bluuebunny/crossref_metadata_2025 huggingface dataset:
The absolute configuration of the enantiomers of 6‐chloro‐9‐(4′‐diethylamino‐1′‐methylbutyl)‐amino‐2‐methoxyacridine (quinacrine)
Authors: Craig J. Cymerman , Labelle Bruce , Ohnsorge Ulrich
Published: January 2005

Absolute configurations have been assigned to the enantiomers of the antimalarial drug quinacrine dihydrochloride. Condensation of (−)‐(R)‐4‐amino‐1‐diethylaminopentane (from L‐glutamic acid) with 6,9‐dichloro‐2‐methoxyacridine gave (−)‐(R)‐6‐chloro‐9‐(4′‐diethylamino‐1′‐methylbutyl) amino‐2‐methoxyacridine [(−)‐(R)‐quinacrine] while (+)−(S)‐quinacrine was obtained from the enantiomeric diamine.
Steric aspects of agonism and antagonism at β‐adrenoceptors: Synthesis of and pharmacological experiments with the enantiomers of formoterol and their diastereomers
Authors: Trofast Jan , ÖSterberg Kristina , Källström Britt‐Louise , Waldeck Bertil
Published: January 2005

The enantiomers of formoterol (R;R and S;S) and their diastereomers (R;S and S;R) were synthesized and purified using a new procedure which required the preparation of the (R;R)‐ and (S;S)‐forms of N‐(1‐phenylethyl)‐N‐(1‐(ρ‐methoxyphenyl)‐2‐propyl)‐amine as important intermediates. The enantiomeric purity obtained was greater than 99.3%, usually > 99.7%. The four stereoisomers were examined with respect to their ability to interact in vitro with β‐adrenoceptors in tissues isolated from guinea pig. The effects measured were (1) relaxation of the tracheal smooth muscle (mostly β2), (2) depression of subtetanic contractions of the soleus muscle (β2), and (3) increase in the force of the papillary muscle of the left ventricle of the heart (β1). All enantiomers caused a concentration‐dependent and complete relaxation of the tracheal smooth muscle which was inhibited by propranolol. The order of potency was (R;R) > > (R;S) = (S;R) > (S;S). There was a 1,000‐fold difference in potency between the most and the least potent isomer. The presence of the (S;S)‐isomer did not affect the activity of the (R;R)‐isomer on the tracheal smooth muscle. Also on the skeletal and cardiac muscles (R;R)‐formoterol was more potent than its (R;S)‐isomer. The selectivity for β2‐adrenoceptors appeared to be slightly higher for the (R;R)‐isomer than for the (R;S)‐isomer. The potency of the (S;R)‐ and (S;S)‐isomers on the papillary muscle was too low to be determined accurately. The present study shows that determination of enantiomeric ratios and conclusions regarding structure–effect relationships are critically dependent on a very high degree of stereochemical purity.
Stereoselective inhibition of diphenylhydantoin metabolism by p‐hydroxyphenyl‐phenylhydantoin enantiomers in rats
Authors: Huang Jin‐Ding , Hsieh Ching‐Yi
Published: January 2005

Different doses of rac‐p‐HPPH (0.4 and 4 mg/h) were given repeatedly to rats infused with [14C]phenytoin. The serum levels of 14C‐labeled and unlabeled p‐HPPH, and [14C]phenytoin were measured by an HPLC method and radiometric analysis. The clearance of phenytoin and p‐HPPH was determined by rate of dosing divided by the steady‐state concentration. The phenytoin clearance was significantly lower in the high dose p‐HPPH injection group than in the low dose group (87 versus 262 ml/h), whereas p‐HPPH clearance showed no difference. The formation clearance of [14C]p‐HPPH was also significantly lower in rats injected with high dose of p‐HPPH (35 versus 169 ml/h). The clearance of other elimination pathways was also lower in rats with high dose of p‐HPPH (53 versus 89 ml/h). The serum protein binding of phenytoin was lower in rats injected with high dose of p‐HPPH. The result indicated that injections of rac‐p‐HPPH mainly inhibited on the formation of p‐HPPH itself. The formation of (R)‐p‐HPPH and (S)‐p‐HPPH in microsomal preparation was measured by a ligand‐exchange chromatographic method. The formation of (S)‐p‐HPPH or (R)‐p‐HPPH was not only inhibited by the enantiomer itself, but also cross‐inhibited by the other enantiomer. To the formation of either (S)‐p‐HPPH or (R)‐p‐HPPH, (S)‐p‐HPPH showed a higher inhibitory activity. The use of rac‐p‐HPPH to inhibit phenytoin metabolism in vivo involved several mechanisms. In addition to binding displacement on the serum proteins, one is the product inhibition by the respective p‐HPPH metabolite, the other is the competitive inhibition by the other p‐HPPH enantiomer.
Enantiomeric analysis of terfenadine in rat plasma by HPLC
Authors: Zamani Kaveh , Conner Dale P. , Weems Henri B. , Yang Shen K. , Cantilena Louis R.
Published: January 2005

Enantiomeric pairs of the antihistaminic drug terfenadine and its carboxylic acid derivative were directly separated by HPLC using an ovomucoid protein column. Absolute configurations of terfenadine enantiomers were assigned by comparing their circular dichroism spectra with those of 1‐phenyl‐1‐butanol enantiomers of known absolute stereochemistry. Terfenadine and its major carboxylic acid metabolite extracted from blood plasma following an oral administration of a racemic terfenadine to rats were found to be enriched in the (S)‐ and (R)‐enantiomers, respectively. The results indicated that the (R)‐enantiomer of an orally administered racemic terfenadine was preferentially oxidized in rats to form a carboxylic acid metabolite enriched in the (R)‐enantiomer.
Living enantiosymmetric and enantioasymmetric polymerization of methylthiirane in homogeneous phase
Authors: Dumas PH. , Sigwalt P.
Published: January 2005

The polymerization of racemic methylthiirane in homogeneous phase, initiated by bis(isopropyl‐S‐cysteinato) cadmium is a living process. The resulting polymers are isotactic and optically active at partial conversion. The optical purity of the residual monomer may reach 27% at half conversion. The propagation occurs mainly on one valency of Cd, however oligomers grow slowly on the second valency. The stereoregularity of the polymer chain appears only when the length of the oligomer becomes high enough, making possible a bicoordination of the Cd counterions. The stereoregularity of the polymer is characterized by the molar fraction σ of isotactic diads which varies from 0.5 for atactic chains—formed at the beginning—to about one for isotactic segments formed for longer chains. The stereospecifictity also depends on temperature of propagation and on initiator concentration. The kinetics observed (zero order in monomer and one‐half in Cd) are explained by monomer coordination before insertion and dimeric association of the thiolate end groups. The enantioasymmetric process observed results from an unbalance in the number of the two different types of active sites and possibly from a difference in their reactivities. Enantioasymmetry has been found to decrease significantly when the dielectric constant ε of the medium increases.
Chiroptical properties of lecithin reverse micelles and organogels
Authors: Colombo Luca M. , Nastruzzi Claudio , Luisi Pier Luigi , Thomas Richard M.
Published: January 2005

The ultraviolet absorbance and circular dichroism (CD) spectra of lecithin reverse micelles and gels were investigated in order to establish whether the formation of these noncovalent macromolecular aggregates, which was induced by the addition of water to solutions of lecithin in organic solvents, was accompanied by specific spectroscopic changes. Systems containing the synthetic short‐chain lecithins, 1,2‐hexanoyl‐, 1,2‐diheptanoyl‐, 1,2‐dioctanoyl‐, and 1,2‐dinonaoyl‐sn‐glycero‐3‐phosphatidylcholines were used as models for the long‐chain lecithins, soybean phosphatidylcholine and palmitoyl‐oleoyl‐phosphatidylcholine. All the molecules studied had asymmetric centres, formed reverse micelles under appropriate conditions, and, while both the long‐chain lecithins also formed gels, none of the short‐chain molecules did. As well as having CD spectra that were simpler to interpret, spectroscopic observations on solutions of the short‐chain lecithins could be carried out over a large water content range. The ester chromophore of these compounds was shown to be highly sensitive to variation in both the solvent environment and the temperature, and components of both direct solvent effects and conformational change upon the addition of water were detected in the spectra.

The spectra of the longer chain lecithins were complicated by the presence of double bonds although, here again, it was found that significant changes occurred as the water content increased, as monitored by the ester chromophore. However, no specific effect that could be ascribed to gelation alone was detected.

The overall picture that emerged was that the ester chromophore of anhydrous micelles gave rise to a specific negative band in the CD spectrum (λmax ≈ 210 nm) whereas a positive CD signal (λmax ≈ 233 nm) was associated with the same chromophore in filled (i.e., hydrated) micelles. The two signals correspond to two different conformational states of the lecithin molecule, the hydrated state being not only more conformationally restricted but also providing a less polar environment for the ester groups, while the addition of water to the system shifts the conformational equilibrium. These observations have been interpreted as showing that only a limited range of lecithin conformation is compatible with the formation of the micellar structure and that it is this constraint, together with those introduced by the overall geometry of the aggregated state, that gives rise to the changes observed in the CD spectrum.
Racemization of the aqua‐{N‐salicylidene‐(S)‐alaninato}copper(II) by reaction with potassium cyanate
Authors: Krätsmár‐Šmogrovič J. , Blahová M. , Kettmann V.
Published: January 2005

Copper(II) N‐salicylidene‐(S)‐alaninate trihydrate reacting as the S‐enantiomeric parent compound with KOCN in hot diluted methanol yielded by slow crystallisation from the cooled reaction mixture (in the course of 1 day) the racemic product K[Cu{sal‐(RS)‐ala}(NCO)]. The parameters of the axial type EPR spectrum in X‐band region and the LF band position in the electronic spectrum are typical of an axially distorted square pyramidal coordination of the Cu(II) atom in this complex. The spectral properties of the complex cuprate prepared and its basal crystallographic data are consistent with those of the earlier studied15 K2[Cu2{sal‐(RS)‐ala}2(μ‐NCO)2] synthetized by using [Cu{sal‐(RS)‐ala}(H2O)].H2O as the racemic parent complex in the reaction mixture with KOCN.
Stereoselective aliphatic hydroxylation of 6‐n‐propylchromone‐2‐carboxylic acid by female Dutch rabbits
Authors: Winter Steven M. , Caldwell John
Published: January 2005

6‐n‐Alkylchromone‐2‐carboxylic acids are metabolized solely by aliphatic oxidation. In the rabbit, the 6‐n‐propyl congener (PCCA) undergoes ω‐1 hydroxylation exclusively. Following administration of PCCA to female Dutch rabbits (500 μmol/kg), some 77% of the dose was excreted in the urine, 41% as PCCA and 36% as 6‐(2'‐hydroxy‐n‐propyl)chromone‐2‐carboxylic acid. Since this metabolite is chiral, we have examined the stereochemistry of the excreted material. Diastereoisomeric (as camphanate and α‐methoxy‐α‐(trifluoromethyl)phenylacetate esters) and direct chiral HPLC and chiral lanthanide shift NMR have each shown the S:R ratio of the excreted metabolite to be 76:24. When rabbits were dosed with the racemic metabolite, excretion of the compound was not stereoselective. The regio‐ and stereo‐selectivity of the aliphatic hydroxylation of PCCA are thus reflections of the selectivities of the enzyme systems responsible for its formation and suggest PCCA to be an appropriate probe compound for the study of prochiral‐chiral hydroxylations.
Enantiospecificity of kappa receptors: Comparison of racemic compounds and active enantiomers in two novel series of kappa agonist analgesics
Authors: Colle Roberto , Clarke Geoffrey D. , Dondio Giulio , Giardina Giuseppe , Petrone Giuseppe , Sbacchi Massimo , Vecchietti Vittorio
Published: January 2005

Two novel series, Ia,b and IIa,b, of kappa opioid antinociceptive agents have recently been described. 2a,b,3a,b,c The biological activities of 16 racemic compounds and their corresponding (−) enantiomers are now compared in a battery of tests. Enantiomers of unsubstituted piperidines Ia were synthesized starting from S(−) pipecolic acid, whereas the enantiomerically pure substituted piperidines (Ib), tetrahydroisoquinolines (IIa), and thienopiperidines (IIb) were, in general, obtained after diastereomeric crystallization of the corresponding tartrate salts. The absolute stereochemistry of one representative enantiomer from series IIa was determined to be (1S) by X‐ray crystallographic analysis. Antinociceptive activity in the mouse abdominal constriction and tail‐flick tests following subcutaneous administration, and binding affinity for κ and μ receptors, were found to reside predominantly in the (−) enantiomers. Consequently, racemic compounds showed approximately half potency of the corresponding enantiomers. This potency difference was less clear after oral administration presumably due to small differences in bioavailability of the two corresponding enantiomers.

For compounds with some affinity also for μ receptors (Ki <1,000 nM), the κ/μ selectivity was maintained within each enantiomeric pair, in contrast to results found for other κ agonists.
Stereoselectivity at α‐adrenoreceptor subtypes: observations with the enantiomers of WB 4101 separated through their amides of N‐Tosyl‐(S)‐proline
Authors: Andrisano Vincenza , Marucci Gabriella , Melchiorre Carlo , Tumiatti Vincenzo
Published: January 2005

We present a chromatographic method for the separation and determination of the optical purity of the enantiomers of WB 4101 [(±)‐1], one of the most potent and selective α1‐adrenoreceptor antagonists. (±)‐1 was converted into the amide of N‐tosyl‐(S)‐proline. The two diastereoisomers were separated on silica gel and analysed by HPLC reversed phase. The analytical method described is both accurate and sensitive and allows the optical purity to be determined at very low concentrations and to obtain WB 4101 enantiomers with a purity of more than 99.95%.
Use of cyclodextrins in capillary zone electrophoresis for the separation of optical isomers: Resolution of racemic tryptophan derivatives
Authors: Nardi Annalisa , Ossicini Luigia , Fanali Salvatore
Published: January 2005

In this study capillary zone electrophoresis has been used for the separation of racemic tryptophan derivatives in their enantiomers. The effect of cyclodextrins with different shape, added to the background electrolyte, on the migration time of 10 compounds, including methyl tryptophan, hydroxy tryptophan, and tryptophan ester derivatives, has been studied. Furthermore, the effect of cyclodextrins with different shape and that of the composition of the background electrolyte on the enantiomer resolution are discussed. Among different cyclodextrins used α‐cyclodextrin and heptakis(2,6‐di‐O‐methyl)‐β‐cyclodextrin were found to possess the best complexing capacity and thus the resolution power toward analysed compounds.
The disposition of venlafaxine enantiomers in dogs, rats, and humans receiving venlafaxine
Authors: Paul Wang C. , Howell Stanley R. , Scatina Joann , Sisenwine Samuel F.
Published: January 2005

A stereospecific high‐performance liquid chromatographic (HPLC) method was developed for the quantitation of the enantiomers of venlafaxine, an antidepressant, in dog, rat, and human plasma. The procedure involves derivatization of venlafaxine with the chiral reagent, (+)‐S‐naproxen chloride, and a postderivatization procedure. The method was linear in the range of 50 to 5,000 ng of each enantiomer per ml of plasma. No interference by endogenous substances or known metabolites of venlafaxine occurred. Studies to characterize the disposition of the enantiomers of venlafaxine were conducted in dog, rat, and human, following oral administration of venlafaxine. The Cmax, area under the curve (AUC) and (S)/(R) concentration ratios of the (R)‐ and (S)‐enantiomers were compared. In rats, the mean plasma ratio of (S)‐venlafaxine to that of (R)‐venlafaxine over 0.5 to 6.0 h varied from 2.97 to 8.50 with a mean value of 5.51 ± 2.45. The Cmax, AUC0—∞, and t1/2 values of the (R)‐ and (S)‐enantiomers in dogs were not significantly different from one another (P>0.1). The mean ratios [(S)/(R)] of enantiomers of venlafaxine in human over a 2 to 6 h interval ranged from 1.33 to 1.35 with an overall ratio of 1.34 ± 0.26 (n = 12). These ratios of the enantiomers [(S)/(R)] were not statistically different from unity (P>0.1) indicating that the disposition of venlafaxine enantiomers in humans is not stereoselective and is more similar to that in dogs than that in rats.
Unusual amino acids I: Asymmetric synthesis of furylalanine derivatives
Authors: Krause H.W. , Wilcke F.W. , Kreuzfeld H.‐J. , Döbler Ch.
Published: January 2005

Nonproteinogenic amino acids are valuable active compounds from their pharmacological and biochemical effects and also as novel building blocks for peptides. The preparation of furylalanine derivatives by asymmetric hydrogenation is described. Amino‐phosphine‐phosphinite‐rhodium complexes catalyzed the hydrogenation of the prochiral dehydroamino acid precursors in high rate and with enantioselectivities of 70—90% ee. Substrate‐catalyst ratios up to 2,000 can be used depending on the catalyst applied. The procedure turns out to be suitable for larger scale preparations.
Effective methods for enantioselective analysis of glycidol derivatives by liquid chromatography
Authors: Kennedy Joseph H. , Weigel Leland O.
Published: January 2005

Methodology for determination of the enantiomeric purity of sixteen 2,3‐epoxy‐1‐propanols (glycidols) is delineated. Conversion of these epoxy alcohols and 1‐naphthyl isocyanate (NIC) into the 1‐naphthyl carbamates is catalyzed by dibutyltin diacetate. Enantiomers of these carbamates are resolved on a Chiralcel® OD column. Advantages of this method include mildness of reaction conditions, nonreliance on diastereomeric derivatization, and appendage of a UV‐absorbing chromophore to the analyte.
Enantio‐ and regioselectivity in the epoxide‐hydrolase‐catalyzed ring opening of simple aliphatic oxiranes: Part I: Monoalkylsubstituted oxiranes
Authors: Wistuba D. , Schurig V.
Published: January 2005

The in vitro conversion of chiral aliphatic monoalkylsubstituted oxiranes into 1,2‐diols catalyzed by epoxide hydrolase of rat liver microsomes occurs with substrate enantioselectivity and regioselectivity. Substrate enantioselectivity is generally low, and has the same sense, for methyloxirane, vinyloxirane, epichloro‐, and epibromohydrin. In the hydrolysis of t‐butyloxirane inhibitory effects are involved leading to a complex pattern of enantioselectivity. All investigated monosubstituted aliphatic oxiranes are hydrolyzed with high regioselectivity by nucleophilic attack of water at the unsubstituted ring carbon atom. The enantiomeric excess of the unreacted oxirane substrates and the diol metabolites formed were determined by complexation and inclusion gas chromatography. © 1992 Wiley‐Liss, Inc.
Chiral α‐substituted α‐aryloxy acetic acids: Synthesis, absolute configuration, chemical resolution, and direct separation by hplc
Authors: Bettoni G. , Ferorelli S. , Loiodice F. , Tangari N. , Tortorella V. , Gasparrini F. , Misiti D. , Villani C.
Published: January 2005

Several α‐monoalkyl‐α‐aryloxyacetic acids have been synthesized and resolved into their optical antipodes; their absolute configuration was also established by chiroptical and chemical methods. The two enantiomers of a series of these compounds show opposite effects on skeletal muscle fibers chloride conductance. Therefore a HPLC procedure was developed for the direct determination of the optical purity of the antipodes before submitting them to biological tests. The chromatographic study was performed on DACH‐DNB chiral stationary phase which shows a remarkable enantioselectivity for the considered compounds as free acids, esters and amides under different conditions with essentially the same chiral mechanism of separation. © 1992 Wiley‐Liss, Inc.
Synthesis and pharmacological investigation of stereoisomeric muscarines
Authors: Amici Marco De , Dallanoce Clelia , Micheli Carlo De , Grana Enzo , Dondi Giuseppina , Ladinsky Herbert , Schiavi Giovannibattista , Zonta Franco
Published: January 2005

The synthesis of the eight stereoisomers of muscarine has been efficiently accomplished by utilizing the two enantiomers of lactic esters as starting material. The synthetic strategy is based on a SnCl4‐catalyzed addition of allyltrimethylsilane to O‐protected lactic aldehydes followed by an iodocyclization process. All the final derivatives possess an enantiomeric excess higher than 98%. The four pairs of enantiomers bound to M1, M2, and M3 muscarinic receptor subtypes in membranes from cerebral cortex, heart, and salivary glands, respectively, and recognized heterogeneous states of the receptors. Of the eight isomers, only natural muscarine (+)‐1 recognized three affinity states of the M2 receptor. The compound was also the only one to show selectivity in the binding study, demonstrating 37‐ to 44‐fold higher affinity for the M2 than for the M1 or M3 receptors. In addition, the compounds were tested in functional assays on isolated guinea pig atria (M2 receptors) and ileum (mixed population of M2 and M3 receptors) and their muscarinic potencies were determined. Among the eight isomers, again only (+)‐1 enantiomer was found to be very active on both tissues. Its potency was more than two orders of magnitude higher than that of its enantiomer (−)‐1 as well as the other six isomers. The eudismic ratios (E.R.) deduced from the two functional tests were 324 and 331. © 1992 Wiley‐Liss, Inc.
Stereoselective binding of etodolac to human serum albumin
Authors: Muller Noëlle , Lapicque Françoise , Monot Claudine , Payan Elisabeth , Dropsy Rémi , Netter Patrick
Published: January 2005

The protein binding of etodolac enantiomers was studied in vitro by equilibrium dialysis in human serum albumin (HSA) of various concentrations varying from 1 to 40 g/liter, by addition of each enantiomer at increasing concentrations. In the 1 g/liter solution, at the lowest drug levels, the (R)‐form is more bound than its antipode, the contrary being observed at the highest drug levels. For higher albumin concentrations, S was bound in a larger extent than R. Using the displacement of specific markers of HSA sites I and II, studied by spectrofluorimetry, it was suggested that R and S are both bound to site I, while only S is strongly bound to site II. © 1992 Wiley‐Liss, Inc.
Stereospecific gas chromatographic method for determination of methadone in serum
Authors: Kristensen K. , Angelo H.R.
Published: January 2005

rac‐Methadone is used clinically for the chronic maintenance treatment of heroin addiction and for the relief of pain. As the pharmacological activity of methadone is due primarily to the (−)‐(R)‐enantiomer, stereospecific measurements of methadone serum concentrations in methadone‐treated patients are expected to be more relevant for clinical studies than earlier described total drug measurements. This study describes a stereospecific gas chromatographic (GC) method for the determination of methadone in serum. The extracted methadone was derivatizised with (−)‐menthyl chloroformate. The diastereometric derivatives were analysed by GC on a capillary column and detected with a nitrogen‐phosphorus detector. The resolution factor obtained for the methadone enantiomers was 1.1 with a relatively short time of analysis (30 min). By analysing the pure (−)‐(R)‐enantiomer, no racemization was seen during the analysis. The lower limit of quantitation was 75 nmol/1 for each enantiomer. Measurements of the ratio between (−)‐(R)‐ and (+)‐(S)‐methadone concentrations in serum from five methadone‐treated patients showed interindividual differences (range 0.5–1.1). The patient results correlated well with those from another GC method measuring total methadone.
Asymmetric synthesis polymerization of meso oxiranes and thiiranes
Authors: Spassky Nicolas , Momtaz Ardéchir , Kassamaly Asmina , Sepulchre Maurice
Published: January 2005

The asymmetric synthesis polymerization or “enantiogenic” polymerization of some meso oxiranes, cis‐dimethyloxirane (cis‐DMO) and cyclohexene oxide (CHO), and thiiranes, cis‐dimethylthiirane (cis‐DMT) and cyclohexene sulfide (CHS), initiated with different chiral systems was examined. Strong differences in behaviour were observed between oxiranes and thiiranes depending on the initiator used. The initiators based on ZnEt2 or CdMe2 and a chiral diol give optically active polymers from meso thiiranes but fail to induce an asymmetric polymer synthesis with meso oxiranes. A new chiral initiator based on ZnEt2 and (1S,2R)‐ephedrine allowed us to prepare optically active poly CHOs, which can be fractionated into fractions exhibiting opposite optical activities. © 1992 Wiley‐Liss, Inc.
High enantiofacial selectivity in the OsO4 dihydroxylation of e‐stilbene with a chiral biphenyl diamine catalyst
Authors: Haubenstock Howard , Subasinghe Kamani
Published: January 2005

The chiral biphenyl‐containing diamine 1 complexed with OsO4 oxidized trans‐stilbene at –80°C to (+)‐(1R;2R)‐1,2‐diphenyl‐1,2‐ethanediol in high enantiomeric excess. On the other hand, (R)‐ or (S)‐2,2'‐bis(dimethylamino)‐6,6'‐dimethylbiphenyl proved to be ineffective in promoting oxidation. © 1992 Wiley‐Liss, Inc.
Separation of enantiomeric amines and acids using chiral ion‐pair chromatography on porous graphitic carbon
Authors: Karlsson A. , Pettersson C.
Published: January 2005

The application of porous graphitic carbon as adsorbing phase for direct separation of enantiomeric acids and amines using chiral ion‐pair chromatography is described. The enantiomeric amines were separated as diastereomeric ion pairs with N‐benzyloxycarbonylglycyl‐L‐proline, N‐benzyloxycarbonylglycylglycyl‐L‐proline, or captopril as the chiral counterion. High enantioselectivities were obtained for amines having a hydrogen bonding function in the vicinity of the asymmetrical carbon atom. Quinine was the chiral counterion used to separate the enantiomeric acids. The strongly UV‐absorbing quinine improved detection of solutes having low UV‐absorbing properties, e.g., (R,S)‐2‐chloropropionic acid, by “indirect detection.” Retention and stereoselectivity of enanticmeric acids were regulated by the quinine concentration and by the addition of carboxylic acids as well as polar modifiers, e.g., methanol and 2‐propanol, to the mobile phase. © 1992 Wiley‐Liss, Inc.
Pulmonary inversion of 2‐arylpropionic acids: Influence of protein binding
Authors: Hall S.D. , Hassanzadeh‐Khayyat M. , Knadler M.P. , Mayer P.R.
Published: January 2005

The possible contribution of pulmonary metabolism to the putative first‐pass metabolism of 2‐arylpropionic acid nonsteroidal antiinflammatory drugs has not been documented. Isolated perfused rabbit lungs, perfused with 4.5% bovine serum albumin or 5% dextran, were used to study the pulmonary elimination of (R)‐ and rac‐ibuprofen, fenoprofen, and flurbiprofen. In the absence of protein binding, ibuprofen was metabolized via inversion and other pathways, whereas fenoprofen metabolism was essentially restricted to inversion of the (R)‐enantiomer; fraction inverted (± SE) was 0.37 ± 0.05 for (R)‐ibuprofen and 0.85 ± 0.03 for (R)‐fenoprofen. In the presence of protein, neither ibuprofen nor fenoprofen was metabolized. Flurbiprofen did not undergo pulmonary elimination under any condition studied. This study illustrates that even though a tissue is capable of metabolism, particularly inversion of 2‐arylpropionics, the quantitative importance of such elimination pathways may be minimal in the presence of the high degree of protein binding that is characteristic of these drugs. © 1992 Wiley‐Liss, Inc.
Stoichiometry of interaction between soluble (—)‐dopa melanin and enantiomers of ephedrine by NMR spectroscopy
Authors: Salazar‐Bookaman M.M. , Fowble J.W. , Patil P.N.
Published: January 2005

Synthetic soluble (—)‐dopa melanin was prepared in deuteriated buffer, pH 8, by autooxidation of the precursor. At 6 mM of the precursor, the incorporation was over 90%. The changes in the line width measurements of N‐CH3 protons of enantiomers of ephedrine in the soluble melanin were quantified by NMR spectroscopy. The dissociation constants of (—)‐1R,2S‐ephedrine, (+)‐1S,2R‐ephedrine, (—)‐1R,2R‐ψ‐ephedrine, and (+)‐1S,2S‐ψ‐ephedrine were 11.7, 4.20, 3.60, and 4.80 mM, respectively. Since the concentration of (—)‐dopa was known and since the conversion of (—)‐dopa to indole units of melanin was considered as 1:1, the stoichiometry of the interaction between the drug and the indole unit was calculated. Based on the dissociation constants of the enantiomers, it appears that up to four molecules of (—)‐ephedrine can interact with one indole unit of the melanin, while such a ratio for other isomers appear to be 2:1. The preference by indole units of melanin is stereoselective. © 1992 Wiley‐Liss, Inc.
Optical resolution of unusual amino acids using microbial proteases
Authors: Miyazawa Toshifumi , Iwanaga Hitoshi , Yamada Takashi , Kuwata Shigeru
Published: January 2005

We have developed novel enzymatic methods for the optical resolution of unusual amino acids. In this work, we tried two microbial proteases, available inexpensively in a crude state, from Aspergillus oryzae and from Bacillus subtilis. The enantioselective hydrolysis of the methyl esters of the N‐benzyloxycarbonyl (Z) derivatives of a number of amino acids, both aliphatic and aromatic, was examined using these microbial proteases. The enantiomeric purities of the resolved Z‐amino acids were determined accurately by methods based on the reversed‐phase HPLC separation of diastereomeric derivatives or the HPLC separation of enantiomeric derivatives on chiral stationary phases. In general, B. subtilis protease yielded better results than A. oryzae protease. Using the former protease, the amino acids bearing aliphatic side chains were resolved with good to excellent enantioselectivities and reasonable hydrolysis rates. The speed of hydrolysis was reduced significantly when the length of the side chain was longer than 5 carbon atoms. Phenylalanine, halogenated phenylalanines, and phenylalanine homologs were also resolved, generally with high enantiomeric purities, though the hydrolysis rates were not always reasonably fast. In all the cases examined, the L‐enantiomers were preferentially hydrolyzed as in the lipase‐catalyzed enantioselective hydrolysis reported previously. © 1992 Wiley‐Liss, Inc.
Resolution and adrenergic activities of the optical isomers of 4‐[1‐(1‐Naphthyl)ethyl]‐1H‐imidazole
Authors: Hong Seoung S. , Romstedt Karl J. , Feller Dennis R. , Hsu Fu‐Lian , George Clifford , Cupps Thomas L. , Lyon Robert A. , Miller Duane D.
Published: January 2005

Recently we synthesized a naphthalene analog of medetomidine, 4‐[1‐(1‐naphthyl)ethyl]‐1H‐imidazole hydrochloride (1), and found it to be highly potent in adrenergic systems. The separation of optical isomers of this naphthalene analog was achieved by using the isomers of tartaric acid. The optical purities of the isomers were determined by HPLC using a chiral column. Using X‐ray analysis the (+)‐isomer was determined to have the S absolute configuration. It has been reported that the (+)‐isomer of medetomidine (2) is the most potent enantiomer on α2‐adrenergic receptors. There were both qualitative and quantitative differences in biological activities of the optical isomers of 1 in α1‐ and α2‐adrenergic receptor systems of guinea pig ileum and human platelets. (+)‐(S)‐1, but not (—)‐(R)‐1 was a selective agonist of α2‐mediated responses in ileum whereas (—)‐(R)‐1 was more potent than (+)‐(S)‐1 as an inhibitor of α2‐mediated platelet aggregation. © 1992 Wiley‐Liss, Inc.
Improved resolution of (±)‐trans‐2'‐hydroxy‐5,9‐dimethyl‐6,7‐benzomorphans
Authors: Wetzel Joseph R. , Grego John D. , Mallamo John P.
Published: January 2005

An efficient resolution of (±)‐trans‐2'‐hydroxy‐5,9‐dimethyl‐6,7‐benzomorphan has been developed employing (—)‐(R)‐ and (+)‐(S)‐O‐acetylmandelic acids. Measurement of optical rotations on the resolved bases, NMR analyses of diastereomeric urea derivatives, as well as gas chromatographic analyses of diastereomeric amide derivatives indicate a net improvement over previous resolution methodology and an enantiomeric excess ≥ 99%. © 1992 Wiley‐Liss, Inc.
Enantioselective pharmacodynamics of the nonsteroidal antiinflammatory drug ketoprofen: In vitro inhibition of human platelet cyclooxygenase activity
Authors: Hayball Peter J. , Nation Roger L. , Bochner Felix
Published: January 2005

The pharmacological activity of ketoprofen enantiomers was investigated in humans by an in vitro method. The antiplatelet effect of ketoprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood obtained from each of four healthy volunteers. Ketoprofen was added separately to whole blood as a range of concentrations of (1) predominantly (S)‐ketoprofen, (2) racemic ketoprofen, and (3) predominantly (R)‐ketoprofen. (S)‐Ketoprofen was found to be solely active at inhibiting human platelet TXB2 production; (R)‐ketoprofen was devoid of such activity and did not modify the potency of its optical antipode. A relationship between the percentage inhibition of TXB2 generation and the unbound concentration of (S)‐ketoprofen in serum was modelled according to a sigmoidal Emax equation. The mean (±SD) serum unbound concentration of (S)‐ketoprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 0.320 (±0.062) ng/ml. This value for ketoprofen is considerably lower than previously reported values for (S)‐ibuprofen and (S)‐naproxen. © 1992 Wiley‐Liss, Inc.
Direct coupled column separation and determination of the diastereomeric glucuronides of almokalant, a new class III antiarrhythmic drug, in human urine
Authors: Stefansson Morgan , Hoffmann Kurt‐Jürgen
Published: January 2005

A reversed‐phase coupled column separation (CCS) system for the analysis of two diastereomeric glucuronides of almokalant, a new class III antiarrhythmic drug, in human urine is described. After direct injection of urine samples (50 μl) the glucuronides were isolated by complex formation on a terbium(III) loaded strong cation exchanger at alkaline pH. The solutes were eluted from the precolumn by an acidic mobile phase, enriched and separated on Hypercarb (porous graphitic carbon) as analytical column with 0.1 M acetic acid pH 2.8 and 30% acetonitrile as mobile phase. The calibration graph was linear (r2 = 0.9999) and the detection limits were in the low picomole (UV) or femtomole (fluorescence) range. Optimization of the analytical column revealed that elution order and selectivity for the glucuronides were dependent on the buffer agent and temperature used. By appropriate choice of mobile phase conditions all four diastereomers could be separated. © 1992 Wiley‐Liss, Inc.
Influence of uncharged mobile phase additives, pH, and structure differences on retention and enantioselectivity of chiral hexa‐ and octa‐hydrobenzo(g) quinolines on an ovomucoid glycoprotein column
Authors: Küsters Ernst , Spöundlin Christoph , Redey Stephan , Widmer Armin
Published: January 2005

The enantiomeric resolution of six closely related hexa‐ and octa‐hydrobenzo(g) quinoline racemates by HPLC on an ovomucoid column (Ultron ES‐OVM) is described. First, the influence of uncharged mobile phase additives (with different hydrogen bonding properties) and pH on retention and enantioselectivity is investigated. It is shown that an optimum pH of around 6 for the given separations is much more important than the choice of modifier. Second, the influence on enantioselectivity of small differences in molecular structure is examined. In one case a large difference is obtained for diastereomeric racemates depending on the cis‐ or trans‐configuration of the quinoline skeleton. Higher flexibility of the solute seen in the cis enantiomers seems to improve enantioselectivity. © 1993 Wiley‐Liss, Inc.
Influence of the route of administration on the pharmacokinetics of pirprofen enantiomers in the rat
Authors: Brocks Dion R. , Liang William T.C. , Jamali Fakhreddin
Published: January 2005

The pharmacokinetics of the enantiomers of the non‐steroidal anti‐inflammatory drug pirprofen were studied in male Sprague‐Dawley rats after oral and intravenous (iv) doses of the racemate. No significant differences were detected between the enantiomers after oral or iv dosing in t½, Vd, or ∑Xu. However, the R:S area under the plasma concentration (AUC) ratio after oral doses (0.92 ± 0.13) was slightly but significantly lower than after matching iv doses (1.05 ± 0.036). The absolute bioavailability of the active S‐enantiomer (78.5%) after oral doses was higher than the inactive R‐enantiomer (69.3%). The plasma protein binding of both enantiomers was saturable over a fivefold range of plasma concentrations. At higher plasma concentrations, the S‐enantiomer was less bound than the R‐enantiomer. In an in vitro experiment using everted rat jejunum, no chiral inversion was discernible. The dependency of the AUC ratio of the enantiomers on the route of administration may be due to stereoselective first‐pass metabolism. © 1993 Wiley‐Liss, Inc.
Enantioselective determination of hydroxychloroquine and its major metabolites in urine and the observation of a reversal in the (+)/(−)‐hydroxychloroquine ratio
Authors: Fieger Hiltrud , Iredale Joanna , Wainer Irving W.
Published: January 2005

A sequential achiral‐chiral high‐performance liquid chromatographic system has been developed for the quantitation in urine of the enantiomers of hydroxychloroquine (HCQ), and of its 3 major metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ). HCQ and its metabolites were separated and quantified on a cyano‐bonded phase, and the enantiomeric ratios were determined using a Chiral‐AGP chiral stationary phase. The assay validation and application of this method to a preliminary study in a human volunteer are presented. In this subject, the initial 0‐4 h urine contained the 2 HCQ enantiomers in a ratio of (+)‐HCQ:(−)‐HCQ of 3:2; by the 2,064 h of the study, this ratio had reversed to (+)‐HCQ:(−)‐HCQ of 3:7. © 1993 Wiley‐Liss, Inc.
Influence of specific albumin ligand markers used as modifiers on the separation of benzodiazepine enantiomers by chiral liquid chromatography on a human serum albumin column
Authors: Chosson Elizabeth , Uzan Serge , Gimenez Françclois , Wainer Irving W. , Farinotti Robert
Published: January 2005

Specific ligand markers for the various binding sites of human serum albumin (HSA) have been described in the literature. Some of these markers (medium chain fatty acids, warfarin, digoxin, and bilirubin) were used as mobile phase modifiers. Using a high performance liquid chromatographic (HPLC) column containing HSA as stationary phase, their influence was investigated on the separation in this phase of the enantiomers of three benzodiazepines (temazepam, oxazepam, and lorazepam). Displacement effects were observed with medium chain fatty acids. This influence was proportional to the chain length and to the concentration of acid. Allosteric cooperative effects were noted with digoxin for the three benzodiazepines. Both displacement and cooperative effects were observed with warfarin. Stereoselectivity was decreased for temazepam and oxazepam and increased for lorazepam. © 1993 Wiley‐Liss, Inc.
Acid‐Catalyzed nucleophilic substitution and racemization of 3‐methoxy‐N‐desmethyldiazepam enantiomers in methanol
Authors: Yang Shen K. , Lu Xiang‐Lin
Published: January 2005

pKa1 values of 3‐methoxy‐N‐desmethyldiazepam in acetonitrile and methanol containing various acid concentrations were determined by spectrophotometry to be 3.5 and 1.3, respectively. Temperature‐dependent racemization of enantiomeric 3‐methoxy‐N‐desmethyldiazepam in methanol containing 0.5 M H2SO4 was studied by circular dichroism spectropolorimetry and the racemization reactions were found to follow apparent first‐order kinetics. Thermodynamic parameters of the racemization reaction were found to be: Eact = 18.8 kcal/mol, and at 25°C: ΔH‡ = 18.3 kcal/mol, ΔS‡ = −14.8 entropy unit, and ΔG‡ = 22.7 kcal/mol, respectively. The racemization had an isotope effect (kH/kD) of 1.6 at 42°C. Based on the results of this report and those of earlier reports by other investigators, a nucleophilically solvated C3 carbocation intermediate resulting from either a P (plus) or an M (minus) conformation is proposed to be an intermediate and responsible for the stereoselective nucleophilic substitution and the subsequent racemization of 3‐methoxy‐N‐desmethyldiazepam enantiomers. © 1993 Wiley‐Liss, Inc.
New optically active 1,3‐oxathiolanes
Authors: Kraus Jean‐Louis , Attardo Giorgio
Published: January 2005

cis‐ and trans‐5‐Ethoxy‐1,3‐oxathiolane‐2‐carboxylic acids were obtained in pure form. The cis isomer was resolved into its enantiomers through diastereoisomeric salt formation with enantiomerically pure α‐methylbenzylamine. Reduction of the salt followed by benzoylation led to 2‐benzoyloxymethyl‐5‐ethoxy‐2(R)‐5(S)‐1,3‐oxathiolane and 2‐benzoyloxymethyl‐5‐ethoxy‐2(S)‐5(R)‐1,3‐oxathiolane, useful intermediates in nucleoside chemistry. © 1993 Wiley‐Liss, Inc.
The so‐called “interconversion” of stereoisomeric drugs: An attempt at clarification
Authors: Testa Bernard , Carrupt Pierre‐Alain , Gal Joseph
Published: January 2005

A variety of reactions can be categorized under the global concept of the “interconversion of stereoisomers.” Thus, racemization or epimerization can result from inversion of labile chiral centers. From the examples available, some predictive rules are suggested for a chiral center of the type R″R′RCH undergoing base‐catalyzed inversion and a provisional table of affecting groups is presented. Unimolecular inversion of nonsymmetrical, nonplanar ring systems can also result in racemization or epimerization, but no generalization can yet be offered. Beside these cases of nonenzymatic reactions, a limited variety of enzymatic reactions can operate to interconvert stereoisomers, the outcome rarely being a racemic mixture. An important aspect of stereoisomer interconversion is the time scale in which the phenomenon is observed. Thus, several reactions to nonezymatic racemization or epimerization are fast compared to the duration of action of the drug and therefore have pharmacological significance, while other are slower and are of pharmaceutical relevance only. © 1993 Wiley‐Liss, Inc.
Stereoselective protein binding of ketoprofen: Effect of albumin concentration and of the biological system
Authors: Dubois Nathalie , Lapicque Françloise , Abiteboul Michel , Netter Patrick
Published: January 2005

Equilibrium dialysis was used to study in vitro the enantioselective binding of R, S, and racemic ketoprofen at physiological pH and temperature in human serum albumin (HSA) (1, 20, and 40 g/liter) and in plasma. The binding of enantiomers in a racemic mixture was studied to see the effect of each isomer on the other's interaction with the protein. The free fractions were determined by high‐performance liquid chromatography. The binding of ketoprofen enantiomers to albumin was enantioselective, depending on both drug and protein concentrations. Enantioselectivity was observed in plasma too but was the opposite of that in HSA at 40 g/liter. The percentage of each isomer unbound was higher in the racemic mixture than with the isomer alone. The displacement of probes specific for HSA sites I and II, studied by spectrofluorimetry, suggests that all three preparations of ketoprofen are bound mainly to site I and secondarily to site II. © 1993 Wiley‐Liss, Inc.
CHIRBASE, a graphical molecular database on the separation of enantiomers by liquid‐, supercritical fluid‐, and gas chromatography
Authors: Koppenhoefer Bernhard , Nothdurft Andreas , Pierrot‐Sanders Joanna , Piras Patrick , Popescu Cristina , Roussel Christian , Stiebler Matthias , Trettin Ulrich
Published: January 2005

In order to cope with the increasing number of publications on the separation of enantiomers by chromatography on a chiral stationary phase, the graphical molecular database CHIRBASE was created. In the present state, the database package covers information (structural, bibiographic, and chromatographic data) on liquid‐, supercritical fluid‐, and gas chromatography; other methods will follow. CHIRBASE, running on the MDL software Chembase®, meets the requirements of contemporary information management in the chemical and pharmaceutical industry. (Detailed information including a demo‐version of each part of CHIRBASE can be obtained from the authors on request.) © 1993 Wiley‐Liss, Inc.
Benzoylcellulose derivatives as chiral stationary phases for open tubular column chromatography
Authors: Francotte Eric , Grolimund Karl , Juvancz Zoltan
Published: January 2005

The application of cellulose‐based stationary phases for chiral separations has been extended to open tubular column chromatography. Efficient columns were obtained by coating the capillaries with mixtures of chiral cellulose materials and conventional achiral stationary phases for gas chromatography. In this study, various siloxane and polyethylene glycol polymers were used as achiral components and mixed with different substituted benzoylcellulose derivatives as chiral components. Systematic investigations were carried out to determine the optimal ratio for the components of the stationary phase. Depending on the chromatographic mode—gas chromatography (GC) or supercritical fluid chromatography (SFC)—the stationary phases were found to behave differently. The applicability of the technique was demonstrated by the resolution of various racemic compounds. © 1993 Wiley‐Liss, Inc.
Use of cyclodextrins as chiral selectors for direct resolution of the enantiomers of fluoxetine and its metabolite norfluoxetine by HPLC
Authors: Piperaki Stavroula , Parissi‐Poulou Maria
Published: January 2005

The goal of this work is to investigate the direct chromatographic separation of the enantiomers of fluoxetine and its active metabolite norfluoxetine. The liquid chromatographic retention behavior of these enantiomers on a β‐cyclodextrin bonded‐phase column was investigated with respect to mobile phase composition, pH, ionic strength, and solvent selectivity. Relationships were established between these factors and the three most important chromatographic parameters: retention time, resolution, and selectivity. Most of the evidence suggests that the unique selectivity of this column isdue to inclusion complex formation, which provides the physical basis for enantiomeric resolution. After these studies a set of optimum chromatographic conditions was chosen for the simultaneous separation/determination of a mixture of the four enantiomers using fluorescence detector. © 1993 Wiley‐Liss, Inc.
Optical resolution by crystalline inclusion formation using new lactic acid derived hosts
Authors: Weber Edwin , Wimmer Claus
Published: January 2005

New optically active host compounds for chiroselective crystalline inclusion formation derived from natural lactic acid are synthesized. They enable useful enantiomer separations of different chiral compounds via cocrystallization and sorption on preparative scale including various ketones, lactones, alcohols, sulfoxides, and methyloxiranes. In the cases of 3‐methylcyclohexanone, 4‐methyl‐δ‐valerolactone, and 2‐phenylpropanol, ees > 99% were obtained from one cocrystallization step using these hosts. © 1993 Wiley‐Liss, Inc.
Enantioselective epoxidation by an optically active hydroperoxide
Authors: Hamann Hans‐Jürgen , Höft Eugen , Chmielewski Marek , Maciejewski Sylvester
Published: January 2005

Enantioselective epoxidation of prochiral allylic alcohols with optically active 4,6‐di‐O‐acetyl‐2,3‐dideoxy‐α‐D‐threo‐hex‐2‐enopyranosyl hydroperoxide in the presence of Ti(O‐i‐Pr)4 gives chiral epoxy alcohols with moderate enantiomeric excess. © 1993 Wiley‐Liss, Inc.