Theoretical study of X- · 1 · YF (1 = triazine,X = Cl,Br and I,Y = H,Cl, Br,I, PH2 and AsH2): noncovalently electron-withdrawing effects on anion-arene interactions

The ternary complexes X^- · 1 · YF (1 = triazine, X = Cl, Br and I, Y = H, Cl, Br, I, PH₂ and AsH₂) have been investigated by MP2 calculations to understand the noncovalently electron-withdrawing effects on anion-arene interactions. The results indicate that in binary complexes (1 · X^-), both weak σ-type and anion-π complexes can be formed for Cl^- and Br^-, but only anion-π complex can be formed for I^-. Moreover, the hydrogen-bonding complex is the global minimum for all three halides in binary complexes. However, in ternary complexes, anion-π complex become unstable and only σ complex can retain in many cases for Cl^- and Br^-. Anion-π complex keeps stable only when YF = HF. In contrast with binary complexes, σ complex become the global minimum for Cl^- and Br^- in ternary complexes. These changes in binding mode and strength are consistent with the results of covalently electron-withdrawing effects. However, in contrast with the covalently electron-withdrawing substituents, Cl^- and Br^- can attack the aromatic carbon atom to form a strong σ complex when the noncovalently electron-withdrawing effect is induced by halogen bonding. The binding behavior for I^- is different from that for Cl^- and Br^- in two aspects. First, the anion-π complex for I^- can also keep stable when the noncovalent interaction is halogen bonding. Second, the anion-π complex for I^- is the global minimum when it can retain as a stable structure.     

Theoretical potential scans and vibrational spectra of vinyl selenonyl halides CH2=CH–SeO2X (X is F, Cl and Br)

The structure and conformational stability of vinyl selenonyl fluoride, chloride and bromide CH₂=CH–SeO₂X (X is F, Cl and Br) were investigated using density functional B3LYP/6-311+G** and ab initio MP2/6-311+G** calculations. From the calculations the molecules were predicted to exist only in the non-planar gauche conformation with the vinyl C=C group almost eclipsing one of the selenonyl Se=O bonds as a result of conjugation between the two moieties. Single-minimum potential scans were calculated at the DFT level for the molecules. The vibrational frequencies were computed using B3LYP/6-311+G**. Normal coordinate calculations were then carried out and potential energy distributions were calculated for the three molecules in the gauche conformation.Figure Potential function for the asymmetric torsion in vinyl selenonyl fluoride (dotted line), chloride (dashed line) and bromide (solid line) as determined at the DFT-B3LYP/6-311+G** level     

X,Y精子分离技术的进展

自本世纪伊始,就有许多有关分离X精子(具有X染色体的精子)和Y精子(具有Y染色体的精子)的研究报告.近年来,美国、日本等国相继报道分离人和牛的X、Y精子获得成功,然而其实验效果的重复性极低.本文仅就最近有关X、Y精子的分离研究进展情况作以扼要的介绍.     

Do X and Y spermatozoa differ in proteins?

This article reviews the current knowledge about X- and Y-chromosomal gene expression during spermatogenesis and possible differences between X- and Y-chromosome-bearing spermatozoa (X and Y sperm) in relation to whether an immunological method of separation of X and Y spermatozoa might some day be feasible. Recent studies demonstrated that X- and Y-chromosome-bearing spermatids do express X- and Y-chromosomal genes that might theoretically result in protein differences between X and Y sperm. Most, if not all, of these gene products, however, are expected to be shared among X and Y spermatids via intercellular bridges. Studies on aberrant mouse strains indicate that complete sharing might not occur for all gene products. This keeps open the possibility that X and Y sperm may differ in proteins, but until now, this has not been confirmed by comparative studies between flow-cytometrically sorted X and Y sperm for H-Y antigen or other membrane proteins.     

The competition of C-X⋯O=P halogen bond and π-hole⋯O=P bond between halopentafluorobenzenes C6F5X (X=F, Cl, Br, I) and triethylphosphine oxide

Calculation predicted the interacting forms of halopentafluorobenzene C₆F₅X (X=F, Cl, Br, I) with triethylphosphine oxide which is biologically interested and easily detected by ³¹P NMR. The interaction energy and geometric parameters of resultant halogen or π-hole bonding complexes were estimated and compared. Moreover, the bonding constants were determined by ³¹P NMR. Both theory and experiments indicated the C₆F₆ and C₆F₅Cl interact with triethylphosphine oxide by π-hole bonding pattern, while C₆F₅I by halogen/σ-hole bonding form. For C₆F₅Br, two interactions are comparative and should coexist competitively. The calculated interaction energies of σ-hole bonding complexes, ?5.07 kcal mol^?1 for C₆F₅Br?O=P and ?8.25 kcal mol^?1 for C₆F₅I?O=P, and π-hole bonding complexes, ?7.29 kcal mol^?1 for C₆F₆?O=P and ?7.24 kcal mol^?1 for C₆F₅Cl?O=P, are consistent with the changing tendency of bonding constants measured by ³¹P NMR, 4.37, 19.7, 2.42 and 2.23 M^?1, respectively.

Interplay between halogen bonds and hydrogen bonds in OH/SH···HOX···HY (X = Cl, Br; Y = F, Cl, Br) complexes

The character of the cooperativity between the HOX···OH/SH halogen bond (XB) and the Y―H···(H)OX hydrogen bond (HB) in OH/SH···HOX···HY (X = Cl, Br; Y = F, Cl, Br) complexes has been investigated by means of second-order Møller?Plesset perturbation theory (MP2) calculations and “quantum theory of atoms in molecules” (QTAIM) studies. The geometries of the complexes have been determined from the most negative electrostatic potentials (V _S,min) and the most positive electrostatic potentials (V _S,max) on the electron density contours of the individual species. The greater the V _S,max values of HY, the larger the interaction energies of halogen-bonded HOX···OH/SH in the termolecular complexes, indicating that the ability of cooperative effect of hydrogen bond on halogen bond are determined by V _S,max of HY. The interaction energies, binding distances, infrared vibrational frequencies, and electron densities ρ at the BCPs of the hydrogen bonds and halogen bonds prove that there is positive cooperativity between these bonds. The potentiation of hydrogen bonds on halogen bonds is greater than that of halogen bonds on hydrogen bonds. QTAIM studies have shown that the halogen bonds and hydrogen bonds are closed-shell noncovalent interactions, and both have greater electrostatic character in the termolecular species compared with the bimolecular species.

Efficient Preparation of Cyclic 3′,5′-Phosphoramidites and -Amidates of Antiviral and Antitumor 5-X-2′-Deoxyuridines (X = H,CH3, I,F, CF3, trans-CH=CHBr)

Abstract

Direct cyclization of the title nucleosides with (Me₂N)₃P followed by oxidation with N₂O₄ or t-BuOOH affords the individual cyclic 3′,5′-phosphoramidate diastereomers shown to be isolable in 45-77% yields.     

The cooperativity between hydrogen and halogen bond in the XY···HNC···XY (X,Y = F,Cl, Br) complexes

The cooperativity between hydrogen and halogen bonds in XY···HNC···XY (X, Y = F, Cl, Br) complexes was studied at the MP2/aug-cc-pVTZ level. Two hydrogen-bonded dimers, five hydrogen-bonded dimers, and ten trimers were obtained. The hydrogen- and halogen-bonded interaction energies in the trimers were larger than those in the dimers, indicating that both the hydrogen bonding interaction and the halogen bonding interaction are enhanced. The binary halogen bonding interaction plays the most important role in the ternary system. The hydrogen donor molecule influences the magnitude of the halogen bonding interaction much more than the hydrogen bonding interaction in the trimers with respect to the dimers. Our calculations are consistent with the conclusion that the stronger noncovalent interaction has a bigger effect on the weaker one. The variation in the vibrational frequency in the HNC molecule was considered. The NH antisymmetry vibration frequency has a blue shift, whereas the symmetry vibration frequency has a red shift. A dipole moment enhancement is observed upon formation of the trimers. The variation in topological properties at bond critical points was obtained using the atoms in molecules method, and was consistent with the results of the interaction energy analysis.     

Antiplatelet Activity,P2Y1 and P2Y12 Inhibition,and Metabolism in Plasma of Stereoisomers of Diadenosine 5′,5′″-P1,P4-dithio-P2,P3-chloromethylenetetraphosphate

Background

Diadenosine tetraphosphate (Ap₄A), a constituent of platelet dense granules, and its P¹,P⁴-dithio and/or P²,P³-chloromethylene analogs, inhibit adenosine diphosphate (ADP)-induced platelet aggregation. We recently reported that these compounds antagonize both platelet ADP receptors, P2Y₁ and P2Y₁₂. The most active of those analogs, diadenosine 5′,5″″-P¹,P⁴-dithio-P²,P³-chloromethylenetetraphosphate, (compound 1), exists as a mixture of 4 stereoisomers.

Objective

To separate the stereoisomers of compound 1 and determine their effects on platelet aggregation, platelet P2Y₁ and P2Y₁₂ receptor antagonism, and their metabolism in human plasma.

Methods

We separated the 4 diastereomers of compound 1 by preparative reversed-phase chromatography, and studied their effect on ADP-induced platelet aggregation, P2Y₁-mediated changes in cytosolic Ca²⁺, P2Y₁₂-mediated changes in VASP phosphorylation, and metabolism in human plasma.

Results

The inhibition of ADP-induced human platelet aggregation and human platelet P2Y₁₂ receptor, and stability in human plasma strongly depended on the stereo-configuration of the chiral P¹- and P⁴-phosphorothioate groups, the S_PS_P diastereomer being the most potent inhibitor and completely resistant to degradation in plasma, and the R_PR_P diastereomer being the least potent inhibitor and with the lowest plasma stability. The inhibitory activity of S_PR_P diastereomers depended on the configuration of the pseudo-asymmetric carbon of the P²,P³-chloromethylene group, one of the configurations being significantly more active than the other. Their plasma stability did not differ significantly, being intermediate to that of the S_PS_P and the R_PR_P diastereomers.

Conclusions

The presently-described stereoisomers have utility for structural, mechanistic, and drug development studies of dual antagonists of platelet P2Y₁ and P2Y₁₂ receptors.     

Synthesis, structure and characterization of new complexes [Fe2(μ-OMe)2(PAP)(X)4] (PAP= 1,4-di(2-pyridyl)aminophthalazine, X=Cl, OAc) and their oxidation catalysis

Two dinuclear iron(III) complexes with tetradentate N-donor ligand 1,4-di(2^′-pyridyl)aminophthalazine (PAP), [Fe₂(μ-OMe)₂(PAP)Cl₄] (2) and [Fe₂(μ-OMe)₂(PAP)(OAc)₄] (3) were prepared and characterized. Single crystal X-ray molecular structure of [Fe₂(μ-OMe)₂(PAP)Cl₄] · 2MeOH have been elucidated. The six-coordinate iron atoms are in distorted octahedral environment bridged by the oxygen atoms of two methoxy groups and the PAP ligand. The Mössbauer spectra of both complexes show one quadrupole doublet and the isomer shift and quadrupole splitting values indicate the presence of octahedral high-spin Fe^III ions. Complex 2 showed catalytic activity for alkane oxidation with hydrogen peroxide.     

Opposite effects of P2X7 and P2Y2 nucleotide receptors on α-secretase-dependent APP processing in Neuro-2a cells

The amyloid precursor protein (APP) is proteolytically processed by β- and γ-secretases to release amyloid-β peptide (Aβ), the main component found in senile plaques of Alzheimer's disease (AD) patient brains. Alternatively, APP can be cleaved within the Aβ sequence by α-secretase, thus precluding the generation of Aβ. We have demonstrated that activation of the P2X7 receptor leads to a reduction of α-secretase activity in Neuro-2a cells. Moreover, the P2X7 ligand 2'(3')-O-(4-benzoylbenzoyl) ATP (BzATP) can also activate a different P2 receptor in these cells. This receptor, whose pharmacology resembles that of the P2Y(2) receptor, has an opposite effect, leading to increases in α-secretase activity. Our study suggests that P2X7R and P2Y(2)R could be novel therapeutic targets in AD.     

A chemometrical study of intermolecular properties of hydrogen-bonded complexes formed by C2H4O⋅⋅⋅HX and C2H5N⋅⋅⋅HX with X = F, CN, NC, and CCH

We presents a chemometrical study of the intermolecular properties of the C₂H₄O⋅⋅⋅HX and C₂H₅N⋅⋅⋅HX hydrogen-bonded complexes with X = F, CN, NC, and CCH. Through the MP2 perturbation theory and B3LYP hybrid functional, as well as modifications on 6-31ijGk basis sets with i = triple-zeta, j = diffuse and k = polarization functions, systematic tendencies in the R_{(n⋅⋅⋅HX)} hydrogen bond distances and υ_{(n⋅⋅⋅HX)} stretch frequencies were determined by the hierarchical cluster analysis, two level factorial designs and principal component analysis. Based on well-fitted math models, not only because polarization functions provide a great variance on statistical analysis, but this basis set reproduces more efficiently the available experimental results. Moreover, independent of whether the quality on basis set is increased, the effects yielded by both DFT and MP2 were not considered important in the statistical analysis.     

45,X及46,XX男性的起因——X—Y交换机制的探讨

自1957年弗格森-史密斯(Ferguson-Smith)对男性不育进行研究,已发现某些染色体异常可导致不育症,其中XX或X男性是男性不育原因之一。本文收集的68例X及XX男性,其中46,XX男性37例,约占54%,45,X男性8例,占11%,两性畸形17例,约占25%,1例46,XX/47,XXX男性嵌合体,5例Y染色体不同程度的缺失和1例Y染色体长臂与15号染色体短臂易位表现为女性。其中丹麦哥本哈根实验室从1973-1980年对5.580例孕妇进行羊膜穿     

Interplay between halogen and chalcogen bonding in the XCl∙∙∙OCS∙∙∙NH3 (X = F,OH, NC,CN, and FCC) complex

The interplay between halogen and chalcogen bonding in the XCl???OCS and XCl???OCS???NH₃ (X = F, OH, NC, CN, and FCC) complex was studied at the MP2/6-311++G(d,p) computational level. Cooperative effect is observed when halogen and chalcogen bonding coexist in the same complex. The effect is studied by means of binding distance, interaction energy, and cooperative energy. Molecular electrostatic potential calculation reveals the electrostatic nature of the interactions. Cooperative effect is explained by the difference of the electron density. Second-order stabilization energy was calculated to study the orbital interaction in the complex. Atoms in molecules analysis was performed to analyze the enhancement of the electron density in the bond critical point.     

Biosynthesis,isolation, purification and separation of nivalenol,fusarenone — X and zearalenone

Fusarium, graminearum KF 370 isolate is able to simultaneous biosynthesis of three toxic metabolites, namely: fusarenone-X (FUS), nivalenol (NIV) and zearalenone (F-2). After metabolites extraction with methanol — water (3:1) and defatting with n-heptane toxins were partitioned into chloroform layer. Purification of the? compounds was performed on Celite 545 — charcoal — Aluminiumoxid 90 column then metabolites were separated on Kieselgel 60 (200–300 mesh) column with developing solvent chloroform — methanol. This way FUS, NIV and F-2 were obtained as crystalline or high purity standards.     

How relevant are S=O and P=O Double Bonds for the Description of the Acid Molecules H2SO3, H2SO4, and H3PO4, respectively?

The acid molecules H₂SO₃, H₂SO₄, and H₃PO₄ are usually drawn using "Lewis structures" which exhibit the octet extension by 3d-orbitals on sulfur and phosphorus, respectively. Thus, S=O and P=O double bonds are assumed to be formed. The natural d-orbital occupancies on S and P, however, were calculated to be as low as 0.1 e, and therefore, an octet extension can hardly be expected. After the natural bond orbitals (NBO) search procedure was forced to attempt to form different Lewis structures of bonds and lone pairs, we defined the optimal Lewis structure, if a dominant structure exists at all, by the maximum electronic charge in Lewis orbitals. Indeed, sulfur obeys the octet rule in the optimal zwitterionic Lewis structures and does not form S=O double bonds. No dominant resonance structure could be found for H₃PO₄ where polarized PO ?-bond and zwitterionic PO bond structures exhibit similar weights.     

A theoretical study on unusual intermolecular T-shaped X–H...π interactions between the singlet state HB=BH and HF, HCl, HCN or H2C2

The unusual T-shaped X–H...π hydrogen bonds are found between the B=B double bond of the singlet state HB=BH and the acid hydrogen of HF, HCl, HCN and H₂C₂ using MP2 and B3LYP methods at 6-311++G(2df,2p) and aug-cc-pVTZ levels. The binding energies follow the order of HB=BH...HF>HB=BH...HCl>HB=BH...HCN>HB=BH...H₂C₂. The hydrogen-bonded interactions in HB=BH...HX are found to be stronger than those in H₂C=CH₂...HX and OCB≡BCO...HX. The analyses of natural bond orbital (NBO) and the electron density shifts reveal that the nature of the T-shaped X–H...π hydrogen-bonded interaction is that much of the lost density from the π-orbital of B=B bond is shifted toward the hydrogen atom of the proton donor, leading to the electron density accumulation and the formation of the hydrogen bond. The atoms in molecules (AIM) theory have also been applied to characterize bond critical points and confirm that the B=B double bond can be a potential proton acceptor. The unusual T-shaped X–H...π hydrogen bonds are found between the B=B double bond of the singlet state HB=BH and the acid hydrogen of HF, HCl, HCN and H₂C₂     

Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X₇ receptor

The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vd(ss) of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd(ss) after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.