The recognition of proteins and their post-translational modifications using synthetic molecules is an active area of research. A common post-translational modification is the phosphorylation of serine, threonine or tyrosine residues. The phosphorylation of proximal tyrosine residues occurs in over 1000 proteins in the human proteome, including in disease-related proteins, so the recognition of this motif is of particular interest. We have developed a luminescent europium(III) complex, , capable of the discrimination of proximally phosphorylated tyrosine residues, from analogous mono- and non-phosphorylated tyrosine residues, more distantly-related phosphotyrosine residues and over proximally phosphorylated serine and threonine residues. was used to continuously monitor the phosphatase catalysed dephosphorylation of a peptide containing proximally phosphorylated tyrosine residues.

Once chemical contaminants are released into the environment, there are a number of concerns that arise regarding the environmental persistence of the contaminants, their known and suspected toxicities, and their potential disruption to the ecosystem. One class of contaminants that is of continuing concern is polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants that are significant components of oil spills. PAHs have been found in the breast milk of nursing mothers living in oil spill affected regions, and can harm the nursing children. We report herein the sensitive and selective detection of 10 PAHs and PAH metabolites in human breast milk using fluorescence energy transfer from the PAH to a high quantum yield fluorophore, and array-based statistical analyses of the resulting fluorescence responses. This detection system was able to separate and identify the PAHs with 100% success in human breast milk and at concentrations as low as 0.17 μM. These results have significant implications in public health and in the monitoring and mitigation of environmental disasters.

The study of hydrogen bonding organocatalysis is rapidly expanding. Much research has been directed at making catalysts more active and selective, with less attention on fundamental design strategies. This study systematically increases steric hindrance at the active site of pH switchable urea organocatalysts. Incorporating strong intramolecular hydrogen bonds from protonated pyridines to oxygen stabilizes the active conformation of these ureas thus reducing the entropic penalty that results from substrate binding. The effect of increasing steric hindrance was studied by single crystal X-ray diffraction and by kinetics experiments of a benchmark reaction.

Molecular recognition in water is challenging but water-soluble molecularly imprinted nanoparticle (MINP) receptors were produced readily by double cross-linking of surfactant micelles in the presence of suitable template molecules. When the micellar surface was decorated with different polyhydroxylated ligands, significant interactions could be introduced between the surface ligands and the template. Flexible surface ligands worked better than rigid ones to interact with the polar moiety of the template, especially for those template molecules whose water-exposed surface is not properly solvated by water. The importance of these hydrophilic interactions was examined in the context of different substrates, density of the surface ligands, and surface-cross-linking density of the MINP. Together with the hydrophobic interactions in the core, the surface hydrophilic interactions can be used to enhance the binding of guest molecules in water.

Sirtinol, a Schiff base derived from 2-hydroxy-1-naphthaldehyde, is an inhibitor of sirtuin proteins, a family of deacetylases active in gene regulation and relevant to the study of cancer growth. The formation of copper(II) and zinc(II) complexes of sirtinol is investigated by spectroscopic and structural methods. The molecular structure of this protein inhibitor allows for coordination of first-row transition metals in both tridentate and bidentate fashion. In addition, assays in cultured breast cancer cells reveal that Cu(sirtinol-) and previously reported Fe(sirtinol-)(NO) present enhanced cytotoxicity when compared to the free ligand, and that the ferric complex causes an increase in intracellular oxidative stress. Transition metal coordination in the biological milieu could therefore contribute additional effects to the biological profile of sirtinol.

We report preparation of (bis)aniline ligand which contains a central viologen binding domain and its subcomponent self-assembly with aldehyde and Fe(OTf) in CHCN to yield tetrahedral assembly . Complexation of ligand with CB[7] in the form of CB[7]••2PF allows the preparation of assembly which contains an average of 1.95 (range 1-3) mechanically interlocked CB[7] units. Assemblies and are hydrolytically unstable in water due to their imine linkages. Redesign of our system with water stable 2,2'-bipyridine end groups was realized in the form of ligands and which also contain a central viologen binding domain. Self-assembly of with Fe(NTf) gave tetrahedral MOP as evidenced by H NMR, DOSY, and mass spectrometric analysis. In contrast, isomeric ligand underwent self-assembly with Fe(OTf) to give cubic assembly . Precomplexation of ligands and with CB[7] gave the acetonitrile soluble CB[7]••2PF and CB[7]••2PF complexes. Self-assembly of CB[7]••2PF with Fe(OTf) gave tetrahedron which contains on average 1.8 mechanically interlocked CB[7] units as determined by H NMR, DOSY, and ESI-MS analysis. Self-assembly of CB[7]••2PF with Fe(OTf) gave cube which contains 6.59 mechanically interlocked CB[7] units as determined by H NMR and DOSY measurements.

Dynamic light scattering (DLS) is a useful tool for the study of the solution-based behavior of colloids and molecular assemblies. The aim of this methods paper is to provide perspective on how this technique can be used by supramolecular chemists. As this technique is not extensively used within the field, we also provide a historical background of its development, summarize data interpretation and the strengths and limitations of the technique, and provide a perspective on some of the important features for supramolecular chemists that can be found in an instrument.

We report here NMR and ITC studies of the binding of ionizable guests (carboxylate acids) to a deep-cavity cavitand. These studies reveal that the shortest guests favored 1:1 complex formation, but the longer the alkyl chain the more the 2:1 host-guest capsule is favored. For intermediate-sized guests, the equilibrium between these two states is controlled by pH; at low values the capsule containing the carboxylic acid guest is favored, whereas as the pH is raised deprotonation of the guest favors the 1:1 complex. Interestingly, for one host-guest pair the energy required to de-cap the 2:1 capsular complex and form the 1:1 complex is sufficient to shift the p of the guest by ~ 3-4 orders of magnitude (4.1-5.4 kcal mol). The two largest guests examined form stable 2:1 capsules, with in both cases the guest adopting a relatively high energy J-shaped motif. Furthermore, these 2:1 complexes are sufficiently stable that at high pH guest deprotonation occurs without de-capping of the capsule.

Although computer-aided drug design has greatly improved over time, its application in the pharmaceutical industry is still limited by the accuracy of association constant predictions. Towards improving this situation, the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) is a series of community-wide blind challenges aimed to advance computational techniques as standard predictive tools in rational drug design (https://en.wikipedia.org/wiki/SAMPL_Challenge). As an empirical contribution to the sixth assessment (SAMPL6), we report here the association constant ( ) and thermodynamic parameters (∆, ∆, -∆) of eight guests (-) binding to two subtly different hosts ( and ) using ITC. Both hosts contain a unique, well-defined binding pocket capable of storing guests with up to ten non-hydrogen atoms, whilst the selection of amphiphilic guests contain a range of saturated and unsaturated substituents from C6 to C10. The thermodynamic data from this study will allow the challenge participants of SAMPL6 to test the accuracy of their computational protocols for calculating host-guest affinities.

Calixarenes are known to form host-guest complexes and supramolecular nanoassemblies with well-defined architectures. However, the use of these materials in conjunction with drug moieties is still under explored. One reason is the insuffcient biocompatibility studies. Our present study represents a systematic investigation of the cytotoxicity associated with -methylresorcin[4]arene, -methylpyrogallol[4]arene, p-phosphonated calix[8]arene and a metal-seamed calixarene-copper(II) complex, using human HEK293 and rat C6G cell lines and two different cell viability assays (MTT and CellTiter-Glo) to avoid species-biased results. All compounds showed low to moderate toxicity. The trend in the CC values indicated that the suppression of the coordination ability and the presence of phosphonate groups decrease the overall cytotoxicity of the compounds. The results of this study not only establish calixarenes and their immediate families as potential drug carriers and drug modifiers, but also reveal a pathway for fine-tuning their toxicological behaviour by appropriate chemical modification.

We report the synthesis of the conformationally mobile S-shaped glycoluril pentamer building block and two new acyclic CB[n]-type receptors and . (9 mM) and (11 mM) have moderate aqueous solubility but their host•guest complexes are poorly soluble. Host does not undergo intermolecular self-association whereas does (K = 189±27 M). H NMR titrations show that and are poor hosts toward hydrophobic (di)cations - (: K = 375-1400 M; : K = 1950-19800 M) compared to and (: K = 3.09 × 10 to 4.69 × 10 M; : K = 4.59 × 10 to 1.30 × 10 M). Molecular modelling shows that and 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 and do not feature a well-defined central cavity. In the presence of guests, adapts its conformation to form 1:1 •guest complexes; the binding free energy pays the energetic price of conformer selection. This energetically unfavorable conformer selection results in significantly decreased K values of and compared to and .

The emergence of drug delivery using water stable metal-organic frameworks has elicited a lot of interest in their biocompatibility. However, few studies have been conducted on their stability in common buffers, cell media, and blood proteins. For these studies, single crystal ZIF-8 approximately 1 um in diameter were synthesized, incubated with common laboratory buffers, cell media, and serum, and then characterized by PXRD, IR, DLS, and SEM. Time-resolved SEM and PXRD demonstrate that buffers containing phosphate and bicarbonate alter the appearance and composition of ZIF-8; however, cargo inside the ZIF-8 does not appear to leak out, in most of these buffers, even when the ZIF-8 itself is displaced by phosphates. On the other hand, blood proteins in serum dissolve ZIF-8, causing trapped biomolecules to escape. The study presented here suggests that ZIF-8 can undergo dramatic surface chemistry changes that may affect the interpretation of cellular uptake and cargo release data. On the other hand, it provides a rational explanation as to how ZIF-8 neatly dissolves .

We report the design and synthesis of the acyclic cucurbit[n]uril-β-cyclodextrin chimeric host . The goal of the study is to deepen the cavity of the receptor to allow β-CD complexation of moieties on the guest (especially fentanyl) that protrude from the cavity of the primary acyclic CB[n] binding site to enhance binding affinity and deliver new supramolecular antidotes for fentanyl intoxication. H NMR spectroscopy was used to deduce the geometry of the complexes between and and the guest panel ( - and fentanyl) whereas isothermal titration calorimetry was used to determine the thermodynamic parameters of complexation. Hosts and retain the essential molecular recognition features of CB[n] receptors, but chimeric host binds slightly stronger toward the guest panel than for reasons that remain unclear. Compared to tetraanionic hosts and , the dianionic hosts and are less potent receptors which reflects the importance of electrostatic (ion-ion and ion-dipole) interactions in this series of hosts. The work highlights the challenges inherent in the optimization of binding affinity of hosts as potential supramolecular antidotes.

We report the synthesis of which is a tetracationic analogue of our prototypical acyclic CB[n]-type molecular container . Both and possess excellent solubility in DO and do not undergo intermolecular self-association processes that would impinge on their molecular recognition properties. Compounds and do, however, undergo an intramolecular self-complexation process driven by ion-dipole interactions between the ureidyl C=O portals and the OCHCHNH arms along with inclusion of one aromatic wall in its own hydrophobic cavity. The K values for and toward seven nucleotides were determined by H NMR titration and found to be quite modest (K in the 10 - 10 M range) although is slightly more potent. The more highly charged guests (e.g. ATP) form stronger complexes with and than the less highly charged guest (e.g. ADP, AMP). The work highlights the dominant influence of the ureidyl C=O portals on the molecular recognition behavior of acyclic CB[n]-type receptors and suggests routes (e.g. more highly charged arms) to enhance their recognition behavior toward anions.

Tetraphenylethylene (TPE) related (supra)molecules have been intensively investigated due to their aggregation-induced emission (AIE) effect based on the restriction of intramolecular rotation (RIR). Meanwhile, boron-dipyrromethene (BODIPY) tends to emit intense fluorescence with high quantum yields. Herein, we combined TPE, BODIPY and terpyridine (TPY) into one system to study the emissive behaviour of organic building block as well as a self-assembled metallo-supramolecule. The TPY and BODIPY substituents with bulky sizes provide strong hindrance to restrict the rotation of the phenyl groups on TPE, leading to enhancement of emissive properties in both solution and aggregation states. Furthermore, the BODIPY-TPE-TPY ligand () was assembled with Zn (II) through coordination-driven self-assembly to form a cyclic dimer () with typical AIE characteristics.

Bis(sulfonamide) receptors based on the 2,6-bis(2-anilinoethynyl)pyridine scaffold form persistent dimers with water and halides in solution and in the solid-state. The structurally related bis(amide) receptor derived from 3,5-dinitrobenzoyl chloride is a dimer in the solid-state with two HCl molecules directing the self-assembly. The 2+2 dimer, with a twisted "S"-shaped backbone, is held together by six hydrogen bonds. Dissolution of the ( ) adduct in CHCl results, however, in a monomeric structure. DOSY and H NMR experiments were used to identify the dominance of monomer in solution for both and . The 'OFF-ON' fluorescence response of 2, 6-bis(2-anilinoethynyl)pyridine is retained with amide arms.

Two acyclic CB[]-type hosts ( and ) which possess four 2° or 3° amide arms are reported; and are slightly soluble in water and do not self-associate. Host has four 3° amide arms that exist as a mixture of E- and Z-isomers. H NMR was used to qualitatively investigate the binding properties of and which indicates they retain the essential binding features of macrocyclic CB[] hosts (e.g. cavity binding of hydrophobic residues and portal binding of cationic groups). We measured the K values of and toward guests - , methamphetamine, and fentanyl by ITC to evaluate their potential as sequestration agents. Neutral hosts and bind less tightly than tetraanionic hosts , , and . We attribute the lower K values to the absence of secondary ion-ion (ammonium•••sulfonate or ammonium•••carboxylate) electrostatic interactions for host•guest complexes of and . The secondary amide functionality on decreases affinity by formation of intramolecular NH•••O=C H-bonds. Tertiary amide host binds even more weakly than due to backfolding of the amide N-CH-groups of into its own cavity. The x-ray crystal structure of supports this conclusion.

Calix[6]arene hexacarboxylic acid binds instantly and with low symmetry to Pb, Sr and Ba. Later a highly symmetric up-down alternating conformation emerges. The solution structures are identical to their p-tert-butylcalix[6]arene hexacarboxylic acid counterparts. With either receptor an octahedral cage is formed around the metal. The transformation from low to high symmetry however proceeds at significantly faster rates for the de-t-butylated host.

The binding properties of the pyrrole-strapped calix[4]pyrrole for cesium halide ion pairs were studied H NMR spectroscopic and single crystal X-ray diffraction analyses. Receptor was found to bind CsF, CsCl, and CsBr in the solid state and in chloroform/methanol (4/1, v/v) solution with relatively high affinity as compared with the parent calix[4]pyrrole . It was also revealed by solid-liquid extraction experiments that receptor was capable of solubilizing CsF in CDCl, a medium in which this salt is otherwise insoluble. Single crystal X-ray diffraction analyses and H NMR spectroscopic data recorded in 20% CDOD in CDCl provide support for the suggestion that the strap pyrrolic NH proton of , as well as those of the calix[4]pyrrole framework, contribute to anion recognition, thus increasing affinity for cesium halide salts relative to the parent system . In the solid state, receptor interacts with CsF to form a two dimensional coordination polymer in the presence of methanol. A linear coordination polymer is observed in the case of CsCl and CsBr. Receptor was also found to form a complex with CsF in chloroform/methanol (4/1, v/v) solution, albeit with a different binding mode than is seen in the solid state.

The study of hydrogen bonding organocatalysis is rapidly expanding. Much research has been directed at making catalysts more active and selective, with less attention on fundamental design strategies. This study systematically increases steric hindrance at the active site of pH switchable urea organocatalysts. Incorporating strong intramolecular hydrogen bonds from protonated pyridines to oxygen stabilizes the active conformation of these ureas thus reducing the entropic penalty that results from substrate binding. The effect of increasing steric hindrance was studied by single crystal X-ray diffraction and by kinetics experiments of a benchmark reaction.

Diversity in supramolecular chemistry can showcase itself in many ways. This includes the diversity of thought and topics covered in research (from fundamental science to applications in biology and materials), as well as the diversity of people (e.g., diversity in race, gender, sexual orientation, country of origin, type of higher education institute, career stage,…). At the North American Supramolecular Chemistry (NASC) meetings, we aim to bring together the best that supramolecular chemistry has to offer in North America, create a sense of community and provide a platform for researchers at any stage of their career to present their work. NASC 2023 was the successful second edition of the NASC meeting series, and this proceedings article highlights the research and impressions of some of the speakers at NASC 2023.