Hemicucurbit[n]urils and Their Derivatives – Synthesis and Applications

The first hemicucurbit[n]uril macrocycles were described in 2004, and since then a series of functionalised hemicucurbit[n]uril derivatives have been prepared and studied. The original hemicucurbit[n]urils suffer from sparse solubility, which limits their applications in supramolecular chemistry. Recent progress in the synthesis of a range of derivatives such as the biotin[n]urils, the bambus[n]urils, and the cyclohexylhemicucurbit[n]urils have enabled studies of the supramolecular chemistry of the hemicucurbituril system, both in water and in a range of organic solvents. In contrast to the popular cucurbit[n]uril macrocycles that are state-of-the-art hosts for cations, the hemicucbit[n]urils host anions. Herein we provide a survey of the literature covering the syntheses of the hemicucurbituril derivatives and their supramolecular chemistry.     

Inclusion Complexes of Hymexazol with Three Different Cucurbit[n]uril: Preparation,and Physicochemical and Antifungal Characterization

Host-guest inclusion complexes of hymexazol with three different cucurbit[n]uril, cucurbit[7]uril (Q[7]), hemimethyl-substituted cucurbit[6]uril (HHMeQ[6]), and twisted cucurbit[14]uril (tQ[14]) have been investigated by means of ¹H NMR spectroscopy, quadrupole-time of flight mass spectrometry (Q-TOF), and isothermal titration calorimetry (ITC). ¹H NMR experimental results revealed that hymexazol resides within the respective cavities of the selected Q[n], and mass spectrometric experimental results revealed that it interacts with these three Q[n] through the formation of 1 : 1 inclusion complexes. ITC experimental results indicated moderate binding constants. In vitro assays showed that the complexation of hymexazol by the Q[n] increased its inhibitory effect on the mycelia growth of Botrytis cinerea Pers.     

Self-healing supramolecular hydrogels fabricated by cucurbit[8]uril-enhanced π-π interaction

Novel self-healing supramolecular hydrogels have successfully been fabricated through reversible cucurbit[8]uril (CB[8])-enhanced π-π interaction. Naphthaline groups in the side chains of copolymers and CB[8] molecules are employed as cross-linkers to form 1:2 ternary complex by host-guest interaction. Furthermore, the dipole-dipole interaction between the polar carbonyl groups of CB[8] and quaternary ammonium cation also contributes to the formation of self-healing property. It is found that the molar ratio of CB[8] to naphthaline units has a great influence on its self-healing property. This work represents a facile approach for fabricating cucurbituril-based self-healing supramolecular hydrogels, which can be potentially applied in several fields.     

Stimuli-responsive Supra-biomolecular Nanoassemblies of Cucurbit[7]uril with Bovine Serum Albumin: Drug Delivery and Sensor Applications

Construction and characterization of stimuli-responsive supra-biomolecular nanoassembly between cucurbit[7]uril (CB7) and bovine serum albumin (BSA), uptake and release of doxorubicin (DOX) in live cells, the enhanced sensitivity of brilliant green (BG) and the metal ion-induced relocation of neutral red (NR) dye to BSA have been discussed in this review. The fluorescence intensity of DOX is largely quenched in the presence of nanoassembly which recovers with adamantylamine or by changing the pH of the solution, indicating the significant uptake and release of DOX. Whereas, the interaction of BG with CB7-BSA assembly leads to a huge fluorescence enhancement ∼350-fold through ternary complex formation. In another study, the supramolecular pK_a tuning of nanoassembly encapsulated NR dye with metal ion and the consequent relocation of NR from CB7 cavity to the hydrophobic pocket of BSA have been demonstrated. All these studies show promising applications in drug delivery and on-off sensor.     

Dynamic supramolecular polymers built from cucurbit[n]urils and viologens

This review article focuses on supramolecular assemblies involving cucurbit[n]uril‐based containers and viologen guests as key building elements. Cucurbit[n]urils (CB[n], n = 5–8,10) are fascinating hosts forming a wide range of inclusion complexes (caviplexes) with 4,4′‐bipyridinium salts, known as viologens, either as discrete 1:1 inclusion compounds with CB[7] or as ternary inclusion compounds involving two hosts or two guests (2:1 with CB[7] and 1:2 or 1:1:1 with CB[8]). This property is currently being actively exploited to design and prepare self‐assembled dynamic stimuli‐responsive supramolecular polymers including gels, vesicles, films and organized arrays of polymeric microspheres or nanoparticles. This review highlights the main benefits of such polymers and gives an overview of the achievements and progress made in this field over the past decades. © 2018 Society of Chemical Industry     

The Potential of Cucurbit[n]urils in Drug Delivery

In this paper we review cucurbit[n]urils (CB[n]), a relatively new family of macrocycles that has shown potential in improving drug delivery. Encapsulation of drugs within the homologues CB[6], CB[7], or CB[8] can impart enhanced chemical and physical stability, improve drug solubility, and control drug release. The formulation of CB[n] into a dosage form suitable for clinical use is a non-trivial task, because the free macrocycle and its host-drug complex generally exhibit pseudo-polymorphism in the solid state. Despite this, cucurbiturils have been included in tablets for oral delivery and inserts for nasal delivery. Here we examine the potential use of cucurbiturils in drug delivery in the context of getting a new drug into clinical trials and discuss what further research is needed in this area.     

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.     

Assessing the Recyclability of Supramolecularly Assembled Organocatalytic Species: A Theoretical Insight

Asymmetric organocatalytic synthesis is a powerful tool in organic chemistry to achieve desired stereoisomers in high purity via mild catalytic routes. The immobilization of homogeneous catalytic species onto heterogeneous phases embodies the evolution of asymmetric catalysis, since it allows the recycling of the catalyst for several runs until degradation. Previously reported non-covalent immobilization of proline-based catalysts for aldol reaction onto magnetic nanoparticles functionalized with β-cyclodextrin (MNP-β-CB) demonstrated the viability of the methodology. This paper proposes two new catalyst recycling strategies based on Cucurbit[7]uril (CB[7]) for the aldol reaction and the Robinson annulation. These recycling methodologies are conceptually different. The former relies on the homogeneous encapsulation of the catalyst in cucurbituril, CB[7] ⋅ Cat, and its recycling in the aqueous phase by extraction of the aldol product with organic solvents. The latter relies on the heterogeneous encapsulation of the catalyst as MNP-CB[7] ⋅ Cat2 system and its recycling by magnetic harvesting. Density functional theory (DFT) calculations have been employed to rationalize the thermodynamics of experimental results, and to suggest caveats and plausible improvements in view of a future catalytic design.     

Potential Applications of Cucurbit[n]urils Inclusion Complexes in Photodynamic Therapy

Cucurbit[n]urils (CB[n]s) have emerged as potential candidates for drug delivery in several areas due to their strong binding interactions and low toxicity. More recently, their benefits for a type of cancer treatment termed Photodynamic Therapy (PDT) have been recognized. The outcomes of this therapy rely on better drug delivery strategies and improving overall photoactivity of the drugs, which is where CB[n]s could have a strong impact. The effects of these molecular containers on photoactivity are discussed and new interesting work is highlighted.     

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.     

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.     

混合溶剂体系中葫芦[6]脲溶解度的测定

以NaCl水溶液作为基础溶剂,选取EtOH、DMSO、DMF 3种有机溶剂与之混合作为溶剂,通过紫外分光光度法测定了葫芦[6]脲(CB[6])在不同比例含量混合溶剂中的溶解度。结果表明,随着有机溶剂的加入,CB[6]的溶解度不断减小。在DMF/NaCl水溶液混合体系中,CB[6]的溶解度降低是最大的,而且在体积比5:5,CB[6]的溶解度是几个混合体系中最小的。对于DMSO/NaCl水溶液混合体系,DMSO比例超过1/2时,对CB[6]溶解度影响增大。EtOH/NaCl水溶液混合体系对CB[6]溶解度影响是最小的,说明极性较小的有机溶剂对CB[6]溶解度的影响较小。     

Cucurbit[n]urils-related Multitopic Supramolecular Components: Design,Properties, and Perspectives

Cucurbit[n]urils (CBns) are an intriguing family of macrocyclic hosts whose chemistry has undergone rapid developments in recent decades. The initial interest in the synthesis, modifications and binding properties has shifted to areas focused on applications in drug storage, delivery, and release, external-stimuli responsive devices, and molecular nano-reactors. Since CBns are fruitfully complemented by cyclodextrins (CDs) in such systems, guest molecules that contain several binding sites are needed. These multitopic guests provide not only a scaffold for holding CBns and CDs together in appropriate arrangements but also allow for manipulation with supramolecular aggregates, e. g., reorganization or release of macrocycles. In this review, we summarize recent studies related to the design of multitopic guests. Binding motifs properties, the role of attractive or repulsive lateral interactions, the competition-compensation effect, and rotaxane versus pseudorotaxane manner are discussed.     

Gas Phase Cucurbit[n]uril Chemistry

The chemistry of cucurbit[n]urils is commanding increasing interest because of potential applications of these molecules in supramolecular structures; in drug encapsulation, protection, and delivery; and in sensitive new analytical assays. It is widely recognized that the binding properties of cucurbit[n]urils are sensitively dependent on solvents and counterions. Hence, gas phase studies, where neither solvent nor counterion species are present, are vital to gain fundamental understanding of cucuribituril complexes and to facilitate future applications. We use Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and ion mobility techniques to investigate the gas phase chemistry of cucurbit[n]urils and related species, addressing problems such as how trapping molecules inside the cucurbit[n]uril cavity affects the binding of cations on the rims, the mechanism of exchange of bound/trapped species, and the origin of the large pK_a shifts that occur for trapped guests. This paper is a review of our work.     

瓜环的固载化过程及其对甲基橙的吸附动力学

研究了羟基瓜环在氯甲基化聚苯乙烯株（氯球）上的固载动力学及固载影响因素,并研究了固载化瓜环对甲基橙染料的吸附动力学.结果表明,羟基瓜环通过亲核取代反应固载到氯球上,提高固载温度和提高羟基瓜环的投加量有利于瓜环的固载.羟基瓜环在氯球上的固载动力学符合准二级动力学方程.固载化瓜环对甲基橙的吸附动力学符合准二级动力学模型,而准一级动力学模型适合吸附过程的初始阶段,吸附过程受颗粒内扩散控制,但不是吸附速率的唯一控制因素,整个吸附过程是多种动力学机理共同作用的结果.     

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].     

Nitroxide Radicals with Cucurbit[n]urils and Other Cavitands

The interface of nitroxide radicals with cucurbit[n]urils (CB[n]) is covered in this review. Either used as spin probes, spin labels, or stoppers for paramagnetic rotaxanes, nitroxides offer new opportunities to investigate CB[n] and their inclusion complexes, especially thanks to EPR spectroscopy. On the other hand, CB[n] also offer interesting opportunities to modulate nitroxide properties such as protection or structuring. The multiple back and forth between the two well-established areas where nitroxides bring information about CB[n], and CB[n] modulate nitroxide properties, have enabled to shed some light at this new interesting interface.     

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.     

A Fluorescent Unnatural Mannosamine Derivative with Enhanced Emission Upon Complexation with Cucurbit[7]uril

Metabolic incorporation of unnatural functionality on glycans has allowed chemical biologists to observe and affect cellular processes. Recent work has resulted in glycan-fluorophore structures that allow for direct visualization of glycan-mediated processes, shining light on their role in living systems. This work describes the serendipitous discovery of a small chemical reporter-fluorophore. Investigations into the mechanism of fluorescence arising from (trimethylsilyl)methylglycine appended on mannosamine suggest rigidity and restriction of lone pair geometry contribute to the fluorescent behaviour. In fact, in situ cyclization and encapsulation in cucurbit[7]uril enhance fluorescence to levels that can be observed in live cells. While the reported unnatural mannosamine does not traverse the sialic acid biosynthetic pathway, this discovery may lead to small, “turn-on” chemical reporters for incorporation in living systems.