bluuebunny/crossref_metadata_2025 huggingface dataset:
Stereospecific HPLC method for the quantitation of the enantiomers of MK‐0571, a potent leukotriene D4 receptor antagonist, in biological specimens
Authors: Lee Ling L. , Zacchei Anthony G.
Published: January 2005

A stereospecific HPLC bioanalytical method was developed for quantitation of the enantiomers of MK‐0571, a leukotriene D4 receptor antagonist. The procedure involves the addition of an internal standard analog to the biological matrix followed by extraction of the free acids into ethyl acetate. The acids are subsequently reacted with the homochiral reagent, (+)‐(R)‐α‐(1‐naphthyl)ethylamine (NEA) to form diastereomers. Following removal of excess reagent and side products by a dilute acid wash, the NEA‐MK‐0571 diastereomers are separated on a phenyl urea chiral column using a mobile phase containing hexane, isopropanol, and acetonitrile and are detected with a fluorescence detector. The sensitivity of the method is such that 50 ng of each enantiomer can be quantitated. In the 0.05 to 10 μg range the recoveries of the enantiomers of MK‐0571 from plasma were 100.4 ± 7.9% and 100.0 ± 7.2%. NMR and mass spectral data confirmed the structure of the derivative. The method has been utilized in drug safety evaluation studies to demonstrate enantioselectivity in disposition of the enantiomers of MK‐0571 in rats and monkeys but not in mice.
Pharmacokinetics of ibuprofen enantiomers in dogs
Authors: Beck Winfried S. , Geisslinger Gerd , Engler Heidrun , Brune Kay
Published: January 2005

Inversion of inactive (R)‐ibuprofen to active (S)‐ibuprofen has been suggested to occur presystemically only. In order to investigate the site of inversion in dogs we administered both enantiomers either intravenously or intraduodenally (10 mg/kg) to adult, male beagle dogs (n = 3) in a crossover design. Plasma, urine, and bile were collected for up to 6 h and analyzed stereospecifically by HPLC, according to a previously published method. Pharmacokinetic parameters were calculated using a linear computer program. Absorption after intraduodenal administration occurred rapidly, resulting in maximum plasma concentrations 0.2 h after giving the enantiomer. Approximately 70% of the (R)‐enantiomer (according to AUC) was inverted to the S‐enantiomer independent of route of administration. No R‐ibuprofen could be detected in plasma after (S)‐ibuprofen administration. Mean residence time was found to be 2 to 3 times longer for (S)‐than for (R)‐ibuprofen. Total systemic clearance from plasma was twice as high for (R)‐ than for (S)‐ibuprofen. There were no differences between plasma clearances after intravenous and intraduodenal administration. Between 8 and 17% of dose was recovered in bile [especially as free and conjugated (S)‐ibuprofen] and 3–12% in urine [as (S)‐ibuprofen, hydroxy‐ and carboxyibuprofen, free and conjugated forms]. Small amounts of (R)‐ibuprofen were detected in bile after intraduodenal administration of (R)‐ibuprofen only (1.8% of dose). In short, the unidirectional inversion of R‐ibuprofen appears to occur systemically rather than presystemically in dogs.
Evaluation of chiroptical properties of molecules by asymmetric photochemistry
Authors: Cavazza Marino , Festa Crescenzo , Veracini Carlo Alberto , Zandomeneghi Maurizio
Published: January 2005

The physics involved in photochemistry with circularly polarized light, the warnings on its inherent limitations, as well as some examples of application on organic molecules are briefly reviewed.
Absolute configuration of feroxidin: An experimental support to snatzke's helicity rules for tetralins
Authors: Speranza Giovanna , Manitto Paolo , Pezzuto Donata , Monti Diego
Published: January 2005

The configuration of carbon‐8 in feroxidin (1) was proven to be (S) by chemical correlation with (S)‐methylsuccinic acid. Previous demonstration that 6‐hydroxy and 8‐methyl groups are equatorial and pseudoaxial, respectively, in a half‐chair conformation of the cyclohexene ring (relative configuration) allowed the absolute stereochemistry of the whole molecule to be established (Fig. 3). The CD spectrum of feroxidin represents the first experimental test confirming the applicability of Snatzke's helicity rules to tetralins m‐disubstituted on the aromatic ring.
Absolute configuration for peptidomimetic residues in bioactive peptides
Authors: Yamazaki Toshimasa , Goodman Murray
Published: January 2005

A modern method is reported for the assignment of absolute configuration for peptidomimetics in bioactive peptides by use of 1H‐NMR parameters in solution. Four peptide systems incorporating either retro‐inverso modifications or 2‐aminocyclopentanecarboxylic acid (2‐Ac5c) as a peptidomimetic for proline are discussed. (1) Two 14‐membered cyclic dermorphin analogs Tyr‐c[D‐A2bu‐Phe‐gPhe‐(S and R)‐mLeu] with a reverse amide bond between gPhe and mLeu residues where gPhe denotes a gem‐diamino analog of Phe and mLeu refers to a malonyl analog of Leu. (2) Two cyclic hexapeptides related to somatostatin, c[gSar6‐(S and R)‐mPhe7‐D‐Trp8‐Lys9‐Thr10‐Phe11], with a reverse amide bond between the gSar and mPhe residues where the gSar and mPhe denote the gem‐diamino and malonyl analogs of the Sar and Phe residues, respectively. The superscript numbers refer to positions in native somatostatin. (3) Cyclic hexapeptide somatostatin analogs containing 2‐Ac5c [trans‐(1S,2S)‐2‐Ac5c, trans‐(1R,2R)‐2‐Ac5c, cis‐(1R,2S)‐2‐Ac5c, and cis‐(1S,2R)‐2‐Ac5c] in place of proline c[(2‐Ac5c)6‐Phe7‐D‐Trp8‐Lys9‐Thr10‐Phe11]. (4) Morphiceptin related analogs incorporating a cis‐2‐Ac5c residue as shown in Tyr‐cis‐2‐Ac5c‐Phe‐Val‐NH2. The methodology described in this investigation could be applied to a wide variety of peptide systems.
Chiroptical and photochromic properties of stereoregular copolymers of 4‐methacryloxyethylenoxyazobenzene with (−)‐menthyl methacrylate
Authors: Altomare A. , Ciardelli F. , Lima R. , Solaro R.
Published: January 2005

Copolymers of the photochromic monomer 4‐methacryloxyethylenoxyazobenzene with the optically active comonomer (‐)‐menthyl methacrylate, having different stereoregularity, were investigated in order to obtain a better understanding of the relationship between microstructure and photochromism in synthetic macromolecules. No appreciable effect was observed by copolymer composition, sequence distribution, and microtacticity on the photoinduced trans → cis isomerization of the azobenzene side chains. This last, however, is reflected in changes of the chiroptical properties, type and entity of the photoinduced variation being dependent on chain structure. The long spacer separating the azo chromophore from the main chain limits the extent of chiroptical properties dependence on irradiation.
Chiral liquid‐crystalline side chain polymers by enantioselective modification of prochiral parent polymers
Authors: Angeloni A. S. , Laus M. , Caretti D. , Chiellini E. , Galli G.
Published: January 2005

The preparation is reported of two side chain polyacrylate samples 1a,b containing a sulfide group linked to the mesogenic core. By oxidation with a preferentially chiral oxaziridine, samples 1a,b were chemoselectively and enantioselectively converted to the corresponding sulfoxide containing polymers 2a,b with an estimated 20% asymmetric induction. The mesophasic behaviour of the parent and oxidized polymer samples is analyzed by thermal and optical techniques. The modification of the prochiral sulfide groups into chiral sulfoxide groups slightly depresses the propensity of the resulting polymers to give stable and persistent mesophases.
An alternative to Urry's model for the gramicidin transmembrane channels
Authors: Lorenzi Gian Paolo
Published: January 2005

It is suggested that the conducting transmembrane channels formed by the linear gramicidins A, B and C may be head‐to‐head (formyl end‐to‐formyl end) dimers of double‐stranded parallel β‐helices. This possibility is not in conflict with any of the various experimental findings bearing on the molecular organization of the channels and represents a plausible alternative to Urry's model of a head‐to‐head dimer of single‐stranded β6.3‐helices.
Polypeptide models of elastin: CD and NMR studies on synthetic poly(X‐Gly‐Gly)
Authors: Tamburro A. M. , Guantieri V. , Scopa A. , Drabble J. M.
Published: January 2005

Poly(X‐Gly‐Gly), simple structural models for the hydrophobic, proline‐devoid, regions of elastin, have been synthesized and studied by circular dichroism and NMR spectroscopies. The results gave evidence of type II β‐turns as the only ordered structure present in the polymers. The stability of the turns has been shown to decrease on hydration and to increase in the series Leu < Ala < Val < Ile.
In vitro assessment of stereoselective hepatic metabolism of disopyramide in humans: Comparison with in vivo data
Authors: Le Corre Pascal , Ratanasavanh Damrong , Chevanne François , Gibassier Denis , Sado Pierre , Le Verge Roger , Guillouzo André
Published: January 2005

Metabolism of disopyramide (DP) enantiomers has been investigated in primary cultures of adult human hepatocytes. Results were compared with in vivo data obtained from a previous pharmacokinetic study (Le Corre et al. Drug Metab. Dispos. 16:858–864 1988). Metabolism of DP enantiomers as a function of incubation time showed constant velocity over time. The intracellular/extracellular distribution of both DP and mono‐N‐desisopropyldisopyramide did not appear to be stereoselective. Metabolism of DP enantiomers as a function of substrate concentration followed a first order kinetics. The average fractions of (‐)‐(R)‐DP and (+)‐(S)‐DP metabolized in vitro (4.7 ± 2.7 and 7.1 ± 4.2%, respectively, n = 4) were about 5‐fold lower than the fractions metabolized in vivo (26.0 ± 6.0 and 40.2 ± 8.8%, respectively, n = 6). The stereoselective index [(+)‐(S)/(‐)‐(R)] of the N‐dealkylation pathway obtained in vitro (1.51 ± 0.11, n = 4) was very close to the one obtained in vivo (1.55 ± 0.10, n = 6). These results highlight the interest of hepatocyte cultures in the evaluation of drug metabolism and especially in the assessment of stereoselectivity.
An evaluation of ibuprofen bioinversion by simulation
Authors: Romero Alain J. , Rackley Russell J. , Rhodes C. T.
Published: January 2005

Using a pharmacokinetic model recently proposed to explain ibuprofen disposition in man,1 plasma concentrations of pure ibuprofen enantiomers were simulated following oral administration of (‐)‐(R)‐ibuprofen, (+)‐(S)‐ibuprofen, or rac‐ibuprofen. Simulated and literature values for AUC's were used to compare S/R ratios for different cases of the model and for different methods of calculating the fraction of R bioinverted to S. Numerical simulation using STELLA confirmed previous results for different cases of bioinversion. Simulated S/R AUC ratios, for administration of the racemate, ranged from 4.0 (presystemic bioinversion) to 1.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 1.53±0.2 for administration of the racemate; therefore, systemic bioinversion was concluded to be representative of ibuprofen disposition. Additional simulations of S/R AUC ratios, for administration of (‐)‐(R)‐ibuprofen only, ranged from 1.5 (presystemic bioinversion) to 0.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 0.50±0.9 for administration of (‐)‐(R)‐ibuprofen only, which again supported conclusions of systemic bioinversion. Using different equations for estimation of fraction of R inverted to S (FR→S), results based on simulated data were identical; however, FR→S values based on literature data were different. Therefore, assumptions made for different FR→S equations do not appear to be rigorous. Calculations of FR→S, based on literature data, averaged 0.52 overall, indicating bioavailability of (+)‐(S)‐ibuprofen may be similar for a 150 mg dose of (+)‐(S)‐ibuprofen compared to a 200 mg dose of racemate.
Plasma protein binding of ketoprofen enantiomers in man: Method development and its application
Authors: Hayball P. J. , Nation R. L. , Bochner F. , Newton J. L. , Massy‐Westropp R. A. , Hamon D. P. G.
Published: January 2005

The protein binding of ketoprofen enantiomers was investigated in human plasma at physiological pH and temperature by ultrafiltration. 14C‐labelled (RS)‐ketoprofen was synthesized and purified by high‐performance liquid chromatography and utilized as a means of quantifying the unbound species. In vitro studies were conducted with plasma obtained from six healthy volunteers. The plasma was spiked with (R)‐ketoprofen alone, (S)‐ketoprofen alone, and (RS)‐ketoprofen in the enantiomeric concentration range of 1.0 to 19.0 μg/ml. The plasma protein binding of ketoprofen was nonenantioselective. At a racemic drug concentration of 2.0 μg/ml the mean (± SD) percentage unbound of (R)‐ketoprofen was 0.80 (± 0.15)%. The corresponding value for (S)‐ketoprofen, 0.78 (± 0.18)%, was not statistically different (P > 0.05). At this racemic drug concentration (2.0 μg/ml) the percentage unbound of each enantiomer was unaffected (P > 0.05) by the presence of the glucuronoconjugates of ketoprofen (10 μg/ml) in plasma. At clinically relevant concentrations, the plasma binding of ketoprofen did not exhibit enantioselectivity or concentration dependence nor was the binding of either enantiomer influenced by its optical antipode (P > 0.05).
Enantiomeric separation of 2‐(phenoxy)propionate derivatives by chiral high‐performance liquid chromatography
Authors: Lin Shu‐Ling , Chiou Aih‐Jing , Wu Shih‐Hsiung , Wang Kung‐Tsung
Published: January 2005

2‐(Phenoxy)propionate derivatives were separated on three chiral columns, OD, OK, and chiral‐2 columns. The chlorine substitution in the phenyl ring and the alcohol moiety of the ester groups of the derivatives had great influence for separation on the OD and OK columns, but little effect on the chiral‐2 column.
Stereoselective effect of phenprocoumon enantiomers on the binding of benzodiazepines to human serum albumin
Authors: Fitos Ilona , Simonyi Miklós
Published: January 2005

The effect of phenprocoumon enantiomers on the stereoselective binding of 3‐substituted 1,4‐benzodiazepines to human serum albumin (HSA) was studied by chromatography on HSA‐Sepharose column. (S)‐Phenprocoumon exerts stereoselective allosteric interaction on the binding of benzodiazepines. The structural requirements of enhanced stereoselectivities are similar to those found previously with (S)‐warfarin.
Chirality evaluation in flavour and essential oil analysis
Authors: Mosandl Armin , Askari Christiane , Hener Uwe , Juchelka Dieter , Lehmann Detmar , Kreis Peter , Motz Christine , Palm Ursula , Schmarr Hans‐Georg
Published: January 2005

The simultaneous stereodifferentiation of all aromarelevant 4(5) alkylsubstituted γ(δ)‐lactones is described, using enantioselective multidimensional gas chromatography (MDG), and the column combination OV 1701/octakis(3‐O‐butyryl‐2,6‐di‐O‐pentyl)‐γ‐cyclodextrin. The method is applicated to the lactone flavour compounds of fruits, indicating the advance to the analytical differentiation between “natural” and “nature‐identical” aromas. Modified cyclodextrins are also proved to be powerful tools in the chirospecific CGC analysis of monoterpenoid constituents of essential oils. Optical purity control is discussed as an indicator for their natural origin.
Determination of the enantiomeric purity of (−−) 2‐(N‐propyl‐n‐2‐thienylethylamino)‐5‐hydroxytetralin (n‐0923) by chiral stationary phase HPLC
Authors: Witte Dirk T. , Franke Jan‐Piet , Swart Pieter J. , De Zeeuw Rokus A.
Published: January 2005

The determination of the enantiomeric impurity, i.e., the percentage of (+) N−0437 (= N−0924) in several batches of (−−) N‐0437 (= N‐0923) by chiral HPLC is described. Enantiomeric impurities were calculated based on the peak areas of the two baseline separated enantiomers in the chromatogram. The enantiomeric impurities found in different batches ranged from 0.02% to 0.11%. Calibration curves of the two isomers of N‐0437 (Fig. 1,) were made twice to study the reproducibility and linearity of the method. The absorbance ratio, N‐0923/N‐0924, was found to be 1.02 with a relative standard deviation (RSD) of 9% over the whole concentration range used for the calibration curves.
Stereoselective biliary elimination of disopyramide and mono‐N‐desisopropyldisopyramide in humans
Authors: Corre Pascal Le , Malledant Yannick , Chevanne Francois , Sado Pierre , Verge Roger Le
Published: January 2005

The results of a previous pharmacokinetic study of disopyramide (DP) enantiomers in humans suggested that DP and/or mono‐N‐desisopropyldisopyramide (MND) may show stereoselective extrarenal elimination. Thus, the present study investigates the biliary elimination of DP and MND enantiomers in three patients who had undergone cholecystectomy for cholelithiasis. DP and MND enantiomers displayed biliary elimination. In both subjects, this elimination pathway showed the same characteristics: (1) biliary elimination of DP and MND was stereoselective, (2) the stereoselectivity was opposite to that observed for the metabolic and renal elimination pathways, i.e., the elimination of the (−)‐(R)‐enantiomer was higher than that of the (+)‐(S)‐enantiomer, and (3) biliary elimination of MND was higher than that of DP, for both enantiomers. Estimates of the relative contribution of the biliary clearance in the total clearance of DP and MND indicated that this elimination pathway was secondary, especially for DP. The biliary clearance (expressed as % of total clearance) was 1.9 to 4.0% for (−)‐(R)‐DP, 1.2 to 1.7% for (+)‐(S)‐DP, 7.8 to 22.9% for (−)‐(R)‐MND, and 5.2 to 10.5% for (+)‐(S)‐MND.
Optically‐Active compounds via biocatalytic methods
Authors: Sih Charles J. , Gu Qu‐ming , Holdgrün Xenia , Harris Keith
Published: January 2005

Different approaches to improve the enantioselectivity of biocatalytic systems are presented. These methodologies have been successfully applied to the preparation of optically active dihydropyridine, calcium antagonists, and cis‐3‐hydroxy‐6‐acetoxy‐cyclohex‐1‐ene, a valuable chiral building block for natural products synthesis. The phenomenon of enantioselective inhibition is described and several new heterocyclic amines have been shown to be effective enantioselective inhibitors in the Candida lipase system.
Enzymatic resolutions of α‐ and β‐hydroxypropionic acid esters
Authors: Gruber‐Khadjawi M. , Hönig H. , Weber H.
Published: January 2005

The synthesis of some acyloxy‐methoxy‐cinnamic acid derivatives, azidohydroxy butanoates, and azidohydroxy butanedioates in enantiomerically pure form is presented. Racemic diastereomerically pure educts were prepared in few steps. These racemates are resolved with lipases from Candida cylindracea (CC) and Pseudomonas fluorescens (P).
Optical resolution of β‐lactams on 1‐phenylethylcarbamates of cellulose and amylose
Authors: Kaida Yuriko , Okamoto Yoshio
Published: January 2005

Optical resolution of six β‐lactams was examined by HPLC using chiral stationary phases consisting of tris((R)‐, (RS)‐, and (S)‐1‐phenylethylcarbamate)s of cellulose and amylose. All β‐lactams were optically resolved at least by one of the carbamates. Amylose tris((S)‐1‐phenylethylcarbamate) showed high optical resolving abilities for some β‐lactams.
Enantioselective pharmacokinetics of ethotoin in humans following single oral doses of the racemate
Authors: Hooper Wayne D. , O'shea Nerida J. , Qing Mi Sui
Published: January 2005

Racemic ethotoin (1000 mg) was administered orally as a single dose to six healthy adult volunteers. Blood samples were collected at appropriate times for 120 h following the dose. Ethotoin was quantified enantioselectively in plasma using a novel chiral column HPLC procedure. One of the enantiomers of the chiral metabolite, 5‐phenylhydantoin, was also quantified in the HPLC method. The Cmax and AUC0—∞ values for (+)‐(S)‐ethotoin were significantly greater than those for (—)‐(R)‐ethotoin (ratio of mean AUC0—∞ values 0.88), but the elimination half‐lives of the isomers were virtually identical [12.35 ± 5.15 h for (—)‐(R)‐thotoin; 12.28 ± 5.34 h for (+)‐(S)‐ethotoin]. Parameters derived from AUC0—∞ (Cl0/F and Varea/F) also differed slightly between the isomers. The data were interpreted as indicating a small difference in the absorption of the two isomers; it seemed unlikely, in terms of the identical elimination rates, that their metabolic profiles would differ greatly. The 5‐phenyl‐hydantoin was eliminated with a significantly longer half‐life (18.69 ± 6.11 h) than that of ethotoin. Enantioselectivity in the pharmacokinetics of ethotoin is therefore a minor issue. © 1992 Wiley‐Liss, Inc.
Liquid chromatographic separation of chiral diarylcarbinols
Authors: Caccamese Salvatore , Maccagnano Maria Grazia
Published: January 2005

The direct HPLC separation of three chiral carbinols of general formula Mesityl‐CH(OH)‐Aryl has been achieved using Pirkle (R)‐DNBPG ionic or covalent columns and, for Aryl = o‐tolyl, on a Chiralpak OP(+) phase. It is apparent that steric hindrance and hydrogen bonding play important roles in chiral recognition. Two compounds structurally very similar but lacking the hydroxyl group were not resolved in their enantiomeric pairs. © 1992 Wiley‐Liss, Inc.
Structural characteristics of cyclodextrins in the solid state
Authors: Lipkowitz Kenny B. , Green Karen , Yang Jia‐An
Published: January 2005

A comparison of α‐, β and γ‐cyclodextrins in the solid state is made. Monomeric features analyzed include orientations of primary hydroxyl groups and pyran ring pucker. Macromolecular features examined include planarity of the oligomer, tilting of pyran rings, and, deviation from Cn symmetry where n = number of monomers. The mean values and standard deviations of these shape descriptors are given for cyclodextrins with and without guests embedded in their interiors. Molecular mechanics calculations using the MM2, AMBER, and CHARMM force fields show that most solid state cyclodextrins are trapped in high‐energy conformations relative to the most stable forms found in this study. © 1992 Wiley‐Liss, Inc.
Spontaneous racemization of chlorthalidone: kinetics and activation parameters
Authors: Severin Gregory
Published: January 2005

The enantiomers of chlorthalidone (CTD) and a minor, achiral dehydration product, δ2‐CTD, are shown to exist in dynamic equilibrium in aqueous media through a carbonium ion intermediate. The barrier to inversion at carbon is low for an uncatalyzed system: ΔG‡ = 21.6 kcal/mol. This behavior extends to other 3‐hydroxy‐3‐phenylphthalimidines (HPPs), with formation of the analogous Δ2‐HPP blocked by alkyl substitution at the 2‐nitrogen. © 1992 Wiley‐Liss, Inc.
Enzymes in stereoselective pharmacokinetics of endogenous substances
Authors: Marzo A. , Cardace G. , Arrigoni Martelli E.
Published: January 2005

The use of enzymes to assay individual components of the L‐carnitine family in pharmaceuticals, foodstuffs, and biological fluids with various forms of detection is reviewed. The most useful enzyme in the assay of compounds of the L‐carnitine family is carnitine acetyl transferase (CAT), which catalyses the reversible interconversion of L‐carnitine and its short‐chain acyl esters. CAT can be used in one or more coupled reactions combined with U.V., or radiolabelled detection, or combined with HPLC, allowing, enantioselective, structurally specific, and, in the case of radiolabelled tracing, highly sensitive assays to be carried out. When compared with chromatographic separation of enantiomers or diastereoisomers, enantioselective enzyme mediated assays may be cheaper, more sensitive, and simpler, but they do not allow the nonpreferred isomer to be assayed. Consequently, they are appropriate for the specific assay of endogenous enantiomeric substrates of the enzyme concerned, in biological samples. The analysis of the other enantiomer in raw materials or in pharmaceuticals must be more properly approached by enantioselective chromatographic methods.
Direct enantiomeric separation of β‐blockers on ChyRoSine‐a by supercritical fluid chromatography: Supercritical carbon dioxide as transient in situ derivatizing agent
Authors: Siret L. , Bargmann N. , Tambuté A. , Caude M.
Published: January 2005

The direct enantiomeric separation of a series of β‐blockers has been carried out on two chiral stationary phases (CSPs) derived from 3,5‐dinitrobenzoyl tyrosine: the commercially available ChyRoSine‐A and a recent improved version of this CSP.

Using supercritical fluid chromatography (SFC), facile separations are achieved (1.1 <Rs <7) within short analysis times. The parameters affecting the enantioselectivity (temperature, pressure, mobile phase nature, solute structure) have been investigated. The optimal mobile phase consists in a mixture of carbon dioxide‐methanol‐propylamine at 25°C. The solute structure has a great influence on the enantioselectivity. For instance, both amine and hydroxyl protons are necessary for chiral discrimination to occur. Furthermore, the steroselectivity value is directly connected to the amine substituent steric bulkiness.

Surprisingly, these solutes are poorly resolved using normal phase liquid chromatography (NPLC). Accordingly, the specific influence of carbon dioxide on the enantiomeric separation of 1,2‐amino‐alcohols has been investigated using various techniques such as nuclear magnetic resonance (NMR) or molecular modelisation. It has been shown that carbon dioxide acts as a complexing agent toward the amino‐alcohol by setting up of a bridge with the hydroxyl and the amine protons of the solute. In that way, the resulting complex possesses lower acido‐basic properties and a higher conformational rigidity, responsible for chiral discrimination.
Resolution of terfenadine enantiomers by β‐cyclodextrin chiral stationary phase high‐performance liquid chromatography
Authors: Weems Henri , Zamani Kaveh
Published: January 2005

Enantiomers of terfenadine were resolved by high‐performance liquid chromatography (HPLC) using a chiral stationary phase (CSP) column packed with β‐cyclodextrin (β‐CD) covalently bound to silica. Separation was achieved in both the reverse phase and normal phase modes. Resolution of enantiomers was confirmed by ultraviolet‐visible absorption, circular dichroism, and mass spectral analysis.
A proposal for the representation of the stereochemistry of quadrivalent centers
Authors: Lin Shu‐Kun
Published: January 2005

The broken wedge, broken line, solid bar, and broken bar are either not reasonable or can be replaced by only one type of solid wedge in the stereochemical formulation. A convention based on a one‐wedge symbolization is proposed, where a or b is used instead of c, d, e, f, g, or h. © 1992 Wiley‐Liss, Inc.
Application of antibody‐mediated extraction for the stereoselective determination of the active metabolite of loxoprofen in human and rat plasma
Authors: Takasaki Wataru , Tanaka Yorihisa
Published: January 2005

Antibody‐mediated extraction followed by chiral high‐performance liquid chromatography (HPLC) was applied to stereoselective determination in human and rat plasma of the active metabolite [(2S,1]R,2[S)‐trans‐alcohol] with three chiral centers of Loxoprofen, a 2‐arylpropionic acid antiinflammatory agent after oral administration. Antiserum against the (1'R,2'S)‐cyclopentanol moiety was obtained from a rabbit immunized with bovine serum albumin conjugate linked to the propionic acid moiety, in which another chiral center is located. Then, the immunoglobulin G purified by a protein A column was coupled to BrCN‐activated Sepharose 4B. Plasma samples were applied to the immobilized antibody column. After washing the column to remove unrequired stereoisomers, a mixture of two diastereomers whose configurations were 1'R,2'S in the cyclopentanol moiety was extracted with 95% methanol. The solvent was evaporated and the residue was derivatized with (+)‐(R)‐1‐(1‐naphthyl)ethylamine as a chiral reagent to separate the diastereomers by HPLC. This combined analytical method showed the stereoselective metabolism of Loxoprofen in human, that is, 64% of the total amount of four trans‐alcohol stereoisomers was in the 2S, 1'R,2'S form, which is the active metabolite. This phenomenon was also observed in rats given Loxoprofen and its (2S)‐ and (2R)‐isomers, and is explained by stereoselective ketone reduction of Loxoprofen to the (1'R,2'S)‐trans‐alcohol and inversion from 2R to 2S in the propionic acid moiety. Antibody‐mediated extraction should be a selective and simple clean‐up method for determining haptens with complicated structures, combined with an appropriate analytical method. © 1992 Wiley‐Liss, Inc.
Resolution of the enantiomers of drugs containing amino alcohol structure after derivatization with bromoacetic acid
Authors: Gübitz G. , Pierer B. , Wendelin W.
Published: January 2005

The separation of the enantiomers of drugs containing an amino alcohol structure like adrenergic drugs or β‐blockers is described. The compounds are resolved on chiral ligand‐exchange chromatography phases after derivatization with bromoacetic acid. © 1992 Wiley‐Liss, Inc.
Stereochemical studies of chiral h‐1 antagonists of histamine: The resolution, chiral analysis, and biological evaluation of four antipodal pairs
Authors: Casy A.F. , Drake A.F. , Ganellin C.R. , Mercer A.D. , Upton C.
Published: January 2005

The resolution of the H‐1 antihistamines chloropheniramine, dimethindene, carbinoxamine, and mebrophenhydramine is described. The optical purity of antipodal products is investigated by chiral HPLC (use of α1 ‐acid glycoprotein and β‐cyclodextrin columns) and NMR (spectra of β‐cyclodextrin inclusion complexes). Configurational relationships among the group are reviewed and assignments are confirmed and extended by circular dichroism evidence. Affinity constants of antipodal pairs for guinea pig ileum and cerebellum sites, determined by gut bath and binding experiments respectively, are reported together with some in vivo tests in man for central effects. Results are discussed in terms of configurational requirements for activity and variations in antipodal potency ratios within the group. © 1992 Wiley‐Liss, Inc.
Strategy combining chiral chromatography with β‐cyclodextrin and stereospecific enzyme reaction detection with hydroxysteroid dehydrogenases for resolving steroid epimers
Authors: Lam S. , Malikin G.
Published: January 2005

Steroids are chiral molecules with multiple stereogenic centers. Studies of their intermediary metabolism often require analytical techniques to separate the isomers and determine their stereochemistry. Methods for resolving steroid stereoisomers by HPLC using β‐cyclodextrin in the mobile phase are reported. Even with the improved selectivity of cyclodextrin chromatography, not all isomers within a steroid series can be resolved. Additional specificity is achieved by reaction detection using postcolumn reactors containing hydroxysteroid dehydrogenases stereospecific for the configuration of the hydroxy functions of steroids. The enzymes catalyze the oxidation of hydroxysteroids and reduction of the coenzyme NAD to NADH. NADH, which is highly fluorescent, is detected at the nanogram levels. Isomers not separated by chromatography were effectively resolved by reaction detection with stereospecific enzymes. © 1992 Wiley‐Liss, Inc.
Preparative resolution of some 5,5‐hydantoin derivatives via formation of diastereoisomeric salts
Authors: Coquerel Gérard , Petit Marie‐Noëlle , Bouaziz Roger , Depernet Dominique
Published: January 2005

Several preparative resolutions of 5,5‐disubstituted hydantoins have been achieved via fractional crystallization of diastereoisomeric salts. The process can be extended by making use of the difference between the variation of solubilities of the hydantoins and their salts with α‐methylbenzylamine as a function of the alkalinity of the medium. Optimization for each resolution procedure involves a refinement of the excess amount of base needed. © 1992 Wiley‐Liss, Inc.
Application of γ‐cyclodextrin to enantiomeric purity determination of a new 2‐amino‐tetralin derivative by 1H‐NMR spectroscopy
Authors: Redenti Enrico , Fronza Giovanni , Bovis Giovanni , Ventura Paolo
Published: January 2005

γ‐Cyclodextrin was used to perform chiral discrimination of (±)‐5,6‐diisobutyroyl‐2‐methylaminotetralin hydrochloride by 1H‐NMR; the 95% enantiomeric excess of the (–)‐isomer was determined successfully. © 1992 Wiley‐Liss, Inc.
Glutathione conjugation and pharmacokinetics of 2‐bromo‐3‐phenylpropionic acid in vitro and in the rat in vivo
Authors: Wilco Snel C.A. , Mahadevan Sivi , Polhuijs Martine , Mulder Gerard J.
Published: January 2005

Glutathione (GSH) conjugation of the chiral compound 2‐bromo‐3‐phenylpropionic acid (BPP) was studied in vitro and in the rat in vivo. GSH conjugation of BPP, catalyzed by a mixture of glutathione‐S‐transferases (GST's) from rat liver cytosol in vitro, was stereoselective: at a substrate concentration of 250 μM, (R)‐BPP was more rapidly conjugated than (S)‐BPP (R/S‐ratio = 2.6). The blood elimination kinetics of the separate BPP enantiomers and the biliary excretion kinetics of the corresponding GSH conjugates were studied in the rat in vivo after administration of (R)‐ or (S)‐BPP at a dose level of 50 μmol/kg. Elimination of (R)‐BPP from blood was faster than that of (S)‐BPP: half lives were 9 ± 2 min for (R)‐BPP and 13 ± 1 min for (S)‐BPP. The biliary excretion rate of the GSH conjugate of (R)‐BPP declined monoexponentially, while that of the GSH conjugate of (S)‐BPP displayed a biphasic profile. Half lives of excretion were 13 ± 1 for the GSH conjugate of (R)‐BPP, and 11 ± 2 for the GSH conjugate of (S)‐BPP (second phase). The first phase in the biliary excretion of the GSH conjugate of (S)‐BPP could not be attributed to capacity limitation of biliary transport carriers as higher excretion rates were attained upon administration of higher doses (100 and 200 μmol/kg) of ((S)‐BPP). The blood elimination profiles of (R)‐ and (S)‐BPP differed greatly from the biliary excretion profiles of the corresponding GSH conjugates. This suggests that the kinetics of BPP conjugate excretion are determined by other processes than hepatic GSH conjugation. © 1992 Wiley‐Liss, Inc.
Synthetic D‐ and L‐enantiomers of 2,2‐difluoro‐2‐deoxy‐myo‐inositol 1,4,5‐trisphosphate interact differently with myo‐inositol 1,4,5‐trisphosphate binding proteins: Identification of a potent small molecule 3‐kinase inhibitor
Authors: Safrany Stephen T. , Sawyer Deborah A. , Nahorski Stefan R. , Potter Barry V.L.
Published: January 2005

The ability of two enantiomeric fluoro‐analogues of D‐myo‐inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3] to mobilize intracellular Ca2+ stores in SH‐SY5Y neuroblastoma cells has been investigated. (—)‐D‐2,2‐difluoro‐2‐deoxy‐myo‐Ins(1,4,5)P3 [D‐2,2‐F2‐Ins(1,4,5)P3] was a full agonist [EC50 0.21 μM] and slightly less potent than D‐Ins(1,4,5)P3 [EC50 0.13 μM]. (+)‐L‐2,2‐F2Ins(1,4,5)P3 was a very poor agonist, confirming the stereospecificity of the Ins(1,4,5)P3 receptor. D‐2,2‐F2‐Ins(1,4,5)P3 mobilized Ca2+ with broadly similar kinetics to Ins(1,4,5)P3 and was a substrate for Ins(1,4,5)P3 3‐kinase inhibiting Ins(1,4,5)P3 phosphorylation (apparent Ki = 10.2 μM) but was recognised less well than Ins(1,4,5)P3. L‐2,2‐F2‐Ins(1,4,5)P3 was a potent competitive inhibitor of 3‐kinase (Ki = 11.9 μM). Whereas D‐2,2‐F2‐Ins(1,4,5)P3 was a good substrate for Ins(1,4,5)P3 5‐phosphatase, L‐2,2‐F2Ins(1,4,5)P3 was a relatively potent inhibitor (Ki = 19.0 μM). © 1992 Wiley‐Liss, Inc.
Stereoselective binding and activity of oxotremorine analogs at muscarinic receptors in rat brain
Authors: Messer, William S. , Ngur Dan O. , Abuh Yahaya F. , Dokas Linda A. , Ting Shu‐Mei , Hacksell Uli , Nilsson Bjorn M. , Dunbar Philip G. , Hoss Wayne
Published: January 2005

The activities of the enantiomers of BM‐5 were examined to measure muscarinic cholinergic selectivity in the central nervous system. Autoradiographic studies assessed the ability of each enantiomer to inhibit the binding of [3H]‐(R)‐quinuclidinyl benzilate ([3H]‐(R)‐QNB) to muscarinic receptors in the rat brain. (+)‐(R)‐BM‐5 inhibited [3H]‐(R)‐QNB binding to rat brain sections at concentrations below 1.0 μM, while 100‐fold higher concentrations of (—)‐(S)‐BM‐5 were required for comparable levels of inhibition. Analysis of the autoradiograms indicated that both stereoisomers had a similar distribution of high affinity binding sites. Each enantiomer displayed higher affinity for muscarinic receptors in the superior colliculi and lower affinity for receptors in the cerebral cortex and hippocampus. (+)‐(R)‐BM‐5 and oxotremorine inhibited adenylyl cyclase activity in the cerebral cortex with efficacies comparable to that for acetylcholine. (+)‐(R)‐BM‐5 was 26‐fold more potent than (—)‐(S)‐BM‐5 in inhibiting adenylyl cyclase. Oxotremorine‐M and carbamylcholine stimulated phosphoinositide turnover in the cerebral cortex. Oxotremorine had lower activity and (+)‐(R)‐BM‐5 was essentially inactive at comparable concentrations. The difference in activity of the two enantiomers indicates a remarkable stereochemical selectivity for muscarinic receptors. The stereoselectivity index is comparable for both the autoradiographic assays (48) and measures of adenylyl cyclase activity (26) in the cerebral cortex. © 1992 Wiley‐Liss, Inc.
An in vitro study of the stereoselective dissolution of (rac)‐verapamil from two sustained release formulations
Authors: Aubry Anne‐Françcloise , Wainer Irving W.
Published: January 2005

The stereoselectivity of the in vitro dissolution of two commercially available sustained release formulations of rac‐verapamil (rac‐VER) has been investigated. The studies were carried out using a single‐tablet continuous‐flow apparatus and the concentrations of R‐ and S‐VER released from the formulations were measured using enantioselective chromatography on a high performance liquid chromatography (HPLC) chiral stationary phase containing immobilized α1‐acid glycoprotein (Chiral AGP‐column). The data from this study demonstrates that the two formulations have different dissolution profiles and that the amount of drug dissolved was highly dependent on pH. In addition, between pH 3 and 8, the total cumulative amount of R‐VER released was greater than the amount of S‐VER and a statistically significant difference (P < 0.01) was detected at pH 6. The results of this study indicate that bioavailability and bioequivalency studies should consider the possibility of enantioselective dissolution when racemic compounds are present in the formulations. © 1993 Wiley‐Liss, Inc.
In vitro and in vivo irreversible plasma protein binding of beclobric acid enantiomers
Authors: Mayer Sascha , Mutschler Ernst , Spahn‐Langguth Hildegard , Benet Leslie Z.
Published: January 2005

Acyl glucuronides are known to be labile conjugates, which undergo hydrolysis and bind irreversibly to proteins. The lipid‐regulating agent (±)‐beclobrate is immediately converted to the free acid after oral administration. Further metabolism leads to formation of the corresponding diastereomeric acyl glucuronides. Beclobric acid glucuronides were quantified by indirect measurement with an HPLC method based on chiral fluorescent derivatization of the carboxylic acid and subsequent normal‐phase chromatography. The renal clearance of unchanged drug is low, with almost all drug excreted into urine as glucuronic acid conjugates. Beclobric acid glucuronide is also detectable in plasma. In vitro degradation studies with beclobric acid glucuronide (at a concentration of 5 μM in 150 mM phosphate buffer pH 7.4) exhibited a minor tendency for acyl migration and hydrolysis, i.e., a higher stability than has been observed for the acyl glucuronides of most other drugs. The in vitro degradation half‐lives of the two beclobric acid β‐1‐O‐acyl glucuronides were 22.7 and 25.7 h. After incubation with pooled plasma and human serum albumin in buffer pH 7.4 irreversible binding was measured in vitro. No significant difference between the two enantiomers was detected with respect to the magnitude of in vitro irreversible binding. In 3 healthy male volunteers the extent of irreversible binding of both beclobric acid enantiomers to plasma proteins was investigated after single and multiple oral doses of racemic beclobrate (100 mg once daily). Irreversible binding of both enantiomers was observed in all volunteers. The adduct densities for (−)‐ and (+)‐beclobric acid after single 100 mg beclobrate doses were 0.147 × 10−4 and 0.177 × 10−4 mol/mol protein. Multipie dosing increased irreversible binding 3‐ to 4‐fold. © 1993 Wiley‐Liss, Inc.
Stereoselectivity in central analgesic action of tocainide and its analogs
Authors: Franchini Carlo , Noja Francesca Chiaia , Corbo Filomena , Lentini Giovanni , Tortorella Vincenzo , Bartolini Alessandro , Ghelardini Carla , Matucci Rosanna , Giotti Alberto
Published: January 2005

The antiarrhythmic drug tocainide (5a) and some related chiral α‐amino and α‐imino anilides (5b–e) were synthesized in optically active form. The antinociceptive effects of the different stereoisomers of these compounds were examined and it was found that the analgesic effect of tocainide is due only to its (−)‐(R)‐enantiomer. Benzyl replacement for methyl group at the stereogenic centre of tocainide causes loss of activity while both enantiomers of the αiminoxilidide 5e and of the strictly related tocainide analog 5d produce an analgesic effect without any stereoselectivity. Pharmacological tests and [3H] quinuclidinyl benzilate ([3H]QNB) binding assay, taken together, seem to show that the antinociceptive effect of (−)‐(R)‐tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action. © 1993 Wiley‐Liss, Inc.
Enantioselective lipase‐catalyzed ester hydrolysis: Effects on rates and enantioselectivity from a variation of the ester structure
Authors: Bojarski Jacek , Oxelbark Joachim , Andersson Christina , Allenmark Stig
Published: January 2005

In order to make a preliminary study of substituent effects on the rate and enantioselectivity obtained in esterolytic reactions catalyzed by a lipase from Candida rugosa, a series of racemic esters, derived from some α‐alkyl and α‐halo phenylacetic acids, were prepared. The reactions were studied at pH 6.0 and 50°C under which conditions uncatalyzed hydrolysis was relatively slow. Reaction samples were studied at different points of time by means of analytical chiral reversed‐phase liquid chromatography, which permitted the simultaneous determination of product enantiomeric excess and of the degree of total ester hydrolysis. These data were then used to calculate initial rates as well as enantioselectivity. An increase of the steric bulk of the α‐substituent was found to highly decrease the rate of the reaction. On the other hand, rates were higher for the p‐nitrophenyl esters than for the corresponding 2‐chloroethyl esters. Consistently, the enantioselectivity was found to be higher for the latter type of ester. The esters of the α‐halo (bromo and chloro) phenylacetic acids gave mandelic acid as the final product. This was caused by a rapid solvolysis of the α‐halo phenylacetic acid initially formed. © 1993 Wiley‐Liss, Inc.
Chiral stationary phases in concert with homologous chiral mobile phase additives: Push/pull model
Authors: Duff Keith J. , Gray Hannah L. , Gray Rachael J. , Bahler Caroline C.
Published: January 2005

A new “push/pull” model has been developed to explain synergistic effects observed in a system in which a chiral stationary phase (CSP) is used in combination with its homologous chiral mobile phase additive (CMPA). The model predicts the beneficial CMPA enantiomer and the counterproductive CMPA enantiomer a priori. Thus, an (R)‐CSP will obtain positive synergism from a homologous (S)‐CMPA and negative synergism from a homologous (R)‐CMPA. The reverse is true for an (S)‐CSP. The importance of structural homology between the CSP and the CMPA is demonstrated. Furthermore, the analysis time is decreased relative to the use of a CSP alone, because the retention time of the analyte peaks decreases when the CMPAs are used. © 1993 Wiley‐Liss, Inc.
Separation of N‐arylthiazoline‐2‐(thi)‐one atropisomers on p‐methylbenzoyl cellulose beads: A factorial design approach
Authors: Roussel Christian , Lehuédé Stephan , Popescu Cristina , Stein Jean‐Louis
Published: January 2005

A two level full factorial design has been applied to quantify the effect of three selected structural parameters on the capacity factors and chiral separation of atropisomers in N‐arylthiazoline‐2‐(thi)‐ones derivatives on tris(p‐methylbenzoyl) cellulose beads. The behavior of the two enantiomers is influenced by different factors which might result from different retention sites within the same stationary phase. It appears that the two enantiomers behave independently on the CSP, the order of elution and separation being controlled by a minor steric modification in a very precise location in the molecule for one enantiomer. The methodology of the experimental design allows the comparison of equations generated from data issued from designed compounds. These equations afford much more information than the step by step comparison of individual molecules. In our case, the tris(p‐methylbenzoyl)cellulose beads and microcrystalline cellulose triacetate appear as complementary CSPs for the resolution of atropisomers of the series studied. © 1993 Wiley‐Liss, Inc.
Quantification of trace levels of β‐cyclodextrin and substitution patterns in hydroxypropyl‐β‐cyclodextrin using high‐performance liquid chromatography with polarimetric detection
Authors: Liu Gaoyuan , Goodall David M. , Loran John S.
Published: January 2005

A high‐performance liquid chromatographic (HPLC) method has been developed for separation and determination of components in hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD). The method involves separation on an amino‐bonded HPLC column using water–acetonitrile as a mobile phase with a polarimetric HPLC detector for quantification. It provides good selectivity and sensitivity and can also be used to compare different sources of HP‐β‐CD and to measure batch to batch variation. The similarity of the values of molar optical rotation for β‐cyclodextrin (β‐CD) and HP‐β‐CD suggests that a polarimetric HPLC detector may be used with a straightforward area normalization method, to quantify the proportion of β‐CD in any HP‐β‐CD sample. Trace amounts of β‐CD in HP‐β‐CD have been measured to a precision of 0.01%. © 1993 Wiley‐Liss, Inc.
Enantiomeric separations of remoxipride, propranolol, and trimipramine on CHIRAL‐AGP using micellar chromatography and anionic additives
Authors: Haupt Dan , Pettersson Curt , Westerlund Douglas
Published: January 2005

The retentions and enantiomeric resolutions of remoxipride, propranolol, and trimipramine were studied using a CHIRAL‐AGP column with micellar mobile phases and aliphatic, anionic additives. The retentions of the compounds, which in neat buffer solution were very high (k′ > 50), could be decreased to k′ < 10 by adding a mixture of Tween® 20 and heptanoic acid to the mobile phase. The presence of the aliphatic acid was essential in order to increase the enantiomeric selectivity. An efficiency enhancement was obtained by increasing the temperature. With a mobile phase composition optimized for the separation of remoxipride, the possibility of detecting levels of the enantiomeric impurity (R‐remoxipride) down to 0.025% in the drug was demonstrated. © 1993 Wiley‐Liss, Inc.
Chiral separation of amines using reversed‐phased ion‐pair chromatography
Authors: Pettersson Curt , Gioeli Carlo
Published: January 2005

The direct separation of enantiomeric amines has been carried out using a chiral counter ion, (−)‐2,3:4,6,‐di‐O‐isopropylidene‐2‐keto‐L‐gulonic acid [(−)‐DIKGA] dissolved in polar mobile phases, water:methanol or isopropanol:acetonitrile. High separation factors, α = 1.2–1.7, were obtained for several compounds of pharmacological interest such as metoprolol, oxprenolol, remoxipride, mefloquine and p‐OH‐ephedrine. © 1993 Wiley‐Liss, Inc.