Stereochemical Studies of the Karlotoxin Class Using NMR Spectroscopy and DP4 Chemical‐Shift Analysis: Insights into their Mechanism of Action

After publication of karlotoxin 2 (KmTx2; 1 ), the harmful algal bloom dinoflagellate Karlodinium sp. was collected and scrutinized to identify additional biologically active complex polyketides. The structure of 1 was validated and revised at C49 using computational NMR tools including J‐based configurational analysis and chemical‐shift calculations. The characterization of two new compounds [KmTx8 ( 2 ) and KmTx9 ( 3 )] was achieved through overlaid 2D HSQC NMR techniques, while the relative configurations were determined by comparison to 1 and computational chemical‐shift calculations. The detailed evaluation of 2 using the NCI‐60 cell lines, NMR binding studies, and an assessment of the literature supports a mode of action (MoA) for targeting cancer‐cell membranes, especially of cytostatic tumors. This MoA is uniquely different from that of current agents employed in the control of cancers for which 2 shows sensitivity.     

Hydrogen bonding interaction between 1,4‐dioxane and water

This work reports an interaction of 1,4‐dioxane with one, two, and three water molecules using the density functional theory method at B3LYP/6‐311++G* level. Different conformers were studied and the most stable conformer of 1,4‐dioxane‐(water)_n (n = 1–3) complex has total energies ?384.1964038, ?460.6570694, and ?537.1032381 hartrees with one, two, and three water molecules, respectively. Corresponding binding energy (BE) for these three most stable structures is 6.23, 16.73, and 18.11 kcal/mol. The hydrogen bonding results in red shift in O? O stretching and C? C stretching modes of 1,4‐dioxane for the most stable conformer of 1,4‐dioxane with one, two, and three water molecules whereas there was a blue shift in C? O symmetric stretching and C? O asymmetric stretching modes of 1,4‐dioxane. The hydrogen bonding results in large red shift in bending mode of water and large blue shift in symmetric stretching and asymmetric stretching mode of water. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

A Blocking Group Scan Using a Spherical Organometallic Complex Identifies an Unprecedented Binding Mode with Potent Activity In Vitro and In Vivo for the Opioid Peptide Dermorphin

Herein, the selective enforcement of one particular receptor‐ligand interaction between specific domains of the μ‐selective opioid peptide dermorphin and the μ opioid receptor is presented. For this, a blocking group scan is described which exploits the steric demand of a bis(quinolinylmethyl)amine rhenium(I) tricarbonyl complex conjugated to a number of different, strategically chosen positions of dermorphin. The prepared peptide conjugates lead to the discovery of two different binding modes: An expected N‐terminal binding mode corresponds to the established view of opioid peptide binding, whereas an unexpected C‐terminal binding mode is newly discovered. Surprisingly, both binding modes provide high affinity and agonistic activity at the μ opioid receptor in vitro. Furthermore, the unprecedented C‐terminal binding mode shows potent dose‐dependent antinociception in vivo. Finally, in silico docking studies support receptor activation by both dermorphin binding modes and suggest a biological relevance for dermorphin itself. Relevant ligand‐protein interactions are similar for both binding modes, which is in line with previous protein mutation studies.     

Pyridine adsorption on small Nin‐cluster (n = 2,3,4): A study of geometry and electronic structure

Adsorption of pyridine on Ni_n‐clusters (with n = 2,3,4) is studied by quantum chemical calculations at B3LYP/LANL2DZ and B3LYP/6‐311G^** levels. First, Ni_n‐clusters are investigated for accessible structure and electronic states. The lowest electronic state with four unpaired electrons is predicted for Ni₄‐cluster based on geometry and electronic structure, showing that the cluster stability nicely depends on number of unpaired electrons. Correction for basis set superposition error of metal‐metal bond is appreciable and has increasing effect on cluster binding energy. Next, adsorption of pyridine in planar and vertical adsorption modes is investigated on rhombus Ni₄‐cluster. The vertical mode is found (at B3LYP/6‐311G^** level) as the most favorable adsorption mode. Adsorption energy (ΔE_ads) depends on cluster size; adsorption on Ni₄‐cluster is most favorable with ΔE_ads = ?207.33 kJ/mol. The natural bond orbital analysis reveals the charge transfer in adsorbate/metal‐cluster. Results of investigations for the Ni₂‐ and Ni₃‐cluster are also presented. © 2012 Wiley Periodicals, Inc.     

Template‐Assembled Synthetic G‐Quadruplex (TASQ): A Useful System for Investigating the Interactions of Ligands with Constrained Quadruplex Topologies

A new biomolecular device for investigating the interactions of ligands with constrained DNA quadruplex topologies, using surface plasmon resonance (SPR), is reported. Biomolecular systems containing an intermolecular‐like G‐quadruplex motif 1 (parallel G‐quadruplex conformation), an intramolecular G‐quadruplex 2 , and a duplex DNA 3 have been designed and developed. The method is based on the concept of template‐assembled synthetic G‐quadruplex (TASQ), whereby quadruplex DNA structures are assembled on a template that allows precise control of the parallel G‐quadruplex conformation. Various known G‐quadruplex ligands have been used to investigate the affinities of ligands for intermolecular 1 and intramolecular 2 DNA quadruplexes. As anticipated, ligands displaying a π‐stacking binding mode showed a higher binding affinity for intermolecular‐like G‐quadruplexes 1 , whereas ligands with other binding modes (groove and/or loop binding) showed no significant difference in their binding affinities for the two quadruplexes 1 or 2 . In addition, the present method has also provided information about the selectivity of ligands for G‐quadruplex DNA over the duplex DNA. A numerical parameter, termed the G‐quadruplex binding mode index (G4‐BMI), has been introduced to express the difference in the affinities of ligands for intermolecular G‐quadruplex 1 against intramolecular G‐quadruplex 2 . The G‐quadruplex binding mode index (G4‐BMI) of a ligand is defined as follows: G4‐BMI=K_D^intra/K_D^inter, where K_D^intra is the dissociation constant for intramolecular G‐quadruplex 2 and K_D^inter is the dissociation constant for intermolecular G‐quadruplex 1 . In summary, the present work has demonstrated that the use of parallel‐constrained quadruplex topology provides more precise information about the binding modes of ligands.     

Comparison of Immobilization Modes in pH-Sensitive Phase Separation Immunoassay

Three immobilization modes of antigen to the polymers in the pH‐sensitive phase separation immunoassay were investigated and compared. The results showed that the immobilization mode in the presence of N‐ethyl‐N′‐(3‐dimethylaminopropyl)carbodiimide hydrochloride (EDCI) rendered the most desirable results. The immobilization efficiencies and immunological reaction activities of immobilized antigen of this mode were improved over the other two modes. The novel immobilization mode by EDCI was used in the pH‐sensitive phase separation immunoassay for rabbit IgG (Ag). In the competitive immunoassay, immobilized Ag and the standard Ag (or sample) competed for binding to a horseradish peroxidase labeled antibody at 37°C in a homogeneous format. After changing the pH to separate the polymer‐immune complex, the complex precipitate was re‐dissolved and determined by coupling with the color reaction of hydrogen peroxide and o‐phenylenediamine. The linear range of this determination was between 100–1400 ng/mL. Compared to the traditional enzyme‐linked immunosorbent assays (ELISA) using the same reactants, the proposed method was quiet fast (the time decreased from 100?120 to 30 min) and showed similar sensitivity, i.e., 6.0 ng/mL.     

Molecular Recognition of DNA by Hoechst Benzimidazoles: Exploring Beyond the Pyrrole‐Imidazole‐Hydroxypyrrole Polyamide‐Pairing Code

A series of three‐ring analogs of the minor‐groove‐binding molecule Hoechst 33258 ( 1 ), consisting of benzimidazole (B), imidazopyridine (P), and hydroxybenzimidazole (H) monomers, have been synthesized in order to investigate both their sequence specificity and binding modes. MPE⋅Fe^II Footprinting has revealed the preference of both PBB and BBB ligands for 5′‐WGWWW‐3′ and 5′‐WCWWW‐3′ tracts, as well as A⋅T‐rich sequences. Affinity‐cleavage titrations show no evidence for a 2 : 1 binding mode of these Hoechst analogs. Importantly, all derivatives are oriented in one direction at each of their binding sites. The implications of these results for the design of minor‐groove‐binding small molecules is discussed.     

A comparison of positive and negative ion collision‐induced dissociation for model heptapeptides with one basic residue

The effects of the identity and position of basic residues on peptide dissociation were explored in the positive and negative modes. Low‐energy collision‐induced dissociation (CID) was performed on singly protonated and deprotonated heptapeptides of the type: XAAAAAA, AAAXAAA, AAAAAXA and AAAAAAX, where X is arginine (R), lysine (K) or histidine (H) residues and A is alanine. For [M + H]⁺, the CID spectra are dominated by cleavages adjacent to the basic residues and the majority of the product ions contain the basic residues. The order of a basic residue's influence on fragmentation of [M + H]⁺ is arginine > histidine ≈ lysine, which is also the order of decreasing gas‐phase basicity for these amino acids. These results are consistent with the side chains of basic residues being positive ion charge sites and with the more basic arginine residues having a higher retention (i.e. sequestering) of the positive charge. In contrast, for [M ? H]^? the identity and position of basic residues has almost no effect on backbone fragmentation. This is consistent with basic residues not being negative mode charge sites. For these peptides, more complete series of backbone fragments, which are important in the sequencing of unknowns, can be found in the negative mode. Spectra at both polarities contain C‐terminal y‐ions, but y_n″⁺ has two more hydrogens than the corresponding y_n^?. Another major difference is the production of the N‐terminal backbone series b_n⁺ in the positive mode and c_n^? in the negative mode. Thus, comparison of positive and negative ion spectra with an emphasis on searching for pairs of ions that differ by 2 Da (y_n″⁺ vs y_n^?) and by 15 Da (b_n⁺ vs c_n^?) may be a useful method for determining whether a product ion is generated from the C‐terminal or the N‐terminal end of a peptide. In addition, a characteristic elimination of NH?C?NH from arginine residues is observed for deprotonated peptides. Copyright © 2010 John Wiley & Sons, Ltd.     

A Small Molecule Affecting the Replication of Trinucleotide Repeat d(GAA)n

A newly designed ligand, methylcarbamoylnaphthyridine dimer (MCND), was synthesized and characterized. Ligand binding to d(GAA)₁₀ was investigated by UV thermal denaturation, circular dichroism spectroscopy, surface plasmon resonance, and cold‐spray‐ionization time‐of‐flight mass spectrometry. The results indicated that MCND bound to the d(GAA)_n repeat to form a stable hairpin structure with a major binding stoichiometry of 3:1. The most likely binding site was identified as the G? G mismatch in the AGA/AGA triad. The polymerase stop assay showed that MCND binding to the d(GAA)_n repeat effectively interfered with the extension of the primer at the first two GAA sites on the template with both prokaryotic Taq DNA polymerase and human DNA polymerase α.     

Interactions of Zn(II) with single and multiple amino acids. Insights from density functional and ab initio calculations

Calculations were performed to study the interactions of metal ions (M) with (multiple) amino acids (AA) and fill the gap between single AA and proteins. A complete conformational search results in nine and eleven ZnGly isomers at B3P86 and MP2 levels, respectively, and four populated conformers of glycine are responsible for production of these isomers. For all M, the isomers via the OO and NO binding modes are the main constituents, and the OO mode is favored by stronger electrostatic interactions. Binding with more glycines causes larger structural distortions, improves relative stabilities of monodentate binding isomers and generates new binding modes (e.g. ZnB_III via only the hydroxyl group). The scaling factor of Zn(Gly)_n structures, the ratio of its binding affinity versus the sum of comprising ZnGly isomers, is linear with glycine number (n), and the linear relationship may not be altered by mutations of glycines and M. It thus allows to estimate M(AA)_n binding affinities (n ≥ 2) from the comprising MAA structures and analyze their structures with kinetic methods. The DFT and MP2 results become comparable by increasing metal coordination, e.g. the ZnB_III versus ZnA_I (zwitterionic) relative energy differs by 41.9 kcal mol^?1 at B3P86 and MP2 levels and is close by addition of three water molecules (4.1 kcal mol^?1). The presence of water solvent improves the relative stabilities of monodentate binding isomers and results in a broader conformational distribution. Copyright © 2012 John Wiley & Sons, Ltd.     

A computational study on the ring stretching modes of halogen‐substituted pyridine involved in H‐bonding

Density functional method B3LYP plus the AUG‐cc‐pVDZ and AUG‐cc‐pVTZ basis sets is used to investigate ring normal modes of halogen‐substituted pyridines involved in the N ··· H? X H‐bonds with HX (X = F, Cl). The results demonstrated that the formation of hydrogen bond leads to an increase in the frequencies of the ring breathing mode v₁, the N‐para‐C stretching mode v_6a and the meta‐CC stretching mode v_8a, whereas there is no change in the triangle mode v₁₂ for free pyridine and a smaller blue shift for substituted pyridines. There is a strong coupling between the C? Y stretching vibration and the triangle mode (ortho‐ and para‐substituted) or the breathing mode (meta‐substituted) in substituted pyridines, which leads to the frequency decrease in the triangle or breathing modes. The natural bond orbital analysis suggests that electrostatic interaction and charge transfer caused by the intermolecular and intramolecular hyperconjugations are the origin of the frequency blue shift in the ring stretching modes. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

Intermolecular interactions of a size‐expanded guanine analogue with gold nanoclusters

The interactions between a size‐expanded Guanine analogue x‐Guanine (xG) and gold nanoclusters, Au_n (n = 2, 4, 6, and 8), were studied theoretically using density functional theory. Geometries of neutral complexes were optimized using the B3LYP functional with the 6‐31+G(d,p) basis set for xG and the LANL2DZ basis set for gold clusters. The binding modes, interaction strength, and the charge‐transfer properties of different Au_n‐xG complexes were investigated. Natural population analysis was performed for natural bond order charges. It was found that gold nanoclusters form stable complexes with xG and these binding results in a substantial amount of electronic charge being transferred from xG to the gold clusters. The vertical first ionization potential, electron affinity, Fermi Level, and the HOMO–LUMO gap of xG and its complexes with gold nanoclusters were also analyzed. © 2013 Wiley Periodicals, Inc.     

Adsorption of Proline and Glycine on the TiO2(110) Surface: A Density Functional Theory Study

The optimal adsorption modes for the amino acids glycine and proline on the ideal TiO₂(110) surface are investigated by using density functional theory (PBE) applying periodic boundary conditions. Binding modes with anionic acid moieties bridging two titanium atoms after transferring a proton to the surface are the most stable configurations for both molecules investigated—similar to previous results for carboxylic acids. In contrast to the latter compounds, amino acids can form hydrogen bonds via the amino group towards the surface‐bound proton; this provides an additional stabilisation of 15–20 kJ mol^?1. Zwitterionic binding modes are less stable (by 10–20 kJ mol^?1) and are less important for proline. Neutral modes are energetically even less favourable. Calculations of vibrational frequencies and core‐level shifts complement the adsorption study and provide guidance for future experimental investigations. Control of the computational parameters is crucial for the derivation of accurate results. The layout and thickness of the slab model used are also shown to be decisive factors. Calculations with a different GGA‐functional (PW91) provide very similar relative energies, although the absolute energies change by about 20 kJ mol^?1. Results derived with the hybrid functional PBE0 show an even greater stabilisation of the anionic binding modes with respect to the zwitterionic modes. A previously observed discrepancy between experimental and theoretical results for glycine could be solved, although the experimentally proposed free rotation of the C? C bond could not be reproduced.     

Evaluating the biological potential of some new cobalt (II) complexes with acrylate and benzimidazole derivatives

This paper presents the synthesis, physico‐chemical and biological properties of four new coordination compounds with mixed ligands: acrylate ion (acr) and benzimidazole/benzimidazole derivatives with the general formula [Co(L) ₂ (acr) ₂ ]·nH ₂ O [ (1) L: benzimidazole (HBzIm), n: 0.5; (2) L: 2‐methylbenzimidazole (2‐MeBzIm), n: 0.5; (3) L: 5‐methylbenzimidazole (5‐MeBzIm), n: 0; (4) L: 5,6‐dimethylbenzimidazole (5,6‐Me₂BzIm), n: 0]. Their chemical formulae were achieved correlating the chemical analysis with mass spectrometry data, the ligands coordination modes were assigned by Fourier transform‐infrared measurements, and the trigonal bipyramidal geometry of cobalt ion in complexes was assigned by data correlation of UV–Vis‐NIR spectra and magnetic moments measurements. Single‐crystal X‐ray diffraction reveals a mononuclear structure with a pentacoordinated cobalt (II) ion, connected to two acrylato coordinated in different modes and two unidentate 5,6‐dimethylbenzimidazole ligands for compound (4) . The biological tests were performed against several microbial strains, the cytotoxicity was evaluated on HCT8 cellular lines and the cell cycle analysis was performed on HT29 cellular lines. Microbiological assays indicated that Co (II) complexes present a very good to good activity against Candida albicans 1760, Enterococcus faecium E5, Bacillus subtilis ATCC 6683 and Escherichia coli ATCC 25922. Predictive pharmacokinetic (ADME), toxicity and drug‐likeness profiles were evaluated for Co (II) complexes. Our results highlight that Co (II) complexes depicted in the present study are suitable to be used as efficient pharmacological agents.     

Unsymmetrical Binding Modes of the HOPNO Inhibitor of Tyrosinase: From Model Complexes to the Enzyme

The deciphering of the binding mode of tyrosinase (Ty) inhibitors is essential to understand how to regulate the tyrosinase activity. In this paper, by combining experimental and theoretical methods, we studied an unsymmetrical tyrosinase functional model and its interaction with 2‐hydroxypyridine‐N‐oxide (HOPNO), a new and efficient competitive inhibitor for bacterial Ty. The tyrosinase model was a dinuclear copper complex bridged by a chelated ring with two different complexing arms (namely (bis(2‐ethylpyridyl)amino)methyl and (bis(2‐methylpyridyl)amino)methyl). The geometrical asymmetry of the complex induces an unsymmetrical binding of HOPNO. Comparisons have been made with the binding modes obtained on similar symmetrical complexes. Finally, by using quantum mechanics/molecular mechanics (QM/MM) calculations, we studied the binding mode in tyrosinase from a bacterial source. A new unsymmetrical binding mode was obtained, which was linked to the second coordination sphere of the enzyme.     

One—dimensional Network Constructed by Salicylate and Phenanthroline Ligands with Copper（Ⅱ）

A novel complex,[Cu2(phen)(sal)(Hsal)2]n(1),was synthesized and structurally characterized.The basic dimeric units are hold by sal ligands and extended into 1-D network.The carboxylate grougs of salicylates coordinate to the central ion in three different coordination modes:chelating,bridging and bridging-chelating.In the case of bridging-chelating of the carboxylate group of the salicylate,all three oxygen atoms of salicylate are bidentately coordinated to copper ion,namely,μ4-η^3 binding mode.     

Synthesis,Structures, and Properties of Four Novel Coordination Compounds based on a Flexible Tetrakis(imidazol‐1‐ylmethyl)methane Ligand

Four coordination polymers, namely, [Zn₂(TIYM)(2,6‐PYDC)₂]_n · n(CH₃OH) · 3n(H₂O) ( 1 ), [Cu(TIYM)(2,6‐PYDC)]_n · 3n(H₂O) ( 2 ), [Co(TIYM)(2,6‐PYDC)]_n · n(CH₃OH) · 3n(H₂O) ( 3 ), and [Cd₂(TIYM)(2,6‐PYDC)₂(H₂O)]_n · n(H₂O) ( 4 ) with the flexible N‐containing ligand [tetrakis(imidazol‐1‐ylmethyl)methane (TIYM)] and the N‐containing dicarboxylic acid [2,6‐pyridinedicarboxylic acid (2,6‐PYDC)] were prepared. Compounds 1 – 4 show various structures because of different N–C_center–N angles (θ) of TIYM ligands and changing coordination modes of 2,6‐PYDC. Compounds 1 , 2 , and 3 display a similar 1D ladder‐like chain, whereas 4 gives a 1D quad‐core lifting platform shaped belt. The structural diversities in 1 – 4 suggest that the multiple coordination modes or the different freely twist angles of ligands and the presence of different metal atoms play important roles in the resulting structures of the coordination polymers. Furthermore, the solid‐state luminescence properties of 1 and 4 , and the magnetic properties of 3 were investigated.     

Fixation of Sulphur Dioxide by Manganese(II)‐Schiff Base Complexes: Thermal Stability of these Adducts and the Possible Conversion of the Coordinated SO2 to Sulphate

A series of manganese(II) complexes of general formula MnLⁿ(H₂O)_m (where H₂Lⁿ are substituted N,N′‐bis(salicylidene)‐1,2‐diimino‐2,2‐dimethylethane) have been prepared by electrochemical synthesis and characterized by analytical and spectroscopic techniques, magnetism and by studying their redox reversibility character by cyclic and normal pulse voltammetry. The reactivity of these complexes with sulphur dioxide has been investigated in the solid state and in toluene slurries at room temperature. The studies of the reversibility of the reaction (desorption studies) by thermogravimetrical analysis (TGD) have shown a different behaviour among the SO₂‐adducts (from irreversible to totally reversible fixing), pointing to different SO₂ binding modes. Thus, adducts 10 , 12 and 14 , kept the SO₂ after TGD, signifying S–bridged SO₂ binding mode, while TGD for 8 , 9 and 13 revealed the lability of their SO₂, attributable to ligand bound SO₂ coordination. The manganese(II) precursor 4 is that one which has the ability of reversily fixing a major quantity of SO₂ and undergoes the sulphato reaction to form 11 also.     

Theoretical study of structure and vibrational properties of MgnOn (n = 3–10) clusters

The structure and harmonic vibrations of Mg_nO_n (n = 3–10) clusters have been investigated using density functional theory. All structures are found to be cumulenic D_nh rings (equal bonds, alternating angles), with one intense out‐of‐plane mode and three infrared (IR)‐active degenerate modes, of which the highest one is extremely intense and increases asymptotically to 1000 cm^?1 for n = 10 at the B3LYP/6‐311++G(2d,2p) level. Comparisons with C_2n clusters show that B_nN_n and Be_nO_n clusters, the structure and bonding type for the Mg_nO_n clusters are consistent with those of the C_2n (n = 3, 5, 7,…) clusters B_nN_n(n = 3–10) and Be_nO_n(n = 3–10) clusters. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007