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.     

Supramolecular Analysis of Monosaccharide Derivatives Using Cucurbit[7]uril and Electrospray Ionization Tandem Mass Spectrometry

Identification of monosaccharide derivatives using an analytical technique is difficult due to their isomeric structures and similar physical properties. Although mass spectrometry (MS) has emerged as a prominent technique for this purpose, a comprehensive MS-based method for analyzing diverse monosaccharide species is yet to be developed. Herein, we employ host-guest chemistry using cucurbit[7]uril (CB[7]) with MS to identify four different monosaccharide derivative species. Tandem MS analysis distinguishes the monosaccharide derivatives based on the unique fragmentation pattern produced when forming gas-phase complexes with CB[7]. The ion mobility studies combined with computational calculations reveal that subtle differences in isomers cause distinct orientations inside CB[7] cavity, resulting in different fragmentation patterns of the isomers. This unique study demonstrates that host-guest chemistry combined with MS can be used for developing effective isomer analysis techniques.     

State transition of macroscopic supramolecular hydrogel by the host-guest coverage effect

In this work, a hydrophobic guest monomer containing adamant end-group was synthesized and introduced into the acrylamide hydrogel system to prepare macroscopic guest hydrogel. The swelling, transparency, and mechanical properties of the guest hydrogels can be significantly changed by soaking the guest hydrogel into hydrophilic cyclodextrin solution because the hydrophobic guest groups were recognized and covered by the hydrophilic host molecules. In addition, the surface lubrication property could be adjusted by changing the proportion of acrylamide and adamantane monomers in the hydrogel system. More importantly, cyclodextrin can bind with adamantane through host-guest interactions, enabling the adjustment of the hydrophilicity/hydrophobicity properties of the hydrogel system. By controlling the assembly time, the hydrogel with different lubrication behaviors can be obtained. The controllable surface friction that this specific binding of host-guest interaction has broad application prospects in intelligent device, bionic lubrication and other fields.     

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.     

Stimuli-Responsive Cucurbit[n]uril-Mediated Host-Guest Complexes on Surfaces

Supramolecular functional surfaces are at the heart of many materials and medical applications. Increasing interest can be seen for devising new supramolecular functionalization strategies of surfaces. In this review we place particular emphasis on the use of cucurbit[n]uril-mediated host-guest complexation as surface functionalization strategy. The state of the art of cucurbit[n]uril-mediated host-guest complexes on surfaces is reviewed. Cucurbit[n]urils (CB[n]) are able to form strong host-guest complexes with affinities that span several orders of magnitudes up to the regime of the biotin-streptavidin pair and that can be modulated by applying remote stimuli provided suitably sensitive guests were selected. Strategies to fabricate stimuli-responsive surfaces creates versatile supramolecular systems and several applications of these types of surfaces are outlined.     

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.     

Kinetics Inside,Outside and Through Cucurbiturils

This review describes the kinetics at play in Cucurbituril (CB[n])/guest recognition within a very wide time frame, from picoseconds to days. We cover the kinetics of (1) radiative and non-radiative decays of fluorophores inside and outside CB[n]s, (2) guest motions in the CB[n] cavity, and (3) ingression, egression and threading mechanisms into, out of and through the macrocycles. We then show that the kinetics of guest release or capture can be controlled using CB[n]-capped mesoporous systems and micelles, or by coupling those processes to the kinetics of ancillary reactions. The last section is devoted to the latest examples of reactions catalyzed and inhibited by CB[n]s.     

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.     

Switch-peptides: design and characterization of controllable super-amyloid-forming host-guest peptides as tools for identifying anti-amyloid agents

Several amyloid-forming proteins are characterized by the presence of hydrophobic and highly amyloidogenic core sequences that play critical roles in the initiation and progression of amyloid fibril formation. Therefore targeting these sequences represents a viable strategy for identifying candidate molecules that could interfere with amyloid formation and toxicity of the parent proteins. However, the highly amyloidogenic and insoluble nature of these sequences has hampered efforts to develop high-throughput fibrillization assays. Here we describe the design and characterization of host-guest switch peptides that can be used for in vitro mechanistic and screening studies that are aimed at discovering aggregation inhibitors that target highly amyloidogenic sequences. These model systems are based on a host-guest system where the amyloidogenic sequence (guest peptide) is flanked by two beta-sheet-promoting (Leu-Ser)(n) oligomers as host sequences. Two host-guest peptides were prepared by using the hydrophobic core of Abeta comprising residues 14-24 (HQKLVFFAEDV) as the guest peptide with switch elements inserted within (peptide 1) or at the N and C termini of the guest peptide (peptide 2). Both model peptides can be triggered to undergo rapid self-assembly and amyloid formation in a highly controllable manner and their fibrillization kinetics is tuneable by manipulating solution conditions (for example, peptide concentration and pH). The fibrillization of both peptides reproduces many features of the full-length Abeta peptides and can be inhibited by known inhibitors of Abeta fibril formation. Our results suggest that this approach can be extended to other amyloid proteins and should facilitate the discovery of small-molecule aggregation inhibitors and the development of more efficacious anti-amyloid agents to treat and/or reverse the pathogenesis of neurodegenerative and systemic amyloid diseases.     

Block copolymer aggregates with photo-responsive switches: Towards a controllable supramolecular container

Herein, we present a concept of combining host-guest chemistry with block copolymer self-assembly to fabricate an inner cross-linking block copolymer aggregate with photo-responsive switches on the basis of the reversible interaction between azobenzene and β-cyclodextrin, which can serve as a controllable supramolecular container to load and release guest molecules reversibly. The inner cross-link makes the block copolymer aggregates exhibit good stability, and the aggregates can keep their spherical morphologies during photo-irradiation treatment. When the switches are in on-state, cyclodextrins can bind with hydrophobic pyrene molecules; and when the switches are in off-state, pyrene molecules will get away from the cyclodextrins. The photo-controllable switches embedded in the aggregates endow this new supramolecular container with the capability to load and release guest molecules reversibly without structure disruption. It is anticipated that this line of work may open an avenue for fabricating new polymeric containers which can be used for controllable molecular transfer and catalysis.     

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].     

Dual Stimuli-Responsive Cross-Linked AIE Supramolecular Polymer Constructed through Hierarchical Self-Assembly

Herein, we report the successful construction of a new family of dual stimuli-responsive AIE cross-linked supramolecular polymer through the strategy of hierarchical self-assembly. A novel dipyridyl donor building block G1 containing tetraphenylethylene (TPE) moiety was designed and synthesized. Notably, two nitrile units were attached onto G1 , which were employed as the guest for the further host-guest interaction with pillar[n]arene derivatives. The rhomboidal metallacycle G2 with four nitrile units was firstly constructed through coordination-driven self-assembly. Subsequently, the cross-linked supramolecular polymers H₂⊃G2 were then generated through host-guest interactions. It should be noted that the obtained supramolecular polymer displayed interesting AIE properties due to the restriction of TPE intramolecular motions within the polymeric network. More importantly, by taking advantages of dynamic nature of both coordination bonds and host-guest interactions, the resultant supramolecular polymer displayed dual stimuli-responsive fluorescent transitions under different stimuli such as the competitive guest and halide anion.     

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.     

FRET-Based In-Cell Detection of Highly Selective Supramolecular Complexes of meso-Tetraarylporphyrin with Peptide/BODIPY-Modified Per-O-Methyl-β-Cyclodextrins

Artificial supramolecular systems capable of self-assembly and that precisely function in biological media are in high demand. Herein, we demonstrate a highly specific host-guest-pair system that functions in living cells. A per-O-methyl-β-cyclodextrin derivative (R8-B-CD^Me) bearing both an octaarginine peptide chain and a BODIPY dye was synthesized as a fluorescent intracellular delivery tool. R8-B-CD^Me was efficiently taken up by HeLa cells through both endocytosis and direct transmembrane pathways. R8-B-CD^Me formed a 2 : 1 inclusion complex with tetrakis(4-sulfonatophenyl)porphyrin (TPPS) as a guest molecule in water, from which fluorescence resonance energy transfer (FRET) from R8-B-CD^Me to TPPS was observed. The FRET phenomenon was clearly detected in living cells using confocal microscopy techniques, which revealed that the formed supramolecular R8-B-CD^Me/TPPS complex was maintained within the cells. The R8-B-CD^Me cytotoxicity assay revealed that the addition of TPPS counteracts the strong cytotoxicity (IC₅₀=16 μM) of the CD cavity due to complexation within the cells. A series of experiments demonstrated the bio-orthogonality of the supramolecular per-O-methyl-β-CD/tetraarylporphyrin host-guest pair in living cells.     

Deep Inside Cucurbiturils: Physical Properties and Volumes of their Inner Cavity Determine the Hydrophobic Driving Force for Host–Guest Complexation

Cucurbit[n]urils (CBn) bind guest molecules through a combination of electrostatic interactions with the carbonyl rims and hydrophobic interactions with the inner cavity. Investigations with solvatochromic probes in CB7 reveal that the polarity of the cavity resembles that of alcohols (e.g., n-octanol), while its polarizability (P=0.12) and apparent refractive index (n_D=1.10±0.12) are extremely low, close to the gas phase. The calculated molecular quadrupole moments of CBs are extremely large (Θ_zz=−120 to −340 Buckingham). A survey of reported binding constants of neutral guests and hydrophobic residues that form 1 : 1 inclusion complexes with CB6, reveals a preferential inclusion of C3–C5 residues in its cavity. The largest guests which show non-negligible binding contain 7 heavy atoms (excluding hydrogen). For CB7, the strongest binding is observed for guests with adamantyl (10 heavy atoms) and ferrocenyl groups (11 heavy atoms), while the largest guests known to be complexed are carborane and the adduct of two pyridine derivatives (12 heavy atoms). The evaluation of different volumes shows that the most meaningful cavity, namely that responsible for binding of hydrophobic residues, is confined by the planes through the oxygen carbonyls. The volume of this inner cavity follows the formula V/ų=68+62(n−5)+12.5(n−5)², affording representative cavity volumes of 68 ų for CB5, 142 ų for CB6, 242 ų for CB7, and 367 ų for CB8. The volume of the 2 bond dipole regions is comparably smaller, amounting, for example, to 2×35 ų for CB6. The analysis of packing coefficients for representative sets of known guests with clearly defined hydrophobic binding motifs reveals average values of 47 % for CB5, 58 % for CB6, 52 % for CB7, and 53 % for CB8, which are well in line with the preferred packing (“55 % solution”, see S. Mecozzi, J. Rebek, Chem. Eur. J. 1998 , 4, 1016–1022) in related supramolecular host–guest assemblies. The driving force for binding of hydrophobic guests and residues by CBs is interpreted in terms of the unimportance of dispersion interactions (owing to the low polarizability of their cavity) and the dominance of classical and nonclassical hydrophobic effects related to the removal of very-high-energy water molecules (2 for CB5, 4 for CB6, 8 for CB7, and 12 for CB8) from the cavity.     

Immobilization of Ferrocene-Modified SNAP-Fusion Proteins

The supramolecular assembly of proteins on surfaces has been investigated via the site-selective incorporation of a supramolecular moiety on proteins. To this end, fluorescent proteins have been site-selectively labeled with ferrocenes, as supramolecular guest moieties, via SNAP-tag technology. The assembly of guest-functionalized SNAP-fusion proteins on cyclodextrin- and cucurbit [7]uril-coated surfaces yielded stable monolayers. The binding of all ferrocene fusion proteins is specific as determined by surface plasmon resonance. Micropatterns of the fusion proteins, on patterned cyclodextrin and cucurbituril surfaces, have been visualized using fluorescence microscopy. The SNAP-fusion proteins were also immobilized on cyclodextrin vesicles. The supramolecular SNAP-tag labeling of proteins, thus, allows for the assembly of modified proteins via supramolecular host-guest interaction on different surfaces in a controlled manner. These findings extend the toolbox of fabricating supramolecular protein patterns on surfaces taking advantage of the high labeling efficiency of the SNAP-tag with versatile supramolecular moieties.     

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.     

Synthesis, characterization and properties of side-chain pseudopolyrotaxanes consisting of cucurbituril[6] and poly-N-(4-vinylbenzyl)-1,4-diaminobutane dihydrochloride

Pseudopolyrotaxanes 3 is synthesized from cucurbituril[6] (CB[6]) and polymer 2 (poly-N¹-(4-vinylbenzyl)-1,4-diaminobutane dihydrochloride) in water by simple stirring at room temperature. The monomer 1, polymer 2 and pseudopolyrotaxanes 3 are characterized by ¹H NMR, ¹³C NMR, FT-IR and elemental analysis. In 3, the CB[6] beads are localized on tetramethylene units in side chains of 2, and combine N⁺ by noncovalent bonds. The degree of threading (number of CB[6] beads per repeat unit) can be controlled from 0 to 1.0 by controlling the amount of CB[6] added. The properties of polymer 2 and pseudopolyrotaxanes 3 are researched by TGA, X-ray powder diffraction (XRD), environment scanning electron microscope (ESEM) and potentiometric titrations. The pseudopolyrotaxanes have higher thermal stability and chain regularity than the parent polymer which are attributed to the bulkiness and the rigidity of the CB[6] threaded. The decomposition temperature and chain regularity of the pseudopolyrotaxanes increase with increasing amount of CB[6] threaded. The effects of salts (NaCl, NaBr or NaI) to pseudopolyrotaxanes are studied by the transmittance with UV-vis, and the results show that NaI is the satisfied precipitant to the pseudopolyrotaxanes. The surface morphologies of pseudopolyrotaxanes 3 observed by ESEM shows a series of spherical particle with different diameter. The results of potentiometric titrations show that the pseudopolyrotaxanes 3 have larger pK_av and smaller n than polymer 2.     

Template control of framework topology and charge in new phosphate- and arsenate-based sodalite analogs

Hydrothermal synthesis and structural characterization of three new sodalite analog structures are reported. By using mixed metal cations to achieve the host-guest charge matching and tetramethylammonium (TMA) and piperazine as structure-directing agents, ternary sodalite analog structures are synthesized in zinc gallophosphate, zinc galloarsenate. and gallium cobalt phosphate systems. The framework charge, composition, and symmetry are controlled by the charge and geometry of organic structure-directing agents. The host-guest charge matching also dictates the preferred framework T-atom sites, for Co²⁺ and Ga³⁺ respectively, and is an important aspect of the synthesis mechanism. The host guest interaction that allows the communication of symmetry information from the guest species to the inorganic framework is C-H…O hydrogen bonds in TMA sodalites and N-H…O and C-H…O hydrogen bonds in the piperazine sodalite. As a result of symmetry-templating, TMA sodalite analog structures are cubic whereas the piperazine-templated structure is body-centered tetragonal.     

Supramolecular Assemblies of Thioflavin T with Cucurbiturils: Prospects of Cooperative and Competitive Metal Ion Binding

Of late, molecular-recognition-guided supramolecular assembly and its relevance in the development of highly stable and active photofunctional materials have drawn much attention. In this review, the non-covalent interaction of a biologically important dye, thioflavin T (ThT), with cucurbituril macrocycles, especially, cucurbit[7]uril (CB7) and cucurbit[8]uril (CB8), and the response of the resulting molecular assemblies towards the metal ions have been discussed. The interaction of ThT with CB7 leads to significant enhancement in the fluorescence yield, lifetime and modifications in the spectral features of ThT. These changes are assigned to the formation of 1 : 1 and 2 : 1 (CB7⋅ThT) complexes. However, with CB8 a distinct evolution of a hitherto unexplored strong excimer emission band having maximum at 570 nm is observed. The strong ion–dipole interactions provided by the carbonyl portals of the CB8 adequately support the stabilization of two π-stacked ThTs, both in 1 : 2 (CB8⋅ThT) and 2 : 2 stoichiometric ratio. In case of the 1 : 1 (CB7⋅ThT) system, the metal ion addition leads to the usual competitive binding interaction and decreases the fluorescence intensity. However, the addition of the same metal ion to the 2 : 1 (CB7⋅ThT) complex results in a novel cooperative metal ion binding to the complex, leading to the formation of a highly fluorescent supramolecular capsule. Further addition of amantadine hydrochloride induces rupture of the capsular complex, projecting potential application in targeted drug delivery. The 2 : 2 (CB8⋅ThT) complex responds to the metal ion presence in a competitive way, which allows demonstration of a fluorescence on–off mechanism.