side chains of 3 as found by NMR studies, and the hydrophobic and charge-dipole interactions are the driving force. The degree of threading (q/n, the average number of CB[6] beads per repeat recognition unit of 3) can be controlled from 0.2 to 1.0 by controlling the amount of CB[6] added. The reduced viscosity of pseudopolyrotaxanes in aqueous solution has smaller change with the change of the concentration or temperature, which is consistent with the hydrodynamic radius and more rigid chain conformation because of the threaded CB[6]. DLS results show the average hydrodynamic diameter (D_h) of the pseudopolyrotaxanes in solution increases with the increasing of CB[6] threaded. The pseudopolyrotaxanes have higher thermal stability and intensity of absorption band than the parent polymer 3 as found by TGA and UV-vis studies. The decomposition temperature and intensity of absorption increase with increasing amount of CB[6] threaded. The effect of NaI to pseudopolyrotaxanes is studied by the transmittance with UV-vis, and the result shows that NaI is the satisfied precipitant to the pseudopolyrotaxanes.