Acyclic CB Research Articles

Insoluble Acyclic Cucurbit[n]uril-Type Receptors Capture Iodine from the Vapor Phase.

Nuclear energy makes large contributions toward meeting global energy needs, but societal concerns remain high given the impacts of the intended release of radioactive materials including 129I and 131I. In this paper we explore the use of a homologous series of acyclic CB[n] type hosts (H1 - H4) as adsorbents of iodine from the vapor phase. We find that H2 - H4, but not H1 - perform well in this application with uptake capacities of 2.2 g g-1, 1.5g g-1, and 1.9g g-1, respectively. The chemisorptive uptake process involves partial oxidation of catechol walled H2 to quinone walled host and capture of I3- and I5-. Solid H2 can be regenerated by treatment with Na2S2O4 and reused at least five times. The x-ray crystal structure of H2 is also reported.

Acyclic Cucurbit[n]uril Receptors Function as Solid State Sequestrants for Organic Micropollutants

AbstractThe accumulation of organic micropollutants (OMP) in aquatic systems is a major societal problem that can be addressed by approaches including nanofiltration, flocculation, reverse osmosis and adsorptive methods using insoluble materials (e.g. activated carbon, MOFs, nanocomposites). More recently, polymeric versions of supramolecular hosts (e.g. cyclodextrins, calixarenes, pillararenes) have been investigated as OMP sequestrants. Herein, we report our study of the use of water insoluble dimethylcatechol walled acyclic cucurbit[n]uril (CB[n]) hosts as solid state sequestrants for a panel of five OMPs. A series of hosts (H1–H4) were synthesized by reaction of glycoluril oligomer (monomer–tetramer) with 3,6‐dimethylcatechol and fully characterized by spectroscopic means and x‐ray crystallography. The solid hosts sequester OMPs from water with removal efficiencies exceeding 90 % in some cases. The removal efficiencies of the new hosts parallel the known molecular recognition properties of analogous water soluble acyclic CB[n]. OMP uptake by solid host occurs rapidly (≈120 seconds). Head‐to‐head comparison with CB[6] in batch‐mode separation and DARCO activated carbon in flow‐through separation mode show that tetramer derived host (H4) performs very well under identical conditions. The work establishes insoluble acyclic CB[n]‐type receptors as a promising new platform for OMP sequestration.

Acyclic Cucurbit[n]uril Receptors Function as Solid State Sequestrants for Organic Micropollutants.

The accumulation of organic micropollutants (OMP) in aquatic systems is a major societal problem that can be addressed by approaches including nanofiltration, flocculation, reverse osmosis and adsorptive methods using insoluble materials (e.g. activated carbon, MOFs, nanocomposites). More recently, polymeric versions of supramolecular hosts (e.g. cyclodextrins, calixarenes, pillararenes) have been investigated as OMP sequestrants. Herein, we report our study of the use of water insoluble dimethylcatechol walled acyclic cucurbit[n]uril (CB[n]) hosts as solid state sequestrants for a panel of five OMPs. A series of hosts (H1-H4) were synthesized by reaction of glycoluril oligomer (monomer-tetramer) with 3,6-dimethylcatechol and fully characterized by spectroscopic means and x-ray crystallography. The solid hosts sequester OMPs from water with removal efficiencies exceeding 90 % in some cases. The removal efficiencies of the new hosts parallel the known molecular recognition properties of analogous water soluble acyclic CB[n]. OMP uptake by solid host occurs rapidly (≈120 seconds). Head-to-head comparison with CB[6] in batch-mode separation and DARCO activated carbon in flow-through separation mode show that tetramer derived host (H4) performs very well under identical conditions. The work establishes insoluble acyclic CB[n]-type receptors as a promising new platform for OMP sequestration.

Anthracene-Walled Acyclic CB[n] Receptors: in vitro and in vivo Binding Properties toward Drugs of Abuse.

We report studies of the interaction of six acyclic CB[n]-type receptors toward a panel of drugs of abuse by a combination of isothermal titration calorimetry and 1 H NMR spectroscopy. Anthracene walled acyclic CB[n] host (M3) displays highest binding affinity toward methamphetamine (Kd =15 nM) and fentanyl (Kd =4 nM). Host M3 is well tolerated by Hep G2 and HEK 293 cells up to 100 μM according to MTS metabolic and adenylate kinase release assays. An in vivo maximum tolerated dose study with Swiss Webster mice showed no adverse effects at the highest dose studied (44.7 mg kg-1 ). Host M3 is not mutagenic based on the Ames fluctuation test and does not inhibit the hERG ion channel. In vivo efficacy studies showed that pretreatment of mice with M3 significantly reduces the hyperlocomotion after treatment with methamphetamine, but M3 does not function similarly when administered 30 seconds after methamphetamine.

In Vitro and In Vivo Sequestration of Methamphetamine by a Sulfated Acyclic CB[n]-Type Receptor.

We report the synthesis of two new acyclic sulfated acyclic CB[n]-type receptors (TriM0 and Me4 TetM0) and investigations of their binding properties toward a panel of drugs of abuse (1-13) by a combination of 1 H NMR spectroscopy and isothermal titration calorimetry. TetM0 is the most potent receptor with Ka ≥106 M-1 toward methamphetamine, fentanyl, MDMA and mephedrone. TetM0 is not cytotoxic toward HepG2 and HEK 293 cells below 100 μM according to MTS metabolic and adenylate kinase release assays and is well tolerated in vivo when dosed at 46 mg kg-1 . TetM0 does not inhibit the hERG ion channel and is not mutagenic based on the Ames fluctuation test. Finally, in vivo efficacy studies show that the hyperlocomotion of mice treated with methamphetamine can be greatly reduced by treatment with TetM0 up to 5 minutes later. TetM0 has potential as a broad spectrum in vivo sequestrant for drugs of abuse.

Conformationally mobile acyclic cucurbit[n]uril-type receptors derived from an S-shaped methylene bridged glycoluril pentamer

ABSTRACT We report the synthesis of the conformationally mobile S-shaped glycoluril pentamer building block 3a and two new acyclic CB[n]-type receptors P1 and P2. P1 (9 mM) and P2 (11 mM) have moderate aqueous solubility but their host•guest complexes are poorly soluble. Host P1 does not undergo intermolecular self-association whereas P2 does (Ks = 189 ± 27 M−1). 1 H NMR titrations show that P1 and P2 are poor hosts towards hydrophobic (di)cations 6–11 (P1: Ka = 375–1400 M−1; P2: Ka = 1950–19,800 M−1) compared to Tet1 and Tet2 (Tet1: Ka = 3.09 x 106 to 4.69 × 108 M−1; Tet2: Ka = 4.59 x 108 to 1.30 × 1010 M−1). Molecular modelling shows that P1 and P2 exist as a mixture of three different conformers due to the two S-shaped methylene bridged glycoluril dimer subunits that each possess two different conformations. The lowest energy conformers of P1 and P2 do not feature a well-defined central cavity. In the presence of guests, P2 adapts its conformation to form 1:1 P2•guest complexes; the binding free energy pays the energetic price of conformer selection. This energetically unfavourable conformer selection results in significantly decreased Ka values of P1 and P2 compared to Tet1 and Tet2.

Acyclic Cucurbit[n]uril-Type Receptors: Optimization of Electrostatic Interactions for Dicationic Guests.

The synthesis of acyclic CB[n]-type host (1) is reported. By optimizing the placement of the sulfate groups nearby the electrostatically negative ureidyl C═O portals, the binding affinity of this class of receptors toward hydrophobic (di)ammonium guest molecules (5-23) is maximized. The X-ray crystal structures of 1·6a and 1·6d are reported.

Triptycene Walled Glycoluril Trimer: Synthesis and Recognition Properties.

We report the synthesis of a new acyclic CB[n]-type host (1) that features a central glycoluril trimer capped by triptycene sidewalls. Host 1 has good solubility in water (≈ 3 mM) and does not undergo strong self-association (Ks = 480 M-1). We probed the geometry of the complexes by analyzing the complexation induced changes in the 1H NMR spectra and measured the complexation thermodynamics by isothermal titration calorimetry. The conformation of 1 and its packing in the solid state was revealed by single crystal x-ray diffraction measurements.

Acyclic cucurbit[n]uril type receptors: secondary versus tertiary amide arms

ABSTRACTTwo acyclic CB[n]-type hosts (1 and 2) which possess four 2° or 3° amide arms are reported. Host 2 has four 3° amide arms that exist as a mixture of E- and Z-isomers. 1H NMR was used to qualitatively investigate the binding properties of 1 and 2 which indicates they retain the essential binding features of macrocyclic CB[n] hosts. We measured the Ka values of 1 and 2 toward guests 6–14 by ITC. Neutral hosts 1 and 2 bind less tightly than tetraanionic hosts M1, ACB1, and ACB2. We attribute the lower Ka values to the absence of secondary ion-ion electrostatic interactions for host•guest complexes of 1 and 2. The secondary amide functionality on 1 decreases affinity by the formation of intramolecular NH•••O=C H-bonds. Tertiary amide host 2 binds even more weakly than 1 due to backfolding of the amide N-CH3-groups of 2 into its own cavity.

Complexation of bipyridinium guests in the cavity of Acyclic Cucurbit[n]uril receptor

ABSTRACTA series of bipyridinium guests have been synthesised, and their inclusion complexes with acyclic CB[n]-type receptor have been investigated by NMR, UV-Vis spectroscopy, and X-ray diffraction. Novel [3]pseudorotaxane was formed by C-H … O, π-π and ion–dipole interactions. The impact of their complexation on the equilibrium between monomer and dimer of bipyridinium cation radicals has also been studied by UV-Vis-NIR and EPR spectroscopy. Upon reduction, the bipyridinium units linked by flexible pentylene chain preferred the formation of the dimer in the presence of acyclic CB[n]-type receptor, whereas those connected by rigid xylene bridge were suppressed as monomeric form due to the steric effect.

Molecular recognition properties of acyclic cucurbiturils toward amino acids, peptides, and a protein

ABSTRACTThe binding of 1 and 2 toward 19 amino acid amides by 1H NMR and ITC is reported. Hosts 1 and 2 bind to aromatic or hydrophobic residues by cavity inclusion leaving the cationic residues at the C=O portals. Ka values range from 102 to >106 M−1 with H-Phe-NH2, H-Trp-NH2, and H-Tyr-NH2 displaying sub-micromolar Kd values. Hosts 1 and 2 bind tightly to dicationic H-Lys-NH2 and H-Arg-NH2 which are poor guests for CB[7]. Comparison of the affinity of 1 and 2 toward the amino acid amide, N-acetyl-amino-acid amide, and amino acid forms of Phe revealed that the removal of the NH3+ to O=C and SO3− electrostatic interactions costs 3.8 kcal/mol whereas the introduction of an unfavourable CO2− to O=C and SO3− electrostatic interactions costs 2.1 kcal/mol. Hosts 1 and 2 bind to insulin with low micromolar affinity. Acyclic CB[n] display high affinity toward a wider range of N-terminal amino acids residues than CB[n] which suggests a broad range of applications.

Paclitaxel interaction with cucurbit [7]uril and acyclic Cucurbit[4]uril nanocontainers: A computational approach

Paclitaxel (PTX) is a natural terpenoid compound that has been broadly studied for its antitumor activities and widely used as a chemotherapy medication. The treatment efficacy of PTX is affected by its low aqueous solubility, thus causing a subject of extensive research. In recent years, synthetic molecular containers such as cucurbit[n]urils (CB[n]s) and their derivatives have been significantly developing because of their remarkable ability to bind hydrophobic and cationic drugs. Recent experimental studies have shown that acyclic CB[n]-type containers (aCB[n]s), as new derivatives of the family of CB[n]s, increase the solubility of insoluble pharmaceuticals. However, the nature by which the drug interacts with carriers remains largely unknown. In this study, molecular docking and molecular dynamics (MD) simulation were performed to understand how CB[7] and aCB[4] nanocontainers interact with PTX which affect its aqueous solubility. The results clarify how the flexibility of containers is influenced by their structure and how this affects their interactions with PTX. Our results reveal that although both CB[7] and aCB[4] are capable of binding to PTX, the affinity to aCB[4] is higher than that of CB[7]. It has also been shown that the binding to both CB[7] and aCB[4] is probably an entropy-driven process. This research supports the potential use of the cucurbit[n]urils and their acyclic derivatives as drug delivery systems.

Transformative Supramolecular Vesicles Based on Acid-Degradable Acyclic Cucurbit[n]uril and a Prodrug for Promoted Tumoral-Cell Uptake.

Smart supramolecular vesicles constructed by host-guest interactions between "acid-degradable" acyclic cucurbit[n]uril (CB[n]) and a doxorubicin prodrug are reported. "Acid-degradable" acyclic CB[n] is a high-affinity host for several common antitumor drugs, and its degradation leads to a more dramatic decrease in binding affinity than that observed for "acid-sensitive" hosts. Supramolecular complexation between acid-degradable acyclic CB[n] and a doxorubicin prodrug resulted in the formation of negatively charged supramolecular vesicles. The prodrug strategy allowed doxorubicin to be conjugated to vesicles in a stable manner with a high drug-loading ratio of 20 %. The resulting supramolecular vesicles were responsive to tumor acidity (pH 6.5). Induced by mildly acidic conditions (pH 6.5-5.5), acid-degradable acyclic CB[n] could be degraded, and this led to a vesicle-to-micelle transition to form positively charged micelles. This transition resulted in a pH-dependent change in size and surface charge, which improved tumoral-cell uptake for doxorubicin.

Interactions between acyclic CB[n]-type receptors and nitrated explosive materials

The binding ability of acyclic CB[n]-type receptors M1, M2 and macrocyclic CB[7] toward explosive materials was investigated. Acyclic M2 demonstrates an overall better binding and solubilizing ability, and lower fluorescence in the presence of aromatic explosive compounds, suggesting its future application for the detection of harmful explosive materials.

Acyclic Cucurbit[n]uril-Type Containers as Receptors for Neuromuscular Blocking Agents: Structure-Binding Affinity Relationships.

Acyclic cucurbit[n]uril molecular containers 1 and 2C3 have previously been shown to strongly bind to the neuromuscular blocking agents rocuronium, vecuronium, pancuronium, and cisatracurium in vitro by optical methods and to reverse neuromuscular block in vivo in rats. In this paper we study the in vitro binding of a panel of acyclic CB[n]-type receptors toward the four neuromuscular blocking agents and acetylcholine to develop structure-binding affinity relationships. The selected variants include those with different aromatic sidewalls (e.g. 1Me4 with dimethyl o-xylylene walls; 3 with 1,8-linked naphthalene walls), with different glycoluril oligomer lengths (e.g. 4 and 5 based on glycoluril trimer), and with different linker lengths between aromatic wall and SO3 - solubilizing group (e.g. 2C2 - 2C4). Based on the analysis of complexation induced changes in 1H NMR chemical shift we conclude that the hydrophobic regions of the guests bind in the hydrophobic cavity of the hosts with the cationic moieties of the guest binding at the ureidyl C=O portals by ion-dipole and ion-ion interactions. The thermodynamic parameters of binding were determined by direct and competition isothermal titration calorimetry experiments. We find that hosts 4 and 5 based on glycoluril trimer form significantly weaker complexes with the streroidal NMBAs than with the analogues hosts based on glycoluril tetramer (1 and 2C3). Similarly, hosts 1Me4 and 3 with different length and height aromatic walls do not exhibit the extreme binding constants displayed by 2C3 but rather behave similarly to 1. Finally, we find that hosts 2C2 and 2C4 bind only slightly more weakly to the NMBAs than 2C3, but retain the ability to discriminate against acetylcholine, and possess higher inherent water solubility than 2C3. Host 2C4, in particular, holds potential for future in vivo applications.

Acyclic cucurbit[n]urils capped with alkylene linkers: synthesis and molecular recognition properties

ABSTRACTWe report the synthesis and characterization of three new acyclic cucurbit[n]uril-type receptors that feature a covalent capping group in the form of an alkylene linker (2a – 2c) that we hypothesized would have higher binding affinity toward alkylammonium ions in water. Hosts 2a – 2c have lower aqueous solubility (≤2 mM) than the prototypical acyclic CB[n]-type host 1 (346 mM). Hosts 2a – 2c do not undergo significant intermolecular self-association over the experimentally accessible concentration range. In contrast, the results of 1H NMR experiments shows that the alkylene linkers of 2b and 2c undergo self-inclusion and that this process is reversed upon addition of ammonium ions 6–10 as guests. The host•guest Ka values were determined for hosts 1 and 2a – 2c toward guests 6–10 by isothermal titration calorimetry. We find that 2a – 2c bind less strongly toward guests 6–10 than host 1 due to the energetic penalty associated with expulsion of the alkylene linker from its own cavity.

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 nitroamines 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.

Acyclic cucurbit[n]uril conjugated dextran for drug encapsulation and bioimaging.

An acyclic cucurbit[n]uril (CB[n]) conjugated dextran is developed as a new biomaterial for drug delivery and bioimaging. This biomaterial retains the host-guest recognition properties of acyclic CB[n]s. It is able to directly encapsulate anti-tumor drugs 5-fluorouracil and temozolomide. This polymeric material can form a supramolecular assembly with polyethyleneimine (PEI). Although there is no conventional chromophore in these supramolecular systems, they exhibit aggregation-induced emission (AIE) in water with a quantum yield of 10%. This supramolecular assembly is used for bioimaging in vitro with good biocompatibility.

Uptake of Hydrocarbons in Aqueous Solution by Encapsulation in Acyclic Cucurbit[n]uril-Type Molecular Containers.

The ability of two water-soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. (1) H NMR spectroscopy studies and phase-solubility diagrams establish that the naphthalene-walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host-hydrocarbon complexes. The naphthalene-walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution.

Uptake of Hydrocarbons in Aqueous Solution by Encapsulation in Acyclic Cucurbit[n]uril‐Type Molecular Containers

AbstractThe ability of two water‐soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. 1H NMR spectroscopy studies and phase‐solubility diagrams establish that the naphthalene‐walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host–hydrocarbon complexes. The naphthalene‐walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution.