Analysis of species-dependent hydrolysis and protein binding of esmolol enantiomers

The stereoselective hydrolysis of esmolol in whole blood and in its separated components from rat,rabbit and human was investigated.Blood esterase activities were variable in different species in the order of rat>rabbit>human.Rat plasma showed the high esterase activity and had no stereoselectivity to enantiomers.Rabbit red blood cell(RBC) membrane,RBC cytosol and plasma all hydrolyzed esmolol but with different esterase activity,whereas the hydrolysis in RBC membrane and cytosol showed significant stereoselectivity towards R-(+)-esmolol.Esterase in RBC cytosol from human blood mainly contributed to the esmolol hydrolysis,which was demonstrated with no stereoselctivity.Esterase in human plasma showed a low activity,but a remarkable stereoselectivity with R-(+)-esmolol.In addition,the protein concentration affected the hydrolysis behavior of esmolol in RBC suspension.Protein binding of esmolol enantiomers in human plasma,human serum albumin(HSA) and α_1-acid glycoprotein(AGP) revealed that there was a significant difference in bound fractions between two enantiomers,especially for AGP.Our results indicated that the stereoselective protein binding might play a role in the different hydrolysis rates of esmolol enantiomers in human plasma.

Separation and determination of acetyl-glutamine enantiomers by HPLC–MS and its application in pharmacokinetic study

A high-performance liquid chromatography coupled with mass spectrometry(HPLC–MS) method was established for the separation and determination of acetyl-glutamine enantiomers(acetylL-glutamine and acetylD-glutamine) simultaneously. Baseline separation was achieved on Chiralpak AD-H column(250 mm ×4.6 mm, 5 μm). n-Hexane(containing 0.1% acetic acid) and ethanol(75:25, v/v) were used as mobile phase at a flow rate of 0.6 m L/min. The detection was operated in the negative ion mode with an ESI source. [M-H]-m/z187.0540 for enantiomers and [M-H]-m/z 179.0240 for aspirin(IS) were selected as detecting ions. The linear range of the calibration curve for each enantiomer was 0.05–40 μg/m L. The precision of this method at concentrations of 0.5–20 μg/m L was within 7.23%, and the accuracy was 99.81%–107.81%. The precision at LOQ(0.05 μg/m L) was between 16.28% and 17.56%, which was poor than that at QC levels. The average extraction recovery was higher than 85% for both enantiomers at QC levels. The pharmacokinetics of enantiomers was found to be stereoselective. There was not chiral inversion in vivo or in vitro between enantiomers.

Transport and uptake of clausenamide enantiomers in CYP3A4-transfected Caco-2 cells： an insight into the efflux-metabolism alliance

Aim The present study developed a CYP3A4-expressed Caco-2 monolayer model at which effects of the efflux-metabolism alliance on the transport and uptake of clausenamide（CLA） enantiomers as CYP3A4 substrates were investigated. The apparent permeability coefficients （Papp） of （ - ） and （ ＋ ）CLA were higher in the ab- sorptive direction than those in the secretory direction with efflux ratios（ER） of 0. 709 ± 0.411 and 0. 867± 0. 250 （ Х10^-6 -1 cm · s ）, respectively. Their bidirectional transports were significantly reduced by （75.6 ± 87.5）% af- ter treatment with verapamil （ a P-glycoprotein inhibitor） that increased the rate of metabolism by CYP3 A4, whereas the CYP3A4 inhibitor ketoconazole treatment markedly enhanced the basolateral to apical flux of （ - ） and （ ＋ ） CLA with ERs being 2. 934 ± 1. 432 and 1. 877 ± 0. 148 （ Х 10^-6 cm/s） respectively. These changes could be blocked by the duel CYP3A4/P-glycoprotein inhibitor cyclosporine A, consequently, Papp values for CLA enanti- omers in both directions were significantly greater than those obtained by using verapamil or ketoconazole, and their ERs were similar to those following （ - ） or （ ＋ ）-isomer treatment alone. Furthermore, the uptake of （ - ）CLA was more than that of （ ＋ ）CLA in the transfected cells. Incubation with ketoeonazole decreased the intracellular concentrations of the two enantiomers. This effect disappeared in the presence of a CYP3A4 inducer dexametha- sone. These results indicated that CYP3A4 could influence P-gp efflux, transport and uptake of CLA enantiomers as CYP3A4 substrates and that a duel inhibition to CYP3A4/ P-glycoprotein could enhance their absorption and bioavailability, which provides new insight into the efflux-metabolism alliance and will benefit the clinical pharma- cology of （？） CLA as a candidate drug for treatment of Alzheimer＇ s disease.

Separation of tryptophan enantiomers with molecularly imprinted polypyrrole electrode column

In this study,we have fabricated molecularly imprinted polypyrrole(PPy) packed electrode columns and investigated their effects on separation of tryptophan(Trp) enantiomers by using potential control.The results indicate that the imprinted PPy electrode columns could efficiently enhance the L-Trp uptake and separate Trp enantiomers effectively,implying the great potential for the enantioselective recognition of other amino acids enantiomers.

Enantioselective extraction of terbutaline enantiomers by lipophilic tartaric acid

Distribution behavior of terbutaline enantiomers was examined in the aqueous and organic solvent of a two-phase system containing L-dibenzoyltartaric acid and lipophilic phase transfer reagent of Na-tetraphenylborate. The influences of pH, organic solvents, concentrations of Na-tetraphenylborate and L-dibenzoyltartaric acid on the partition coefficients and enantioselectivity of terbutaline enantiomers, were investigated. The results show that tetraphenylborate lipophilic anion and terbutaline enantiomers form two lipophilic salt complexes , which facilitates the solubility of the enantiomers in the organic phase. L-dibenzoyltartaric acid forms more stable complexes with enantiomer Ⅱ than with enantiomer I . Enantioselectivity and partition coefficient increase with the addition of the length of alkyl chain of alcohols. pH and concentrations of lipophilic anion and L-dibenzoyltartaric acid influence them obviously and differently.

Thin-Layer Chromatographic Separation of Amino Acid Enantiomers using Ligand Exchange

Silica gel thin-layer plates covered with L-arginine and copper acetate were used for the separation of amino acid enantiomers.The chromatographic selectivity and the effects of plate different preperation methods,sample molecular structure and solvent compositions on resolution performance were also discussed.

Enantiomers Present in Serum Carry Cancer and/or Recovery Status Information

Human blood serum of cancer, cancer-recovered and healthy patients contains laevorotatory and dextrorotatory B2 active molecules. The laevorotatory B2 active carriers in patient serum carry information on the cancer status while the dextrorotatory B2 active carriers carry information on the recovered and/or healthy patient status. Their magneto-optical characteristic is analysed by the B2 Magneto Optical Circular Birefringence. By applying the MOCB experimental technique, it is possible to differentiate between the cancer and non-cancer patients. The paper introduces a purely molecular physics approach for description of the cancer/recovered and also non-cancer patients status.

Determination of Enantiomers in ET-26-HCl by Ultra Performance Convergence Chromatography

[Objectives]To establish an ultra performance convergence chromatography(UPC2)method to determine the content of enantiomers in(R)-2-methoxyethyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate hydrochloride(ET-26 HCl).[Methods]ChiralpakAD-3 chromatographic column(4.6 mm×100 mm,3μm)was used,with 0.1%diethylamine methanol solution-supercritical carbon dioxide(1∶9)as mobile phase;flow rate 2.0 mL/min;back pressure 2000 psi,detection wavelength 240 nm,and column temperature 35℃.[Results]ET-26-HCl was completely separated from the enantiomers,and the linear relationship was good;the detection limit was 1.5μg/mL.[Conclusions]This method is suitable for the determination of the content of enantiomers in ET-26-HCl.

Separation of Enantiomers of Clopidogrel on Chiral Stationary Phases by Packed Column Supercritical Fluid Chromatography

A packed column supercritical fluid chromatography (SFC) method for the separation of clopidogrel enantiomers on a chiral stationary phase and CO2 with modifier as mobile phase has been developed at an analytical scale. Among 11 different 2 stationary phases the Chiral cel OD-H column showed by far the best separation properties. The influence of different modifiers, injection solvents, temperature, and pressure, and density of the fluid, respectively, on the separation behaviour has been studied. It was found that the separation behaviour strongly depends on the type of modifier and the modifier content. Temperature and pressure are of less influence.

Preparation of insoluble β-CD polymer and its application to enantiomers and isomers separation

An insoluble β cyclodextrin polymer cross linked with epichlorohydrin was prepared, and its structure was identified with infrared spectrum. Colloid stationary phase was prepared by dissolving the polymer in the mixed solvent of diisopropyl ether, methylene dichloride and benzene and treated for 0.5 h by ultrasonication, and then was coated on a fused silica capillary column. The optimun reaction conditions are as follows: the mole ratio of epichlohydrin to β cyclodextrin is 12.1∶1, reacting at 65 ℃ for 24 h. The Chromatographic performance such as column efficiency, thermal stabilities and polarity were studied, two kinds of disubstituted benzene isomers and eight pairs of enantiomers were separated on the capillary column. The results show that the β cyclodextrin polymer is suitable for use as a capillary gas chromatographic stationary phase, and possess excellent chromatographic properties in separating enantiomers and position isomers.

Development of a UHPLC-MS/MS method for the quantification of ilaprazole enantiomers in rat plasma and its pharmacokinetic application

In Korea and China,ilaprazole is a widely used proton pump inhibitor in the treatment of gastric ulcers.In this study,a specific and sensitive LC-MS/MS method has been developed and validated for the quantification of ilaprazole enantiomers in the rat plasma,using R-lansoprazole as the internal standard.The enantioseparation was achieved on a CHIRALPAK AS-RH column(4.6 mm×150 mm,i.d.5 mm),with a mobile phase composed of 10 m M ammonium acetate aqueous solution and acetonitrile(60:40,V/V),at a flow-rate of 0.5 m L/min.The method was validated over the concentration range of 0.5 e300 ng/m L for both,R-and S-ilaprazole.The lower limit of quantification was 0.5 ng/m L for both enantiomers.The relative standard deviation(RSD)of intra-and inter-day precision of R-ilaprazole and S-ilaprazole was less than 10.9%,and the relative error accuracy(RE)ranged fromà0.5%e2.0%.Finally,the method was successfully evaluated in rats in a stereoselective pharmacokinetic study of the ilaprazole racemate.

Synthesis and Characterization of Both Enantiomers of a Chiral C_(60) Derivative Bearing the 1, 1'-Binaphthyl Group

Both enantiomers R-1 and S-1 of a chiral C60 derivative were synthesized by the reactions of C60 with 1, 1’-bi-2-naphthol bis(azidoacetates) and characterized by FD-MS, fT-IR,1H NMR, 13C NMR, UV-VIS, CD spectra.

Analysis of amino acid enantiomers in ambient aerosols:Effects and removal of coexistent aerosol matrix

Amino acids(AAs)including D-and L-enantiomers are a group of organic nitrogen species in ambient aerosol.Due to the low abundances of AAs(level of ng/m^(3))and the matrix effects by coexistent components,it is challenging to quantify AA enantiomers in ambient aerosols especially under pollution conditions.In this study,we present an optimized method for analyzing AA enantiomers in atmospheric aerosol samples including a pretreatment process and the detection by high performance liquid chromatography coupled to a fuorescence detector(HPLC-FLD).Matrix effects caused by coexistent chemicals on AA enantiomers analysis in ambient aerosol samples were investigated especially for those collected in pollution episodes.The results revealed that the determination of AA enantiomers is significantly affected by the coexistent organic carbon(as a proxy of organic matter)and water-soluble ion of NH_(4)^(+).To remove the matrix effects,we applied a pretreatment using the solid phase extraction column coupled with alkaline adjustment to sample extract.After pretreatment,18 AAs including 6 pairs of D-and L-enantiomers(i.e.,leucine,isoleucine,valine,alanine,serine,and aspartic acid)can be successfully separated and quantified in aerosol samples by HPLC-FLD.The recoveries are in the range of 67%-106%.This method was successfully applied to the urban aerosol samples from pollution and non-pollution periods for AA enantiomers determination.We suggest that the concentrations of D-AAs and the ratio of D-AA/L-AA are indicative of the contribution of bacterial sources and the infuence of biomass burning.

Resolution of α-cyclohexyl-mandelic acid enantiomers by two-phase (O/W) recognition chiral extraction

This paper presents a new chiral separation technology: two-phase (O/W) recognition chiral extraction. Distribution behavior of α-cyclohexyl-mandelic acid enantiomers was studied in the extraction system with D(L)-isobutyl tartrate in 1,2-dichloroethane organic phase and β-CD derivatives in aqueous phase, and the influence of the kind and concentration of extractant and pH on extraction performance was investigated. The experimental results indicate that two-phase (O/W) recognition chiral extraction is of strong chiral separation ability. HP-β-CD, HE-β-CD and Me-β-CD have higher recognition ability for S-CHMA than that for R-CHMA, among which HP-β-CD has the strongest ability; whereas, D-isobutyl tartrate has reversed recognition ability for them. In the extraction system containing HP-β-CD and D-isobutyl tartrate, e.e.% of S-CHMA in aqueous phase reached 27.6% by one stage extraction, and the distribution ratio for R-CHMA(kR) and for S-CHMA(kS) and separation factor (α) are 2.44, 0.89 and 2.49, respectively. Meanwhile, pH and concentration of extractant have great effects on chiral separation ability. Two-phase (O/W) recognition chiral extraction has great significance for preparative separation of racemic compounds.

Air-Stable Dy(III)-Macrocycle Enantiomers:From Chiral to Polar Space Group

Magnetoelectric(ME)multiferroic materials have unique advantages in low-power and high-density information storage,because they can simultaneously display ferroelectricity and ferromagnetism.However,research on how to construct air-stable highperformance ME single-molecule magnets(SMMs)is nonexistent.Herein,by introducing homochirality while reducing molecular symmetry,two doubledecker Dy(III)enantiomers adopting the polar space group P2_(1) and exhibiting excellent thermal stability were obtained.They displayed zero field SMM behavior with an anisotropy barrier(Ueff)of ca.100 cm^(−1).This work establishes a rational chemical design strategy for crystallizing SMMs in polar space groups and elucidates the direction for future research,that is,engineering small-size high-performance SMMs.

Enantiomers of Ohmefentanyl and Its Analgesic Activity

Since the existence of multiple opioid receptors was first proposed by Martin,this concept was subsequently substantiated by the pharmacological tests and receptor binding assays.Now three subclasses of opioid receptor have gained

Kinetic study on reactive extraction for chiral separation of phenylsuccinic acid enantiomers

The kinetics of the extraction of phenylsuccinic acid(PSA) enantiomers by hydroxypropyl-β-cyclodextrin(HP-β-CD) in a modified Lewis cell was studied,in which HP-β-CD dissolved in 0.1 mol L-1 NaH2PO4/H3PO4 buffer solution(pH = 2.5) was selected as the chiral extractant.PSA enantiomers were extracted from organic phase to aqueous phase in the extraction module.The theory of extraction accompanied by a chemical reaction has been used to obtain the intrinsic kinetics of this extraction module.The different parameters affecting the extraction rate such as agitation speed,interfacial area,initial concentration of PSA enantiomers in organic phase as well as HP-β-CD concentration in aqueous phase were separately studied.The experimental results demonstrate that the extraction reactions are fast.The reactions were found to be first order with respect to PSA and second order with respect to HP-β-CD with forward rate constants of 3.4 × 10-2 m6 mol-2 s-1 for R-PSA and 9.96 × 10?3 m6 mol-2 s-1 for S-PSA.These data will be useful in the design of extraction processes.

Discovery of Natural Co-occurring Enantiomers of Monoterpenoid Indole Alkaloids

Main observation and conclusion Two new pairs of monoterpenoid indole alkaloids(MIAs)enantiomers as well as their new congeners were isolated from stems of Tabernaemontana bovina Lour.(Apocynaceae).Their structures were elucidated by spectroscopic analyses and confirmed by X-ray diffractions and computational calculations.Tabovine A,tabovine B and tabovines C-D possessed unprecedented 6/5/5/6/6,6/5/5/6/5 and 6/5/6/6/6 ring systems,respectively.It is the first time to report co-occurring enantiomers of MIAs.Additionally,the explanation concerning biogenesis of MIAs was provided.The findings would open a new window where we could disclose more diverse MIAs.

Isolation of Single-Walled Carbon Nanotube Enantiomers by Density Differentiation

Current methods of synthesizing single-walled carbon nanotubes(SWNTs)result in racemic mixtures that have impeded the study of left-and right-handed SWNTs.Here we present a method of isolating different SWNT enantiomers using density gradient ultracentrifugation.Enantiomer separation is enabled by the chiral surfactant sodium cholate,which discriminates between left-and right-handed SWNTs and thus induces subtle differences in their buoyant densities.This sorting strategy can be employed for simultaneous enrichment by handedness and roll-up vector of SWNTs having diameters ranging from 0.7 to 1.5 nm.In addition,circular dichroism of enantiomer refined samples enables identification of high-energy optical transitions in SWNTs.

Three pairs of alkaloid enantiomers from the root of Isatis indigotica

Three pairs of enantiomerically pure alkaloids with diverse structure features, named isatindigoticoic acid A and epiisatindigoticoic acid A [(—)-1 and(+)-1], phaitanthrin A and epiphaitanthrin A [(—)-2 and(+)-2], and isatindopyrromizol A and epiisatindopyrromizol A [(—)-3and(+)-3], respectively, were isolated from an aqueous extract of the roots of Isatis indigotica. Racemic and scalemic mixtures of these enantiomers were separated by HPLC on a chiral semi-preparative column.Their structures including absolute configurations were determined by extensive spectroscopic analysis in conjunction with the calculation of electronic circular dichroism(ECD) spectra. The enantiomer pairs possess parent structures of 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid, indolo[2,1-b]quinazolinone, and 3-thioxohexahydro-1H-pyrrolo[1,2-c]imidazol-1-one, respectively. Except for phaitanthrin A[(—)-2] which the configuration was previously undetermined, these compounds are new enantiomeric natural products.