bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of ketoprofen enantiomers in monkeys following single and multiple oral administration
Authors: Mauleon David , Mis Ricard , Ginesta Joan , Ortega Elvira , Vilageliu Jaime , Basi Nuria , Carganico Germano 
Published: January 2005

AbstractPharmacokinetic studies are reported after single oral administration of 3 mg/kg of stereochemically pure (S)‐ketoprofen [(S)‐KP] and (R)‐ketoprofen [(R)‐KP] to three male Cynomolgus monkeys and after repeated administration for 6 months of 3, 15 and 75 mg/kg/day of (S)‐KP to both male and female monkeys. A high‐performance liquid chromatographic (HPLC) analysis was performed without derivatization of the samples, using a chiral column. The pharmacokinetic parameters for (S)‐KP after administration of (S)‐KP and for (R)‐KP after administration of (R)‐KP were, respectively, elimination half‐life 2.32 ± 0.36 and 1.64 ± 0.40 h; oral clearance 3.50 ± 0.66 and 7.50 ± 3.20 ml/min/kg; apparent volume of distribution 0.74 ± 0.24 and 1.16 ± 0.76 liter/kg; mean residence time 1.79 ± 0.77 and 1.41 ± 0.65 h; area under the concentration/time curve 14.16 ± 2.93 and 7.31 ± 2.98 μg·h/ml. Forty‐nine percent unidirectional bioinversion of (R)‐KP to (S)‐KP was observed in this species and the pharmacokinetic parameters for the (S)‐KP resulting from this inversion were also calculated. In the study of 6‐month repeated administration of (S)‐KP, linear pharmacokinetic behavior and no evidence of drug accumulation were observed at the three dose levels. © 1994 Wiley‐Liss, Inc.
Chiral lumazines: Preparation, properties, enantiomeric separation
Authors: Klein Roger , Tatischeff Irene , Tham Gisele , Mano Nariyasu 
Published: January 2005

AbstractOptically active lumazines (biolumazine, dictyolumazine, monalumazine, and neolumazine) are prepared from the corresponding pterins by enzymatic reaction, using pterin deaminase excreted by Dictyostelium discoideum. The fluorescence properties, circular dichroism spectra, and chromatographic behavior of these lumazines are studied. D‐ and L‐enantiomers of biolumazine, dictyolumazine, and monalumazine are separated using a chiral flavoprotein column. This column also separates the enantiomeric pterins of the threo form: monapterin and dictyopterin. However, the column does not separate the enantiomeric pterins of the erythro form: neopterin and biopterin. By coupling a reverse‐phase column to the flavoprotein column, the separation of pterins and lumazines in function of their hydrophobicity, as well as the separation of the diastereomers, is achieved. This coupled achiral/chiral high‐performance liquid chromatography method enables determination of the stereoconfiguration of natural lumazines by comparison with optically pure compounds. A lumazine derivative, present in the extracellular medium of Dictyostelium discoideum, is identified as D‐dictyolumazine, i.e., 6‐(D‐threo‐1,2‐dihydroxypropyl)‐lumazine. © 1994 Wiley‐Liss, Inc.
Marked enantioselective protein binding in humans of ketorolac in vitro: Elucidation of enantiomer unbound fractions following facile synthesis and direct chiral hplc resolution of tritium‐labelled ketorolac
Authors: Hayball Peter J. , Holman Jeffrey W. , Nation Roger L. , Massy‐Westropp Ralph A. , Hamon David P.G. 
Published: January 2005

AbstractThe protein binding of the enantiomers of the nonopiate analgesic, ketorolac, was investigated in vitro using human plasma and solutions of human serum albumin (HSA) at physiological pH and temperature. In order to detect the very low levels of unbound enantiomers in protein solutions, tritium‐labelled rac‐ketorolac was synthesised by regiospecific isotopic exchange of the parent drug with tritiated water as the isotope donor. Radio‐chemical purification of this compound by reversed‐phase HPLC followed by direct resolution using a chiral α1‐acid glycoprotein (Chiral‐AGP) HPLC column afforded labelled enantiomers of high specific activity. The in vitro use of (R)‐ and (S)‐[3H4]ketorolac enabled reproducible radiometric detection of enantiomers in protein solution ultrafiltrate. The unbound fractions of (R)‐ and (S)‐ketorolac [fu(R) and fu(S), respectively] were determined when drug was added to various plasma or albumin solutions as either the separate enantiomers or as the racemate. Over an enantiomeric plasma concentration range of 2.0—15.0 μg/ml, fu(S) (mean range: 1.572—1.795%) was more than 2‐fold greater (P < 0.001) than fu(R) (mean range: 0.565—0.674%). Both fu(R) and fu(S) were constant over this concentration range, and each was unaffected by the presence of the corresponding antipode (P > 0.05). At a concentration of 2.0 μg/ml in 40.0 g/liter fatty acid‐free HSA, fu(R) and fu(S) were approximately 0.5 and 1.1%, respectively, and both values declined with increasing concentrations of the long chain fatty acid, oleic acid. We have previously shown that the pharmacokinetics of ketorolac in humans are markedly enantioselective and suggest in this report that these differences are largely the result of substantial differences in the protein binding of ketorolac enantiomers. These findings stress the importance of monitoring the unbound concentrations of the enantiomers of chiral drugs if correct interpretations are to be made of enantioselective pharmacokinetic data. © 1994 Wiley‐Liss, Inc.
Enantioselectivity suggests a cytosolic origin for a commercial pig liver esterase preparation
Authors: Yang Shen K. , Chen Shu‐ju , Huang Jin‐ding 
Published: January 2005

AbstractA widely utilized pig liver esterase preparation has been found to be derived essentially exclusively from the cytosolic fraction of pig livers. Esterases in cytosol and microsomes prepared from a fresh pig liver hydrolyzed the S‐ and R‐enantiomers of racemic oxazepam 3‐acetate (rac‐OXA) with specific activity ratios of approximately 2.3:1 and 1:62, respectively. Product formations were analyzed by chiral stationary phase high‐performance liquid chromatography. The commercial pig liver esterase preparation showed greater activity toward S‐OXA than did the esterases in the cytosolic fraction prepared from fresh pig liver. The results established that (i) esterases contained in microsomes and cytosol of pig liver have opposite enantioselectivity in the hydrolysis of rac‐OXA and (ii) the commercial pig liver esterase preparation has a cytosolic origin. © 1995 Wiley‐Liss, Inc.
Stereoselective binding of benzodiazepines and related compounds on calmodulin‐sepharose
Authors: Fitos Ilona , Visy Jüalia , Kardos Julianna , Simonyi Miklóas 
Published: January 2005

AbstractA method has been presented to evaluate the Ca2+‐dependent binding affinity of ligands to calmodulin (CaM) from their chromatographic retentions obtained on a CaM‐Sepharose column. Enantiomers of benzodiazepines and related compounds could be separated. Among chiral calcium antagonists, verapamil showed stereoselectivity of binding. © 1995 Wiley‐Liss, Inc.
Chiral enamines derived from 2‐(2′‐pyrido)acetophenone and 2‐(2′‐quinolino)acetophenone as ligands in copper(I) catalyzed enantioselective cyclopropanations
Authors: Kirin srećko I. , Vinković Vladimir , Šunjić Vitomir 
Published: January 2005

AbstractOptically active enamines of 2‐(2′‐pyrido)acetophenone or 2‐(2′‐quinolino)acetophenone with (R)‐1‐phenylethylamine, (R)‐1‐(1‐naphthyl)ethylamine, (R)‐cyclohexylethylamine, and (R)‐phenylglycinol were prepared and their copper(I) complexes used in the enantioselective cyclopropanation of styrene with ethyl‐ and menthyldiazoacetate. Enantioselectivities of up to 42% enantiomeric excess were obtained for cis/trans 2‐phenylcyclopropan‐1‐carboxylic acid ethyl esters, as determined by gas‐liquid chromatography (GLC) on chiral chromatographic columns. © 1995 Wiley‐Liss, Inc.
Asymmetric hydroformylation of mono‐ and sesquiterpenes
Authors: Kollár László , Bóadi Gábor 
Published: January 2005

AbstractThe hydroformylation of (+)‐(R)‐limonene (1), (+)‐(1R)‐isolimonene (2), camphene (3), and (+)‐β‐cedrene (4) resulted in the regiospecific formation of the corresponding linear aldehyde in the presence of homogeneous platinum and, in some cases, rhodium catalysts. The epimeric composition could be influenced slightly by optically active catalysts formed with chiral bidentate phosphines. The relative configurations of newly formed stereogenic centers were analyzed by1H and13C NMR. The primarily formed aldehydes of (+)‐8(15)‐cedren‐9‐ol (5) and γ‐gurjunene (6) underwent cyclization, giving a mixture of epimers of tetracyclic terpenes. Despite the moderate diastereoselection, the products are of practical importance due to their highly regioselective formation. © 1995 Wiley‐Liss, Inc.
Direct separation of albuterol enantiomers in biological fluids and pharmaceutical formulations using α1‐acid glycoprotein and pirkle urea type columns
Authors: Aboul‐enein Hassan Y. , Serignese Vince 
Published: January 2005

AbstractA direct, isocratic, and simple chromatographic method is described for the resolution of racemic albuterol using the α1‐acid glycoprotein chiral stationary phase (AGP‐CSP) under reverse phase conditions. The effect of various organic modifiers, temperature, and phosphate buffer ionic strength on the separation factor (α) and stereochemical resolution factor (Rs) has been studied. The enantiomeric separation of albuterol was also achieved using a urea‐type CSP of (S)‐indoline‐2‐carboxylic acid and (R)‐1‐(α‐naphthyl)ethylamine, known as Chirex 3022, running in the normal phase mode. The effect of different organic acids added to the mobile phase was examined and the chiral recognition mechanism(s) is discussed. Solid phase extraction with C18 Sep‐Pak cartridges was applied as a clean‐up step to determine the enantiomeric ratio between (−)‐R and (+)‐S‐albuterol in pharmaceutical formulations and in human plasma. © 1995 Wiley‐Liss, Inc.
Aspects of chirality in overcrowded bistricyclic enes
Authors: Biedermann P. Ulrich , Levy Amalia , Stezowski John J. , Agranat Israel 
Published: January 2005

AbstractIntramolecular overcrowding in bistricyclic enes (1) requires out‐of‐plane deformations in order to accommodate the sterically demanding tricyclic moieties without prohibitively close contacts of nonbonded atoms. The nonplanarity of 1 introduces the notion of chirality to the arena of overcrowded aromatic enes. Deviation from coplanarity occurs by twisting around the double bond and out‐of‐plane bending (hence pyramidalization). The bending is realized by folding of the tricyclic moieties. The conformations of homomerous (1, × = Y) and heteromerous (1, × ≠ Y) bistricyclic enes and their mono‐ and disubstituted derivatives are analyzed along with their point group symmetries and chirality. The implications are illustrated using the structures of characteristic examples calculated with the semiempirical method PM3. © 1995 Wiley‐Liss, Inc.
Synthesis of (+)‐(S)‐ibuproxam and preparation of some new complexes of racemic and (+)‐(S)‐ibuproxam with β‐cyclodextrin and its derivatives
Authors: Žmitek Janko , Verhnjak Katarina , Urleb Uroš , Kotnik Sonja 
Published: January 2005

Abstract(+)‐(S)‐Ibuproxam, a prodrug of (+)‐(S)‐ibuprofen, the pharmacologically active component of ibuprofen, was synthesized in order to minimize side effects (especially gastric irritation) and reduce effective dose. The low water solubility of (+)‐(S)‐ibuproxam, which prevents rapid dissolution and absorption from the gastrointestinal tract, was overcome by complexation with β‐cyclodextrin and its derivatives. The inclusion complex formation was confirmed by differential scanning calorimetry (DSC), by 1H‐NMR spectroscopy, and X‐ray powder diffractometry. The physicochemical characteristics of ibuproxam were significantly improved by the complexation. © 1995 Wiley‐Liss, Inc.
Diastereoselective hydrogenations of unsymmetrically substituted aromatics
Authors: Exl Christina , Ferstl Eva , Hönig Helmut , Rogi‐Kohlenprath Renate 
Published: January 2005

AbstractAttempts to induce enantioselectivity in the catalytic hydrogenation of unsymmetrically substituted aromatics using covalently bound, well known chiral auxiliaries are described. Marked differences in stereoselectivity and rate of hydrogenolysis are noted as a function of the auxiliary used. Enantioselectivities obtained in the resulting cyclohexyl derivatives are rather poor. © 1995 Wiley‐Liss, Inc.
Evaluation of the use of cyclodextrins in chiral separation of basic drug substances by capillary electrophoresis
Authors: Bjørnsdottir Inga , Hansen Steen Honoré 
Published: January 2005

AbstractThe influence of the choice of type and/or concentration of cyclodextrin, other additives, the temperature surrounding the capillary, and buffer pH on the separation of some chiral basic drug substances in capillary zone electrophoresis has been evaluated. It was found that pH of the buffer and type and concentration of cyclodextrin had a major influence on the separation. © 1995 Wiley‐Liss, Inc.
Central composite design for the rapid optimisation of ruggedness and chiral separation of amlodipine in capillary electrophoresis
Authors: Small Tracy S. , Fell Anthony F. , Coleman Michael W. , Berridge John C. 
Published: January 2005

AbstractSystematic optimisation with central composite design offers an efficient route for rapid optimisation of resolution with multiple interacting parameters in chiral CE. This is illustrated by separations of amlodipine with α‐CD as chiral selector in the running buffer, for which the predicted performance of central composite design is assessed. The utility of response surface methodology for locating optimum ruggedness in CE is also described. © 1995 Wiley‐Liss, Inc.
Chiral derivatization for separation of racemic amino and thiol drugs by liquid chromatography and capillary electrophoresis
Authors: Leroy Pierre , Bellucci Luc , Nicolas Alain 
Published: January 2005

AbstractSeparation of racemic amino drugs (α‐methylbenzeneethanamine, 6‐amino‐2‐methyl‐2‐heptanol and 1‐aminoethyl‐benzenemethanol) and thiol drugs [N‐(2‐mercapto‐1‐oxopropyl) glycine, 2‐mercaptopropanoic acid, and N‐acetyl‐3‐mercaptovaline] has been evaluated after derivatization. ortho‐Phthalaldehyde (OPA) and naphthalene‐2,3‐dicarboxaldehyde (NDA) were used with either homochiral thiols (N‐acetyl‐L‐cysteine and N‐acetyl‐D‐penicillamine) or amines [(‐)‐(1R,2S)‐norephedrine, L‐phenylalanine, L‐tyrosine, and 3‐hydroxy‐L‐tyrosine] as chiral selectors according to the analyte reactive group. The resulting 36 diastereoisomeric derivatives were studied using reversed‐phase high‐performance liquid chromatography (RP‐HPLC) and capillary electrophoresis (CE). Of the CE modes, micellar electrokinetic chromatography (MEKC) using sodium dodecyl sulfate (SDS) as surfactant, β‐cyclodextrin (β‐CD)‐modified capillary zone electrophoresis (β‐CD‐CZE), and β‐CD‐MEKC were applied. Results highlight respective performance of the reagents and separative techniques. All OPA derivatives of racemic amino drugs were resolved either by MEKC or β‐CD‐MEKC. In the case of racemic thiol drugs, 10 of the 12 OPA derivatives were resolved in β‐CD‐CZE. © 1995 Wiley‐Liss, Inc.
Enantioselective assay of β‐receptor antagonists present in microdialysis and plasma samples of rats
Authors: Johansson Monika , Sjöberg Per , Hesselgren Ann‐Mari , Salmonson Thomas 
Published: January 2005

AbstractThe enantiomers of alprenolol, metoprolol, and propranolol have been separated on an enantioselective cellulase column and analysed using a fully automated HPLC system involving coupled column chromatography and fluorescence detection. The assays had sufficient selectivity and sensitivity to investigate the disposition of these β2‐receptor antagonists in blood and brain extracellular fluid of rats. A cellulase column was used as the first column to separate the enantiomers giving separation factors between 2.9 and 4.3. After the separation, the enantiomers were trapped on two small precolumns by the use of a switching valve and were then introduced on an achiral C18 analytical column by eluting the small columns backward. The enantiomers in blood and brain tissue dialysates were analysed by direct injection of 8 μl samples. The limit of quantitation was 0.025–0.4 μg/ml of the different enantiomers. Plasma samples were analysed after a simple extraction procedure. The intraassay precision of the lowest quality control plasma samples (0.2–0.8 μg rac drug/ml) was 4–8% for the different enantiomers. © 1995 Wiley‐Liss, Inc.
Stereoselective hydrolysis of xenobiotic esters by different cell lines from rat liver and hepatoma and its application to chiral prodrugs for designated growth suppression of cancer cells
Authors: Kageyama Yu‐Ichi , Yamazaki Yoshimitsu , Afify Adel S. , Ogawa Yoshikatsu , Okada Tomoko , Okuno Hiroaki 
Published: January 2005

AbstractStereoselectivity in the hydrolysis of racemic ethyl 2‐phenylacetate derivatives by cultured cells of noncancerous cell lines from rat liver (BRL, BRL 3A, Clone 9, and ARLJ301–3), spontaneously or oncogene transformed rat liver cell lines (ARLJ301–3TR1, Anr4, Anr9–1, and Anr13–1), and cancer cell lines from rat hepatoma (H4‐II‐E, McA‐RH7777, and MH1C1) and sarcoma (XC) was studied. A strong (R)‐enantiomer preference was found in the hydrolysis of ethyl 2‐hydroxy‐ (2c) and 2‐methoxy‐2‐phenylacetate (3c) by the noncancerous and oncogene‐transformed cells and an (S)‐enantiomer preference for ethyl N‐acylphenylalaninates with all the present cell lines. These inclinations were, however, not recognized with ethyl 2‐methoxy‐2‐phenylpropanoate and ethyl N‐difluoroacetyl‐or N‐trifluoroacetylphenylalaninate. Moreover, the R preference for 3c was reversed in the reaction by hepatoma cells. Thus, the stereoselectivity is influenced by both structure of acyl group and species of cell lines. The hepatoma cells were considerably different from the noncancerous or oncogene‐transformed cells in stereoselectivity. This fact was consistent with the order of colony formation in soft agar cultures (index of malignancy) and the resemblance in actively stained esterase patterns in gel electrophoresis. The stereoselective hydrolysis leads to cell‐specific activation of anticancer prodrugs. This has been confirmed for the first time by the stereoselectivity of Anr4 and H4‐II‐E cells in the hydrolysis of a chiral mustard ester, bis(2‐chloroethyl)aminophenyl 2‐methoxy‐2‐phenylacetate (14) and by the difference of IC50 values of (R)‐ and (S)‐14 against the two cell lines. © 1995 Wiley‐Liss, Inc.
A serious problem with computer processing of stereochemistry in chemical structure files: The need for standardisation
Authors: Blessington Bernard 
Published: January 2005

AbstractMany computer programmes exist for drawing and modelling small and large molecules. Small molecules related to the antitubercular drug ethambutol are discussed. Some specific software problems, with stereochemical representations, are illustrated. Incompatibility of molecular structure files produced by different programmes and different hardware are shown. The need for a standardised file format is stressed. © 1995 Wiley‐Liss, Inc.
Chiral separation based on immobilized intact and fragmented cellobiohydrolase II (CBH II): A comparison with cellobiohydrolase I (CBH I)
Authors: Henriksson Hongbin , Jönsson Stefan , Isaksson Roland , Pettersson Göran 
Published: January 2005

AbstractIntact and fragmented cellobiohydrolase II (CBH II) were immobilized to silica and used as chiral stationary phases (CSPs) for liquid chromatographic separations of enantiomers. Both acidic and basic chiral compounds could be resolved into their enantiomers on these phases. The enantioselectivities obtained on intact CBH II and its core were almost equivalent. Comparisons were also made with CBH I silica. It was found that the new materials show quite different chiral and chromatographic properties. The enzymatic activity of the CBH II in free solution was influenced by alprenolol and mexiletine, both separated on the corresponding CSP. It indicates that the sites for catalysis and for chiral recognition overlap. © 1995 Wiley‐Liss, Inc.
Chiral discrimination promoted by (1S,2S)‐1‐phenyl‐2‐amino‐1,3‐propanediol derivatives in the asymmetric Reformatsky reaction
Authors: Mastantuono Alberto , Pini Dario , Rolfini Chiara , Salvadori Piero 
Published: January 2005

AbstractSome 3‐t‐butyldimethylsilyloxy derivatives, synthesized from the cheap commercially available (1S,2S)‐2‐amino‐1‐phenyl‐1,3‐propanediol [(1S,2S)‐1], have been successfully employed as new chiral ligands in the asymmetric Reformatsky reaction on aldehydic substrates. The influence both of the substrate and of the ligand on the stereochemical pathway has been investigated by varying the structure of the carbonyl substrate and of the optically active aminodiols. © 1995 Wiley‐Liss, Inc.
Absolute configurations and conformations of the opioid agonist and antagonist enantiomers of picenadol
Authors: Froimowitz Mark , Cody Vivian 
Published: January 2005

AbstractThe absolute configurations of the enantiomers of the opiod picenadol [cis‐1,3‐dimethyl‐4‐propyl‐4‐propyl‐4‐(3‐hydroxyphenyl)piperidine; cis‐3‐methyl, 4‐propyl] have been determined by an X‐ray crystallographic study of the chloride salt of the (+)‐enantiomer. The agonist (+)‐enantiomer and the antagonist (−)‐enantiomer were found to have the 3R, 4R and 3S, 4S absolute configurations, respectively. The conformational properties of the enantiomers were also examined with MM2–87 calculations. There was good agreement between the computed global minimum and the crystallographic structure with the phenyl ring approximately bisecting the piperidine ring by both methods. This orientation of the phenyl ring differs from that of related opioids such as the phenylmorphans, prodines, meperidine, and ketobemidone in which the phenyl ring tends to eclipse one edge of the piperidine ring. Because the phenyl ring bisects the piperidine ring in picenadol, there is little difference in the three‐dimensional orientations of the phenyl rings of the two enantiomers when one superimposes the piperidine rings. The agonist (+)‐enantiomer is ambiguous with respect to an opioid ligand model, which suggests that agonist activity requires a specific range of dihedral angles for the phenyl ring. While the global minimum of the agonist is not consistent with the model, a second conformer that is only 1.2 kcal/mol above the global minimum is consistent. An alternative explanation is that agonist or antagonist activity is solely due to the presence of the 3‐methyl group on the different edges of the piperidine ring. MM2–87 calculations were also performed on the opioid agonist des‐3‐methyl analog of picenadol and the closely related trans‐1,3,4‐trimethyl‐4‐(3‐hydroxyphenyl)piperidines (trans‐3‐methyl, 4‐methyl) in which both enantiomers are opioid antagonists. The conformational properties of these compounds are consistent with the ligand model. © 1995 Wiley‐Liss, Inc.
High‐Performance liquid chromatographic separation and molecular modelling of diastereomeric isoindole derivatives of amino compounds
Authors: Duchateau A. L. L. , Boesten J. M. M. , Coussens B. B. 
Published: January 2005

AbstractA high‐performance liquid chromatography and molecular modelling study is presented for the diastereomeric adducts of a series of chiral thiol compounds and chiral amine compounds after reaction with o‐phthalaldehyde (OPA). It is shown that the possibility of hydrogen bonds forming between the thiol and amino residues in the diastereomeric adducts is an important factor for obtaining good selectivity. The experimental elution orders were explained on the basis of the strength of the interaction between the polar groups of the thiol and amine constituents; it was found that the diastereomeric form having the largest distance between these groups always eluted first. Moreover, within a series of OPA derivatives, the differences between the Boltzmann weighted averages of the distances between the polar groups of the two diastereomers show a good correlation with the experimental selectivities. © 1995 Wiley‐Liss, Inc.