Enantioseparation of racemic paroxol on an amylose‐based chiral stationary phase by supercritical fluid chromatography

The separation of racemic paroxol, a key precursor of trans‐(?)‐paroxetine, on Chiralpak AD‐H, an amylose‐based chiral stationary phase, by supercritical fluid chromatography was studied. Pulse experiments were investigated using supercritical carbon dioxide modified with methanol (MeOH), ethanol and 2‐propanol at 35°C and 15 MPa. Retention and separation factors were determined under analytical conditions for different mobile phase compositions. Among the modifiers used, MeOH was shown to be the best additive, and 5% v/v of MeOH was the preferable concentration at which selectivity of 1.14 and resolution of 3.0 was obtained. In order to evaluate the potential with respect to preparative separations, the adsorption isotherms of individual enantiomers of paroxol were estimated using the elution by characteristic point method. Isotherm parameters were determined from the overloaded elution profiles that were collected at pressure ranging from 15 to 24 MPa. The isotherms obtained were further validated by comparing experimentally recorded elution profiles with the predictions based on the equilibrium‐dispersive model. The results are important to the process design and optimization of preparative supercritical fluid chromatography application.     

Workshop lecture on products of Fréchet spaces

The general question, “When is the product of Fréchet spaces Fréchet?” really depends on the questions of when a product of α₄ Fréchet spaces (also known as strongly Fréchet or countably bisequential spaces) is α₄, and when it is Fréchet. Two subclasses of the class of strongly Fréchet spaces shed much light on these questions. These are the class of α₃ Fréchet spaces and its subclass of ℵ₀-bisequential spaces. The latter is closed under countable products, the former not even under finite products. A number of fundamental results and open problems are recalled, some further highlighting the difference between being α₃ and Fréchet and being ℵ₀-bisequential.     

The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors

Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metabolites that have been implicated in many diseases and disorders. With many of these illnesses having an inadequate or modest treatment, there exists a need to develop KMO inhibitors that reduce the production of these toxic metabolites. Though prior efforts to find an appropriate KMO inhibitor were unpromising, the development of a KMO crystal structure has provided the opportunity for a rational structure-based design in the development of inhibitors. Therefore, the purpose of this review is to describe the kynurenine pathway, the kynurenine 3-monooxygenase enzyme, and KMO inhibitors and their potential candidacy for clinical use.     

Multifunctional Small Molecules as Potential Anti-Alzheimer’s Disease Agents

Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a–e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer’s disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.     

通用智能数据采集系统的开发

通用智能数据采集系统以单片机为核心,控制模/数转换芯片AD 7715实现对数据的采集,使用串行接口大容量FLA SH存储芯片AT 45D 041对数据进行存储,通过RS232口实现与上微机的通讯,并用LCD实时显示运行状态、测量结果等,重点阐述了单片机对AD 7715以及AT 45D 041的控制.该系统可广泛应用于需要对大量的实时数据进行采集的场合.     

基于积分束流变压器的加速器束团电荷量测量系统

 为满足清华大学加速器实验室光阴极微波电子枪实验平台的发展需求，设计了束团电荷量测量系统，可以实现实时测量加速器束团电荷量的目标。这套测量系统基于积分束流变压器，包括前置放大器、门控积分器、模数转换和数据传输模块。利用信号发生器模拟束流，对整套系统进行了离线测量实验。当前置放大器放大倍数取200和20时，AD转换值和束流电荷的比值分别为2.181 PC-1和0.195 PC-1，与理论值2.070 PC-1和0.207 PC-1基本吻合；其对应的电荷量测量误差分别小于2 PC和15 PC。测量结果和模拟束流电荷量值的拟合曲线线性度好，相关系数的平方均大于0.999 0。该结果验证了系统的可行性。     

Synthesis of novel copolymers obtained from acceptor/donor radical copolymerization of phosphonated allyl monomers and maleic anhydride

A series of four phosphonated‐bearing allyl monomers, that is, diethyl‐1‐allylphosphonate ( AP ), dimethyl‐1‐allyloxymethylphosphonate ( AOP ), 5‐ethyl‐5‐(allyloxymethyl)‐2‐oxo‐1,3,2‐dioxaphosphorinane ( AEDPH ), and 2‐benzyl‐5‐ethyl‐5‐(allyloxymethyl)‐2‐oxo‐1,3,2‐dioxaphosphorinane ( AEDPBn ) were synthesized. These monomers were then copolymerized by free radical polymerization in the presence of maleic anhydride, thus leading to alternated copolymers with phosphonate moieties. It was shown that both monomer conversion and reaction rate were dependent on the phosphonate moieties carried out by the allyl monomer: the bulkier the phosphonate group, the higher the polymerization rate. Thermogravimetric analysis of the copolymers revealed a high content of residue, also varying with the nature of the phosphonate moieties. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Detection and quantification of plasma amyloid-β by selected reaction monitoring mass spectrometry

Amyloid-β (Aβ) in human plasma was detected and quantified by an antibody-free method, selected reaction monitoring mass spectrometry (SRM-MS) in the current study. Due to its low abundance, SRM-based quantification in 10 μL plasma was a challenge. Prior to SRM analysis, human plasma proteins as a whole were digested by trypsin and high pH reversed-phase liquid chromatography (RPLC) was used to fractionate the tryptic digests and to collect peptides, Aβ_1–5, Aβ_6–16, Aβ_17–28 and Aβ_29–40(42) of either Aβ_1–40 or Aβ_1–42. Among those peptides, Aβ_17–28 was selected as a surrogate to measure the total Aβ level. Human plasma samples obtained from triplicate sample preparations were analyzed, obtaining 4.20 ng mL⁻¹ with a CV of 25.3%. Triplicate measurements for each sample preparation showed CV of <5%. Limit of quantification was obtained as 132 pM, which corresponded to 570 pg mL⁻¹ of Aβ_1–40. Until now, most quantitative measurements of Aβ in plasma or cerebrospinal fluid have required antibody-based immunoassays. Since quantification of Aβ by immunoassays is highly dependent on the extent of epitope exposure due to aggregation or plasma protein binding, it is difficult to accurately measure the actual concentration of Aβ in plasma. Our diagnostic method based on SRM using a surrogate peptide of Aβ is promising in that actual amounts of total Aβ can be measured regardless of the conformational status of the biomarker.     

High quality drug screening by capillary electrophoresis: A review

High quality assays are needed in drug discovery to reduce the high attrition rate of lead compounds during primary screening. Capillary electrophoresis (CE) represents a versatile micro-separation technique for resolution of enzyme-catalyzed reactions, including substrate(s), product(s), cofactor(s) and their stereoisomers, which is needed for reliable characterization of biomolecular interactions in free solution. This review article provides a critical overview of new advances in CE for drug screening over the past five years involving biologically relevant enzymes of therapeutic interest, including transferases, hydrolases, oxidoreductases, and isomerases. The basic principles and major configurations in CE, as well as data processing methods needed for rigorous characterization of enzyme inhibition are described. New developments in functional screening of small molecules that modulate the activity of disease-related enzymes are also discussed. Although inhibition is a widely measured response in most enzyme assays, other important outcomes of ligand interactions on protein structure/function that impact the therapeutic potential of a drug will also be highlighted, such as enzyme stabilization, activation and/or catalytic uncoupling. CE offers a selective platform for drug screening that reduces false-positives while also enabling the analysis of low amounts of complex sample mixtures with minimal sample handling.     

X-ray photoelectron spectra of inorganic molecules: XXX. Organometallic derivatives of tungsten(O) and tungsten(II)

The W 4f binding energies of various carbonyl-containing complexes of tungsten are reported. Comparisons between W^II complexes containing the [(η³-allyl)W(CO)₂] moiety and neutral derivatives of the type W(CO)_6-xL_x are made. The absence of a clear-cut correlation between the W 4f binding energies and the value of x in W(CO)_6-xL_x is discussed and these results compared with those obtained for the analogous molybdenum complexes.