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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 (Ka) 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%5fChallenge). As an empirical contribution to SAMPL6, we report here the Ka and thermodynamic parameters (∆G, ∆H, - T∆S) of eight guests binding to two hosts (OA and TEMOA) 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. 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. [ABSTRACT FROM AUTHOR]

The host-guest complexations of fifteen protonated azaspirocyclic, oxa,azaspirocyclic, and diazaspirocyclic guests, three-dimensional analogues of morpholinium, piperidinium, and piperazinium cations, respectively, with cucurbit[7]uril (CB[7]) were investigated using 1H NMR spectroscopy in an acidic aqueous solution. The host-guest stability constants (KCB[7]) for the protonated spirocyclic guests were determined to range from 104-1011 M−1. The relative stability constants have been analyzed in terms of ring sizes and molecular volume (packing coefficient), and the presence and positions of additional oxygen and quaternary nitrogen heteroatoms. The larger the size of both the rings of the guest molecules the higher the observed binding constants for these guests with CB[7]. The largest values for KCB[7] were found for 1- and 2-azaspiro[3.5]nonane, 2- and 8-azaspiro[4.5]decane, and 2-azaspiro[5.5]undecane, when the guest contained 9-11 heavy atoms. Adding oxygen heteroatoms decreased the binding constants by 2-3 orders of magnitude for the azaspirocyclic guests. [ABSTRACT FROM AUTHOR]

Opipramol (OPI), a tricyclic antidepressant and anxiolytic compound, is administered orally in the form of a dihydrochloride. Salt form of the drug has a higher solubility in water and hence bioavailability and stability. A similar effect can be achieved by closing the hydrophobic part of the drug molecule in the cyclodextrin cavity. The paper presents opipramol inclusion complexes with beta-cyclodextrin (β-CD) in 1:1 molar ratio. Studies on the formation of inclusion complexes were carried out both in solution and in the solid state. The formation and physicochemical characterisation of the complexes were determined by UV spectroscopic measurement (UV–vis), Fourier Transform Infrared (FTIR) Spectroscopy,1H Nuclear Magnetic Resonance (1H NMR, 2D NOESY NMR), thermoanalytical methods (TGA – Termogravimetric analysis, DSC – differential scanning calorimetry), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The phase solubility profile with β-CD was classified as the AN- type, indicating the formation of the inclusion complex with a drug. [ABSTRACT FROM PUBLISHER]

The influence of the metallic cation of the base (Li+, Na+or K+) was determined on the acid–base constants ofp-t-butylthiacalix[4]arene (TC4),p-t-butylcalix[4]arene (CA4) andp-t-butylcalix[6]arene (CA6) in ethanol/water in an large interval of pH values by potentiometry and spectrophotometry. The pKavalues determined by both methods correlate very well and these are characteristic for each macrocycle with influence of the cation of the base without a straight evidence of an effect by the size of the metallic cation. In the case ofTC4, pKa1and pKa2were lower to Li+and Na+than with K+. ForCA4, an effect of K+on the pKa2with respect to Li+was observed. A very different behaviour was observed forCA6with Li+and K+showing a lower pKa2and a higher pKa3than with Na+. These effects were interpreted on the basis of the interaction/complexation of each cation with each macrocycle. [ABSTRACT FROM PUBLISHER]

The present study describes non-covalent interaction and complexation behaviour of sodium ascorbate (SA) with cucurbit[6]uril (CB[6]) at neutral pH in aqueous Na2SO4solution. The interaction behaviour is investigated using various analytical techniques like NMR, UV–Vis, fluorescence, TGA and DRS. The substantial increase in the intensity of emission and absorption spectra of sodium ascorbate is observed. The Benesi–Hildebrand evaluation method is used to determine the stoichiometry and equilibrium constant of the cucurbit[6]uril–sodium ascorbate complex, which suggested the 1:1 complex. Time-dependent1H NMR,13C CP MAS and CD studies also echoed non-covalent interaction between SA with CB[6]. [ABSTRACT FROM AUTHOR]

Supramolecular complexation of C60withL1-L5were studied in toluene, chloroform and 1,2-dichlorobenzene solvents using UV–vis, fluorescence,1H,13C NMR spectroscopy as well as density functional theory (DFT) calculations. The Job’s plot of continuous variation method established 1:1 stoichiometry forL1-L5/C60. Binding constants (K) calculated forL1-L5/C60were also determined employing UV–vis and fluorescence spectroscopy. Both steady-state and time-resolved fluorescence spectroscopic surveys showed remarkable fluorescence quenching phenomenon forL1-L5in the presence of C60which was primarily attributed to involvement of a static process. The observed fluorescence quenching inL1–L5was described in terms of both π–π and n–π interactions of the naphthalene moieties and the nitrogen donor groups on the aza-crown macrocyclic ligands with C60, respectively. Moreover, DFT calculations using B3LYP/6-31G* basis set confirmed on the aforesaid π–π interaction of naphthalene groups on the aza-crowns with C60. The DFT calculations also established significant distributions of charge between C60andL1-L5in according to the electronic structure and geometry ofL1-L5/C60, very similar to phthalocycnine/C60systems. [ABSTRACT FROM PUBLISHER]

Cucurbit[8]uril (CB[8]) is robust in encapsulating a stacking dimer of two identical or different aromatic units in water. In recent years, this ternary host–guest complexation motif has found wide applications in constructing supramolecular systems by noncovalently connecting molecular, supramolecular and polymeric precursors. This review summarises the important advance, in particular, in the generation of linear supramolecular polymers and extended supramolecular networks including periodic supramolecular organic frameworks. [ABSTRACT FROM AUTHOR]

A macrocyclic ring comprising multiple hydrogen-bonding sites as well as metal-chelating sites is shown to play the role of ligand in active templated, copper-catalysed [2]rotaxane formation via Huisgen and Glaser reactions. The crystallographic structure and copper ion binding studies are provided for the free macrocycle, along with molecular modelling, barbital, N,N′-trimethyleneurea and copper (I) binding information for the new rotaxanes. [ABSTRACT FROM AUTHOR]

Erlotinib (ERL), the anticancer drug of poor bioavailability, was quantified in terms of bio-relevant physicochemical parameters, such as acid–base properties, lipophilicity and solubility, and a comprehensive study on its inclusion complexation was carried out. The protonation constant of ERL (logK = 5.32) indicates that it exists mainly in deprotonated form at the pH of blood plasma. The high lipophilicity (logp = 2.75) explains its good permeability, while the very low solubility (S0 = 12.46 μM) causes its low bioavailability and renders injection formulation a difficult job. This problem could be alleviated by enhancing ERL solubility through cyclodextrin (CD) inclusion complexation. Therefore, ERL–CD interactions were studied by a number of analytical techniques. The apparent stability constants of ERL with seven different CDs were determined using affinity capillary electrophoresis. Results indicated that the seven-memberedβ-CD and its derivatives were the most suitable hosts. Using UV Job plot titration 1:1 stoichiometry was determined, confirmed by electrospray ionisation-mass spectrometry experiments. The geometry of the inclusion complex was investigated by 2D ROESY NMR techniques, revealing that the ethynylphenyl ring enters theβ-CD cavity. Phase-solubility analysis shows greatly enhanced solution concentration by CD complexation. The determined equilibrium and structural information offer molecular basis to elaborate improved drug formulation with enhanced bioavailability. [ABSTRACT FROM AUTHOR]

A family of calix-crown hybrid molecules containing calix[4]arene and crown-5/6, either at lower rim or at both upper and lower rims, have been synthesised, characterised and their competitive complexation property towards alkali and alkaline earth metal ions in aqueous media have been investigated. The competitive metal ion extraction study, carried out with equimolar mixture of Li+, Na+, K+, Mg2+, Ca2+and Sr2+in aqueous media, revealed that the amount of K+extracted is remarkably high compared to other metal ions. Complexation with K+has been investigated by1H NMR, association constants and thermodynamic parameters have been determined by isothermal calorimetric study. The molecular structures of one of the receptors and two of the K+complexes have been established by single crystal X-ray study. One of the receptors formed bimetallic complex and it exhibited interesting polymeric network structure with bridged picrate anion. These receptors have been applied for extraction of metal ions from bittern. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The formation of inclusion complexes of six essential oil (EO) components (β-caryophyllene,cis-ocimene,trans-ocimene, sabinene hydrate (thujanol), γ-terpinene and α-terpineol) with six cyclodextrins (CDs) (α-CD, β-CD, γ-CD, HP-β-CD, RAMEB and CRYSMEB) was investigated by using static headspace-gas chromatography and UV–visible spectroscopy. Retention studies showed that CDs could efficiently reduce the volatility of EO components except for β-caryophyllene with α-CD. In this case, no inclusion complex was detected while for other compounds the formation of 1:1 inclusion complexes was observed. Results revealed that the inclusion stability mainly depends on geometric complementarity between encapsulated molecule and CD's cavity. Molecular modelling was used to investigate the complementarities between host and guest. Thus, CDs could efficiently be regarded as promising encapsulants for EO components leading to improve their application in cosmetic, pharmaceutical and agriculture fields. [ABSTRACT FROM AUTHOR]

Complexation between the triptycene-derived macrotricyclic polyether containing an anthracene unit and paraquat derivatives in both solution and solid state was investigated. It was found that the macrotricyclic host with multi-cavity structure could form a series of [2]pseudorotaxanes with different terminal functionalised paraquat derivatives in different threading modes, which subsequently resulted in the construction of two novel [2]rotaxanes. [ABSTRACT FROM PUBLISHER]

The inclusion complexation behaviours of 4,4′-dihydroxybenzophenone (DHBP) and 4-hydroxybenzophenone (HBP) with α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD) were investigated using UV–visible fluorescence, time-resolved fluorescence, molecular modelling, scanning electron microscopy (SEM), FTIR, differential scanning calorimeter, X-ray diffraction,1H NMR and molecular modelling techniques. In both molecules, biexponential decay was observed in water, whereas triexponential decay was observed in the CD medium. The DSC thermogram of the DHBP/α-CD and DHBP/β-CD inclusion complex nanomaterials shows the endothermic peak at 60.8, 101.9, 119.6 and 112.8°C. The upfield chemical shift observed for HBP protons reveal that the phenyl ring (without hydroxyl substitution) entered the CD cavity and the hydroxyl group of HBP is exposed outside the CD cavity. The SEM image of DHBP appears as needle-shaped crystals on the micrometre scale, whereas the irregular bar shape was observed for HBP. Transmission electron microscopy images show that both guest molecules formed nano vesicles with α-CD and formed nano rods with β-CD. [ABSTRACT FROM AUTHOR]

A series of novel molecular pincers was successfully synthesised by a copper-free Sonogashira coupling methodology. Complexation of the pincers with Cu(II), Ni(II) and Co(II) was performed in the presence of triethylamine. The formation of the desirable pincer ligands and complexes was confirmed by nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy and mass spectrometry. Electrochemical properties of the complexes of the target pincer dimers investigated by means of cyclic voltammetry suggested that the pincer dimers should be able to serve as an electron donor for phenyl-C61-butyric acid methyl ester and as an electron acceptor for poly(3-hexylthiophene) in bulk heterojunction solar cells. [ABSTRACT FROM AUTHOR]

In this study, we investigated the binding behaviours of three water-solublep-sulfonatocalixarenes with four cinchona alkaloids in aqueous and phosphate buffer solutions (pH 7.2 and 2.0). The complexation stability constants obtained by fluorescence titrations were comparatively discussed from several aspects: host cavity, pH effect and ionic strength. Among three hosts,p-sulfonatocalix[4]arene (SC4A) forms the most stable complexes with cinchona alkaloids, especially in acidic aqueous conditions. Furthermore, SC4A was elected as model drug carrier for cinchona alkaloids, where solubilisation by the complexation of SC4A and mimic release from the calixarene cavity in the presence of negatively charged micelles were initially studied. [ABSTRACT FROM AUTHOR]

A deep-cavity ‘mixed’ octahomotetraoxacalix[2]naphthalene[2]pyridine macrocycle has been synthesised and its single-crystal X-ray structure has been determined. Molecular modeling studies suggested that this macrocycle could be an effective host for guest aromatic diol(s) similar to Wang's methylazacalixpyridines. Binding constants were determined using1H NMR chemical shifts changes and comparisons were made between the diols which were tested. A deep-cavity mixed pyridine-naphthalene homooxacalixarene has been synthesised and its supramolecular complexation properties have been determined with several mono- and di-hydroxylated naphthols. [ABSTRACT FROM AUTHOR]

The 1:1 and 2:1 host–guest complexation of a series of 1,n-bis(isoquinolinium)alkane dications (Iq(CH2)nIq2+,n = 2, 4, 5, 6, 8, 9, 10 and 12, and Iq(p-xylene)Iq2+) by cucurbit[7]uril (CB[7]) in aqueous solution has been investigated by1H NMR spectroscopy and ESI mass spectrometry. The site of binding of the first CB[7] is dependent on the nature of the central linker group, with encapsulation of thep-xylene group or the polymethylene chain whenn = 6–10.With shorter (n = 2–5) or longer (n = 12) chains, the first CB[7] binds over an isoquinolinium group. With a second CB[7], the binding of the central group is abandoned in favour of the CB[7] hosts encapsulating the two cationic isoquinolinium termini. The 1:1 and 2:1 host–guest stability constants are related to modes of binding and the nature of the central linkers, and are compared with dicationic guests bearing different terminal groups. [ABSTRACT FROM AUTHOR]

The binding of lanthanide cations by 2-pyridylmethoxy derivatives ofp-tert-butyldihomooxacalix[4]arene (1b), in the cone conformation, andp-tert-butylhexahomotrioxacalix[3]arene (2b), in both cone and partial cone conformations, was studied. These properties were assessed by extraction studies of the metal picrates from water into dichloromethane and stability constant measurements in methanol and acetonitrile, using spectrophotometric and microcalorimetric techniques. Proton NMR titrations with La3+and Yb3+cations were done in order to get information on the binding sites. Computational methods (density functional theory (DFT) calculations) were also used to complement the NMR data. Thep-tert-butylcalix[4]arene analogue (3b)was also studied, and the results of the four ligands were compared. Partial cone-2bis the best extractant for lanthanide ions, showing some preference for the heavy lanthanides. In complexation, all four ligands show the same trend and a high selectivity for Yb3+(ML, log β ≥ 7). Besides the formation of ML complexes, ML2species were also obtained. In most cases, these species were corroborated by the proton NMR studies. For partial cone-2bwith Pr3+the complexation process is enthalpically driven, whereas for3bthe formation of the ML2species with this cation is due to a favourable entropy term. DFT studies indicate that ligand3bforms the most stable complex with La3+, followed by partial cone-2b. [ABSTRACT FROM AUTHOR]

In this paper, host–guest complexation process of thiacalix[4]arene tetrakis–methylphosphonic and tetrakis–sulphonic acids with amino acids by HPLC and molecular modelling methods has been studied. It was shown that thiacalix[4]arene tetrakis–methylphosphonic acid due to transformability of macrocyclic skeleton and flexibility of methylphosphonic substituents can adopt its conformation for strong multicentre binding of the amino acids with association constant values 530–10,140 M− 1in water. [ABSTRACT FROM PUBLISHER]

The complexation of several local anaesthetics by ? and ?-cyclodextrins was studied by potentiometry with glass electrode. Tetracaine and dibucaine complexation constants were determined at 25°C in the presence of 0.1 M of NaCl. It was found that prilocaine and lidocaine complexes cannot be detected. [ABSTRACT FROM PUBLISHER]