Efficient synthesis of polycyclic dispirooxindoles via domino Diels–Alder cyclodimerization reaction

Three-component reactions of 4-cyanopyridine or ethyl isonicotinate with electron-deficient alkynes and isatins in dimethoxyethane at room temperature afforded spiro[3H-indole-3,2′-[2H,9aH-pyrido[2,1-b][1,3]oxazine] derivatives. Alternately, the similar three-component reaction at elevated temperature resulted in polycyclic dispirooxindole derivatives. The reaction mechanism is believed to involve sequential generation and cycloaddition of Huisgen's 1,4-dipole, and Diels–Alder cyclodimerization reaction. The similar three-component reactions containing acenaphthenequinone and phenanthrenequinone also afforded corresponding polyheterocyclic derivatives.     

Study of Cl−(H2O)n (n = 1–4) using basin‐hopping method coupled with density functional theory

Cl^?(H₂O)_n (n = 1–4) clusters were investigated using a basin‐hopping (BH) algorithm coupled with density functional theory (DFT). Structures, energetics, thermodynamics, vertical detachment energies, and vibrational frequencies were obtained from high‐level ab initio calculations. Through comparisons with previous theoretical and experimental data, it was demonstrated that the combination of the BH method and DFT could accurately predict the global and local minima of Cl^?(H₂O)_n (n = 1–4). Additionally, to optimize larger Cl^?(H₂O)_n (n > 4) clusters, several popular density functionals as well as DF‐LMP2 (Schütz et al., J. Chem. Phys. 2004, 121, 737) (second‐order Møller‐Plesset perturbation theory using local and density fitting approximations) were tested with appropriate basis sets through comparisons with MP2 optimized results. DF‐LMP2 will be used in future studies because its overall performance in describing the relative binding energies and the geometrical parameters of Cl^?(H₂O)_n (n = 1–4) was outstanding in this study. © 2013 Wiley Periodicals, Inc.     

Environmental gamma background measurements in China Jinping Underground Laboratory

To determine the environmental gamma background levels which affects rare events experiments, we measured in situ gamma spectrum at four locations in the China Jinping Underground Laboratory. The integral background count rates (40–2,700 keV) varied from 3.76 to 74.1 cps. The average count rate of the measurements inside the CJPL was 73.4 cps. The spectrometer was calibrated with a ¹⁵²Eu point source and Monte Carlo simulation to obtain the activity conversion factors for the rock and the air, respectively. The rocks that surrounded the CJPL was characterized by very low activity concentrations of ²³⁸U (3.69–4.21 Bq kg^?1), ²³²Th (0.52–0.64 Bq kg^?1) and ⁴⁰K (4.28 Bq kg^?1).     

Radiosynthesis and evaluation of 188Re-c(RGDyK)-His as a novel radiotherapeutic agent for integrin αvβ3 targeting tumour

The successes of noninvasive methods to visualize and quantify integrin α_vβ₃ expression in vivo have paved the way for radiolabeling anti-integrin therapy in clinic. Arginine-glycine-aspartice (RGD) peptide and related derivatives labeled with radionuclides for radio-therapy, which specifically targeting integrin α_vβ₃-positive tumors, could be used to treat these tumors. We have labeled c(RGDyK)-His, a RGD derivative, with ¹⁸⁸Re and the radio-therapy efficiency has been evaluated in model nude mice. c(RGDyK)-His was labeled with ¹⁸⁸Re by chelating with [¹⁸⁸Re(CO)₃(H₂O)₃]⁺ under a slightly basic condition. The in vitro specific binding affinity to U87 MG cell lines and the biodistribution of ¹⁸⁸Re-c(RGDyK)-His in the animal tumor models was measured. The inhibitory effects of ¹⁸⁸Re-c(RGDyK)-His were observed more than 1 month, and evaluated by microPET/CT imaging with ¹⁸F-FDG. Results of in vivo, cell uptake demonstrated ¹⁸⁸Re-c(RGDyK)-His had a high specific binding affinity to receptor integrin α_vβ₃. In biodistribution experiment, ¹⁸⁸Re-c(RGDyK)-His was accumulated in the tumor and cleared fast from the normal tissues. In radiotherapy study, tumor growth inhibition was significantly higher in the treatment groups than in the control groups. These studies showed that ¹⁸⁸Re-c(RGDyK)-His could be effectively used for integrin α_vβ₃ targeting therapy. This may offer a potential therapeutic strategy for the treatment of integrin-positive tumors in clinic.     

Design and preliminary assessment of 99mTc-labeled ultrasmall superparamagnetic iron oxide-conjugated bevacizumab for single photon emission computed tomography/magnetic resonance imaging of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has a very high incidence and mortality. Early diagnosis and timely treatments are therefore required to improve the quality of life and survival rate of HCC patients. Here, we developed a vascular endothelial growth factor (VEGF)-based multimodality imaging agent for single photon emission computed tomography (SPECT), computed tomography (CT) and magnetic resonance imaging (MRI) and used it to assess HCC mice and explore the combinative value of CT/MRI-based morphological imaging and SPECT functional imaging. HCC targeting with ¹²⁵I-labeled bevacizumab monoclonal antibody (mAb) was examined using SPECT/CT in HepG2 tumor-bearing mice after intravenous mAb injection. Based on this, an integrated, bimodal, VEGF-targeted, ultrasmall superparamagnetic iron oxide (USPIO)-conjugated ^99mTc-labeled bevacizumab mAb was synthesized to increase tumor penetration and accumulations. The in vivo pharmacokinetics and HepG2 tumor targeting were explored through in vivo planar imaging and SPECT/CT using a mouse model of HepG2 liver cancer. The specificity of the radiolabeled nanoparticles for HepG2 HCC was verified using in vitro immunohistochemistry and Prussian blue staining. With diethylenetriamine pentaacetic acid as a bifunctional chelating agent, USPIO-bevacizumab achieved a ^99mTc labeling efficiency of >90 %. The in vivo imaging results also exhibited the targeting of USPIO on HepG2 HCC. The specificity of these results was confirmed using in vitro immunohistochemistry and Prussian blue staining. Our preliminary findings showed the potential of USPIO as an imaging agent for the SPECT/MRI of HepG2 HCC.     

分子动力学模拟研究点突变(Met108→Leu108)对树胶醛糖结合蛋白与配体作用的影响

为了研究点突变(Met108→Leu108)对树胶醛糖结合蛋白(ABP)与配体结合能力的影响,对ABP、ABP结合树胶醛糖复合物及ABP结合半乳糖复合物以及它们各自的突变体分别进行60 ns的分子动力学模拟.模拟结果表明,108号残基突变前后,电子等排体的两个氨基酸残基,使蛋白与配体间的范德华相互作用发生明显变化,同时导致蛋白的内部运动也发生变化,进而影响蛋白与配体的相互作用.进一步分析表明,突变前后的蛋白构象变化都趋向于两个结构域张开,而与配体的结合可减缓张开程度.     

高硫煤镜质组热解过程中结构变化及有机硫形态变迁规律研究

用手选富集与离心分离相结合的方法,从两种全硫含量相近的新西兰煤（NXL;S_t,ad=1.84%）和山西煤（SX;S_t,ad=1.80%）中分离出高纯度镜质组。在高纯Ar气氛下,分别制备了300、500、700和1 000 ℃下的镜质组焦。用FT-IR研究了两种镜质组中的脂肪氢、芳香氢随温度的变化,结果表明,SX镜质组中脂肪氢的相对含量较高,在热解过程中活性高于同温度下的NXL镜质组;两种镜质组中的脂肪氢相对含量都随温度升高而降低,温度高于500 ℃时,SX镜质组中脂肪氢相对含量基本不变,当温度高于700 ℃时,NXL镜质组中的脂肪氢相对含量基本保持不变;热解过程芳香氢都表现出先增大后减小的趋势。用XPS研究了镜质组中的有机硫含量及形态随温度的变化,结果表明,SX镜质组中易分解的有机硫化物较多,在300 ℃以下即可分解完全;NXL镜质组中的有机硫化物分解完全在700 ℃左右,两种镜质组中的噻吩类硫的含量都随热解温度的升高而增加,砜类硫的含量随热解温度的升高而降低。     

Aspects of trapping efficiency and matrix effects in the development of a restricted‐access‐media‐based trap‐and‐elute liquid chromatography with mass spectrometry method

Online restricted access media with liquid chromatography and tandem mass spectrometry for the direct analysis of small molecules in biological fluids represents an interesting alternative to time‐demanding traditional sample preparation techniques. In this study, important considerations concerning the development of a restricted access media with liquid chromatography and tandem mass spectrometry method for the analysis of dansylated estrogens in biological matrix are presented. Parameters influencing peak tailing and trapping efficiency were evaluated. The key factors included the ion strength of the mobile phase, a loading flow rate of the sample onto the trap column, and selection of a proper stationary phase of the trap column for a given set of analytes. These parameters have proven to be essential for minimizing any unwanted chromatographic peak tailing. The bulk derivatization of the analytes in the biological fluids and its relationship to the observed matrix effects was evaluated as well.     

Tissue imaging and serum lipidomic profiling for screening potential biomarkers of thyroid tumors by matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry

Changes in serum lipidome and in tissue lipidome are associated with cancer. In this study, tissue mass spectrometry imaging (MSI) and serum lipid profiling by matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR MS) were performed to investigate significantly changed lipids in both tumor (malignant thyroid cancer (MTC) and benign thyroid tumor (BTT)) tissues and sera. Y-scatterplots of variable importance in the projection (VIP) values vs. fold change values indicate that change trends in the levels of ten lipids (i.e., phosphatidylcholine (PC)(34:1), PC(36:1), PC(38:6), phosphatidic acid (PA) (36:2), PA(36:3), PA(38:3), PA(38:4), PA(38:5), PA(40:5), and sphingomyelin (SM)(34:1)) in both tissues and sera from MTC patients, BTT patients, and normal individuals are significantly associated with these three types of pathophysiological status. In order to examine their diagnostic ability, 289 serum samples from 124 MTC patients, 43 BTT patients, and 122 normal controls were randomly divided into the training set and validation set. A biomarker of PC(34:1) exhibited excellent diagnostic ability to differentiate both MTC and BTT patients from normal individuals, with an area under the receiver operating characteristic (ROC) curve value of 0.984, a sensitivity of 96.4 %, and a specificity of 92.7 %. A panel which included PA(36:3) and SM(34:1) could distinguish between MTC and BTT, with an area under receiver operating characteristic curve (AUC) of 0.961, a sensitivity of 87.8 %, and a specificity of 92.9 %. It is worth noting that a panel consisting of PC(34:1), PA(36:3), and SM(34:1) could differentiate MTC patients from both BTT patients and normal individuals, with an AUC of 0.841, a sensitivity of 86.6 %, and a specificity of 75.5 %.

A turn-on fluorescence-sensing technique for glucose determination based on graphene oxide–DNA interaction

Graphene is a two-dimensional carbon nanomaterial one atom thick. Interactions between graphene oxide (GO) and ssDNA containing different numbers of bases have been proved to be remarkably different. In this paper we propose a novel approach for turn-on fluorescence sensing determination of glucose. Hydrogen peroxide (H₂O₂) is produced by glucose oxidase-catalysed oxidation of glucose. In the presence of ferrous iron (Fe²⁺) the hydroxyl radical (?OH) is generated from H₂O₂ by the Fenton reaction. This attacks FAM-labelled long ssDNA causing irreversible cleavage, as a result of the oxidative effect of ?OH, producing an FAM-linked DNA fragment. Because of the weak interaction between GO and short FAM-linked DNA fragments, restoration of DNA fluorescence can be achieved by addition of glucose. Due to the excellent fluorescence quenching efficiency of GO and the specific catalysis of glucose oxidase, the sensitivity and selectivity of this method for GO-DNA sensing are extremely high. The linear range is from 0.5 to 10 μmol L^?1 and the detection limit for glucose is 0.1 μmol L^?1. The method has been successfully used for analysis of glucose in human serum. Figure

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