Combined use of l‐alanine tert butyl ester lactate and trimethyl‐β‐cyclodextrin for the enantiomeric separations of 2‐arylpropionic acids nonsteroidal anti‐inflammatory drugs

In this study, a new CE method, employing a binary system of trimethyl‐β‐CD (TM‐β‐CD) and a chiral amino acid ester‐based ionic liquid (AAIL), was developed for the chiral separation of seven 2‐arylpropionic acid nonsteroidal anti‐inflammatory drugs (NSAIDs). In particular, the enantioseparation of ibuprofen, ketoprofen, carprofen, indoprofen, flurbiprofen, naproxen, and fenoprofen was improved significantly by supporting the BGE with the chiral AAIL l ‐alanine tert butyl ester lactate (l ‐AlaC₄Lac). Parameters, such as concentrations of TM‐β‐CD and l ‐AlaC₄Lac, and buffer pH, were systematically examined in order to optimize the chiral separation of each NSAID. It was observed that the addition of the AAIL into the BGE improved both resolution and efficiency significantly. After optimization of separation conditions, baseline separation (R_s>1.5) of five of the analytes was achieved in less than 11 min, while the resolution of ibuprofen and flurbiprofen was approximately 1.2. The optimized enantioseparation conditions for all analytes involve a BGE of 5 mM sodium acetate/acetic acid (pH 5.0), an applied voltage of 30 kV, and a temperature of 20°C. In addition, the results obtained by computing the %‐RSD values of the EOF and the two enantiomer peaks, demonstrated excellent run‐to‐run, batch‐to‐batch, and day‐to‐day reproducibilities.     

Capillary electrophoresis determination of nonsteroidal anti‐inflammatory drugs in wastewater using hollow fiber liquid‐phase microextraction

The presence of pharmaceuticals in the environment due to growing worldwide consumption has become an important problem that requires analytical solutions. This paper describes a CE determination for several nonsteroidal anti‐inflammatory drugs (ibuprofen, naproxen, ketoprofen, diclofenac, ketorolac, aceclofenac and salicylic acid) in environmental waters using hollow fiber membrane liquid‐phase microextraction. The extraction was carried out using a polypropylene membrane supporting dihexyl ether and the electrophoretic separation was performed in acetate buffer (30 mM, pH 4) using ACN as the organic modifier. Detection limits between 0.25 and 0.86 ng/mL were obtained, respectively. The method could be applied to the direct determination of the seven anti‐inflammatories in wastewaters, and five of them have been determined or detected in different urban wastewaters.     

Chiral amines as reagents for HPLC-MS enantioseparation of chiral carboxylic acids

Mass spectrometry (MS) has become a popular analytical technique because of its high sensitivity and specificity. Therefore, the use of a chiral derivatization reagent for the MS detection seems to be efficient for the enantiomeric separation of racemates. However, the number of chiral reagents for the liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis is very limited. The applicability of commercially available chiral amines as the derivatization reagents for the enantiomeric separation of chiral carboxylic acids is reported in this paper by using non-steroidal anti-inflammatory drugs (NSAIDs), i.e. ibuprofen, flurbiprofen, and loxoprofen. The efficiency of the chiral reagents was evaluated in terms of tagging easiness, separation by reversed-phase chromatography, and detection sensitivity by electrospray ionization (ESI)-MS/MS. Among the tested eight chiral amines, i.e. (R)-(+)-4-(3-aminopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-APy), (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (PMP), L-prolinamide, (3R)-(-)-1-benzyl-3-aminopyrrolidine, (S)-(+)-1-cyclohexyl-ethylamine, (3R)-(+)-3-(trifluoroacetamido)-pyrrolidine (TFAP), (R)-(-)-1-aminoindan (AI), and (S)-(+)-tetrahydrofurfuryl-amine, DBD-APy, PMP, AI, and TFAP could be used as the chiral reagents for the enantiomeric separation of the NSAIDs. The Rs values and the detection limits of the derivatives were in the range of 1.29-3.85 and 0.57-0.96 fmol, respectively. These four reagents were applied for the determination of the NSAIDs in rat plasma.     

Chemical constituents from the rhizomes of Polygonatum sibiricum Red. and anti-inflammatory activity in RAW264.7 macrophage cells

Chemical investigation of the rhizomes of Polygonatum sibiricum Red. led to the identification of 27 constituents. Among them, a total of 16 compounds were obtained from Polygonatum for the first time, in which, 3 and 4 were also firstly isolated as natural products. Anti-inflammatory activity studies on 13 isolated compounds showed that β-carboline constituents, especially compounds 1 and 2, significantly inhibited the expression of NO, TNF-α, IL-6 and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells. Moreover, western blotting analysis demonstrated that compound 1 significantly inhibited the expression of COX-2, iNOS and the activation of NF-κB, suggesting that β-carboline structures may play an important role in inhibition of NF-κB signaling pathway, which thereby inhibits the production of inflammatory factors. The present research may not only help further elucidation of the anti-inflammatory mechanism of P. sibiricum Red., but also provide the potential bioactive molecules for inflammatory diseases research.     

Synthesis,reactions, and biological study of some new thienopyrimidine derivatives as antimicrobial and anti‐inflammatory agents

Pyrimidine and thienopyrimidine derivatives play a very important role in organic chemistry because of their wide applications as bioactive compounds with multiple biological activities. However, a literature survey revealed that the merger of different groups in the thieno[2,3‐d]pyrimidine heterocyclic ring enhances its antibacterial, antifungal and anti‐inflammatory activities. This encouraged us to prepare a new series of thieno[2,3‐d]pyrimidine heterocyclic compounds and to test them as antimicrobial and anti‐inflammatory agents. These compounds have shown remarkable activity toward fungi, bacteria, and inflammation. Thus, these compounds have been prepared by the chloroacylation of 5‐amino‐4‐phenyl‐2‐(p‐tolylamino)thieno[2,3‐d] pyrimidine‐6‐carboxamide ( 4 ) using chloroacetyl chloride under neat condition to afford the target compound ( 6 ), which was used as precursor for the synthesis of a number of bioactive compounds. Thus reaction of the chloromethylpyrimidine derivative ( 6 ) with triphenylphosphine in dry benzene gave the corresponding ((4‐oxo‐9‐phenyl‐7‐(p‐tolylamino)‐3,4‐dihydropyrimido[4′,5′:4,5]thieno[2,3‐d]pyrimidin‐2‐yl)methyl) triphenylphosphonium chloride ( 7 ). Compounds 8a – 8c and 9a – 9c were obtained by the reaction of 7 with some selected aromatic aldehydes and ketones in methanol and sodium methoxide under Wittig reaction condition. The structures of the all new synthesized compounds were established on the basis of their analytical and spectral data (IR, ¹H NMR, ¹³C NMR, and MS).     

Synthesis and anti‐inflammatory effect of morachalcone B,morachalcone C,and analogs

An efficient method to synthesize morachalcones B and C ( 1 and 2 ) is described. Rap?Stoermer condensation and 1,3‐prenyl rearrangement were used as two key synthetic methods. Morachalcone C was obtained by photo‐oxygenation of morachalcone B. Morachalcones B and C showed moderate anti‐inflammatory activity.     

Synthesis and rational design of anti‐inflammatory compounds: N‐phenyl‐cyclohexenyl sulfonamide derivatives

The synthesis of (±)‐ethyl 6‐[N‐(2‐chloro‐4‐fluorophenyl)sulfamoyl]cyclohex‐1‐ene‐1‐carboxylate ( 5n ) has been reproduced from a method previously described and served as the background for the preparation of a nitro derivative, potentially useful as an anti‐inflammatory agent. Furthermore, a structure‐based QSAR analysis of a series of N‐arylsulfamoyl congeners derived a highly predictive model for the activities of novel small‐molecule inhibitors of NO and cytokine production, whose preparation may be successfully achieved according to a similar procedure as above. Copyright © 2009 John Wiley & Sons, Ltd.     

羰化法合成α-芳基丙酸研究进展

本文综述了羰化法合成A2芳基丙酸的最新研究进展。     

Determination of enantiomeric purity of a novel COX-2 anti-inflammatory drug by capillary electrophoresis using single and dual cyclodextrin systems

E-6087 is the most advanced compound among the cyclooxygenase-2 (COX-2) inhibitor drugs developed in our company. Its activity is mainly associated with the S(-)-enantiomer (E-6232), whereas the R(-)-enantiomer (E-6231) becomes an impurity whose content should be determined. Five main impurities and degradation products of E-6232 have been found (E-6144, E-6024, E-6072, E-6397 and E-6132), and some of them co-elute with the distomer when using a chiral high-performance liquid chromatography (HPLC) method. Consequently, we have optimized the separation of all the impurities from the two enantiomers of E-6087 by capillary electrophoresis (CE), in order to use the method for the enantiomeric purity determination of E-6232. The effect of the methanol (MeOH) content in the background electrolyte (BGE), the sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD) and heptakis-(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CD) concentration, and the capillary temperature have been studied. Separation of all compounds could be achieved in different systems, either in a single CD-system (with SBE-beta-CD) or in a dual CD-system (with DM-beta-CD as a neutral CD). By using the dual CD system a limit of detection (LOD) and a limit of quantitation (LOQ) of 0.03% and 0.1% of distomer, respectively, were achieved*.     

超声指标对类风湿关节炎的疗效评估价值

目的探究超声指标在类风湿性关节炎(RA)治疗效果评估方面的临床价值。方法选取2014年5月到2016年5月期间于彭泽县人民医院治疗RA的50例患者(膝关节80个),观察其膝关节的肿胀体征和压痛症状,对其C反应蛋白(CRP)与血沉(ESR)进行检测,并使用超声对膝关节进行扫描,评估其骨侵蚀、灰阶滑膜炎以及能量多普勒(PD)信号。结果 1超声检查阳性率:PD为18.75%(15/80),滑膜炎为83.75%(67/80),骨侵蚀为31.25%(25/80)。2临床检查阳性率:压痛为42.5%(34/80),肿胀为33.75%(27/80)。超声的滑膜炎阳性和膝关节的压痛、肿胀阳性分别比较,前者高于后两者,且与后两者均存在统计学差异(P0.05)。行相关性分析,滑膜炎阳性、PD阳性与CRP和ESR均有相关性(P0.05),而骨侵蚀仅与CRP有相关性(P0.05),与ESR则无相关性(P0.05)。结论超声与炎性指标之间有相关性,其敏感性要优于临床检查,更适用于RA的疗效评估。