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IR prediction of Novichok candidates is performed by establishing an accurate DFT calculation method on organophosphorus compounds.

International interests in chemical warfare agents (CWAs) have been increased recently because of the use of sarin (GB) in Syrian civil war which caused around 1,300 casualties in 2013. After exposing to natural environments, CWAs undergo hy- drolysis or photodegrade to non-toxic degradation byproducts. Generally, CWAs and their degradation byproducts are present at very low concentration (e.g. several ppb), thus pretreatment processes including separation, extraction and concentration are required prior to any analyses. Liquid-liquid extraction and solid-phase extraction (SPE) are common techniques to pretreat environmental samples. Recently, a novel pretreatment method, liquid phase miecoextraction (LPME), has been applied to CWAs analysis, which could reduce amounts of solvent used but promote analytical efficiencies. Fundamental backgrounds of LPME and its application to CWAs analysis were reviewed.

The Klotho (KL) gene is a classical “aging suppressor” gene. Although recent studies have shown that KL participates in the progression of several types of human cancers, the relationship between KL polymorphism and prostate cancer was unknown. The present study aimed to investigate the association between KL genetic polymorphisms and prostate cancer. Twenty-five common single nucleotide polymorphisms (SNPs) in KL gene (including KL gene polymorphism C1818T in exon 4) were assessed in 272 prostate cancer cases and 173 controls. Single-locus analyses were conducted using unconditional logistic regression. In addition, we did a haplotype analysis for the 25 KL SNPs tested. CC genotype of C1548T KL polymorphism had approximately twofold increased prostate cancer risk compared with the homozygous genotype TT and heterozygote CT (odds ratio 1.85 [95 % CI, 1.09–3.12], P = 0.02). We also found that non-T allele carriers had significantly higher prostate cancer risk associated with the prostate cancer clinical characteristics (tumor stage or Gleason score). Our findings suggested that the C1548T polymorphism of KL gene is associated with the prostate cancer and may act as a risk factor for the development of prostate cancer.

Ion-pair single-drop microextraction (SDME) coupled to gas chromatography–mass spectroscopy (GC–MS) methods for the determination of four degradation products of chemical warfare agents were investigated in water. Acidic analytes were converted into their ion-pair complexes with cation surfactants in aqueous sample and then extracted into the organic single drop containing the derivatising agent. Upon injection, the analytes were derivatised in the GC injection hot port. Parameters, such as type of extraction solvent, ion-pairing (IP) reagent, reagent concentration, salt concentration, stirring speed and pH, were all optimized. This method is reproducible for spiked water sample for four different analytes (RSDs 0.9945). The limit of detection (LOD) is in the range of 0.08–0.01 ng mL−1 (S/N = 5) under GC–MS selected ion monitoring mode. The method was successfully applied to the proficiency test samples from the Organization for Prohibition of Chemical Weapons (OPCW).

Solution phase synthetic method for amyloid-cleaving catalysts was developed, which bears triazine core, scaffold with bulky and that have various solubility properties; Co(III) complex of cyclen (1,4,7,10-tetraazacyclododecane) for catalytic group, and two imaging agents for binding group. This synthetic method was identified by H-NMR, C-NMR for intermediates and MS for the last products. The yields by this method surpassed solid phase synthesis and took much lower labor, expense, and time. The products which were synthesized by solution phase synthetic method showed good catalytic activities.

Lithium stannides were prepared from lithium naphthalenide and tin (II) chloride or tin (0) powder in THF solvent at room temperature under dry argon atmosphere. They were characterized with elemental analysis, XRD, and solid 6,7Li NMR. Stabilities and reactivities of lithium stannides prepared from different conditions were tested and showed they were stable for a limited time at low temperatures. Best reactivity was obtained when they were prepared from tin (II) chloride and an excess of lithium naphthalenide. The lithium stannide mixture can reductively cleave carbon–halogen bonds and yield pinacol coupling with aldehydes. Organolithium compounds prepared from lithium stannides and organic halides add to ketones or aldehydes under Barbier conditions.

A 14N solid-state NMR single crystal study was used to determine the 14N quadrupolar, chemical shift, and 14N−1H dipolar tensors of sulfamic acid. The quadrupolar tensor is nearly axially symmetric, with the quasi-unique axis aligned 3° away from the N−S bond. The quadrupole coupling constant of 0.794 MHz is substantially less than the gas-phase value (1.6682 MHz); ab initio calculations show that the difference can be attributed almost entirely to the significantly shorter N−S bond in the solid state. The single crystal study, together with 15N CP/MAS and CP/static experiments, yields an isotropic chemical shift that lies close to its solution value, and a chemical shielding anisotropy of about −80 ppm, and the dipolar couplings are about 10% smaller than computed from the neutron structure, probably because of vibrational averaging. All three tensors are almost collinear. HF, MP2, CI, and DFT(B3LYP) calculations of the nitrogen quadrupole coupling constant and shielding are also reported.

Type 2 diabetes mellitus (T2DM) is a fatal disorder disease that is characterized by substantial β-cell mass reduction in the context of insulin deficiency. Previous researches have demonstrated that human islet amyloid polypeptide (h-IAPP), an oligopeptide monomer with 37 amino acid residues, induces apoptotic cell-death in β-cells and causes a development of T2DM. Previous studies have also shown that fibrils, which are the final form of aggregated h-IAPP, are not necessarily the most toxic form of amyloid protein in general. Oligomers may induce βcell apoptosis. Therefore, tremendous efforts have been conducted to develop drugs which prevent h-IAPP from forming oligomers. For instance, the use of oligomerspecific antibodies has been investigated, as well as the use of Cu(II) ion, which prevents h-IAPP from forming the βsheet conformers, and cleavage agents with Co(III) cyclen and Cu(II) cyclen. Cleavage agent with Cu(II) cyclen has been proposed as novel catalytic drug. Candidates for catalytic drug are mainly composed of two parts. One part is the catalytic group that hydrolyzes the peptide bond of h-IAPP. This part is composed of Cu(II) cyclen complex, which allows for secreted Cu(II) ions to act as oligomer inhibitors. The other part is the binding group that binds to h-IAPP through hydrophobic interactions. In regards to the hydrolysis reaction by Cu(II) cyclen complex, reaction time is critical and closely connected with the binding group’s capacity since the cleavage agent cleaves only the oligomer form and has limited reaction time. Therefore, it is necessary to synthesize the catalytic drug candidate with the other binding group. Proposed binding group is I-Box-derived one. Benzothiazoleanilines (BTAs) functional group has higher affinity for the hydrophobic amyloid than I-Box(2-(4'-dimethylaminophenyl)-6-iodobenzoxazole) and BTAs also have a ability to cross the blood-brain barrier (BBB) well. Figure 1 shows the proposed structure of Cu(II) cyclen cleavage agent with BTA-derived binding group (Fig. 1). New Cu(II) cleavage agent with BTA-derived binding group was synthesized and the efficiency of this noble agent for h-IAPP cleavage was tested. Figure 2 shows that the MALDI-TOF TOF MS spectrum of fragmentation pattern when h-IAPP was incubated with new Cu(II) cleavage agent with BTA-derived binding group. According to the previous literatures, residues 20-29 and 30-37 of h-IAPP (37mer) are considered as amyloidogenic region. Peaks shown in Figure 2 indicate the fragments of h-IAPP. This spectrum demonstrates that highly amyloidogenic regions of h-IAPP can exist as dissolved form in solution. This indicates that self aggregation of h-IAPP can be inhibited by this noble agent. In our previous study, we

Familial British Dementia (FBD) is the early-onset autosomal dominant disorders characterized by cognitive impairment. The ABri is a 34-mer peptide which is the main component of amyloid deposits in FBD. As a first step toward shedding light for the discovery of amyloid inhibition drugs for FBD, we set the optimal conditions for quantification ABri peptide by the fluorescamine and alpha imager assay, which can provide a precise peptide quantity for determination of amyloid inhibition rate at micromolecular level and estimate aggregation rate by measuring monomer and dimer quantity which are filtered through 10,000 Da MW cutoff filter.

The 14N NMR spectrum of hexamethylenetetramine (HMT) is dominated by the very large electric quadrupole coupling constant of 4.412 MHz at room temperature. Nonetheless, by carefully accounting for this interaction one can subtract its first- and second-order effects on the spectrum, leaving the much smaller anisotropic chemical shift interaction. The chemical shielding anisotropy of HMT is −8.3±3.2 ppm, small but different from zero, with an isotropic chemical shift in good agreement with the value in aqueous solution. This study illustrates how even very tiny chemical shift tensors can be extracted from the NMR spectra of quadrupolar nuclei using appropriate techniques. Copyright © 1999 John Wiley & Sons, Ltd.

Type 2 diabetes mellitus (T2DM) is characterized by a substantial reduction in beta-cell mass and the amyloid fibrils which are formed by the aggregation of the human islet amyloid polypeptide (h-IAPP) in the islet of Langerhans. Cleavage agents with Co(III) cyclen as the catalytic group have been studied as a novel therapeutic option for T2DM patients. However, recent research has suggested that the cytotoxicity of h-IAPP might be mediated by interactions with Cu(II); furthermore, it has been shown in vitro that Cu(II) prevents h-IAPP from forming the beta-sheet conformers. Therefore, we synthesized a cleavage agent using Cu(II) cyclen. The resulting cleaved fragments and estimated cleavage yield (8.3mol%) were evaluated after incubation with h-IAPP.

The complex formed between 4-methylpyridine and pentachlorophenol (4MPPCP) crystallises in a triclinic space group. If the same complex is synthesized from deuterated pentachlorophenol, it crystallizes in an entirely different monoclinic polymorph. Using solid-state NMR of samples synthesized with a full range of deuteration levels, crystallized from solution or the melt, and in the presence or absence of seeds, we have confirmed that the isotopomers indeed have different thermodynamically stable crystal structures. The roots of this phenomenon of isotopomeric polymorphism apparently lie in the differences in hydrogen bonding between the polymorphs. The triclinic form has a relatively short hydrogen bond. High-field solid-state NMR shows both the 1H chemical shift and the 2H electric quadrupole coupling of the hydrogen involved in the bond to be strongly temperature-dependent, indicating a low-lying excited state of the hydrogen bond longitudinal vibration. Inelastic neutron scattering of isotopomers of 4MPPCP has allowed us to identify the three orthogonal vibrational modes of the hydrogen in the hydrogen bond, at 29.7, 145, and 205 meV (240, 1168, and 1651 cm(-1)). The longitudinal mode is the lowest in energy, and it indicates a slightly asymmetric low-barrier double-well potential. Intrinsic to such potentials is a very small difference in zero-point energies (ZPEs) between the protonated and deuterated forms. As a contrast, the monoclinic form has a comparatively normal hydrogen bond, in which the proton and deuteron ZPEs should be different by approximately 500 cm(-1). A scenario can be envisaged where the triclinic protonated form is lower in energy than the monoclinic protonated form, but the triclinic deuterated form is higher in energy than the monoclinic deuterated form. This evidently accounts for the difference in relative stabilities of the two forms upon isotope substitution.

We have derived analytical expressions for determining the orientation of high-symmetry single crystals from line-crossings in a single rotation plot. We demonstrate the utility of the method using the strontium-87 resonance in stron- tium nitrate. Employing our new method, which we call orientation of single crystals using linear approximations to NMR transits (OSCULANT), in combination with fourth-order perturbation theory, we obtain a highly accurate value for the quadrupole coupling constant, and an estimate for the chemical shielding anisotropy.

A method was developed for preparing N-hydroxysuccinimide (NHS)-activated silica for use in immobilizing human serum albumin (HSA) within HPLC columns. This support was made by reacting aminopropyl silica with disuccinimidyl suberate (DSS). Solid state 13C NMR was used to examine the steps in this synthesis. The number of NHS groups on the silica's surface was controlled by varying the amount of DSS or density of surface amine groups used in the preparing this material. Items considered in the use of this material for the immobilization of HSA included the amount of protein added to the support, the reaction time, and the pH of the coupling buffer. These supports were then evaluated in terms of their ability to perform chiral separations for R/S-warfarin and D/L-tryptophan. Advantages of this method compared to current immobilization techniques for HSA included its better long-term stability and the fact that it did not require the use of any reducing agents. The approaches developed in this work are not limited to HSA but can be used with other proteins or amine-containing ligands.

Researches on the discovery of drugs against amyloidogenic proteins or oligopeptides which cause amyloidoses, such as AD (Alzheimer disease), type 2 diabetes mellitus, Parkinson’s disease, and mad cow disease, have focused on reducing the level of amyloid formation, cleaving amyloidogenic peptides, or blocking aggregation with organic molecules that selectively bind and inhibit aggregation and fibril formation.

Lead, strontium and barium nitrates, like the titanates of the same cations, form a continuous set of solid solutions. 207Pb NMR spectra of mixed crystals of lead/strontium nitrate and lead/barium nitrate each show up to 13 lines, arising from lead ions with from zero to twelve Pb2+ nearest-neighbor cations replaced by Sr2+ or Ba2+. In the case of (Pb,Sr)(NO3)2 these shifted lines are further split by the multiplicity of inequivalent nearest-neighbor replacements. The average shift per Sr2+ ion is 21.8 ppm; that for Ba2+ is smaller. Using Monte Carlo/Metropolis calculations, the intensities of the resonances can be fit to statistical models of Pb2+ and Sr2+ ion distributions, and used to probe the microenergetics of solid solution formation. The data can be satisfactorily fit by distributions in which the cations are slightly clustered, with like pairs of nearest neighbors being favored by 120 J/mol over unlike pairs. Interestingly, this finding is inconsistent with the conventional interpretation of powder diffraction results for the mixed crystals, where the dependence of lattice parameter on composition shows a slight positive curvature, generally held to indicate a favorable interaction between unlike ions.

207Pb NMR spectra of mixed crystals of anhydrous lead and strontium nitrate show up to 13 lines, arising from lead ions with 0-12 Pb(2+) nearest-neighbor cations replaced by Sr(2+). The shifted lines are further split by the multiplicity of inequivalent nearest-neighbor replacements. The average shift per Sr(2+) ion is 21.8 ppm. Similar but somewhat smaller effects are seen in [Pb,Ba](NO(3))(2) mixed crystals. The intensities of the resonances can be fit to Monte Carlo models of Pb(2+) and Sr(2+) ion distributions and are consistent with like nearest-neighbor pairs being 120 J/mol lower in energy than unlike pairs.