Synthesis,alkali metal picrate extraction,and alkali metal cation binding selectivities of some new cage‐annulated polyoxamacrocyclic crown ethers

Five new cage‐annulated crown ethers, i.e., 4a, 4b, 6b, 11a, and 11b, have been synthesized and their respective alkali metal picrate extraction profiles along with that of a previously synthesized host molecule, 6a, have been obtained. These results are compared with the corresponding results obtained for electrospray ionization mass spectrometric (ESI‐MS) measurements of relative binding selectivities displayed by the same hosts toward a series of alkali metal chlorides. Among the crown‐5 hosts studied, 6a displays enhanced avidity toward complexation with K⁺ picrate in liquid‐liquid extraction experiments. Among the three crown‐6 hosts, 4b proved to be the best alkali metal picrate extractant and displayed significant levels of avidity toward complexation with the larger alkali metal cations (i.e., K⁺, Rb⁺, and Cs⁺). The trends in the picrate extraction and the ESI‐MS results obtained herein show several notable similarities and some differences. The similarities generally stem from size‐selective binding properties that are intrinsic to the different cavity sizes of the cage‐annulated macrocycles, whereas the differences reflect the important influence of solvation effects on the binding properties of the macrocycles.     

Insights into the interactions between a drug and a membrane protein target by fluorine cross-polarization magic angle spinning NMR

The fluorinated anti-psychotic drug trifluoperazine (TFP) has been shown to be a K(+)-competitive inhibitor of gastric H(+)/K(+)-ATPase, a membrane-embedded therapeutic target for peptic ulcer disease. This paper describes how variable contact time (19)F cross-polarization magic angle spinning (VCT-CP/MAS) NMR has been used to probe the inhibitory interactions between TFP and H(+)/K(+)-ATPase in native gastric membranes. The (19)F CP/MAS spectra for TFP in H(+)/K(+)-ATPase enriched (GI) gastric membranes and in control membranes containing less than 5 nmol of the protein indicated that the drug associates with the membranes independently of the presence of H(+)/K(+)-ATPase. The (19)F peak intensities in the VCT-CP/MAS experiment confirmed that TFP undergoes slow dissociation (k(off) < 100 s(-1)) from binding sites in GI membranes, and more rapid dissociation (k(off) < 100 s(-1)) from control membranes. The spectra showed that up to 40% of bound TFP was displaced from GI membranes by 100 mM K(+) and by the K(+)-competitive inhibitor TMPIP, but TFP was not displaced from the control membranes. Hence the spectra of TFP in GI membranes represent the drug bound to the K(+)-competitive inhibitory site of H(+)/K(+)-ATPase and to other non-specific sites. The affinity of TFP for the K(+)-competitive site (K(D) = 4 mM) was determined from a binding curve of (19)F peak intensity versus TFP concentration after correction for non-specific binding. The K(D) was much higher than the IC(50) for ATPase inhibition (8 microM), which suggests that the substantial non-specific binding of TFP to the membranes contributes to ATPase inhibition. This novel approach to probing ligand binding can be applied to a wide range of membrane-embedded pharmaceutical targets, such as G-protein coupled receptors and ion channels, regardless of the size of the protein or strength of binding.     

Relative binding affinities of alkali metal cations to

The binding affinity and selectivity of a new ionophore, [1(8)]starand (1), toward alkali metal cations in methanol were examined through NMR titration experiments and free energy perturbation (FEP) and molecular dynamics simulations. The preference was determined to be K(+) > Rb(+) > Cs(+) > Na(+) > Li(+) in both FEP simulations and NMR experiments. The FEP simulation results were able to predict the relative binding free energies with errors less than 0.13 kcal/mol, except for the case between Li(+) and Na(+). The cation selectivity was rationalized by analyzing the radial distribution functions of the M-O and M-C distances of free metal cations in methanol and those of metal-ionophore complexes in methanol.     

Pharmacophore modelling and electronic feature analysis of hydroxamic acid derivatives,the HIV integrase inhibitors

Hydroxamic acid derivatives with metal ion binding properties were collected from the literature to generate a pharmacophore and 3D-QSAR model for HIV strand transfer inhibition. The derived pharmacophore model (AAAHRR) recognizes both metal ion binding site and hydrophobic group. The QSAR model generated using this hypothesis expressed statistical significance (r ² = 0.971 for the training set and q ² = 0.913 for the test set). The ability of this pharmacophore model to retrieve other metal ion binding inhibitors was examined by screening the ChemBank database (ligandinfo) incorporated with 10 known strand transfer inhibitors. The studied favourable and unfavourable contours of chemical features (H-bond donor, acceptor and hydrophobic sites) revealed the role of hydrophobic substitution at the fluorobenzene ring and cyclization of the metal ion binding hydroxamic acid in effective integrase inhibition. Analysis of the frontier orbitals, HOMO and LUMO revealed that the nucleophilic / electrophilic interactions depend on the significant overlapping observed at the azaindole and hydroxamic acid groups. In essence, the generated pharmacophore model is competent enough to disclose the essential site-specific interactions involved in the inhibition of HIV integrase, and hence can be used in virtual screening to identify novel scaffolds as leads with increased anti-viral potency.     

Determination of Binding Selectivities by Electrospray lonization Mass Spectrometry

Electrospray ionization mass spectrometry is used for the measurement of binding selectivities of four model hosts, 18-crown-6, dibenzo-18-crown-6, dicyclohexano-18-crown-6, and 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, for both alkali and transition metal ions. Based on the intensities of the metal complexes observed in the mass spectra, the relative binding selectivities can be directly estimated. Results are compared to theoretical selectivities obtained by solving simultaneous equilibria equations that define the competing complexation reactions in solution. Good agreement is found in most cases, thus allowing rapid determination of binding selectivities of hosts in a variety of solvents.     

The Synthesis and Complexing Properties of Chiral Diaza Crown Ethers and Cryptands Incorporating D-Mannopyranoside Units

Abstract

Several chiral macrocyclic molecular receptors based on D-mannose as a source of chirality, have been synthesized by standard methods. Three types of host molecules have been designed: cryptands, diaza crown ethers with ligating groups, and hosts (or both types) with convergent binding sites. All hosts displayed enantioselectivity upon complexation with primary ammonium cations (RS), and alkali metal carboxylates (SR) in organic solvents. Hosts featuring convergent binding sites exhibited higher enantioselectivity. The latter was observed by extraction experiments followed by NMR spectroscopy.     

Influence of Cd2+, Hg2+ and Pb2+ on (+)-catechin binding to bovine serum albumin studied by fluorescence spectroscopic methods

The effect of heavy metal ions, Cd(2+), Hg(2+) and Pb(2+) on (+)-catechin binding to bovine serum albumin (BSA) has been investigated by spectroscopic methods. The results indicated that the presence of heavy metal ions significantly affected the binding modes and binding affinities of (+)-catechin to BSA, and the effects depend on the types of heavy metal ion. One binding mode was found for (+)-catechin with and without Cd(2+), while two binding modes - a weaker one at low concentration and a stronger one at high concentration were found for (+)-catechin in the presence of Hg(2+) and Pb(2+). The presence of Cd(2+) decreased the binding affinities of (+)-catechin for BSA by 20.5%. The presence of Hg(2+) and Pb(2+) decreased the binding affinity of (+)-catechin for BSA by 8.9% and 26.7% in lower concentration, respectively, and increased the binding affinity of (+)-catechin for BSA by 5.2% and 9.2% in higher concentration, respectively. The changed binding affinity and binding distance of (+)-catechin for BSA in the presence of Cd(2+), Hg(2+) and Pb(2+) were mainly because of the conformational change of BSA induced by heavy metal ions. However, the quenching mechanism for (+)-catechin to BSA was based on static quenching combined with non-radiative energy transfer irrespective of the absence or presence of heavy metal ions.     

Competition between pi and non-pi cation-binding sites in aromatic amino acids: a theoretical study of alkali metal cation (Li+, Na+, K+)-phenylalanine complexes

To understand the cation-pi interaction in aromatic amino acids and peptides, the binding of M(+) (where M(+) = Li(+), Na(+), and K(+)) to phenylalanine (Phe) is studied at the best level of density functional theory reported so far. The different modes of M(+) binding show the same order of binding affinity (Li(+)>Na(+)>K(+)), in the approximate ratio of 2.2:1.5:1.0. The most stable binding mode is one in which the M(+) is stabilized by a tridentate interaction between the cation and the carbonyl oxygen (O[double bond]C), amino nitrogen (--NH(2)), and aromatic pi ring; the absolute Li(+), Na(+), and K(+) affinities are estimated theoretically to be 275, 201, and 141 kJ mol(-1), respectively. Factors affecting the relative stabilities of various M(+)-Phe binding modes and conformers have been identified, with ion-dipole interaction playing an important role. We found that the trend of pi and non-pi cation bonding distances (Na(+)-pi>Na(+)-N>Na(+)-O and K(+)-pi>K(+)-N>K(+)-O) in our theoretical Na(+)/K(+)-Phe structures are in agreement with the reported X-ray crystal structures of model synthetic receptors (sodium and potassium bound lariat ether complexes), even though the average alkali metal cation-pi distance found in the crystal structures is longer. This difference between the solid and the gas-phase structures can be reconciled by taking the higher coordination number of the cations in the lariat ether complexes into account.     

Symmetric ethereal hosts for lithium: factors for high affinity and selectivity upon ion recognition

Abstract

Since the host-guest chemistry field has been formulated, organic hosts for various ions have been studied extensively. It is now widely accepted that structural and electrostatic complementarity is very important in host-guest chemistry. However, the detailed understanding which enables the chemists to design useful hosts is still in paucity. Although the calculated gas-phase binding energy is not of direct use for many practical applications, this could provide an objective measure for the intrinsic affinity. Here, we have calculated approximate binding energies for famous organic hosts for lithium. The selectivity between lithium and sodium was also investigated. 6-311++G(d,p) basis set with B3LYP functional was used to calculate binding energy of Li⁺ and Na⁺ with four famous hosts. They are spherand, [2,1,1]cryptand, 12-crown-4 and [1₆]starand. We examined several factors such as coordination number, partial charge of oxygen, distance from metal to its coordinating oxygen and metal-dipolar moiety interactions. Within the boundary of the chosen four symmetric hosts in this work, charge–dipolar moiety orientation was the factor that roughly explains the calculated binding affinity.     

A DFT study of the complexation behavior of hemispherands toward alkali metal cations

A density functional theory study of the behavior of hemispherands toward alkali metal ions (Li⁺, Na⁺, and K⁺) is performed. The effect of the replacement of the rigid anisyl group(s) by the mobile ether group(s) on the binding energy of hemispherands with alkali metal ions is investigated. The results indicated that the binding energies are inversely proportional to the ionic radius of the cations. Moreover, increasing the flexibility of the ligand results in decreasing the binding toward small ions. The structures of the hosts and the guests are correlated to the binding energies, and the correlations are interpreted in terms of the principle of preorganization. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

Biomimetic Taste Receptors with Chiral Recognition by Photoluminescent Metal–Organic Frameworks Chelated with Polyaniline Helices

The adsorption of phenylaniline (Phe) enantiomers on (+)‐polyaniline (PAN)‐chelated [In(OH)(bdc)]_n microcrystals was carefully designed and studied by using the Job titration, circular dichroism, X‐ray photoelectron spectroscopy, and photoluminescence to mimic heterotrimeric guanine nucleotide‐binding protein (G protein)‐coupled receptors in selective, but not specific, ligand binding with chiral recognition and signal transduction. Six essential working principles across different length scales are unraveled: 1) a chiral (+)‐PAN (host), 2) specific sites for Phe‐(+)/PAN (guest–host) binding, 3) a conformational change of (+)‐PAN after binding with Phe enantiomers, 4) different degrees of packing for (+)‐PAN, 5) interactions between (+)‐PAN and the underlying signal‐generating framework (i.e., [In(OH)(bdc)]_n microcrystals), and 6) a systematic photoluminescent signal combination by using principal‐component analysis from the other three polymer‐chelated metal–organic frameworkds (MOFs), such as poly(acrylic acid) (PAA), sodium alginate (SA), and polyvinylpyrrolidone (PVP) to enhance the selectivity and discrimination capabilities.     

Voltammetric study of the ion-exchange binding of non-electroactive metal cations to DNA-modified surfaces

We describe a simple electrochemical protocol for studying the ion-exchange binding of non-electroactive ions, specifically mono- and divalent metal cations of biological relevance (Mg(2+), Ca(2+), and K(+)), to DNA-modified surfaces. After incubation in a dilute solution of multiply charged transition metal complex (5.0 microM [Ru(NH(3))(6)]Cl(3)), gold electrodes modified with thiolate-DNA monolayers respond to the presence of these non-electroactive metal cations by producing significant changes in the cyclic voltammograms (i.e., decrease of the integrated charge and shift of formal potential) of the surface-bound redox complex ([Ru(NH(3))(6)](3+)). The divalent cations (particularly Mg(2+)) can be detected at very low concentrations (<10 microM), while the on-set value for K(+) is substantially higher (50 mM). The equilibrium binding constants for Mg(2+) and Ca(2+) to DNA-modified surfaces were calculated.     

Switching on Supramolecular Catalysis via Cavity Mediation and Electrostatic Regulation

Synthetic supercontainers constructed from divalent metal ions, carboxylate linkers, and sulfonylcalix[4]arene‐based container precursors exhibit great promise as enzyme mimics that function in organic solvents. The capacity of these artificial hosts to catalyze Knoevenagel condensation can be switched on when the aldehyde substrate possesses a molecular size and shape matching the nanocavity of the supercontainers. In contrast, little reactivity is observed for other aldehydes that do not match the binding pocket. This substrate‐dependent catalytic selectivity is attributed to the Brønsted acidity of the metal‐bound water molecules located inside the nanocavity, which is amplified when the size/shape of the aldehyde substrate fits the binding cavity. The electrostatic environment of the binding cavity and the Brønsted acidity of the supercontainer can be further modulated using tetraalkylammonium‐based regulators, leading to higher reactivity for the otherwise unreactive aldehydes.     

Imine- and Amine-Type Macrocycles Derived from Chiral Diamines and Aromatic Dialdehydes

The condensation of aromatic dialdehydes with chiral diamines, such as 1,2-trans-diaminocyclohexane, leads to various enantiopure or meso-type macrocyclic Schiff bases, including [2 + 2], [3 + 3], [4 + 4], [6 + 6] and [8 + 8] condensation products. Unlike most cases of macrocycle synthesis, the [3 + 3] macrocycles of this type are sometimes obtained in high yields by direct condensation without a metal template. Macrocycles of other sizes from this family can often be selectively obtained in high yields by a suitable choice of metal template, solvent, or chirality of the building blocks. In particular, the application of a cadmium(II) template results in the expansion of the [2 + 2] macrocycles into giant [6 + 6] and [8 + 8] macrocycles. These imine macrocycles can be reduced to the corresponding macrocyclic amines which can act as hosts for the binding of multiple cations or multiple anions.     

Chirality-induced conformational preferences in peptide-metal ion binding revealed by IR spectroscopy

Chirality reversal of a residue in a peptide can change its mode of binding to a metal ion, as shown here experimentally by gas-phase IR spectroscopy of peptide-metal ion complexes. The binding conformations of Li(+), Na(+), and H(+) with the LL and DL stereoisomers of PhePhe were compared through IR ion spectroscopy using the FELIX free-electron laser. For the DL isomer, both Li(+) and Na(+) exclusively coordinate to the amide O atom, the carboxyl O atom, and one of the aromatic rings (the OOR conformation), while for the LL isomer, a mixture of the OOR and NOR conformations was found. The stereochemically induced change in conformation is shown to reflect the strength of an NH···π interaction remote from the metal ion site. Protonated PhePhe shows no stereochemically induced variation in binding geometry.     

Insight into the cation-π interaction at the metal binding site of the copper metallochaperone CusF

The periplasmic Cu(+)/Ag(+) chaperone CusF features a novel cation-π interaction between a Cu(+)/Ag(+) ion and Trp44 at the metal binding site. The nature and strength of the Cu(+)/Ag(+)-Trp44 interactions were investigated using computational methodologies. Quantum-mechanical (QM) calculations showed that the Cu(+) and Ag(+) interactions with Trp44 are of similar strength (~14 kcal/mol) and bond order. Quantum-mechanical/molecular-mechanical (QM/MM) calculations showed that Cu(+) binds in a distorted tetrahedral coordination environment in the Trp44Met mutant, which lacks the cation-π interaction. Molecular dynamics (MD) simulations of CusF in the apo and Cu(+)-bound states emphasized the importance of the Cu(+)-Trp44 interaction in protecting Cu(+) from water oxidation. The protein structure does not change over the time scale of hundreds of nanoseconds in the metal-bound state. The metal recognition site exhibits small motions in the apo state but remains largely preorganized toward metal binding. Trp44 remains oriented to form the cation-π interaction in the apo state and faces an energetic penalty to move away from the metal ion. Cu(+) binding quenches the protein's internal motions in regions linked to binding CusB, suggesting that protein motions play an essential role in Cu(+) transfer to CusB.     

Theoretical and gas-phase studies of specific cationized purine base quartet

Guanine tetraplexes are biological non-covalent systems stabilized by alkali cations. Thus, self-clustering of guanine, xanthine and hypoxanthine with alkali cations (Na(+), K(+) and Li(+)) is investigated by electrospray ionization mass spectrometry (ESI-MS) in order to provide new insights into G-quartets, hydrogen-bonded complexes. ESI assays displayed magic numbers of tetramer adducts with Na(+), Li(+) and K(+), not only for guanine, but also for xanthine bases. The optimized structures of guanine and xanthine quartets have been determined by B3LYP hybrid density functional theory calculations. Complexes of metal ions with quartets are classified into different structure types. The optimized structures obtained for each quartet explain the gas-phase results. The gas-phase binding sequence between the monovalent cations and the xanthine quartet follows the order Li(+) > Na(+) > K(+), which is consistent with that obtained for the guanine quartet in the literature. The smallest stabilization energy of K(+) and its position versus the other alkali metal ions in guanine and xanthine quartets is consistent with the fact that the potassium cation can be located between two guanine or xanthine quartets, for providing a [gua(or (xan))(8)+K](+) octamer adduct. Even if an abundant octamer adduct with K(+) for xanthine was detected by ESI-MS, it was not the case for guanine.     

The effect of donor atoms on the complexation of alkali cations with spherands: A density functional investigation

Spherands are highly preorganized hosts composed of methoxy 1, fluoro 2, and cyano 3 benzene units attached to one another at their 2,6‐positions. Density functional theory calculations were used to investigate the complexation between these spherands and alkali metal ions (Li⁺, Na⁺, and K⁺) to understand the intrinsic factors affecting cation complexation. A comparison of binding energies for these spherands shows that, this order O? Me ? F ? CN. Although anisyl units are basically poor ligands for metal ions, the rigid placements of their oxygen during synthesis rather than during complexation are undoubtedly responsible for the enhanced binding and selectivity of the spherand. The ion–dipolar moiety interactions are found to be the main factors affecting the preference of external binding in the CN‐spherands. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2009     

Significance of charge‐dipolar moiety interaction: Computational study of cyanospherands

Cyanospherands (CN‐spherands) are highly preorganized hosts which bind cations. Density functional theory calculations were used to investigate the complexation between cyanospherands and alkali metal ions (Li⁺, Na⁺, and K⁺). CN8‐spherand undergoes significant shape change upon complexation, i.e., the oval free host becomes spherical when complexed with cations. All cationic guests prefer external binding to encapsulation in spite of spherically well organized charged moieties and the spacious cavity of hosts. The ion‐dipolar moiety interaction has been found to be a decisive factor for the preference for external binding. This demonstrates the importance of ion‐dipolar moiety orientations as well as the host‐guest size complementarity, to design novel ionophores. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

Resorcinarene Bis‐Thiacrowns: Prospective Host Molecules for Silver Encapsulation

Mixed‐donor atom tetramethoxy resorcinarene bis‐thiacrown hosts, in which the crown unit contains both hard oxygen and soft sulfur donor atoms, were synthesized for soft metal cation binding. The binding properties were investigated both in solution and in the solid state by NMR spectroscopy and X‐ray crystallography. It was found that the resorcinarene bis‐thiacrowns were able to complex silver cations with remarkable affinity forming readily 1:2 host–guest complexes in solution. The solid state structures also revealed that the bis‐thiacrowns form silver complexes in an unanticipated endo‐ and exo‐cavity fashion within the same host molecule. Both the solution and solid state studies indicated the sulfur atoms to be the major contributing donor atoms in forming the binding interactions with silver cations.