In Ssarch of new anti-bacterial target genes: a comparative/structural genomics approach

We outline a joint academic/industrial (CNRS/AVENTIS) functional genomics project aiming at the discovery of new anti-bacterial gene targets. Starting from all publicly available bacterial genomes, a subset of the most evolutionary conserved protein-coding genes has been identified. We retained genes with clear homolog in E. coli and at least one gram-positive bacterium among B.subtilis, M. tuberculosis, L. lactis or S. pyogenes. This subset was further reduced to genes encoding non-membrane proteins of unknown or hypothetical functions. The 221 E. coli Open Reading Frames (ORFs) identified through this comprehensive bioinformatic analysis are now submitted to a systematic 3-D structure determination protocol including cloning, protein expression and purification, crystallisation and X-ray diffraction. Our strategy was designed to focus on promising wide-spectrum targets as well as original biochemical pathways. Bioinformatics is used throughout all phases of project, including the initial large-scale comparative genomics analyses, the purification/expression and crystallisation stages for the detection of helpful sequence-specific features (e.g. cofactor binding motifs, non-structured N- or C- term extremities, etc ), and finally for the interpretation of the structures in conjunction with multiple sequence alignments for the identification of key residues, interaction areas on molecular surfaces, and overall function predictions.     

Isoagatholactone,a diterpene of a new structural type from the sponge Spongia officinalis

A new diterpene, isoagatholactone, isolated from the sponge Spongia officinalis, is the first natural compound with the carbon skeleton of isoagathic acid (2), the acid-catalyzed cyclization product of agathic acid (1). Structure 4 was assigned to isoagatholactone on spectral grounds and chemical correlation with grindelic acid (5).     

Triazolopyridine,a new derivative for the structural determination of fatty acids by gas chromatography/mass spectrometry

Triazolopyridine is proposed as a new derivative for the location of branches and double bonds in fatty acids. It is compared with previously used derivatives and found to be clearly superior to the pyrrolidide and slightly superior to the β-picolinyl ester with regard to the structure-specific fragmentation pattern. It is prepared by reacting the activated acid with 2-hydrazinopyridine followed by cyclization.     

Reactions of P/S-containing proligands with coinage metal salts: a new route to polynuclear complexes with unusual structural types

The reactions of P/S-precursors with coinage metal alkoxides and carboxylates offer new perspectives for the synthesis of complex metal aggregates.     

Asparinins, asparosides, curillins, curillosides and shavatarins: structural clarification with the isolation of shatavarin V, a new steroidal saponin from the root of Asparagus racemosus

A new steroidal saponin, shatavarin V, (3-O-{[α-l-rhamnopyranosyl(1→2)][β-d-glucopyranosyl(1→4)]-β-d-glucopyranosyl}-(25S)-5β-spirostan-3β-ol), was isolated from the roots of Asparagus racemosus by RP-HPLC, and its structure determined by 1D and 2D NMR studies. This data permits clarification of the structures reported for several known saponins: asparinins A and B; asparosides A and B; curillin H; curillosides G and H and shavatarins I and IV.     

From superhydrophilicity to superhydrophobicity: the wetting behavior of a methylsilicone/phenolic resin/silica composite surface

A methylsilicone/phenolic resin/silica composite surface was prepared by a casting method. The wetting behavior of the surface was investigated. It was found that the as-prepared surface can be varied from superhydrophilicity to superhydrophobicity as the drying temperature increased. Methylsilicone/silica and phenolic resin/silica composite surfaces were also prepared as comparisons. Both of them cannot achieve superhydrophobicity. A mechanism was proposed to explain this phenomenon.     

Isolation of four new CoII/CoIII and NiII complexes with a pentadentate Schiff base ligand: syntheses, structural descriptions and magnetic studies

In this paper we report the temperature and pH dependent syntheses and systematic characterization of four new Co(II)/Co(III) and Ni(II) complexes with a pentadentate Schiff base ligand H(3)L obtained by condensing 1,3,-diaminopropan-2-ol with 2-hydroxyacetophenone in 1:2 molar ratio. The room temperature syntheses involving Co(II) and Ni(II) nitrates and the ligand H(3)L lead to the isolation of the dinuclear species [Co(2)L(2)(H(2)O)] (1), and the mononuclear complex [Ni(LH)] (3), respectively, whereas refluxing at basic pH leads to the tetranuclear complexes, [Co(II)(2)Co(III)(2)L(2)(μ(3)-OMe)(2)(NO(3))(H(2)O)(2)]NO(3)·2(H(2)O) (2), and [Ni(4)L(2)(μ(3)-OMe)(2)(H(2)O)(2)]·2H(2)O (4). 1 is found to be a simple mono alkoxo-bridged Co(III) dinuclear species, whereas 2 and 4 are both rhomb-like tetrameric complexes with double oxo bridges and μ(3)-methoxo bridges, derived from the methanol solvent, in an open dicubane arrangement. Moreover 2 shows six coordinate ordered Co(II) and Co(III) ions and 4 has both six- and five-coordinate Ni(II) centers. Compound 3 is assigned a tentative mononuclear structure based on IR, UV-Vis spectroscopic, (1)H-NMR and ESI mass study results and is supposed to have one Ni(II) center coordinated with a ligand fragment in square planar geometry. The variable temperature magnetic susceptibility study for 2 and 4 is performed which indicate for both 2 and 4 the presence of intracluster dominant ferromagnetic interactions.     

Expanding the structural landscape of niclosamide: a high Z′ polymorph,two new solvates and monohydrate HA

Three new crystalline phases are reported for the drug niclosamide [5‐chloro‐N‐(2‐chloro‐4‐nitrophenyl)‐2‐hydroxybenzamide], C₁₃H₈Cl₂N₂O₄. A new high‐Z′ polymorph (denoted Form II) is described, with four molecules in the asymmetric unit in the space group P2/n. The structure exhibits pseudosymmetry, including local translations and screw‐type operations. The niclosamide molecules are linked by O—H...O hydrogen bonds into chains, and the chains are packed so that the molecules form face‐to‐face (stacking) and end‐to‐end interactions within layers perpendicular to the chains. There are two different layer arrangements, giving a structure that is relatively complex. In the acetone and acetonitrile solvates, the incorporated solvent molecules accept hydrogen bonds from the OH groups of niclosamide, and the niclosamide molecules are stacked in a face‐to‐face manner. In the acetone solvate, C₁₃H₈Cl₂N₂O₄·C₃H₆O, V‐shaped arrangements are formed in which the nitrobenzene ends of the niclosamide molecules are brought into face‐to‐face contact. In the acetonitrile solvate, C₁₃H₈Cl₂N₂O₄·CH₃CN, stacking occurs by translation along a short axis (ca 3.8 Å) and the crystals are frequently observed to be twinned by twofold rotation around that axis. The acetonitrile molecules occupy channels in the structure. A complete structure is provided for niclosamide monohydrate, C₁₃H₈Cl₂N₂O₄·H₂O, polymorph H_A, obtained by Rietveld refinement against laboratory powder X‐ray diffraction data. It has been suggested that this compound is related to the methanol solvate of niclosamide [Harriss, Wilson & Radosevljevic Evans (2014). Acta Cryst. C 70 , 758–763], but it is found that the two are not fully isostructural: they contain isostructural two‐dimensional layers, but the layers are arranged differently in the two structures. This suggests that H_A may have the potential for polytypism, and features in the Rietveld difference curve indicate that a polytype fully isostructural with the methanol solvate might be present.     

Hanasanagin: a new antioxidative pseudo-di-peptide, 3,4-diguanidinobutanoyl-DOPA, from the mushroom, Isaria japonica

The ‘Hanasanagitake’ mushroom, Isaria japonica, is a folk medicine and a traditional health food. Fractionation of the 60% ethanol extract of the mushroom, guided by the antioxidant activity test, led to the isolation of a new pseudo-di-peptide, and it was called ‘hanasanagin’. Spectral analysis and chemical transformation determined the structure of hanasanagin as 3,4-diguanidinobutanoyl-DOPA.     

From inert to explosive, the hydrolytic reactivity of R-NSO compounds understood: a computational study

We present a computational study on the concerted hydrolysis of several classes of N-sulfinylamines of generic formula R-N═S═O, such as the -amines themselves (R-NSO), -hydrazines (R-NH-NSO), -hydrazides (R-CO-NH-NSO) and -amides (R-CO-NSO), as these species are known to possess a wide range of hydrolytic reactivity. Two possible mechanisms of hydrolysis, with a water dimer across the S═O and N═S bonds, in the gas phase are investigated. The reactivity is discussed with respect to the electronic structures, established with the use of the quantum theory of Atoms in Molecules, Natural Bond Orbital and Natural Resonance Theory approaches. For the inert N-sulfinylhydrazines and the keto tautomers of N-sulfinylhydrazides, extended π-conjugation adds a sulfide-like resonance structure that is responsible for their insensitivity toward moisture. Activation barriers for hydrolysis, where water acts as a nucleophilic reagent, decrease with increasing positive charge on the NSO sulfur atom, a finding that might prove useful as a predictive tool in the determination of the general reactivity of an N-sulfinyl compound by experimentalists.     

From A to B: a ride in the free energy surfaces of protein G domains suggests how new folds arise

Metamorphic proteins are an extremely intriguing case of protein evolution and a golden opportunity to challenge the current simplified models. In a recent work, we showed that a coarse-grained Go? model can be used to study the thermodynamics of lymphotactin, a naturally occurring metamorphic protein. Here, we extend such model by including the necessary atomic detail to study the effects of the single mutations that artificially bring the GA domain of protein G to fold into the GB domain of the same protein. The results of this all-atom Go? model show how the residual structure of the denatured state is an early indicator of a forthcoming fold and function switch. These findings reconcile the results of previous studies on similar systems highlighting the different role played by secondary and tertiary interactions and suggesting a possible way for new folds to arise.     

Cytosporacin,a highly unsaturated polyketide: application of the ACCORD-ADEQUATE experiment to the structural determination of natural products

Cytosporacin (1), a novel antibacterial polyketide containing naphthopyranone and isochromandione moieties, was isolated from the fermentation broth of the fungus Cytospora rhizophorae. A (1)H-detected ACCORD-ADEQUATE pulse sequence that distinguished (2)J(CH) from (3)J(CH) correlations provided critical information for structural determination. NOE studies established the relative configuration and revealed the presence of two rotamers. A biosynthetic (13)C-labeling experiment indicated that cytosporacin was derived from acetate origin.     

From N-sulfonyl,C-homoallyl-hydrazones to pyrazole and pyridazine (N2)-heterocycles: the ultimate aromatization process

Isomeric six- and five-membered (N₂)-aromatics, 6-methylpyridazines and 5-vinylpyrazoles, which energetic topological aromaticity is comparable to that of benzene, are shown to be efficiently produced by sequential isomerization–elimination processes from the corresponding 6-methylidene-1,4,5,6-tetrahydropyridazines and 5-vinylpyrazolines, respectively. The latter precursors are available from the same N-sulfonyl,C-homoallyl-hydrazone substrates by a suitable choice of previously reported conditions for Pd-catalyzed CH-oxidative C,N-ring closing processes. The generality of these cyclization, isomerization, and aromatization reactions, for which detailed mechanisms are proposed, provides a systematic access to wide ranges of 3,4,6-trisubstituted 6-methyl-1,4-dihydropyridazines and 6-methylpyridazines, and their 3,4,5-trisubstituted 5-vinylpyrazole isomers.     

Mononuclear and polynuclear copper(I) complexes with a new N,N',S-donor ligand and with structural analogies to the copper thionein core

The N,N',S-donor ligand 4-methoxy-3,5-dimethyl-2-((3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)methyl)pyridine (L) was prepared from 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride and 3-(2-(methylthio)phenyl)-1H-pyrazole. The Cu(I) complexes [Cu2(L)2CH3CN][Cu(L)CH3CN](BF4)3 (1), [Cu(L)PPh3]BF4 (2), and [Cu6(L)2(C6F5S)6] (3) were prepared and characterized by X-ray crystallography (PPh3=triphenylphosphine, C6F5S-=pentafluorothiophenolate). The unit cell of compound 1 consists of cocrystallized mononuclear and dinuclear entities in which all of the copper atoms exhibit distorted tetrahedral coordination. Compound 2 is monomeric with L bound in the kappa3-N,N',S mode and a PPh3 molecule that completes the coordination environment. Compound 2 presents a fluxional behavior in CDCl3 solution due to the boat inversion of the six-membered N,N' chelate ring (DeltaH=+43.6(3) kJ mol(-1), DeltaS=-16(1) J mol(-1) K(-1)). Crystallization of 3 in acetonitrile leads to a polynuclear structure that contains a CH3CN molecule coordinated to one of the copper atoms: [Cu6(L)2(C6F5S)6CH3CN] (3a). The core of 3a partially resembles a {Cu4S6} adamantane-like moiety, the only difference being that the Cu-NCCH3 interaction leads to the opening of the cluster by disrupting a Cu-Cu interaction. Part of this assembly is found in the yeast metallothionein copper(I)-cysteinate core whose crystal structure has recently been reported. Two additional [Cu(L)]+ peripheral moieties interact with the cluster by means of bridging thiolates. ESI-mass spectrometry, conductivity measurements, and 1H/19F pulsed gradient spin echo (PGSE) NMR experiments suggest that 3a dissociates in acetonitrile solution: 3a+CH3CN-->[Cu4(C6F5S)6]2-+2[Cu(L)CH3CN]+. The stability of the cluster with respect to the hypothetical mononuclear species, [Cu(L)(C6F5S)], is confirmed by DFT calculations (B3LYP), which illustrate the exergonic character of the reaction: 6[Cu(L')(C6H5S)]-->[Cu6(L')2(C6H5S)6]+4L' (DeltaG298=-58.6 kJ mol(-1), where L' and C6H5S- are simplified models for L and C6F5S-, respectively). The energetics pertinent to the ionic dissociation of the cluster in acetonitrile is computed using the polarizable continuum model (PCM) approach.     

A2VNb6Cl18 (A=Rb, In, Tl): synthesis, crystal structure and magnetic properties of a new series of quaternary niobium chloride cluster compounds

A new series of quaternary niobium chloride cluster compounds corresponding to the general formula, A₂VNb₆Cl₁₈ (A=Rb, Tl or In), has been prepared in sealed quartz tubes from a mixture containing NbCl₅, Nb, VCl₃ and RbCl, or In or Tl metal by solid state reactions at 750°C. The structure of Tl₂VNb₆Cl₁₈ was determined using single-crystal X-ray diffraction: Crystal data: rhombohedral, (No. 148), a=9.1122(17), c=25.178(7) Å, V=1810.5(7) ų and Z=3. The full-matrix least-squares refinement against F² converged to R₁=0.0515, wR₂=0.1104 (all data). The structure consists of discrete octahedral cluster units, [Nb₆Clⁱ₁₂Cl^a₆]⁴⁻ linked by V²⁺ and A⁺ cations, located in a 6-coordinated octahedral and 12-coordinated anticubeoctahedral chloride environment, respectively. The intra-cluster bond lengths indicate 16 valence electrons per cluster. Magnetic susceptibility studies show paramagnetic behavior with a magnetic moment of 3.37 μ_B per formula unit. Electrical resistivity measurements indicate a semiconducting behavior.     

Xylogranatins F-R: antifeedants from the Chinese mangrove, Xylocarpus granatum, a new biogenetic pathway to tetranortriterpenoids

Thirteen limonoids with a new carbon skeleton, the xylogranatins F-R (1-13), have been isolated from the seeds of a Chinese mangrove, Xylocarpus granatum; two recently reported compounds, xylogranatins C and D were also isolated. Their structures were elucidated on the basis of spectroscopic data and chemical methods. The absolute configurations of these compounds were determined by using the modified Mosher MTPA ester method and by quantum chemical circular dichroism (CD) calculations. Xylogranatins F-Q are the first aromatic B-ring limonoids found in nature. They belong to two substructural classes, of which one (1-3) contains a pyridine ring while the other one (4-12) contains a central furan core. Xylogranatins C and R can be considered to be key biosynthetic intermediates, while xylogranatin D, the only limonoid found so far with a carbon skeleton that conatains a C(30)-C(9) linkage, is apparently an artifact. The structures of these compounds suggest a new biogenetic pathway to tetranortriterpenoids. Xylogranatins F, G and R were found to exhibit marked antifeedant activity against the third instar larvae of Mythimna separata (Walker) at a concentration of 1 mg mL(-1). The most potent compound tested was xylogranatin G. Its AFC(50) (concentration for 50 % antifeedant activity) values at the exposure times of 24 and 48 h were 0.31 and 0.30 mg mL(-1), respectively.     

Synthesis, structural studies, theoretical calculations, and linear and nonlinear optical properties of terpyridyl lanthanide complexes: new evidence for the contribution of f electrons to the NLO activity

The synthesis and structural, photophysical, and second-order nonlinear optical (NLO) properties of a novel lanthanide terpyridyl-like complex family LLn(NO(3))(3) (Ln = La, Gd, Dy, Yb, and Y) are reported. The isostructural character of this series in solution and in the solid state has been established on the basis of X-ray diffraction analysis in the cases of yttrium and gadolinium complexes, theoretical optimization of geometry (DFT), and NMR spectroscopy. The absorption, emission, and solvatochromic properties of the free terpyridyl-like ligand L were thoroughly investigated, and the twist intramolecular charge transfer (TICT) character of the lowest energy transition was confirmed by theoretical calculation (TDDFT and CIS). The similar ionochromic effect of the different lanthanide ions was evidenced by the similar UV-visible spectra of the complete family of complexes. On the other hand, the quadratic hyperpolarizability coefficient beta, measured by the harmonic light scattering (HLS) technique, is clearly dependent on the nature of the metal, and a careful examination of the particular case of yttrium unambiguously confirms the contribution of metal f electrons to the NLO activity.     

Synthesis, structure, and photocatalysis in a new structural variant of the Aurivillius phase: LiBi4M3O14 (M = Nb, Ta)

Two new compounds, LiBi4Nb3O14 and LiBi4Ta3O14, have been synthesized by the solid-state method, using Li2CO3, Bi2O3, and M2O5 (M = Nb, Ta) in stoichiometric quantities. These compounds crystallize in the monoclinic C2/c space group with a = 13.035(3) A, b = 7.647(2) A, c = 12.217(3) A, beta = 101.512(4) degrees , V = 1193.4(5) A3 , and Z = 4 and a = 13.016(2) A, b = 7.583(1) A, c = 12.226(2) A, beta = 101.477(3) degrees , V = 1182.6(5) A3, and Z = 4, respectively. These are isostructural and the structure along the b axis consists of layers of [Bi2O2]2+ units separated by layers of LiO4 tetrahedra and NbO6 octahedra hence depicting an unusual variation in the Aurivillius phase isolated for the first time. The presence of lithium has been confirmed by 7Li NMR studies. ac impedance measurements and variable temperature (7)Li NMR studies indicate oxygen ion conductivity in these materials. The UV-visible spectra suggest a band gap of 3.0 eV for LiBi4Nb3O14 and 3.5 eV for LiBi4Ta3O14, respectively, and the associated studies on degradation of dyes and phenols render these materials suitable for photocatalysis.     

Solid-state NMR spectroscopy of anionic framework aluminophosphates: a new method to determine the al/p ratio

A series of anionic framework aluminophosphates, with different Al/P ratios, have been investigated by various solid-state NMR techniques, including 27Al, 31P magic angle spinning (MAS), 27Al-->31P cross polarization (CP), 27Al{31P} rotational echo double resonance (REDOR), and 31P{27Al} transfer of population double resonance (TRAPDOR). Different Al coordinations (AlO4b, AlO5b, and AlO6b) and P coordinations (PO4b, PO3bOt, PO2bO2t, and PObO3t), where b represents bridging oxygens and t represents terminal oxygens, can be unambiguously determined based on the solid-state NMR spectroscopy. Furthermore, a new method to determine the Al/P ratio of open-framework aluminophosphates has been established, which is useful for the understanding of unknown aluminophosphate structures.