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排序方式: 共有169条查询结果,搜索用时 31 毫秒
61.
Naiyu Zheng Jianing Zeng Amy Manney Lakenya Williams Anne-Françoise Aubry Kimberly Voronin Adela Buzescu Yan J. Zhang Alban Allentoff Carrie Xu Hongwu Shen William Warner Mark E. Arnold 《Analytica chimica acta》2016
To quantify a therapeutic PEGylated protein in monkey serum as well as to monitor its potential in vivo instability and methionine oxidation, a novel ultra high performance liquid chromatography-high resolution mass spectrometric (UHPLC-HRMS) assay was developed using a surrogate disulfide-containing peptide, DCP(SS), and a confirmatory peptide, CP, a disulfide-free peptide. DCP(SS) was obtained by eliminating the step of reduction/alkylation before trypsin digestion. It contains an intact disulfide linkage between two peptide sequences that are essential for drug function but susceptible to potential in vivo cleavages. HRMS-based single ion monitoring (SIM) on a Q Exactive™ mass spectrometer was employed to improve assay specificity and sensitivity for DCP(SS) due to its poor fragmentation and low sensitivity with SRM detection. The assay has been validated for the protein drug in monkey serum using both surrogate peptides with excellent accuracy (within ±4.4%Dev) and precision (within 7.5%CV) with a lower limit of quantitation (LLOQ) at 10 ng mL−1. The protein concentrations in monkey serum obtained from the DCP(SS)-based assay not only provided important pharmacokinetic parameters, but also confirmed in vivo stability of the peptide regions of interest by comparing drug concentrations with those obtained from the CP-based assay or from a ligand-binding assay (LBA). Furthermore, UHPLC-HRMS allowed simultaneous monitoring of the oxidized forms of both surrogate peptides to evaluate potential ex vivo/in vivo oxidation of one methionine present in each of both surrogate peptides. To the best of our knowledge, this is the first report of using a surrogate disulfide-containing peptide for LC-MS bioanalysis of a therapeutic protein. 相似文献
62.
Thomas K. David Nayak K. Prashanth M. Rajendraswami Devendrareddy Pallalu Arlindo L. Castelhano Michael J. Kates Anna L. Blobaum Carrie K. Jones Kyle A. Emmitte P. Jeffrey Conn Craig W. Lindsley 《Tetrahedron letters》2017,58(36):3554-3558
This communication details the kilogram-scale synthesis of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238, auglurant), a novel mGlu5 negative allosteric modulator (NAM) developed as an alternative treatment for depression. The process highlights a challenging pyridine N-oxidation sequence, an SNAr reaction, and the elimination of all chromatography steps (required in the medicinal chemistry route) with replacement by highly efficient recrystallizations (save one silica plug). The improved process was utilized for the preparation of a 1.2 kg toxicology batch, as well as a 2.82 kg GMP batch to support the Phase I trial, in very high purity (99.8%). 相似文献
63.
CE-based methods have increasingly been applied to the analysis of a variety of different type proteins. One of those techniques is imaged capillary isoelectric focusing (icIEF), a method that has been used extensively in the field of protein-based drug development as a tool for product identification, stability monitoring, and characterization. It offers many advantages over the traditional labor-intensive IEF slab gel method and even standard cIEF with on-line detection technologies with regard to method development, reproducibility, robustness, and speed. Here, specific examples are provided for biopharmaceutical glycoprotein products such as mAbs, erythropoietin (EPO), and recombinant Fc-fusion proteins, though the technique can be adapted for many other therapeutic proteins. Applications of iCIEF using a Convergent Bioscience instrument (Toronto, Canada) with whole-field imaging technology are presented and discussed. These include a quick method to establish an identity test for many protein-based products, product release, and stability evaluation of glycoproteins with respect to charge heterogeneity under accelerated temperature stress, different pH conditions, and in different formulations. Finally, characterization of glycoproteins using this iCIEF technology is discussed with respect to biosimilar development, clone selection, and antigen binding. The data presented provide a "taste' of what icIEF method can do to support the development of biopharmaceutical glycoprotein products from early clone screening for better product candidates to characterization of the final commercial products. 相似文献
64.
Hong K Liu Y Porcar L Liu D Gao CY Smith GS Herwig KW Cai S Li X Wu B Chen WR Liu L 《J Phys Condens Matter》2012,24(6):064116
Polyamidoamine (PAMAM) dendrimers and their charged state in deuterium oxide have been investigated with proton pulsed field gradient diffusion nuclear magnetic resonance (PFG-NMR) and small-angle neutron scattering (SANS) techniques. NMR measurements suggest that significant variation of the hydrodynamic radius, calculated by the Stokes-Einstein relation with appropriate surface conditions, is observed upon increasing the molecular protonation. However, a comparative SANS experiment indicates little dependence of the dendrimer global size, in terms of its radius of gyration, on molecular protonation. The inconsistency indicates the necessity of incorporating the effect of molecular interface modification and molecular porosity provided by dressed counterions, when dynamical measurements are used for the determination of the structural characteristics of ionic soft colloids even in dilute suspensions. 相似文献
65.
Lie-Ding Shiau 《Molecules (Basel, Switzerland)》2021,26(21)
Stripping crystallization (SC) was introduced in this work to purify p-chlorophenol from the p-chlorophenol-rich liquid mixture and to purify m-chlorophenol from the m-chlorophenol-rich liquid mixture, respectively. Essentially, SC combines melt crystallization and vaporization to produce the solid product and the vapor from a liquid mixture via a series of three-phase transformations at reduced pressures during the cooling process. At the end of the SC, only the solid product remained while the liquid mixture was almost eliminated and the produced vapor was removed. A set of differential equations based on the mass and energy balances were proposed to determine the incremental variations of the amounts of remaining liquid, produced solid and produced vapor during the batch SC process. The experimental yield and product purity of the final product obtained from the batch SC experiments were compared with those predicted by the model. 相似文献
66.
Ellison MD Good AP Kinnaman CS Padgett NE 《The journal of physical chemistry. B》2005,109(21):10640-10646
The interaction of water vapor with carbon nanotubes at room temperature has been investigated using Fourier transform (FT) IR spectroscopy and density functional theory (DFT) calculations. FTIR data indicate that water molecules adsorb on single-walled carbon nanotubes at room temperature. Comparison to previous studies suggests that the water forms hydrogen-bonded structures inside the nanotubes. Analysis of the FTIR data demonstrates that a small number of water molecules react with the nanotubes, forming C-O bonds, whereas a majority of the water molecules adsorb intact. The DFT calculations show that cleavage of an O-H bond upon adsorption to form adsorbed -H and -OH groups is energetically favorable at defect sites on nanotubes. 相似文献
67.
Calcined Mg-Al hydrotalcites (CHT) with various Mg/Al atomic ratios were prepared and characterized by XRD, BET and TPD of carbon dioxide. The CHT catalysts were utilized for the synthesis of -pentylcinnamaldehyde (-Pc) from benzaldehyde and n-heptaldehyde in a stirred batch autoclave reactor. An increase of Mg/Al atomic ratio of CHT samples results in the apparent enhancement of catalyst basicity with concomitant decrease of surface areas. Both the catalytic activity and the -Pc selectivity increase with the catalyst basicity and the reaction temperature. 相似文献
68.
The vapochromic and vapoluminescent compound Pt(CN-p-(C(2)H(5))C(6)H(4))(2)(CN)(2) (abbreviated PtC(2)) is conveniently synthesized by the thermal rearrangement of [Pt(CN-p-(C(2)H(5))C(6)H(4))(4)][Pt(CN)(4)]. Recrystallization of PtC(2) gives a crystalline orange morph (O-PtC(2)) and an amorphous purple morph (P-PtC(2)) that both contain the cis isomer and differ only in their solid-state packing arrangements. Both compounds were fully characterized by elemental analysis, X-ray powder diffraction, NMR, IR, and TGA. O-PtC(2) is vapochromic and vapoluminescent: it reversibly sorbs aromatic hydrocarbons and ethanol from air or nitrogen with resulting color changes and shifts in the emission spectrum. The lambda(max) values (nm) for emission from O-PtC(2) x (guest) are as follows: no guest, 611; toluene, 565; benzene, 586; chlorobenzene, 592; p-xylene, 585; mesitylene, 565; ethanol, 587. In the case of toluene and mesitylene, intermediate emitting phases are observed. Recrystallization of O-PtC(2) from dichloromethane/toluene gave single crystals of PtC(2) x 0.5(toluene). The single-crystal X-ray structure of PtC(2) x 0.5(toluene) contains infinite stacks of cis geometry and planar molecules with chains of platinum atoms parallel to the c axis of the monoclinic unit cell. The average Pt-Pt separation in PtC(2) x 0.5(toluene) is c/4 = 3.288(2) A. There are solvent channels parallel with the c axis that contain the toluene molecule guests. Thin films of O-PtC(2) rapidly sorb toluene from the gas phase to form PtC(2) x 0.25(toluene) and PtC(2) x 0.5(toluene). Long-term exposure gives PtC(2) x 1.0(toluene). Removal of the toluene source causes rapid desorption to PtC(2) x 0.5(toluene) and then to PtC(2) x 0.25(toluene). The remaining 0.25(toluene) lattice guests require heating for rapid removal. X-ray powder diffraction identified the PtC(2),PtC(2) x .25(toluene), and PtC(2) x 0.5(toluene) phases and showed that the sorption of toluene is accompanied by small changes in the unit cell dimensions that include lengthening the Pt-Pt distances in the structure. The sorption process improves the packing in the structure by utilizing some of the free volume for the toluene lattice guests. 相似文献
69.
Crot CA Wu C Schlossman ML Trainor TP Eng PJ Hanley L 《Langmuir : the ACS journal of surfaces and colloids》2005,21(17):7899-7906
Long-period X-ray standing wave fluorescence (XSW) and X-ray reflectivity techniques are employed to probe the conformation of a Br-poly(ethylene glycol) (PEG)-peptide adsorbate at the hydrated interface of a polystyrene substrate. The Br atom on this Br-PEG-peptide construct serves as a marker atom allowing determination by XSW of its position and distribution with respect to the adsorption surface with angstrom resolution. Adsorption occurs on native or ion-beam-modified polystyrene films that are spin-coated onto a Si substrate and display either nonpolar or polar surfaces, respectively. A compact, oriented monolayer of Br-PEG-peptide can be formed with the peptide end adsorbed onto the polar surface and the PEG end terminating with the Br tag extending into the aqueous phase. The 108-141 A distance of the Br atom from the polystyrene surface in this oriented monolayer is similar to the estimated approximately 150 A length of the extended Br-PEG-peptide. This Br-polystyrene distance depends on adsorption time and surface properties prior to adsorption. Incomplete multilayers form on the polar surface after sufficient adsorption time elapses. By contrast, adsorption onto the nonpolar surface is submonolayer, patchy, and highly disordered with an isotropic Br distribution. Overall, this combination of X-ray surface scattering techniques with a novel sample preparation strategy has several advantages as a real space probe of adsorbed or covalently bound biomolecules at the liquid-solid interface. 相似文献
70.
The reaction of sodium methylate with 2-phenyl-3-benzoyl (or 3-phenyl) isoxazolidine leads, depending on the substituents of the heterocycle, to enamines, hydroxy lactams, enol lactams resulting from cleavage or rearrangement of the isoxazolidine. Formation of enamines in the reaction mixture during the course of the cycloaddition between C-benzoyl N-phenyl nitrone and certain olefins is due to hydrogen abstraction at carbon 3 of the isoxazolidine ring by the nitrone. 相似文献