AT(1) receptor ligands: virtual-screening-based design with TOPP descriptors, synthesis, and biological evaluation of pyrrolidine derivatives

As a continuing effort to establish the structure-activity relationships (SARs) within the series of the angiotensin II antagonists (sartans), a pharmacophoric model was built by using novel TOPP 3D descriptors. Statistical values were satisfactory (PC4: r(2)=0.96, q(2) ((5) (random) (groups))=0.84; SDEP=0.26) and encouraged the synthesis and consequent biological evaluation of a series of new pyrrolidine derivatives. SAR together with a combined 3D quantitative SAR and high-throughput virtual screening showed that the newly synthesized 1-acyl-N-(biphenyl-4-ylmethyl)pyrrolidine-2-carboxamides may represent an interesting starting point for the design of new antihypertensive agents. In particular, biological tests performed on CHO-hAT(1) cells stably expressing the human AT(1) receptor showed that the length of the acyl chain is crucial for the receptor interaction and that the valeric chain is the optimal one.

Oxovanadium(V) complexes of bis(phenolate) ligands with acetylacetone as co-ligand: synthesis, crystal structure, electrochemical and kinetics studies on the oxidation of ascorbic acid

Two vanadium(V) complexes, [VO(L-1)]acac)] (1) and [VO(L-2)(acac)] (2), where H2L1 = N,N-bis(2-hydroxy-3-5-di-tert-butyl-benzyl)propylamine and H2L2 = 2,2'-selenobis(4,6-di-tert-butylphenol), have been synthesized and characterized by elemental analyses, IR, V-51 NMR, both in the solid and in solution, and cyclic voltammetric studies. Single crystal X-ray studies reveal that in complex 1 the vanadium atom is octahedrally coordinated with an O5N donor environment, where the oxygen atom of the V-V=O moiety and the N atom of the ONO ligand occupy the axial sites while two oxygen atoms (O1 and O2) from the bisphenolate ligand and two oxygen atoms (O3 and O4) from the acac ligand occupy the equatorial plane. A similar bonding pattern has also been encountered for 2 with the exception that a Se atom instead of N is involved in weak bonding to the metal center. Both complexes showed reversible cyclic voltammeric responses and E-1/2 appears at -0.18 and 0.10 V versus NHE for complexes 1 and 2, respectively. The kinetics of oxidation of ascorbic acid by complex 1 were carried out in 50% MeCN-50% HO (v/v) at 25 degrees C. The high formation constant value, Q = 63 +/- 7 M-1, reveals that the reaction proceeds through the rapid formation of a H-bonded intermediate. The low k(2)Q(2)/k(1)Q(1) ratio (13.4) for 1 points out that there is extensive H-bonding between the oxygen atom of the V-V=O group and the OH group of ascorbic acid. (c) 2007 Published by Elsevier Ltd.

Synthesis, structure and properties of cobalt(II/III) seleno-bisphenolate complexes containing NN bidentate co-ligands: kinetic studies on the reduction of a cobalt(III) complex by ascorbic acid in 80% MeCN-20% water

Two cobalt complexes, [Co(L-Se)(phen)]center dot CH2Cl2 (1) and [Co(L-Se)(N,N-Me(2)en)(CH3COO-)] (2) have been synthesized and characterized by elemental analyses, magnetic measurements, i.r. studies etc. Single crystal X- ray studies reveal that in complex (1) cobalt atom is in +2 oxidation state with trigonal bipyramidal geometry, while in complex (2) it is in +3 oxidation state and surrounded octahedrally. The asymmetric unit of complex (2) contains two crystallographically independent discrete molecules. Complex (1) was found to be paramagnetic with mu(eff) = 2.19 BM indicating a low spin cobalt(II) d(7) system, whereas complex (2) is found to be diamagnetic with cobalt(III) in low spin d(6) state. The kinetic studies on the reduction of (2) by ascorbic acid in 80% MeCN-20% H2O (v/v) at 25 degrees C reveal that the reaction proceeds through the rapid formation of inner-sphere adduct, probably by replacing the loosely coordinated AcO- group, followed by electron transfer in a slow step and is supported by a large Q (formation constant) value.

Structure and spectroelectrochemical response of arene− ruthenium and arene−osmium complexes with potentially hemilabile noninnocent ligands

Nine of the compounds [M(L2−)(p-cymene)] (M = Ru, Os, L2− = 4,6-di-tert-butyl-N-aryl-o-amidophenolate) were prepared and structurally characterized (Ru complexes) as coordinatively unsaturated, formally 16 valence electron species. On L2−-ligand based oxidation to EPR-active iminosemiquinone radical complexes, the compounds seek to bind a donor atom (if available) from the N-aryl substituent, as structurally certified for thioether and selenoether functions, or from the donor solvent. Simulated cyclic voltammograms and spectroelectrochemistry at ambient and low temperatures in combination with DFT results confirm a square scheme behavior (ECEC mechanism) involving the Ln ligand as the main electron transfer site and the metal with fractional (δ) oxidation as the center for redox-activated coordination. Attempts to crystallize [Ru(Cym)(QSMe)](PF6) produced single crystals of [RuIII(QSMe •−)2](PF6) after apparent dissociation of the arene ligand.

Role of ligands in catalytic water oxidation by mononuclear ruthenium complexes

Since first reported in 2005, mononuclear ruthenium water oxidation catalysts have attracted a great deal of attention due to their catalytic performance and synthetic flexibility. In particular, ligands coordinated to a Ru metal centre play an important role in the catalytic mechanisms, exhibiting significant impact on catalyst efficiency, stability and activity towards water oxidation. This review focuses on finding possible correlations between the ligand effects and activity of mononuclear Ru aqua and non-aqua complexes as water oxidation catalysts. The ligand effects highlighted in the text include the electronic nature of core ligands and their substituents, the trans–cis effect, steric hindrance and the strain effect, the net charge effect, the geometric arrangement of the aqua ligand and the supramolecular effects, e.g., hydrogen bonding and influence of a pendant base. The outcome is not always obvious at the present knowledge level. Deeper understanding of the ligand effects, based on new input data, is mandatory for further progress towards a rational development of novel catalysts featuring enhanced activity in water oxidation.

Parameter sensitivity and predictive uncertainty in a new water quality model, Q(2)

A new dynamic model of water quality, Q(2), has recently been developed, capable of simulating large branched river systems. This paper describes the application of a generalized sensitivity analysis (GSA) to Q(2) for single reaches of the River Thames in southern England. Focusing on the simulation of dissolved oxygen (DO) (since this may be regarded as a proxy for the overall health of a river); the GSA is used to identify key parameters controlling model behavior and provide a probabilistic procedure for model calibration. It is shown that, in the River Thames at least, it is more important to obtain high quality forcing functions than to obtain improved parameter estimates once approximate values have been estimated. Furthermore, there is a need to ensure reasonable simulation of a range of water quality determinands, since a focus only on DO increases predictive uncertainty in the DO simulations. The Q(2) model has been applied here to the River Thames, but it has a broad utility for evaluating other systems in Europe and around the world.

Sonic to ultrasonic Q of sandstones and limestones: Laboratory measurements at in situ pressures

Laboratory measurements of the attenuation and velocity dispersion of compressional and shear waves at appropriate frequencies, pressures, and temperatures can aid interpretation of seismic and well-log surveys as well as indicate absorption mechanisms in rocks. Construction and calibration of resonant-bar equipment was used to measure velocities and attenuations of standing shear and extensional waves in copper-jacketed right cylinders of rocks (30 cm in length, 2.54 cm in diameter) in the sonic frequency range and at differential pressures up to 65 MPa. We also measured ultrasonic velocities and attenuations of compressional and shear waves in 50-mm-diameter samples of the rocks at identical pressures. Extensional-mode velocities determined from the resonant bar are systematically too low, yielding unreliable Poisson's ratios. Poisson's ratios determined from the ultrasonic data are frequency corrected and used to calculate the sonic-frequency compressional-wave velocities and attenuations from the shear- and extensional-mode data. We calculate the bulk-modulus loss. The accuracies of attenuation data (expressed as 1000/Q, where Q is the quality factor) are +/- 1 for compressional and shear waves at ultrasonic frequency, +/- 1 for shear waves, and +/- 3 for compressional waves at sonic frequency. Example sonic-frequency data show that the energy absorption in a limestone is small (Q(P) greater than 200 and stress independent) and is primarily due to poroelasticity, whereas that in the two sandstones is variable in magnitude (Q(P) ranges from less than 50 to greater than 300, at reservoir pressures) and arises from a combination of poroelasticity and viscoelasticity. A graph of compressional-wave attenuation versus compressional-wave velocity at reservoir pressures differentiates high-permeability (> 100 mD, 9.87 X 10(-14) m(2)) brine-saturated sandstones from low-permeability (< 100 mD, 9.87 X 10 (14) m(2)) sandstones and shales.

Probing the receptor interactions ofan H5 avian influenza virus using a baculovirus expression system and functionalised poly(acrylic acid) ligands

Influenza viruses attach to host cells by binding to terminal sialic acid (Neu5Ac) on glycoproteins or glycolipids. Both the linkage of Neu5Ac and the identity of other carbohydrates within the oligosaccharide are thought to play roles in restricting the host range of the virus. In this study, the receptor specificity of an H5 avian influenza virus haemagglutinin protein that has recently infected man (influenza strain A/Vietnam/1194/04) has been probed using carbohydrate functionalised poly(acrylic acid) polymers. A baculovirus expression system that allows facile and safe analysis of the Neu5Ac binding specificity of mutants of H5 HA engineered at sites that are predicted to effect a switch in host range has also been developed. (C) 2007 Elsevier Ltd. All rights reserved.

Investigation of cooperativity in the binding of ligands to the D-2 dopamine receptor

The D 2 dopamine receptor exists as dimers or as higher-order oligomers, as determined from data from physical experiments. In this study, we sought evidence that this oligomerization leads to cooperativity by examining the binding of three radioligands ([H-3] nemonapride, [H-3] raclopride, and [H-3] spiperone) to D 2 dopamine receptors expressed in membranes of Sf9 cells. In saturation binding experiments, the three radioligands exhibited different B-max values, and the B-max values could be altered by the addition of sodium ions to assays. Despite labeling different numbers of sites, the different ligands were able to achieve full inhibition in competition experiments. Some ligand pairs also exhibited complex inhibition curves in these experiments. In radioligand dissociation experiments, the rate of dissociation of [H-3] nemonapride or [H-3] spiperone depended on the sodium ion concentration but was independent of the competing ligand. Although some of the data in this study are consistent with the behavior of a cooperative oligomeric receptor, not all of the data are in agreement with this model. It may, therefore, be necessary to consider more complex models for the behavior of this receptor.

Glycogen phosphorylase inhibitors: a free energy perturbation analysis of glucopyranose spirohydantoin analogues

GP catalyzes the phosphorylation of glycogen to Glc-1-P. Because of its fundamental role in the metabolism of glycogen, GP has been the target for a systematic structure-assisted design of inhibitory compounds, which could be of value in the therapeutic treatment of type 2 diabetes mellitus. The most potent catalytic-site inhibitor of GP identified to date is spirohydantoin of glucopyranose (hydan). In this work, we employ MD free energy simulations to calculate the relative binding affinities for GP of hydan and two spirohydantoin analogues, methyl-hydan and n-hydan, in which a hydrogen atom is replaced by a methyl- or amino group, respectively. The results are compared with the experimental relative affinities of these ligands, estimated by kinetic measurements of the ligand inhibition constants. The calculated binding affinity for methyl-hydan (relative to hydan) is 3.75 +/- 1.4 kcal/mol, in excellent agreement with the experimental value (3.6 +/- 0.2 kcal/mol). For n-hydan, the calculated value is 1.0 +/- 1.1 kcal/mol, somewhat smaller than the experimental result (2.3 +/- 0.1 kcal/mol). A free energy decomposition analysis shows that hydan makes optimum interactions with protein residues and specific water molecules in the catalytic site. In the other two ligands, structural perturbations of the active site by the additional methyl- or amino group reduce the corresponding binding affinities. The computed binding free energies are sensitive to the preference of a specific water molecule for two well-defined positions in the catalytic site. The behavior of this water is analyzed in detail, and the free energy profile for the translocation of the water between the two positions is evaluated. The results provide insights into the role of water molecules in modulating ligand binding affinities. A comparison of the interactions between a set of ligands and their surrounding groups in X-ray structures is often used in the interpretation of binding free energy differences and in guiding the design of new ligands. For the systems in this work, such an approach fails to estimate the order of relative binding strengths, in contrast to the rigorous free energy treatment.

Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4,-6 and-7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin

Given the paucity of information on the potential roles of bone morphogenetic proteins (BMPs) in the ruminant ovary we conducted immunolocalization and functional studies on cells isolated from bovine antral follicles. Immunocytochemistry revealed expression of BMP-4 and -7 in isolated theca cells whereas granulosa cells and oocytes selectively expressed RMP-6. All three cell types expressed a range of BMP-responsive type-I (BMPRIB, ActRI) and type-II (BMPRII, ActRII, ActRIIB) receptors supporting autocrine/paracrine roles within the follicle. This was reinforced by functional experiments on granulosa cells which showed that BMP-4, -6 and -7 promoted cellular accumulation of phosphorylated Smad-1 but not Smad-2 and enhanced 'basal' and IGF-stimulated secretion of oestradiol (E2), inhibin-A, activin-A and follistatin (FS). Concomitantly, each BMP suppressed 'basal' and IGF-stimulated progesterone secretion, consistent with an action to prevent or delay atresia and/or luteinization. BMPs also increased viable cell number under 'basal' (BMP-4 and -7) and IGF-stimulated (BMP-4, -6 and -7) conditions. Since FS, a product of bovine granulosa cells, has been shown to bind several BMPs, we used the Biacore technique to compare its binding affinities for activin-A (prototype FS ligand) and BMP-4, -6 and -7. Compared with activin-A (K-d 0.28 +/- 0.02 nM; 100%), the relative affinities of FS for BMP-4, -6 and -7 were 10, 5 and 1% respectively. Moreover, studies on granulosa cells showed that preincubation of ligand with excess FS abolished activin-A-induced phosphorylation of Smad-2 and BMP-4-induced phosphorylation of Smad-1. However, FS only partially reversed BMP-6-induced Smad-1 phosphorylation and had no inhibitory effect on BMP-7-induced Smad-1 phosphorylation. These findings support functional roles for BMP-4, -6 and -7 as paracrine/autocrine modulators of granulosa cell steroidogenesis, peptide secretion and proliferation in bovine antral follicles. The finding that FS can differentially modulate BMP-induced receptor activation and that this correlates with the relative binding affinity of FS for each BMP type implicates FS as a potential modulator of BMP action in the ovary.

Insights into the effects on metal binding of the systematic substitution of five key glutamate ligands in the ferritin of Escherichia coli

Ferritins are nearly ubiquitous iron storage proteins playing a fundamental role in iron metabolism. They are composed of 24 subunits forming a spherical protein shell encompassing a central iron storage cavity. The iron storage mechanism involves the initial binding and subsequent O-2-dependent oxidation of two Fe2+ ions located at sites A and B within the highly conserved dinuclear "ferroxidase center" in individual subunits. Unlike animal ferritins and the heme-containing bacterioferritins, the Escherichia coli ferritin possesses an additional iron-binding site (site C) located on the inner surface of the protein shell close to the ferroxidase center. We report the structures of five E. coli ferritin variants and their Fe3+ and Zn2+ (a redox-stable alternative for Fe2+) derivatives. Single carboxyl ligand replacements in sites A, B, and C gave unique effects on metal binding, which explain the observed changes in Fe2+ oxidation rates. Binding of Fe2+ at both A and B sites is clearly essential for rapid Fe2+ oxidation, and the linking of Fe-B(2+) to Fe-C(2+) enables the oxidation of three Fe2+ ions. The transient binding of Fe2+ at one of three newly observed Zn2+ sites may allow the oxidation of four Fe2+ by one dioxygen molecule.

Molybdenum eta(3)-allyl dicarbonyl complexes as a new class of precursors for highly reactive epoxidation catalysts with tert-butyl hydroperoxide

New Mo(II) diimine derivatives of [Mo(q (3)allyl)X(CO)(2)(CH3CN)(2)] (allyl = C3H5 and C5H5O; X = Cl, Br) were prepared, and [MO(eta(3)-C3H5)Cl(CO)(2)(BIAN)] (BIAN = 1,4-(4-chloro)phenyl-2,3-naphthalene-diazabutadiene) (7) was structurally characterized by single-crystal X-ray diffraction. This complex adopted an equatorial-axial arrangement of the bidentate ligand (axial isomer), in contrast with the precursors, found as the equatorial isomer in the solid and fluxional in solution. The new complexes of the type [Mo(eta(3)-allyl)X(CO)(2)(N-N)l (N-N is a bidentate chelating dinitrogen ligand) were tested for the catalytic epoxidation of cyclooctene using tert-butyl hydroperoxide as oxidant. All catalytic systems were 100% selective toward epoxide formation. While their turnover frequencies paralleled those of related Mo(eta) carbonyl compounds or Mo(VI) compounds bearing similar N-donor ligands, they exhibited similar olefin conversions in consecutive catalytic runs. The acetonitrile precursors were generally more active than the diimine complexes, and the chloro derivatives more active than the bromo ones. Combined vibrational and NMR spectroscopy and computational studies (DFT) were used to investigate the nature of the molybdenum species formed in the catalytic system with [Mo(eta(3)-C3H5)Cl(CO)(2){1,4-(2,6-dimethyl)phenyl-2.3-dimethyldiazabuta diene}] (4) and to propose that the resulting species may be dimeric bearing oxide bridges.

Immobilisation of eta(3)-allyidicarbonyl complexes of Mo-II with bidentate nitrogen ligands within aluminium-pillared clays

Molybdenum(II) complexes [MOX(CO)(2)(eta(3)-allyl)(CH3CN)(2)] (X = Cl or Br) were encapsulated in an aluminium-pillared natural clay or a porous clay heterostructure and allowed to react with bidentate diimine ligands. All the materials obtained were characterised by several solid-state techniques. Powder XRD, and Al-27 and Si-29 MAS NMR were used to investigate the integrity of the pillared clay during the modification treatments. C-13 CP MAS NMR, FTIR, elemental analyses and low-temperature nitrogen adsorption showed that the immobilisation of the precursor complexes was successful as well as the in situ ligand-substitution reaction. The new complex [MoBr(CO)(2)(eta(3)-allyl)(2-aminodipyridyl)] was characterised by single-crystal X-ray diffraction and spectroscopic techniques, and NMR studies were used to investigate its fluxional behaviour in solution. The prepared materials are active for the oxidation of cis-cyclooctene using tert-butyl hydroperoxide as oxidant, though the activity of the isolated complexes is higher. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).