Molecular Modeling Studies of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Combining Molecular Docking and 3D-QSAR Methods

The vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases VEGFR-2 or kinase insertdomain receptor (KDR) have emerged as attractive targets for the design of novel anticancer agents. In the present work, molecular docking method combined with three dimensional quantitative structure-activity relationships (comparative molecular field analysis (CoMFA) and comparative molecular similarity indice analysis (CoMSIA)) to analyze the possible interactions between KDR and those derivatives which acted as selective inhibitors. The CoMFA and CoMSIA models gave a cross-validated coefficient Q2 of 0.713 and 0.549, non-cross-validated R2 values of 0.974 and 0.878, and predicted R2 values of 0.966 and 0.823, respectively. The 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. The information obtained from 3D-QSAR and docking studies were very helpful to design novel selective inhibitors of KDR with desired activity and good chemical property.     

H_6P_2W_（18）O_（62）á18H_2O： A green and reusable catalyst for one-pot synthesis of pyrano[4,3-b]pyrans in water

A convenient,effcient and environmentally benign procedure has been developed for the synthesis of pyrano[4,3-b]pyran derivatives via a one-pot,three-component reaction of 4-hydroxy-6-methylpyran-2-one,aldehydes and malononitrile in water using H6P2W18O62á18H2O as catalyst.Reusability of the catalyst and reaction media,short reaction times and easy isolation of products are some added advantages of the present methodology.     

Novel synthetic 9-benzyloxyacridine analogue as both tyrosine kinase and topoisomerase I inhibitor

Multi-target agents against tyrosine kinases and topoisomerases are potentially useful for the effective treatment of cancers.Discovery of new multi-target scaffolds are important for developing such agents. A series of five novel acridine analogues,LXL 1-5,were synthesized and their antiproliferative activity against HepC-2 cell lines were evaluated,among which the 9-benzyloxyacridine analogue,LXL-5, showed inhibitory activity against tyrosine kinases,VEGFR-2 and Src.The results of UV-visible absorption spectra and fluorescence emission spectra,as well as DNA topoisomerase I inhibition assay, indicated topoisomerase I inhibitory activity.Our study suggested that acridine scaffold,previously shown to have no multi-target kinase and topoisomerase inhibitory activity,might be potentially developed as a multi-target inhibitor of tyrosine kinases and topoisomerase I.     

Discovery and synthesis of N2,N4-substitued-cycloalkyl[d]pyrimidine 2,4-diamine analogs： The first examples of small-molecular FGFR-1 activator

A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.     

CRYSTAL STRUCTURE OF AMMONIUM 18-CROWN-6 DITHIOCYANATO-TETRACHLORO-DIPALLADIUM(Ⅱ)

<正> INTRODUCTION. Crown compounds have formed a rapidly expanding field of chemistry and found application in many areas. Authors have studied the coordination chemistry of a series of crown compounds, such as 18-C-6, DB-18-C-6, DB-30-C-10, 15-C-5 and B-15-C-5 in thiocyanate systems with M and M' cations (M=Na~+, K~+, NH_4~+, Ca~(2+), Sr~(2+), Ba~(2+); M=Ni~(2+), Co~(2+), Zn~(2+), Ag~+, Mg~(2+)[1,2] This paper reports the IR characteristic and crystal structure of the complex of 18-C-6 with ammonium thiocyanate and palladium chloride.     

Particulate capillary precolumns with double-end polymer monolithic frits for on-line peptide trapping and preconcentration

In this work,a novel kind of particulate capillary precolumns with double-end polymer monolithic frits has been developed.Firstly,the polymer monolithic frit at one end was prepared via photo-initiated polymerization of a mixture of lauryl methacrylate and ethyleneglycol dimethacrylate with 1-propanol and 1,4-butanediol as porogens and 2,2-dimethoxy-2-phenylacetophenone as a photo-initiator in UV transparent coating capillary(100 μm i.d.).Subsequently,C18 particles(5 μm,100 A) were packed into the capillary,and sealed with the polymer monolithic frit at another end.To prevent the reaction of monomers and C18 particles,the packed C18 particles were masked during UV exposure.The loading capacity of such a precolumn was determined to be about 9 μg by frontal analysis with a synthetic peptide APGDR1 YVHPF as a model sample.Furthermore,two parallel precolumns were incorporated into a two-dimensional nano-liquid chromatography(2D nano-LC) system with dual capillary trap columns for peptide trapping and concentration.Compared to 2D nano-LC system with a single trap column,such two dimensional separations could be operated simultaneously to improve the analysis throughput.All these results demonstrated that such capillary precolumns with double frits would be promising for high-throughput proteome analysis.     

Reversible phase transition of the 1:1 complex between 18-crown-6 and n-propylammonium triiodide

Solid-state structure of the crystalline 1:1 complex [C 3 H 10 N(18-crown-6)] + [I 3 ](1) between 18-crown-6 and n-propylammonium triiodide has been determined at 293 and 93 K,respectively,showing a change from monoclinic P2 1 /m to monoclinic P2 1 /a.Crystal structural analysis shows that in addition to van der Waals’ forces,conventional N-H···O hydrogen bonds are the key interactions.Measurements of unit cell parameters versus temperature show that the values of one of the three axes and the crystal volume change abruptly and remarkably at 220 K,indicating a first-order phase transition.The lack of the mirror plane in the low temperature structure is the most important differences between the two structural forms.Differential scanning calorimetry(DSC) measurement confirms that 1 undergoes a reversible phase transition at about 220 K with a thermal hysteresis of 3.5 K.The relatively large latent heat makes 1 a good candidate for phase change materials.The phase transition is accompanied by an anomaly of dielectric constant during heating and cooling process near the phase transition temperature.     

A STUDY ON THE RECONSTRUCTION OF THE EIGHTEENTH CENTURY MEIYU (PLUM RAINS) ACTIVITY OF LOWER CHANGJIANG(YANGTZE) REGION OF CHINA

This study presents a scheme for delimiting the meiyu period in the Lower Changjiang (Yangtze) region. This scheme was applied to the Clear and Rain Records of Nanjing, Suzhou and Hangzhou to reconstruct the 1723-1800 meiyu climate series. The beginning and ending dates, length, precipitation, and the intensity grades of meiyu were determined. The years of early, heavy, light, and empty meiyu were also given. Statistical analyses of the 18th century meiyu series indicate the existence of the quasi-periodicities of 2-3, 4-5, and 9 years. Many basic characteristics of the modern meiyu also existed in the 18th century. Some characteristics of the Northwest Pacific Subtropical High in the 18th century in typical meiyu years were inferred from the historical meiyu series.     

NEW EVIDENCE FOR COEXISTENCE OF KETENE AND ACETYL INTERMEDIATES IN SYNGAS CONVERSION TO ETHANOL OVER RHODIUM-BASED CATALYSTS

CH_2DC~(18(16))OOCH_3 and CH_3C~(18(16))OOCH_3 were detected simultane-ously in the trapping reaction with D_2~(18)O as the trapping agent followed bypurging the catalyst with MeOH in N_2 stream,demonstrating the coexistence ofketene and acetyl intermediates in ethanol synthesis from syngas over rhodiumcatalysts.The percentage of deuterated methyl acetate in total AcOMe incrasedwith the ratio of D_2~(18)O/H_2,indicating that the trapping of ketene strongly com-peted with its further hydrogenation,and implying that ketene was a key C_2-in-termediate.     

Synthesis of O-(2-[~(18)F]fluoroethyl)-L-tyrosine and its biological evaluation in B16 melanoma-bearing mice as PET tracer for tumor imaging

O-(2-[18F]fluoroethyl) -L-tyrosine([18F]FET) ,a fluorine-18 labeled analogue of tyrosine,has been syn-thesized and biologically evaluated in tumor-bearing mice. The whole synthesis procedure is com-pleted within 50 min. The radiochemical yield is about 40%(no decay corrected) and radiochemical purity more than 97% after simplified solid phase extraction. [18F]FET shows rapid,high uptake and long retention in the tumor as well as low uptake in the brain. The ratios of tumor-to-muscle(T/M) and tumor-to-blood(T/B) of [18F]FET are similar to those of [18F]FDG,but the ratios of tumor-to-brain(T/Br) are 2-3 times higher than that of [18F]FDG. Autoradiography of [18F]FET demonstrates a remarkable accumulation in melanoma with high contrast. It appears to be a probable competitive candidate for melanoma imaging with PET.     

甲硫氨酸-脑啡肽的分子动力学模拟

The conformational properties of Met-enkephalin (Tyr-Gly-Gly-Phe-Met) were investigated by high temperature quenched molecular dynamics simulations in vapor. Each of these selected structures were then analyzed according to their backbone(φ,Ψ) conformational distributions and sorted into 13 families by computing the rms difference between the Cα-C backbone fragments of each residue over all the structures. Selected lowest energy conformations from each of 13 families were thoroughly energy minimized. The results of simulations show that Met-enkephalin is a flexible molecule. It shows a type Ⅰβ-turn, with the Gly2 carbonyl forming a hydrogen bond with the Met5 amino proton and a type Ⅱβ turn, with the Tyr1 amino proton forming a hydrogen bond with the Phe4 carbonyl. The multiple fit were carried out for all of the 13 conformers with morphine(9 atoms on the pharmacophore groups). F2 and F6 were the most similar to morphine. The rms were 0.0504 nm and 0.0726 nm. The results of simulations also show that Tyr amino N corresponds to N on piperidine ring in morphine, Tyr phenol corresponds to the phenol in morphine, the aromatic ring of Phe corresponds to the cyclohexene ring in morphine. The distances between the three pharmacophores, d1 (Tyr N to Tyr OH), d2 (Tyr N to Tyr du1), d3(Tyr N to Phe du2) and d4(Tyr N to Phe du2) were found to be about 0.8, 0.5, 0.7-0.9 and 0.5 nm, respectively, the corresponding, distances of morphine were found to be 0.7697(N18 to O6),0.5143(N18 to du25), 0.3962(N18 to du24)和0.5566(N18 to O15)nm. Therefore, they may be acted on the same receptor. This model should aid in pharmaceutical design of peptide and nonpeptide ligands with opioid.     

Controlled growth of molecularly pure Au25(SR)18 and Au38(SR)24 nanoclusters from the same polydispersed crude product

We report the controlled growth of Au25(SR)18 and Au38 (SR)24 (where R = CH2CH2Ph) nanoclusters of molecular purity via size-focusing from the same crude product that contains a distribution of nanoclusters. In this method, gold salt was first mixed with tetraoctylammonium bromide (TOAB), and then reacted with excess thiol to form Au(I)-SR polymers in THF (as opposed to toluene in previous work), followed by NaBH 4 reduction. The resultant crude product contains polydisperse nanoclusters and was then used as the common starting material for controlled growth of Au25(SR)18 and Au38(SR)24 , respectively. In Route I, Au25(SR)18 nanoclusters of molecular purify were produced from the crude product after 6 h aging at room temperature. In Route II, the crude product was isolated and further subjected to thermal thiol etching in a toluene solution containing excess thiol, and one obtained pure Au38(SR)24 nanoclusters, instead of Au25(SR)18 . This work not only provides a robust and simple method to prepare both Au25(SR)18 and Au38(SR)24 nanoclusters, but also reveals that these two nanoclusters require different environments for the size-focusing growth process.     

Characterization of 1,4-dihydroxy-2-naphthoyl-coenzyme A synthase (MenB) in phylloquinone biosynthesis of Synechocystis sp. PCC 6803

The gene product Sll1127 is a predicted 1,4-dihydroxy-2-naphthoyl-CoA synthase catalyzing an intramolecular Claisen condensation in the phylloquinone biosynthesis of the cyanobacterium Synechocystis sp.PCC 6803.This predicted catalytic function has been verified and the enzyme has been characterized for the first time with kcat = 0.013 s-1 and KM = 9μM.Its catalytic activity is found to strictly depend on externally added bicarbonate with an apparent KD = 0.60 mM.In addition,this enzyme is inhibited by its 1,4-dihydroxy-2-naphthoyl-CoA product through high-affinity binding,which causes a 18 nm shift of the inhibitor absorption at 392 to 410 nm and engenders a new absorption peak at 345 nm.All these properties of the cyanobacterial enzyme are closely similar to those of the Escherichia coli orthologue from the menaquinone biosynthetic pathway.These results provide additional supporting evidence for the essential role of bicarbonate as a catalytic base in the enzymatic reaction and the eubacterial origin of the enzymes in the cyanobacterial biosynthesis of phylloquinone.     

Organic-inorganic hybrid fluorescent sensor thin films of rhodamine B embedded Ag-SBA 15 for selective recognition of Hg (Ⅱ) ions in water

Nowadays, the rapid and effective detection of low doses of heavy metal pollutants in contaminated water is a timely challenge in environmental pollution research. In this study, a rapid and highly sensitive assay for the detection of Hg~(2+)based on quenching of metal-enhanced fluorescence of rhodamine B(RB)has been fabricated. RB and silver nanoparticle were incorporated into the mesoporous siliceous framework spin cast on a quartz glass through post-synthetic incorporation method. The morphology and crystallinity of mesoporous structure and Ag nanoparticle were characterized by transmission electron microscopy and X-ray diffraction analyses. Photoluminescence assays on the hybrid thin film of RB-Ag-SBA15 showed a high enhancement when compared to the intensity of silver free SBA15-RB in the wavelength of 575 nm. The fluorescence of RB-Ag-SBA15 thin film decreased gradually with the increase in the concentration of Hg~(2+)and the detection limits were 10.54 nmol/L. Furthermore, the fluorescence intensity increased linearly with the concentration of Hg~(2+)in the range from 1.0 ? 10à8mol/L to10 ? 10à8mol/L, with a response time of a few seconds. In addition, this system offers a high selectivity over interfering cations such as Cd~(2+) and Pb~(2+). Overall, we have developed an optical assay having a wellordered mesoporous SBA15 containing Ag-RBfor selective detection of Hg~(2+)in aqueous solution. The scheme combines the advantages of specific binding interactions between Hg~(2+)and RB molecule and optical emission properties of RB. The method is suitable for a single-shot and irreversible analytical assay in a quartz glass/microtiter plate.     

Prediction of the isothermal behaviour of solid-gas systems from non-isothermal data

A new procedure for the prediction of the isothermal behaviour of the solid-gas system from non-isothermal data is suggested. It bypasses the use of various approximations of the temperature integral that ground the integral methods of prediction. The procedure was checked for: (1) simulated data corresponding to a first order reaction; (2) experimental data obtained in the isothermal and non-isothermal decompositions of ammonium perchlorate. For the simulated data, a very good agreement between calculated isotherms and those evaluated by means of the suggested procedure was obtained. A satisfactory agreement (errors in time evaluation corresponding to a given degradation lower than 18%, for 0.10￡a￡0.37 and lower than 10% for 0.37￡a￡0.70) was obtained for the experimental data corresponding to the decomposition of ammonium perchlorate. In this last case, the mentioned differences between experimental and calculated data can be due both to the inherent errors in the evaluation of the decomposition isotherms and to the dependence of the activation energy on the conversion degree. This revised version was published online in July 2006 with corrections to the Cover Date.     

Communication Chain-foldability effect on coaggregation Evidence derived from time-resolved fluorescence spectroscopy

Very recently,we have proposed that all culprit molecules of arteriosclerosis mightpossess a common and measurable inherent property,namely,a coaggregating ten-dency.Extensive kinetic measurements of these tendencies in terms of △CAgC valueshave led to a new and surprising observation,i.e.,the cholesteryl ester with a longsaturated 18-carbon chain(CE-18)actually has a much smaller tendency towardcoaggregation than that of the ester with a“short”8-carbon chain(CE-8).Thisstate of affairs has been coined as the“chain-foldability effect”,i.e.,the 18-carbon     

Synthesis,Crystal Structure and Electrochemistry Properties of an Iron(Ⅲ) Complex Based on the 3,5-Pyridinedicarboxylate and Water Ligands

Reaction of 3,5-pyridine-dicarboxylic acid(3,5-PydcH2) with iron salt in hydrothermal condition results in the formation of a three-dimensional self-assembly network formulated as [C14H14Fe2N2O12]n,and it has been structurally characterized by elemental analysis,IR spectra and X-ray diffraction.It crystallizes in the monoclinic system,space group C2/c with a=9.9633(15),b=12.0942(18),c=7.4297(11) and β=105.822o.The units of Fe2(pydc)2·2H2O are linked into a one-dimensional structure via the chelate carboxylate groups from the 3,5-pyridine-dicarboxylate.The interlayer hydrogen bonding interactions result in a three-dimensional supramolecular architecture.In the complex,the Fe(Ⅲ) ion displays a slightly distorted pentagonal bipyramidal geometry with seven coordination numbers.Cyclic-voltammetry measurement reveals the oxidation and reduction processes for the complex are quasi-reversible in nature.     

Liquid Chromatographic Assay of Peptides Activity with Inhibiting Angiotensin Converting Enzyme

A rapid, simple and interference-free method was developed to evaluate the inhibitory activity of hydro-lyzed peptides from egg white protein against the angiotensin-converting enzyme. The total reaction volume was 60 μL, saving the cost. The assay was based on a HPLC separation and quantification of the synthetic substrate hip-puryl-L-histidyl-L-leucine and its hydrolyzed product―hippuric acid; the separation was performed on a C 18 column eluted by a mobile phase of acetonitrile/water(0.5% TFA) at a volume ratio of 25:75. At a signal to noise ratio(S/N) of 10, the detective limit of the quantitation of hippuric acid was (0.4600±0.0097) μmol/L. The standard curve shows a linear response with a slope of 49488 and a correlation coefficient of 0.9995. The assay was adequate for the study of ACE inhibition by Captopril and peptides derived from food protein, and showed a very good correlation with the previous methods.     

Porous carbon coupled with an interlaced MoP–MoS2 heterojunction hybrid for efficient hydrogen evolution reaction

The design and development of electrocatalysts composed of non-noble-metal catalysts with both large surface area and high electrical conductivities are crucial for the hydrogen evolution reaction(HER).Here,a xylose-based porous carbon is coupled with a MoS2-Mo P heterojunction(MoS2-Mo P/FPC)hybrid and used as a promising catalyst for HER.The hybrid is prepared by immobilizing petal-like MoS2 nanosheets on porous carbon(MoS2/FPC),followed by controlling the phosphidation in Ar/H2 to form MoS2-Mo P/FPC.Red phosphorus provides the P species that can induce the construction of the heterojunction under the reducing atmosphere,along with the generation of a Mo P phase and the splitting of the MoS2 phase.The as-prepared MoS2-Mo P/FPC catalyst offers a low overpotential of 144 mV at a current density of 10 m A cm^-2 and a small Tafel slope of 41 m V dec^-1 for the HER in acidic media,as well as remarkable stability.Apart from the active nature of the hybrid,its outstanding activity is attributed to the MoS2-Mo P heterojunction,and the good charge/mass-transfer ability of porous carbon.This strategy provides a new method to develop and design low-cost and high-performance catalysts for the HER.