Ian W. Wyman

Host—Guest Complexes and Pseudorotaxanes of Cucurbit[7]uril with Acetylcholinesterase Inhibitors

Pseudorotaxanes may be assembled in aqueous solution using dicationic acetylcholinesterase inhibitors, such as succinylcholine, BW284c51, and alpha,omega-bis(trialkylammonium)alkane dications (or their phosphonium analogues), as bolaform axles and cucurbit[7]uril (CB[7]) as the wheel. With the exceptions of the shorter [(CH(3))(3)N(CH(2))(n)N(CH(3))(3)](2+) (n = 6, 8) dications, the addition of a second CB[7] results in the translocation of the first CB[7], such that the hydrophobic -NR(3)(+) and -PR(3)(+) end groups (R = Me or Et) are located in the cavities of the wheels, while the central portion of the axles extend through the CB[7] portals into the bulk solvent. In the case of the [Quin(CH(2))(10)Quin](2+) (Quin = quinuclidinium) dication, the CB[7] host(s) resides only on the quinuclidinium end group(s). The 1:1 host-guest stability constants range from 8 x 10(6) to 3 x 10(10) M(-1) and are dependent on both the nature of the end group as well as the length and hydrophobicity of the central linker. The magnitude of the stability constants for the 2:1 complexes closely follow the trend observed previously for CB[7] binding with the NR(4)(+) and PR(4)(+) cations.

In vivo reversal of general anesthesia by cucurbit[7]uril with zebrafish models

A general anesthetic is a drug that brings about a reversible loss of consciousness, during a surgical or therapeutic procedure to render the patient free of pain and anxiety. However, the effect of anesthetics may linger far beyond the necessary time required and induce adverse effects. In addition, many surgical patients need to recover to a conscious state that allows them to make important decisions soon after their surgery. Unfortunately, there are currently no clinically-available anti-dotes to reverse the effects of anesthetics. In this study, we demonstrate the in vitro supramolecular host–guest complexations between macrocyclic cucurbit[7]uril (CB[7]) and a commonly used general anesthetic in fish, tricaine mesylate (TM), and we report for the first time the in vivo reversal effect of CB[7] to general anesthesia induced by TM with zebrafish models. These findings might lead to a new approach that may allow patients to regain lucidity much faster than their natural recovery from general anesthesia, and may also be used to reverse potentially life-threatening toxic effects encountered by some patients in response to general anesthesia.

Developmental and organ-specific toxicity of cucurbit(7)uril: in vivo study on zebrafish models†

The macrocyclic molecular container cucurbit[7]uril (CB[7]), the most water-soluble homologue in the cucurbit[n]uril family (n = 5–8, 10, 14), has been evaluated for its in vivo toxicity profile, including its developmental toxicity such as its effect on hatching, growth and survival, as well as its potential organ-specific toxicities such as cardiotoxicity, hepatotoxicity, and locomotion and behavioral toxicity, using zebrafish models. The results revealed that CB[7] has measureable cardiotoxicity and locomotion and behavioral toxicity at concentrations of ∼500 μM or higher, and negligible developmental and hepatotoxicity at concentrations up to 750 μM, although extended exposure to CB[7] in the 500–750 μM concentration range induced the mortality of tested fish. These results demonstrate for the first time with live in vivo animal models that CB[7] has relatively low developmental and organic specific toxicity, and support further exploration of the use of CB[7] in biomedical research at sub-toxic concentrations.

Cucurbit[7]uril: an emerging candidate for pharmaceutical excipients

Cucurbit[7]uril (CB[7]), belonging to the cucurbit[n]uril family (CB[n], n = 5–8, 10, or 13–15), may form host–guest complexes with a variety of small molecules of biomedical interest. The physical and chemical properties of the complexed drugs are often improved as a result of this complexation, suggesting the potential application of CB[7] as a pharmaceutical excipient. This review has summarized the most recent research progress reported between 2011 and early 2017 regarding the biocompatibility of CB[7] and the influence of CB[7] on the stability, solubility, biouptake, and biological activities (including therapeutic efficacies and toxicities) of guest drug molecules. Through this systemic summary and analysis, we intend to stimulate further research efforts in this area and promote the use of CB[7] as an emerging pharmaceutical excipient to improve various properties of drug molecules (or active pharmaceutical ingredients).

Enhanced in vitro and in vivo uptake of a hydrophobic model drug coumarin-6 in the presence of cucurbit[7]uril

This report describes, for the first time, cucurbit[7]uril-assisted quantitative in vitro and in vivo uptake of a hydrophobic model drug, coumarin-6, by both an epithelial cell model and a zebrafish model. The transcellular delivery pathway study suggested multiple mechanisms involved, including macropinocytosis, clathrin and lipid raft-mediated endocytosis/exocytosis.

Encapsulation of Vitamin B1 and Its Phosphate Derivatives by Cucurbit[7]uril: Tunability of the Binding Site and Affinity by the Presence of Phosphate Groups

Vitamin B1 (1) and its phosphate derivatives, thiamine monophosphate (2) and thiamine pyrophosphate (3), are shown to form stable 1:1 host-guest complexes with cucurbit[7]uril (CB[7]) in aqueous solution. The binding sites of CB[7] on these guests shift from the ethylthiazolium region of 1 to the pyrimidine moiety of 2 and 3 due to the presence of phosphate groups, leading to variations of binding affinities as well as C(2)-H/D exchange rate constants and C(2)-H pKa values with these guest molecules.

Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor

Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titration, and molecular modeling by density functional theory. The results supported the macrocyclic encapsulation of MPTP and MPP(+), respectively, by CB[7] in aqueous solutions with relatively strong affinities and 1:1 host-guest binding stoichiometries in both cases. More importantly, the progression of MPTP/MPP(+) induced neurodegeneration (often referred to as a Parkinsons disease model) was observed to be strongly inhibited in vivo by the synthetic CB[7] receptor, as shown in zebrafish models. These results show that a supramolecular approach could lead to a new preventive and/or therapeutic strategy for counteracting the deleterious effects of some neurotoxins leading to neurodegeneration.

A roadmap towards green packaging: the current status and future outlook for polyesters in the packaging industry

Approximately 99% of the plastics produced today are petroleum-based, and the packaging industry alone consumes over 38% of these plastics. In this review, we argue that renewable polyesters can provide a key milestone as renewable plastics in the route toward green packaging. This review describes different classes of polyesters with particular regard to their potential use as packaging materials. Some of the families of polyesters discussed include poly(ethylene terephthalate) and its renewable analogs, poly(lactic acid), poly(hydroxyalkanoates), and poly(epoxy anhydrides). The synthesis of polyesters is discussed from a green chemistry perspective. A structure–property correlation among the various polyesters is also discussed. The challenges that currently hinder the widespread adoption of polyesters as leading packaging materials are reviewed. The environmental footprint and end of life scenario of polyesters are discussed. Finally, future research directions are summarized as a possible roadmap towards the widespread adoption of renewable polyesters as sustainable packaging materials.

High-affinity host–guest complex of cucurbit[7]uril with a bis(thiazolium) salt

A biologically- and pharmaceutically-relevant bis(thiazolium) dication model compound, α,α′-bis(thiazolium)-p-xylene (BTX2+), forms a strong 1 : 1 host–guest inclusion complex with cucurbit[7]uril (CB[7]). The complexation stoichiometry, binding affinity and geometry were studied via 1H NMR and UV-visible titrations, ESI-MS, and molecular modeling (ab initio calculations). The hydrogen/deuterium exchange reactions of the C(2)-proton of BTX2+ were conducted in the absence and presence of CB[7] in D2O at 25 °C and at an ionic strength of 0.20 M. The inhibition of C(2)-H/D exchange of the guest bis(thiazolium) dication upon complexation with CB[7] exhibited a second-order rate constant that decreased by more than four-fold in the presence of CB[7]. The supramolecular-controlled stability of thiazolium cations through complexation with CB[7] host molecules is anticipated to have applications for stability enhancement of thiazolium based drugs and to potentially draw interest in the application of CB[n] host molecules with regard to the formulation and delivery of these drugs.

Supramolecular encapsulation of benzocaine and its metabolite para-aminobenzoic acid by cucurbit[7]uril

An ester-type local anesthetic agent, benzocaine (BZC), and its metabolite, para-aminobenzoic acid (PABA), both form 1 : 1 host–guest complexes with cucurbit[7]uril (CB[7]) in aqueous solution and has been observed by 1H NMR, UV-visible spectroscopic titrations (including Jobs plot), electrospray ionization (ESI) mass spectrometry, and density functional theory (DFT) molecular modeling. The host–guest binding affinities are (2.2 ± 0.2) × 104 M−1 and (1.5 ± 0.2) × 104 M−1 for the protonated BZC and PABA, respectively, in acidic solutions. The binding constants decrease by ∼100-fold to approximately 300 and 200 M−1 for BZC and PABA, respectively, upon deprotonation of these guest molecules in PBS buffered solution (pH = 7.4). However, the encapsulation of these guest molecules by CB[7] only resulted in very moderate pKa shifts. This supramolecular encapsulation of BZC and PABA could potentially find applications in drug formulation for the purpose of enhancing bio-absorption as well as reducing methemoglobinemia and allergic reactions caused by the derivation of PABA during the metabolism of BZC.