David Bardelang

Unusual sculpting of dipeptide particles by ultrasound induces gelation.

A readily synthesized dipeptide shows unprecedented gelation behavior when dispersed and submitted to ultrasound in nonsolvents. SEM and FFEM revealed spectacular shape changes from a sheet-like material into a highly interconnected fiber network and ribbons while the dipeptide maintains an anti conformation inside β-sheets at the molecular scale.

Probing cucurbituril assemblies in water with tempo-like nitroxides: A trinitroxide supraradical with spin-spin interactions

Nitroxide free radicals are demonstrated to be useful guests for probing cucurbit[n]uril (CB[n]) assemblies in water by EPR spectroscopy. CB[7] and CB[8] significantly aggregate either in solution or in the solid state (as evidenced by a single-crystal X-ray structure in which CB[8] forms supramolecular triangles with 4-methoxy-TEMPO). The included nitroxides show a striking resistance to biologically relevant reduction, benefiting from the carcerand effect of CB[7] and CB[8] solutions.

Inclusion complexes of coumarin in cucurbiturils.

Coumarin was found to form stable inclusion complexes with cucurbiturils. In the presence of cucurbit[7]uril (CB[7]), 1 : 1 inclusion complexes were observed in aqueous solution, as monitored by (1)H NMR and UV-visible absorption spectroscopies, and further supported by ab initio calculations, whereas with cucurbit[8]uril (CB[8]) a solid phase 1 : 2 host : guest complex was found in a single crystal X-ray diffraction structure determination.

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.

Highly symmetric columnar channels in metal-free cucurbit[n]uril hydrate crystals (n = 6, 8)

Metal-free cucurbit[6]uril and cucurbit[8]uril hydrate crystals present water-filled channels consisting of perfectly aligned one-dimensional macrocycle nanotubes.

New organogelators based on cyclotriveratrylene platforms bearing 2-dimethylacetal-5-carbonylpyridine fragments

Gelators, compounds able to solidify solvents, and in particular hydrogelators are interesting soft materials. In this paper we have synthesized cyclotriveratrylene (CTV) platforms symmetrically end-substituted with pendent primary amines or nicotamic substituents. These non-amphiphilic structures induce self-assembly in a large variety of solvents forming robust and opaque gels. Cyclotriveratrylene gels have for the first time been formed and characterized using FT-IR and freeze fracture electron microscopy. Two hierarchical events are responsible for the gel structure. Individual fibres of 4–5 nm diameter are formed by aggregation of the functionalised CTV molecules. These fibres then further self-assemble into large ribbons several µm long and 20 to 40 nm wide. Within the ribbons the fine striations observed by FFEM are due to individual straight chains organized in a highly compacted state. Within the fibres the individual CTV molecules are held together by hydrogen bonding of the amide function as probed by infra-red spectroscopy.

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.

Spin exchange monitoring of the strong positive homotropic allosteric binding of a tetraradical by a synthetic receptor in water.

The flexible tetranitroxide 4T has been prepared and was shown to exhibit a nine line EPR spectrum in water, characteristic of significant through space spin exchange (J(ij)) between four electron spins interacting with four nitrogen nuclei (J(ij) ≫ a(N)). Addition of CB[8] to 4T decreases dramatically all the Jij couplings, and the nine line spectrum is replaced by the characteristic three line spectrum of a mononitroxide. The supramolecular association between 4T and CB[8] involves a highly cooperative asymmetric complexation by two CB[8] (K1 = 4027 M(-1); K2 = 202,800 M(-1); α = 201) leading to a rigid complex with remote nitroxide moieties. The remarkable enhancement for the affinity of the second CB[8] corresponds to an allosteric interaction energy of ≈13 kJ mol(-1), which is comparable to that of the binding of oxygen by hemoglobin. These results are confirmed by competition and reduction experiments, DFT and molecular dynamics calculations, mass spectrometry, and liquid state NMR of the corresponding reduced complex bearing hydroxylamine moieties. This study shows that suitably designed molecules can generate allosteric complexation with CB[8]. The molecule must (i) carry several recognizable groups for CB[8] and (ii) be folded so that the first binding event reorganizes the molecule (unfold) for a better subsequent recognition. The presence of accessible protonable amines and H-bond donors to fit with the second point are also further stabilizing groups of CB[8] complexation. In these conditions, the spin exchange coupling between four radicals has been efficiently and finely tuned and the resulting allosteric complexation induced a dramatic stabilization enhancement of the included paramagnetic moieties in highly reducing conditions through the formation of the supramolecular 4T@CB[8]2 complex.

Correction to “Comprehensive Synthesis of Monohydroxy–Cucurbit[n]urils (n = 5, 6, 7, 8): High Purity and High Conversions”

During our follow-up work on the conjugation of monohydroxylated cucurbiturils, we found that the reported yields of monohydroxylation of CB[n] (n = 5−8), 90−95%, were incorrect. This was due to the misleading composition of the crude product, with an approximate 0.3/0.3/0.3 ratio of CB[n], CB[n]−(OH)1, and CB[n]−(OH)2, giving NMR signal integrals and peak positions that match the expected values for pure CB[n]−(OH)1. After purification of the product via silica column chromatography using water/acetic acid/formic acid as eluent, the corrected yields are 5−37% for CB[n]− (OH)1, with n = 5−8. These results were confirmed by repeated experiments starting with 100 mg, and using up to 3 g, of CB[n]. The Supporting Information has been revised to include MS spectra of pure CB[n]−(OH)1 and details of the column chromatography purification procedure for all CB[n]−(OH)1. Page 10238. The title should be revised to Comprehensive Synthesis of Monohydroxy−Cucurbit[n]urils (n = 5, 6, 7, 8). Page 10238. In the Abstract, the 95−100% conversion reported for CB[n]−(OH)1 should be corrected to 20−40%, depending on the CB[n] considered. Scale-up experiments were performed using up to 3 g of CB[n] with quartz reactors of 50 or 300 mL. Page 10239. In the Synthesis section, the conversions given in the text and in Table 1 are incorrect due to the misleading H NMR spectra, and should actually be 20−40%. The values in Table 1 are thus apparent conversions determined by H NMR. Isolated yields have been determined and are given in the revised Supporting Information (5−37% for the CB[n]− (OH)1 series). Page 10242. In Table 3, likewise, the conversion of CB[8] toward the formation of CB[8]−(OH)1 is an apparent conversion determined by H NMR, where CB[8] is transformed to CB[8]−(OH)1 and CB[8]−(OH)2. Thus, the title of the table should be revised to “Apparent Conversion of CB[8] toward the Formation of CB[8]−(OH)1”. ■ ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.6b00188. Procedure for the preparation of CB[n]−(OH), C NMR spectra, details of high resolution MS analyses, decay products of CB[8], details for the calculations of BDEs, and structures of each CB[n]· radical (revised) (PDF)

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.