bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparative separation of amino acid enantiomers as N‐TFA, O‐isopropyl derivatives by continuous countercurrent gas‐liquid chromatography
Authors: Sato Katsuya , Watabe Katsunori , Ihara Toshihide , Hobo Toshiyuki
Published: January 2005

Preparative separation of derivatives of amino acid enantiomers was carried out by a countercurrent gas–liquid chromatography (CCGLC) with chiral liquid phases, N‐stearoyl‐L‐valine tert‐butylamide and/or N‐stearoyl‐L‐leucine tert‐butylamide. In order to make effective use of these phases and also to lower the viscosity, Apiezon C was added as diluent. Through a repeated operation of a temperature gradient, purities more than 99% of leucine and α‐amino butyric acid derivatives were proved to be obtained. © 1993 Wiley‐Liss, Inc.
Enzymatic and chromatographic chiral discrimination of racemic (thio)glycidyl esters: Part I. A chemoenzymatic approach to both enantiomers of thioglycidyl esters
Authors: Martin Arnim A. , Offhauss Ulrike , Wagner Jürgen
Published: January 2005

Both hitherto unknown (+)‐(R)‐ and (−)‐(S)‐thioglycidyl esters, (R)‐(2) and (S)‐(2), have been synthesized with different high enantiomeric excesses (ee) by two routes from the corresponding rac‐glycidyl esters rac‐(1). The first includes a porcine pancreatic lipase (PPL)‐mediated kinetic resolution of these esters followed by sulfuration with practically complete inversion to the (+)‐(R)‐enantiomer (+)‐(R)‐(2) (36–86% ee). (−)‐(S)‐Thioglycidyl esters (−)‐(S)‐(2) are obtained by the reverse reaction sequence (43–80% ee). In the latter case the hydrolysis rate is lower than that of analogous glycidyl esters. Moreover, the dependence of enantiomeric excess on the size of the acyl‐group is of the opposite tendency. Therefore, in both cases suitable selection of the acid residue gives rise to maximum enantioselectivity. The irreversible lipase‐catalyzed acylation of rac‐glycidol and rac‐thioglycidol, however, was found to be a less suitable alternative. The enantiomeric excess of recovered homochiral esters was determined by chiral chromatography using modified cellulose stationary phases (OB, OD). © 1993 Wiley‐Liss, Inc.
Preparative scale enantioseparation of a chiral epoxide: Comparison of liquid chromatography and simulated moving bed adsorption technology
Authors: Nicoud Roger‐Marc , Fuchs Géraldine , Adam Philippe , Bailly Michel , Küsters Ernst , Antia Firoz D. , Reuille Robert , Schmid Emil
Published: January 2005

The feasibility of using simulated moving bed technology (SMB) for chiral separation on cellulose triacetate is demonstrated on the preparative scale: 1 kg of a chiral epoxide has been separated. On comparing SMB technology with conventional liquid chromatography it turns out that the main advantage of SMB lies in the significant reduction of mobile phase consumption. The process design for SMB is made theoretically and the predictions are confirmed by our pilot study. © 1993 Wiley‐Liss, Inc.
Chiral discrimination phenomena in mixed‐ligand copper(II) complexes with amino acids and 1,3‐dicarbonyl compounds
Authors: Davankov Vadim A. , Kurganov Alexander A. , Zhuchkova Ludmila Ya. , Ponomareva Tamara M.
Published: January 2005

Circular dichroism (CD) spectra of individual mixed‐ligand copper(II) complexes of 1,3‐dicarbonyl compounds, (1S)‐ or (1R)‐3‐hydroxymethylene camphor, (1S)‐3‐trifluoroacetyl camphor, or (1R)‐2‐hydroxymethylene menthone, and α‐amino acids, alanine, valine, proline, or their N‐alkyl derivatives, were calculated from CD spectra of equilibrium solutions containing the above constituents in methanol or ethylene dichloride. Diastereomeric mixed‐ligand complexes incorporating identical dicarbonyl but enantiomeric N‐alkyl‐α‐amino acid ligands exhibit quasi‐enantiomeric CD spectra. Unsubstituted amino acids, on the contrary, will make no decisive contributions to the net optical activity spectrum of the mixed‐ligand complexes. Formation constants of diastereomeric mixed‐ligand complexes have been calculated from data on disproportionation of the latter into corresponding equally paired complexes. Enantioselectivity was demonstrated to amount to up to 700 cal/mol. Possible steric structures of mixed‐ligand complexes are discussed. © 1993 Wiley‐Liss, Inc.
Enantioselective sequential transformations by use of metal complexes: Tandem‐Knoevenagel‐hetero‐Diels–Alder reactions with new chiral Lewis acids
Authors: Tietze Lutz F. , Saling Peter
Published: January 2005

Enantioselective reaction of the aldehydes 1a‐g and the 1,3‐dicarbonyl compound 2 in the presence of the chiral Lewis acid 5, derived from diacetone glucose, leads in a sequential transformation consisting of a Knoevenagel condensation and an intramolecular Diels Alder reaction to the cycloadducts 4a‐g with an ee value up to 88%. The selectivity is strongly dependent upon the temperature and solvent giving best results at room temperature in isodurene; in agreement with the principle of isoinversion, the ee values decrease at lower and higher temperatures. © 1993 Wiley‐Liss, Inc.
Chiral symmetry breaking: Experimental results and computer analysis of a liquid‐phase autoxidation
Authors: Buhse Thomas , Lavabre Dominique , Micheau Jean‐Claude , Thiemann Wolfram
Published: January 2005

The autoxidation of tetralin is treated as a model reaction system to define the applicability of stereospecific autocatalysis. This concept, predicting a spontaneous amplification of enantiomeric excess generated by an autocatalytic chemical reaction, is used in several theoretical models as an explanation for the origin of natural optical activity. The reaction system investigated obeys the basic criteria of these models: a chiral intermediate (tetralin hydroperoxide) is produced from an achiral substrate (tetralin) via an autocatalytic pathway where the feedback mechanism is expected to generate a state of broken chiral symmetry. In order to test the amplification capacity of this reaction a computer analysis of the kinetic scheme is performed. This simulation is derived from the known kinetic scheme of autoxidation and is validated by fitting the experimentally observed data of hydroperoxide evolution. Calculations show that this model allows powerful amplification of enantiomeric excess and a transient amplification of the optical rotation. It is also demonstrated that the model system exhibits pronounced sensitivity toward any loss of absolute configuration of the involved chiral species. Since an amplification effect results exclusively at a high degree of stereoselectivity, it is concluded that stereospecific autocatalysis is possible in systems which show template reactions, crystallization, or colloidal effects. © 1993 Wiley‐Liss, Inc.
Stereoselective distribution of acenocoumarol enantiomers in human plasma: Chiral chromatographic analysis of the ultrafiltrates
Authors: Fitos Ilona , Visy Júlia , Simonyi Miklós , Hermansson Jörgen
Published: January 2005

Stereoselectivities for the binding of rac‐acenocoumarol to human serum albumin (HSA), α1‐acid glycoprotein (AGP), and human plasma were determined by chiral HPLC analysis of the ultrafiltrates on a Chiral‐AGP column. The results confirmed the previously detected inverse stereoselectivities; for HSA the ratio of the enantiomeric constants was KR/KS ∼ 2, while for AGP it was KR/KS ∼ 0.3. In plasma the contribution of HSA dominates, although in pathological states, elevated AGP levels may compensate for stereoselective distribution. © 1993 Wiley‐Liss, Inc.
Biological significance of the enantiomeric purity of drugs
Authors: Waldeck Bertil
Published: January 2005

The knowledge that enantiomers of chiral compounds may differ widely in biological activity, qualitatively as well as quantitatively, is not new. Nevertheless most of the pharmacological data available to date on chiral drugs are obtained from experiments with racemates which assume that the biological activity generally resides in one of the enantiomers. With the advancements made in stereospecific synthesis and stereoselective analysis of drugs pharmacologists are now offered new possibilities to explore the steric aspects of drug action. This survey will discuss pharmacological data obtained with enantiomer pairs of phenylethylamine derivatives which interact with adrenergic mechanisms. The degree of resolution is seldom specified in published work on stereoselectivity of drugs. In a recent study from our laboratory the enantiomers of the β2‐adrenoceptor agonist formoterol and their diastereomers have been evaluated. We found that the (R;R)‐enantiomer was by far the most potent. However, the relative potencies obtained for the (R;S)‐, (S;R), and (S;S)‐ isomers were critically dependent on the degree of enantiomeric purity. It is concluded that the certainty of potency ratios observed for chiral drugs is limited by the enantiomeric purity and by unspecific effects of the least active enantiomer at very high concentrations. © 1993 Wiley‐Liss, Inc.
Siderophore‐Mediated microbial iron(III) uptake: An exercise in chiral recognition
Authors: Shanzer A. , Libman J. , Yakirevitch P. , Hadar Y. , Chen Y. , Jurkevitch E.
Published: January 2005

Molecular recognition by microbial receptors for siderophores [natural iron(III) carriers] is examined with synthetic iron(III) carriers as structural probes. The iron(III) carriers have been designed to reproduce the two essential features of the natural siderophores: the capability to form octahedral iron(III) binding cavities and to fit specific membrane receptors. Specifically, analogs of tripodal ferrichrome and linear ferrioxamines have been prepared and examined. The ferrichrome analogs rely on C3‐symmetric binders that are assembled from triscarboxylates as anchors, amino acids as bridges, and terminal hydroxamate groups as binding sites. The ferrioxamine analogs are based on linear assemblies of three identical monomers, each derived from a chiral amino acid. The deliberate use of animo acid residues as variable building blocks enables us to systematically modify the molecules' envelopes and the preferred absolute configuration of the iron(III) complexes until optimal performance is reached. Examination of the synthetic analogs in Pseudomonas putida demonstrates that the domains around the iron(III) center and their chiral sense dictate the extent of recognition by the membrane receptors. It is also shown that the synthetic siderophore analogs may be designed to either exert a broader, or a more narrow range of microbial activity than the natural siderophores. The implications of these findings are discussed in relation to the possible design of species‐specific antimicrobial agents. © 1993 Wiley‐Liss, Inc.
Enantioselective and nonenantioselective degradation of organic pollutants in the marine ecosystem
Authors: Hühnerfuss Heinrich , Faller Jörn , Kallenborn Roland , König Wilfried A. , Ludwig Peter , Pfaffenberger Bernd , Oehme Michael , Rimkus Gerhard
Published: January 2005

Enantiomeric ratios of 11 chiral environmental pollutants determined in different compartments of the marine ecosystem by chiral capillary gas chromatography and chiral high‐performance liquid chromatography allow discrimination between the following processes: enantioselective decomposition of both enantiomers with different velocities by marine microorganisms (α‐HCH, β‐PCCH, γ‐PCCH); enantioselective decomposition of one enantiomer only by marine microorganisms (DCPP); enantioselective decomposition by enzymatic processes in marine biota (α‐HCH, β‐PCCH, trans‐chlordane, cis‐chlordane, octachlordane MC4, octachlordane MC5, octachlordane MC7, oxychlordane, heptachlor epoxide); enantioselective active transport through the “blood–brain barrier” (α‐HCH); nonenantioselective photochemical degradation (α‐HCH, β‐PCCH). © 1993 Wiley‐Liss, Inc.
Disposition kinetics of ML‐1035 sulfoxide enantiomers and the prochiral sulfide in rats
Authors: Kuo Be‐Sheng , Poole James C. , Mandagere Arun K. , Hwang Kin‐Kai
Published: January 2005

ML‐1035, 4‐amino‐5‐chloro‐2‐[2‐(methylsulfinyl)ethoxy]‐N‐[2‐(diethylamino)ethyl]benzamide, is a sulfoxide compound and a racemic gastroprokinetic agent with a chiral center at the sulfur atom. We have investigated the disposition kinetics of (R)‐ML‐1035 sulfoxide (R) and (S)‐ML‐1035 sulfoxide (S) after the single enantiomers and the racemic mixture were administered to rats in separate experiments. There was no noticeable chiral inversion after either enantiomer dose. Both enantiomers were rapidly absorbed. After dosing with enantiomers or with the racemate, the resulting plasma concentration‐time curve of R was closely parallel to that of S in both intravenous and oral experiments, suggesting that the two enantiomers have approximately the same disposition kinetics. After intravenous enantiomer doses, only S underwent conversion to sulfide, suggesting that sulfidation in the liver is enantioselective. However, the enantioselective sulfidation after intravenous dosing did not introduce a difference in the global plasma disposition profiles between R and S, since the reduction reaction is a minor metabolic process. Other metabolic reactions such as sulfonation and mono‐N‐desethylations were not enantioselective. After oral administration, conversion to sulfide was observed for both enantioners, implicating the existence of a nonhepatic pathway in sulfidation. Administration of a prochiral sulfide dose was associated with an enantioselective sulfoxidation, in which the R/S concentration ratios increased as a function of time. In addition, enantiomeric interaction causing changes in pharmacokinetic parameters was observed after the oral racemate dose, while the interaction is negligible after an intravenous racemate dose, indicating a route dependency in enantiomeric interaction. © 1993 Wiley‐Liss, Inc.
Matrix synthesis of chiral carboxy derivatives: Aldehyde chiral discrimination due to a two‐point coordination of Mg2+
Authors: Beluzhenko Olga V. , Bogdanova Galina V. , Tumenev Vitalii A. , Zhdanov Yurii A.
Published: January 2005

To control stereoselectivity in aldol‐like reactions with chiral carbohydrate templates, we studied the interaction between completely protected dialdo compounds and magnesium enediolates of arylacetic acids. Diastereomeric mixtures of the highly functionalized acids obtained were esterified to isolate individual methyl uronates. It was found that all the diastereomeric esters exhibit Cotton effects of the same positive sign in the 220–230 nm region and so possess the same S configuration of the aryl chiral center C(6). Chiral center C(5) configurational assignments were performed using IR and ORD spectroscopy. We separated and specified four pairs of diastereomeric methyl uronates. It follows that the precursory acids have the same 5R*, 6S (major isomers) and 5S*, 6S (minor isomers) configurations. A tentative mechanism for complexation and possible models of Mg2+ ‐protected dialdose intermediate complexes has been proposed. We have concluded that a kind of orbital steering is realized, accompanied by some “tuning” of molecular assembly conditioned by two‐point coordination between Mg2+ and potential cation‐binding sites in the substrate molecules. Thus it has been demonstrated that reasonable diastereo‐selectivity can be achieved even through the use of small matrix molecules using rather small functional groups, which do not impose any stringent steric requirements. © 1993 Wiley‐Liss, Inc.
γ‐Cyclodextrin as chiral mobile phase additive in the HPLC separation of the atropisomers of some N‐arylthiazoline‐2‐thiones and N‐arylthiazoline‐2‐ones: Attempts to quantify the effect of selected structural parameters
Authors: Roussel Christian , Favrou Anita
Published: January 2005

The effect of the position and type of the substituent on the chromatographic separation of N‐arylthiazoline‐2‐thione and arylthiazoline‐2‐one atropisomers are described in reversed‐phase HPLC using β‐ or ‐β‐cyclodextrin as chiral mobile phase additive. A quantitative approach to experimental design has been developed. © 1993 Wiley‐Liss, Inc.
Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion
Authors: Musso David L. , Mehta Nariman B. , Soroko Francis E. , Ferris Robert M. , Hollingsworth Elizabeth B. , Kenney Bernard T.
Published: January 2005

The synthesis of the enantiomers of bupropion, (rac)‐2‐tert‐butylamino‐3′‐chloropropiophenone 1 (Wellbutrin®) is described. The enantiomers were compared with the racemate in both the tetrabenazine‐induced sedation model and the inhibition of uptake of biogenic amine assay. No significant differences were found in their potencies to reverse tetrabenazine‐induced sedation in mice or in their IC50 values as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain. © 1993 Wiley‐Liss, Inc.
Enantioselective detoxication of optical isomers of glycidyl ethers
Authors: Chen Ruth , Nguyen Phuong , You Zhengqing , Sinsheimer Joseph E.
Published: January 2005

The detoxication of the enantiomers of glycidyl 4‐nitrophenyl ether (GNPE), (−)‐(R)‐ and (+)‐(S)‐GNPE, and glycidyl 1‐naphthyl ether (GNE), (−)‐(R)‐ and (+)‐(S)‐GNE, by rat liver glutathione transferase and epoxide hydrolase was studied. Enantioselectivity was observed with both enzymes favoring the (R)‐isomers as determined by the formation of conjugate, diol, and remaining substrate measured by HPLC. Enantiomers of GNE were detoxified by cytosolic epoxide hydrolase but those of GNPE were not. Substantial nonenzymatically formed conjugates of enantiomers of GNPE were detected showing (S)‐GNPE the more reactive of the pair. © 1993 Wiley‐Liss, Inc.
Chiral discrimination of the enantiomers of δ‐phenyl‐δ‐valerolactone by cellulose triacetate: A chromatographic and microcalorimetric study of the thermodynamics
Authors: Wolf Romain M. , Francotte Eric , Hainmüller Justus
Published: January 2005

The resolution of racemic δ‐phenyl‐δ‐valerolactone by chromatography on cellulose triacetate CTA I results in one of the best separations of optical antipodes observed so far on this chiral stationary phase. The thermodynamics of the stereoselective interaction of the enantiomers of δ‐phenly‐δ‐valerolactone have been studied by chromatography at different temperatures and by direct microcalorimetric investigations of the complexation with CTA I. This analysis suggests that the separation process is mainly controlled thermodynamically and that kinetic effects, if any, play a minor role. Microcalorimetric titration experiments indicate that specific (optimum) complexation sites on CTA I for the stronger retained enantiomer of δ‐phenly‐δ‐valerolactone are rapidly saturated, whereas the first eluted enantiomer seems to interact much less selectively with defined interaction sites on the chiral polymer matrix. © 1993 Wiley‐Liss, Inc.
An improved method for the direct chromatographic resolution of abscisic acid enantiomers
Authors: Welch Christopher J.
Published: January 2005

An improved method for the direct chromatographic resolution of abscisic acid enantiomers using the commercially available Whelk‐O 1 chiral stationary phase is presented. Previously reported strategies utilized in the chromatographic separation of abscisic acid enantiomers are summarized, and conditions for analytical and semipreparative separations using the Whelk‐O 1 chiral stationary phase are described. This method offers the advantages of rapid analysis time and greatly increased capacity, allowing the resolution of more than 6 mg in 25 min using an analytical column (4.6 mm i.d. × 25 cm length). © 1993 Wiley‐Liss, Inc.
Use of isotopically chiral [4′‐13C]penciclovir and 13C NMR to determine the specificity and absolute configuration of penciclovir phosphate esters formed in HSV‐1‐ and HSV‐2‐infected cells and by HSV‐1‐encoded thymidine kinase
Authors: Hodge R. Anthony Vere , Darlison Sarah J. , Earnshaw David L. , Readshaw Simon A.
Published: January 2005

Penciclovir is a potent antiherpesvirus agent which is highly selective due to its phosphorylation only in virus infected cells. Phosphorylation of one of the hydroxymethyl groups of penciclovir (PCV) creates a chiral centre leading to the possible formation of (R)‐ and (S)‐enantiomers. The absolute configuration and stereospecificity of the PCV‐phosphates produced in cells infected with herpes simplex viruses types 1 and 2 (HSV‐1 and HSV‐2), as well as by HSV‐1‐encoded thymidine kinase, were determined using isotopically chiral [4′‐13C]PCV precursors and 13C NMR spectroscopy of the isolated metabolites. The absolute configuration of penciclovir‐triphosphate (PCV‐TP) produced in HSV‐1‐infected cells was shown to be S with an enantiomeric purity of greater than 95%. However, in contrast to HSV‐1‐infected cells in which none of the (R) enantiomer was detected, about 10% of (R)‐PCV‐TP was produced in HSV‐2‐infected cells. Phosphorylation of PCV by HSV‐1‐encoded thymidine kinase was found to give 75% (S)‐ and 25% (R)‐PCV‐monophosphate. The proportion of the (S)‐isomer appears to be amplified in the subsequent phosphorylations leading to the triphosphate. © 1993 Wiley‐Liss, Inc.
Stereoselective cyclooxygenase inhibition in cellular models by the enantiomers of ketoprofen
Authors: Suesa Nuria , Fernandez Maria Francisca , Gutierrez Marta , Rufat Maria Jose , Rotllan Elisabet , Calvo Lidia , Mauleon David , Carganico Germano
Published: January 2005

The pharmacological activity of rac‐ketoprofen and its enantiomers was investigated in vitro using different cellular models. The effect of these compounds on arachidonic acid metabolism was assessed by measuring the inhibition of prostanoid generation under the action of several agonists. Thus, we have evaluated the inhibition of (1) thromboxane B2 synthesis in rabbit platelets and human polymorphonuclear leukocytes (PMNs), (2) prostaglandin E2 synthesis in three cultured cells, namely human umbilical vein endothelial cells (HUVEC), human keratinocytes, and mouse macrophage‐like P388D1 cells. The IC50 values found for (+)‐(S)‐ketoprofen were in the range between 0.1 nM and 0.8 μM, being slightly lower in all models than those found for rac‐ketoprofen (0.4 nM–3 μM). On the other hand, (−)‐(R)‐ketoprofen showed inhibition of cyclooxygenase only at concentrations two or three orders of magnitude higher than those required for the (+)‐(S) enantiomer. These results, obtained with cell types of relevance for inflammatory processes and with compounds of high optical purity, demonstrate that the prostanoid biosynthesis inhibition caused by the drug rac‐ketoprofen is exclusively due to its dextrorotatory enantiomer. © 1993 Wiley‐Liss, Inc.
Warfarin metabolites: Stereochemical aspects of protein binding and displacement by phenylbutazone
Authors: Chan Eli , McLachlan Andrew J. , Rowland Malcolm
Published: January 2005

The in vitro human serum albumin binding characteristics of the enantiomers of the major metabolites of warfarin [6‐hydroxywarfarin (6‐HW), 7‐hydroxywarfarin (7‐HW), (S)‐warfarin alcohols [(S,S)‐ and (S,R)‐WA], and (R,S)‐warfarin alcohol [(R,S)‐WA]] have been studied, using a stereospecific HPLC assay. Warfarin metabolites are less bound both within plasma and a 40 g/liter solution of human serum albumin than the enantiomers of warfarin. The reduced warfarin metabolites have a lower fraction unbound [1.33% for (S,R)‐WA, 2.09% for (S,S)‐WA, and 1.04% for (R,S)‐WA] than hydroxylated metabolites [3.24% for (R)‐6‐HW, 4.26% (S)‐6‐HW, 4.49% for (R)‐7‐HW and 4.27% for (S)‐7‐HW] to HSA. Phenylbutazone produced a concentration‐dependent increase in the unbound fraction of all metabolites. It was possible to predict the unbound fraction of warfarin metabolites based on the unbound fraction of warfarin enantiomers. © 1993 Wiley‐Liss, Inc.
Enantioselective inhibitory effect of nicardipine on the hepatic clearance of propranolol in man
Authors: Vercruysse Isabelle , Belpaire Frans , Wynant Pascal , Massart Désiré L. , Dupont Alain G.
Published: January 2005

The influence of a single oral dose of 30 mg nicardipine on the pharmacokinetics of (R)‐ and (S)‐propranolol, given orally as rac‐propranolol 80 mg, was studied in 12 healthy volunteers. The plasma concentrations were higher for the (S)‐enantiomer than for the (R)‐enantiomer. The Clo and the Cl′intr of (S)‐propranolol were significantly lower than the Clo and Cl′intr of (R)‐propranolol. The unbound fraction of (R)‐propranolol was significantly higher than that of (S)‐propranolol. Coadministration of nicardipine significantly increased the AUC and Cmax and significantly decreased the Clo and Cl′intr for unbound drug of (R)‐ and (S)‐propranolol. These changes were more important for (R)‐ than for (S)‐propranolol. The protein binding was not altered by nicardipine. The enantioselective effect of nicardipine on the metabolic clearance of propranolol appears to be due to an interaction at the level of the metabolizing enzymes. The effect on blood pressure of rac‐propranolol was little affected when nicardipine was coadministered with rac‐propranolol, and its bradycardic effect was reduced. © 1994 Wiley‐Liss, Inc.
On the other hand: The stereoselectivity of drug action at ion channels
Authors: Triggle David J.
Published: January 2005

Ion channels are pharmacological receptors with specific drug binding sites. These binding sites define specific structure–function relationships for the actions of drug classes. Interpretation of these structure–function relationships may be complex because of state‐dependent drug‐channel interactions. These state‐dependent interactions determine affinity and access of drug to binding sites and may result in both quantitative and qualitative changes in structure–function relationships including stereoselectivity. A channel‐active drug may exhibit antagonist or activator properties according to membrane potential and the stereoselectivity of interaction may also change with channel state. © 1994 Wiley‐Liss, Inc.
Current regulatory (draft) guidance on chiral medicinal products: Canada, EEC, Japan, United States
Authors: Rauws Adalbert Gerard , Groen Kees
Published: January 2005

The rapid development of stereospecific analytical, synthetic, and preparative methods has profoundly changed the prospects for development and application of chiral medicinal products. This has induced regulatory agencies, e.g., in Canada, the EEC, Japan, and the United States, to prepare guidance on this subject. The present draft documents are discussed, with emphasis on the two most important cases: (1) New racemates: How many extra requirements are justified? (2) Development of a single enantiomer from an approved racemate: how few are acceptable? At the moment the opportunities for early harmonisation are favourable and the formulation of one international guidance document seems feasible. © 1994 Wiley‐Liss, Inc.
The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine
Authors: Aspeslet Launa J. , Baker Glen B. , Coutts Ronald T. , Torok‐Both George A.
Published: January 2005

The antidepressant fluoxetine (FLU) and its N‐demethylated metabolite, norfluoxetine (NFLU), each contains a chiral center. The combination of FLU and desipramine (DMI), another antidepressant, has been reported to be useful in treatment of depression, to dramatically increase plasma levels of DMI and also to produce more rapid β‐adrenergic receptor down‐regulation in brain than caused by DMI alone. We have now begun studies on the effects of this drug combination on the levels of FLU and NFLU enantiomers in the rat. In addition, the combination of FLU and iprindole (IPR) was also investigated. Male Sprague–Dawley rats were treated intraperitoneally with either normal saline vehicle, DMI (5 mg/kg/day), (R,S)‐FLU (10 mg/kg/day) or DMI (5 mg/kg/day) + (R,S)‐FLU (10 mg/kg/day) for 4 days. Following the last treatment, 24 h urine samples were collected. Rats were sacrificed and brains were removed. For the IPR study, rats were pretreated with either saline or IPR‐HCl (11.2 mg/kg) and then treated 1 h later with (R,S)‐FLU. After 5 h, the rats were sacrificed and brains were removed. Brain and urine samples were analyzed by gas chromatography with electron‐capture detection for free (R)‐ and (S)‐FLU and (R)‐ and (S)‐NFLU after extraction and reaction with (−)‐(S)‐N‐(trifluoroacetyl)prolyl chloride. The results from the brains of the rats treated with DMI/FLU indicate that levels of the enantiomers of both FLU and NFLU were significantly increased over those seen in the animals receiving (R,S)‐FLU alone. In the IPR/FLU treated rats, an increase in the brain levels of both (R)‐ and (S)‐FLU was noted when compared with rats receiving (R,S)‐FLU alone; however, there appeared to be no increase in the brain levels of NFLU enantiomers. © 1994 Wiley‐Liss, Inc.
Diphenylethanediamine (DPEDA) derivatives as chiral selectors: IV. A comparison of 3,5‐dinitrobenzoylated (S,S)‐ and (S,R)‐DPEDA‐derived chiral stationary phases with Pirkle's standard (R)‐phenylglycine‐derived phase in normal phase HPLC
Authors: Maier Norbert M. , Uray Georg , Kleidernigg Oliver P. , Lindner Wolfgang
Published: January 2005

Undecanoyl bound 3,5‐dinitrobenzoyl‐(S,R)‐1,2‐diphenylethane‐1,2‐diamine [(1S,2R)‐DNB‐DPEDA] as chiral selector (SO) has been synthesized and used as a chiral stationary phase (CSP II) for normal‐phase enantioselective HPLC. It is compared with the already published diastereomeric (1S,2S)‐DNB‐DPEDA‐derived CSP I and with the “standard” Pirkle DNB‐(R)‐phenylglycine‐derived CSP III. Chromatographic data for about 100 racemic analytes reveal that CSP II is able to separate especially well enantiomers of derivatized aromatic carboxylic acids and analytes having a benzyl substituent bound at the chiral center. However, CSP I was found to be superior to CSP II and III in its general applicability and its ability to resolve enantiomers of heterocyclic drugs. © 1994 Wiley‐Liss, Inc.
Experimental studies of competition between enantiomers in chiral liquid chromatography through their system peaks
Authors: Levin Shulamit , Abu‐Lafi Saleh
Published: January 2005

Competition between the (+)‐ and (−) enantiomers of 2,2,2‐trifluoro‐1‐(9‐anthryl) ethanol as mobile phase additives was indicated by the chromatographic behavior of their system peaks. Two types of chiral stationary phases were used, one based on dinitrobenzoylphenylglycine and the other on dinitrobenzylphenylethylamine plus tartaric acid. The racemic mixture was used as the mobile phase additive and k′ of their system peaks was studied as a function of the mixture concentration in the mobile phase in both cases. A shift in k′ of the two system peaks was observed and considered as an indication that competition occurred. The areas of the two system peaks were also studied as a function of the concentration of the enantiomers in the samples, using two different compositions of the mobile phase. The dependency of system peaks' area on the sample composition indicated whether competition between the enantiomers occurred. One mobile phase contained 0.1 mM of the racemic mixture, where the area of the two retained system peaks behaved independently, i.e., only the peak corresponding to the enantiomer was affected by its presence in the sample. The other mobile phase contained 0.75 mM of the racemic mixture, and both peaks were affected by the injection of any one of the enantiomers. The interdependency of the system peaks' area on both the enantiomers indicated that their distribution in the chiral system was interrelated due to mutual interactions. A quantitative treatment of the interdependency and competition was excluded, due to the irreversible adsorption of the two enantiomers on the chiral stationary phase after using overloading concentrations. This irreversible adsorption was visualized by the appearance of two retained system peaks of the two residual enantiomers. These system peaks were detected only when the sample contained pure enantiomers due to competition between the enantiomer in the sample with the residual enantiomers in the stationary phase. © 1994 Wiley‐Liss, Inc.
Stereoselective hydrolysis of ICRF‐187 (dexrazoxane) and ICRF‐186 by dihydropyrimidine amidohydrolase
Authors: Hasinoff Brian B.
Published: January 2005

The enzymatic ring‐opening hydrolyses of the doxorubicin cardioprotective agents (+)‐(S)‐ICRF‐187 (dexrazoxane), (−)‐(R)‐ICRF‐186, and rac‐ICRF‐159 by the enzyme dihydropyrimidine amidohydrolase (DHPase) have been studied. ICRF‐187 underwent enzymatic ring‐opening hydrolysis by DHPase 4.5 times faster than did ICRF‐186. It was also shown that DHPase opens only one ring of ICRF‐186 and does not act on this one‐ring open hydrolysis product, as has been observed for ICRF‐187. Differences in the rates at which the two optical isomers are acted upon by DHPase suggest that they could have differing protective effects. © 1994 Wiley‐Liss, Inc.
Stereoselectivity of the in vitro metabolism of thalidomide
Authors: Knoche Beate , Blaschke Gottfried
Published: January 2005

The stereoselective metabolism of the former sedative thalidomide and the metabolism of its analogue EM 12 were studied in vitro with liver homogenates. In our study we focused on hydroxylated nonhydrolyzed metabolites of thalidomide. An analytical HPLC method was developed to determine these metabolites directly. The investigations showed a highly stereoselective biotransformation of thalidomide. 5‐Hydroxy thalidomide was preferentially formed by (−)‐(S)‐thalidomide, whereas (+)‐(R)‐thalidomide was metabolized to two hitherto unknown compounds (Met A and B). Mass spectrometry of these metabolites Met A and B indicated that oxidation or hydroxylation took place in the glutarimide moiety. Biotransformation studies with the more stable thalidomide analogue EM 12 revealed four new metabolites (Met CF) whose quantities differed in the selected liver homogenate. © 1994 Wiley‐Liss, Inc.
Evaluation of enantiomeric purity of selected amino acids in honey
Authors: Pawlowska Maria , Armstrong Daniel W.
Published: January 2005

Highly sensitive and accurate HPLC methods were used for the determination of total amounts of proline, leucine and phenylalanine and their enantiomeric ratios in a variety of different honey samples. Significant amounts of D‐leucine and D‐phenylalanine and relatively low concentrations of D‐proline have been found in honeys of different botanical and geographical origins. It is suggested that the enantiomeric ratios of amino acids could be used to test for storage effects, age, and the quality of the processing of the honey. © 1994 Wiley‐Liss, Inc.
The direct determination of the enantiomers of ketorolac and parahydroxyketorolac in plasma and urine using enantioselective liquid chromatography on a human serum albumin‐based chiral stationary phase
Authors: Diaz‐Perez Maria J. , Chen John C. , Aubry Anne‐Francoise , Wainer Irving W.
Published: January 2005

An enantioselective assay has been developed for the determination of the enantiomers of ketorolac and its metabolite p‐hydroxyketorolac in plasma and urine. The analytical method utilizes a coupled achiral–chiral HPLC system where the initial separation of ketorolac from p‐hydroxyketorolac and matrix interferences was achieved on a C18‐stationary phase and the enantioselective separations of the two target solutes were accomplished on a human serum albumin‐based chiral stationary phase. The two columns were attached in sequence and the assay was carried out without the necessity of column‐switching techniques. The method has been validated for use in pharmacokinetic and metabolic studies and represents the initial report of the determination of ketorolac and p‐hydroxyketorolac enantiomers in urine. The results of the study indicate that after the administration of racemic ketorolac there was an enantioselective distribution of ketorolac enantiomers in plasma [(R)‐ketorolac: (S)‐ketorolac = 3.89 ± 0.93 (n = 6) and urine (R)‐ketorolac: (S)‐ketorolac = 1.26 ± 0.09 (n = 7)]. The mean ratio of the p‐hydroxyketorolac enantiomers was 1.77 ± 0.46 (n = 7). Both ketorolac and p‐hydroxyketorolac are glucuronized in the acyl carboxyl moiety and the results of this study indicate that this process is not enantiospecific. © 1994 Wiley‐Liss, Inc.
Preparation of milligrams of pure enantiomers using analytical‐scale high‐performance liquid chromatography
Authors: Liu Gaoyuan , Goodall David M. , Hunter Anna T. , Massey Peter R.
Published: January 2005

Pure enantiomers of an agrochemical process intermediate, (RS)‐1‐(4‐chlorophenyl)‐4,4‐dimethyl‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐pentan‐3‐one (1), have been prepared on the milligram scale under overload chromatographic conditions on an analytical chiral column (250 × 4.6 mm i.d.). The effects of variation of temperature and mobile phase composition on retention factor, separation factor, and peak resolution have been investigated. Effects of flow rate, enantiomer ratio, sample concentration, and column load on productivity are also studied. Seven milligrams of the less retained (+)‐enantiomer and 5 mg of the (−)‐enantiomer were obtained from a single injection of 21 mg of (RS)‐1. © 1994 Wiley‐Liss, Inc.
Lack of stereoselectivity of the peroxisome proliferation induced by 2‐phenylpropionic acid: Evidence against a role for lipid disturbance in peroxisome proliferation
Authors: Ahmad Dzulkifly , Caldwell John
Published: January 2005

The significance of disturbances of lipid metabolism caused by xenobiotic acyl‐CoAs as possible causes of peroxisomal proliferation has been studied with the enantiomers of 2‐phenylpropionic acid (2‐PPA), the (R)‐enantiomer of which is converted to the acyl‐CoA in rats while its (S)‐antipode is not. rac‐2‐PPA (250 mg/kg/day ip × 3) was shown to be an hepatic peroxisomal proliferator in male Sprague–Dawley rats on the basis of increases in microsomal cytochrome P‐450 content and lauric acid hydroxylation and hepatic CN−‐insensitive palmitoyl‐CoA oxidation, a peroxisomal marker activity, while electron microscopy revealed a rise in the peroxisome/mitochondria ratio in hepatocytes. Further studies established the dose–response relationships for these biochemical changes. The (R)‐ and (S)‐enantiomers were administered at a dose of 50 mg/kg/day ip × 3 and both were peroxisome proliferators of very similar potency. The effects of 100 mg/kg/day ip × 3 of the racemate, a dose giving ca. 75% of maximal response, were essentially additive of those of 50 mg/kg/day ip × 3 of its two component isomers. The stereoselectivity of acyl‐CoA formation from the enantiomers of 2‐PPA was confirmed by their differential inhibition of microsomal palmitoyl‐CoA synthesis. Taken together, these data indicate that it is very unlikely that the acyl‐CoA of 2‐PPA plays any role in the peroxisomal proliferation which this compound causes in the rat. © 1994 Wiley‐Liss, Inc.
Investigation of the enantioselectivity and enantiomeric elution order of some piperidine‐2,6‐dione drugs on chiralcel OD column
Authors: Aboul‐Enein Hassan Y. , Serignese Vince
Published: January 2005

The enantioselectivity and enantiomeric separation of five racemic piperidine‐2,6‐dione compounds, on the cellulose tris(3,5‐dimethylphenyl carbamate) chiral stationary phase Chiralcel OD‐CSP were investigated under the same chromatographic conditions. This class of drugs includes glutethimide, aminoglutethimide, cyclohexylaminoglutethimide, pyridoglutethimide, and phenglutarimide. The results revealed that chiral recognition and the binding sites of these drugs on the Chiralcel OD column are similar, regardless of the absolute configuration of the individual enantiomers. A possible chiral recognition mechanism(s) for this class of drugs and the CSP is presented. © 1994 Wiley‐Liss, Inc.
Absolute configuration and biological activity of mequitamium iodide enantiomers
Authors: Di Bugno Cristina , Dapporto Paolo , Giorgi Raffaello , Manzini Stefano , Paoli Paola , Subissi Alessandro , Arcamone Federico
Published: January 2005

The enantiomers of 1‐methyl‐3‐(10H‐phenothiazine‐10‐ylmethyl)‐1‐azoniabicyclo[2,2,2]octane iodide (1) were prepared by chiral chromatographic resolution of the precursor mequitazine (2). The (+)‐(S)‐enantiomer 1b is 10‐fold more potent than (−)‐(R)‐enantiomer 1a as a histamine antagonist, while the two enantiomers show the same antimuscarinic activity in vitro. The absolute configuration of the more active dextrorotatory isomer has been determined by X‐ray analysis. Conformational analysis and molecular modeling suggest that the (+)‐(S)‐enantiomer can adopt a conformation similar to that attributed to the receptor binding conformers of classical antihistamines. © 1994 Wiley‐Liss, Inc.
Preparation and configuration of racemic and optically active analgesic dialkylaminoalkylnaphthalenes
Authors: Ghislandi Victor , Azzolina Ornella , Collina Simona , Paroli Eugenio , Antonilli Letizia , Giuseppetti Giuseppe , Tadini Carla
Published: January 2005

The alkylaminoalkylnaphthalene 3 shows interesting opioid‐like analgesic properties, μ‐selective ligand competition, and enkephalin hydrolyzing enzyme inhibition. 3 possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids with the receptor is stereoselective, it was important to have the two racemic pairs as well as the four diastereomers. In this paper the synthesis of the (1R,2R/1S,2S)‐ and (1R,2S/1S,2R)‐racemates and the (1R,2R)‐ and (1S,2S)‐enantiomers of the 1‐ethyl‐1‐hydroxy‐1‐[2‐(6‐hydroxynaphthyl)]‐2‐methyl‐3‐dimethylaminopropane 3 is considered and the determination of absolute configuration is described. The (1R,2R/1S,2S)‐3 and (1R,2S/1S,2R)‐3 racemates and the (1R,2R)‐3 and (1S,2S)‐3 enantiomers were prepared by reaction of the racemic and optically active 1‐dimethylamino‐2‐methylpentan‐3‐one 2, respectively, with the lithiation product obtained from 2‐bromo‐6‐tetrahydropyranyloxynaphthalene and acidic hydrolysis. The optical resolution of aminoketone 2 was carried out via fractional crystallization of salts (+)‐ and (−)‐dibenzoyltartrates. The configuration of the optically active compounds was determined by X‐ray analysis of a crystal of (+)‐(1R,2R)‐3 · HCl · H2O. Preliminary pharmachological tests showed that (+)‐(1R,2R)‐3 enantiomer is able to induce opioid‐like analgesia with a relative potency 2.5 times that of (1R,2R/1S,2S)‐3 and about 4 times that of morphine. © 1994 Wiley‐Liss, Inc.
Evidence of absorption rate dependency of ibuprofen inversion in the rat
Authors: Sattari Saeed , Jamali Fakhreddin
Published: January 2005

Ibuprofen (IB) is a chiral 2‐arylpropionic acid derivative used as a nonsteroidal antiinflammatory drug (NSAID). It undergoes substantial R to S chiral inversion in humans and rats. In addition to systemic inversion, presystemic chiral inversion has been suggested for IB in humans but only after administration of formulations with slow absorption rates. In search for a suitable animal model, the absorption rate dependency of the extent of inversion was examined in male Sprague–Dawley rats given 20 mg/kg of racemic IB in aqueous solution (Tmax, 0.6 h), suspension (Tmax, 1 h) or as sustained release granules (Tmax, 2.3 h). In addition, (R)‐IB (5 mg/liter) was incubated in the presence of everted rat gut segments in an organ bath at 37°. After sustained release granules, the S:R AUC ratios (7.3 ± 1.5) were significantly higher than suspension (3.6 ± 1.1) and solution (3.5 ± 0.2). Accordingly, AUCS and AUCR, as percent of the total AUC (S + R), significantly increased and decreased, respectively, after administration of the sustained released granules as compared with the solution and suspension. A significant positive linear correlation was found between the S:R AUC ratios and the corresponding Tmax for (R)‐IB (r = 0.82). In vitro, (R)‐IB was inverted by everted jejunum (12.2 ± 1.6%), ileum (14.2 ± 2.0%), and colon (4.4 ± 0.6%) segments. IB was also glucuronidated in the presence of the intestinal segments. Therefore, similar to earlier observations made in humans, in the rat, the S:R AUC ratio was positively and significantly correlated with the absorption rate from the dosage form. Rat small intestine was capable of inverting and conjugating (R)‐IB. Hence, rat is a suitable model for studying the chiral inversion of IB. © 1994 Wiley‐Liss, Inc.
Stereoselective pharmacokinetics of methadone in beagle dogs
Authors: Schmidt Norbert , Brune Kay , Williams Kenneth M. , Geisslinger Gerd
Published: January 2005

The pharmacokinetics of methadone were studied in beagle dogs (n = 4) following intravenous administration of the racemate (0.5 mg/kg) and of the individual (R)‐(0.25 mg/kg) and (S)‐enantiomers (0.25 mg/kg) using a stereospecific HPLC assay. There was no significant difference between the pharmacokinetic parameters of (R)‐methadone and (S)‐methadone following administration of the individual enantiomers. Stereoselective differences were evident following administration of the racemate (P values for differences in AUC and CL were 0.001 and 0.046, respectively) and the clearance of the (S)‐enantiomer was increased when administered as part of the racemate (316 ± 81 vs 487 ± 128 ml/min, P = 0.04). The data suggest that stereoselective disposition including potential enantiomer–enantiomer interactions should be considered in pharmacokinetic–pharmacodynamic studies of (R,S)‐methadone. © 1994 Wiley‐Liss, Inc.
Enantiomerization of 2,2′‐diisopropylbiphenyl during chiral inclusion gas chromatography: Determination of the rotational energy barrier by computer simulation of dynamic chromatographic elution profiles
Authors: Jung Martin , Fluck Markus , Schurig Volker
Published: January 2005

By computer simulation of experimental dynamic gas chromatographic elution profiles, the rotational energy barrier ΔG= of racemic 2,2′‐diisopropylbiphenyl has been determined as 114.6–115.0 kJ/mol (75–100°C). These data are in good agreement with a value that was determined previously by measuring the racemization kinetics of an enriched sample. This indicates that there is no measurable catalytic or inhibitory effect of the stationary phase. © 1994 Wiley‐Liss, Inc.
Determination of the enantiomers of mianserin, desmethylmianserin, and 8‐hydroxymianserin in the plasma and urine of mianserin‐treated patients
Authors: Eap Chin B. , Powell Kerry , Campus‐Souche Donatella , Monney Christian , Baettig Dominique , Taeschner Walter , Baumann Pierre
Published: January 2005

An HPLC method is presented which allows the measurement in the same run of the enantiomers of mianserin, desmethylmianserin, and 8‐hydroxymianserin in plasma and urine of mianserin‐treated patients. Limits of quantitation for the (S)‐ and (R)‐ enantiomers of mianserin and desmethylmianserin were 4 and 2.5 ng/ml, respectively, in plasma, and for the (S)‐ and (R)‐enantiomers of mianserin, desmethylmianserin, and 8‐hydroxymianserin 5, 2.5, and 5 ng/ml, respectively, in urine. The measured ratios of (S)‐mianserin/(R)‐mianserin and (S)‐desmethylmianserin/(R)‐desmethylmianserin in the plasmas of 10 mianserin‐treated patients, all extensive metabolizers of debrisoquine as determined by CYP2D6 genotyping, varied, respectively, from 1.0 to 4.06 and from 0.19 to 0.64. As the enantiomers of mianserin differ in their pharmacological profile, these results could partially explain why, until now, no consistent relationship has been established between the therapeutic response and total [(S) + (R)] plasma levels of this antidepressant. © 1994 Wiley‐Liss, Inc.
In vitro inhibition of aromatase by the enantiomers of aminoglutethimide and analogs
Authors: Ogbunude Patrick O.J. , Aboul‐Enein Hassan Y.
Published: January 2005

The in vitro aromatase activity in microsomal fractions from rat ovary and its inhibition by enantiomers of aminoglutethimide (AG), rogletimide (RG), and cyclohexylaminoglutethimide (ChAG) were studied by analysing the [3H]H2O released when [1β‐3H]androstenedione was converted to estrone. Maximum velocity (Vmax) and the Michaelis‐Menten constant (Km) of the microsomal aromatase enzyme were 17.40 ± 0.45 pmol/ml/mg protein/min and 1.02 ± 0.06 μM, respectively. The IC50s for the enantiomers were similar for (+)‐R‐AG and (−)‐R‐ChAG (0.86 ± 0.06 and 0.89 ± 0.15 μM, respectively). (+)S‐ChA'G was most potent with IC50 of 0.075 ± 0.003 μM. The IC50s for (−)‐S‐AG, (+)‐R‐RG, and (−)‐S‐RG were in the same range (23.15 ± 2.74, 24.58 ± 2.46, and 24.43 ± 2.20 μM, respectively). © 1994 Wiley‐Liss, Inc.