bluuebunny/crossref_metadata_2025 huggingface dataset:
A general criterion for molecular recognition: Implications for chiral interactions
Authors: Topiol S.
Published: January 2005

A general criterion is formulated for molecular recognition. The criterion for recognition is the ineqality of the distance matrices of complexes of different compounds with a resolving agent under ambient experimental conditions. It is shown how this criterion provides for an objective, cell‐defined, and simple explanation for recognition of chiral compounds. This approach may be used to explain models (e.g., three‐point of attachment1) and relationships for chiral recognition. It is also shown how one‐, two‐, or three‐point mechanisms are equivalent in this formalism and could result in chiral recognition. Examples are used to illustrate how the so called one‐ or two‐point mechanisms may be operative in many experimental findings. Symmetry rreqirements of resolving agents may also be derived from considerations of distance matrices. Finally, the reciprocal relationship of chiral resolving agents is easily derived from the present method of analysis.
Improved performance of the second generation α1‐AGP columns: Applications to the routine assay of plasma levels of alfuzosin hydrochloride
Authors: Krstulovic A. M. , Vende J. L.
Published: January 2005

Described is a direct enantioselective separation of the enantiomers of alfuzosin hydrochloride on the second generation α1‐AGP column which offers improved efficiency, shorter analysis, and improved stability with respect to the first generation columns. The method has been applied to the analysis of drug substance in rat plasma. This highly efficient extraction method and the use of fluorimetric detection result in selective and sensitive determination of the enantiomers. The analytical validation parameters demonstrate the applicability of this method to pharmacokinetic and metabolic studies.
The interaction of the enantiomers of carvedilol with α1‐ and β1‐adrenoceptors
Authors: Nichols Andrew J. , Sulpizio Anthony C. , Ashton Daryl J. , Hieble J. Paul , Ruffolo Robert R.
Published: January 2005

The stereoselectivity of carvedilol, a novel β‐adrenoceptor antagonist and vasodilator with one asymmetric carbon atom, was examined at α1‐ and β1‐adrenoceptors in vitro and in vivo. (−)‐(S)‐Carvedilol is a potent, competitive antagonist of the β1‐adrenoceptor‐mediated positive chronotropic response to isoproterenol in guinea pig atrium, with a dissociation constant (KB) of 0.4 nM. (+)‐(R)‐Carvedilol was more than 100‐fold less potent than the (−)‐S‐enantiomer as an antagonist of β;1‐andrenoceptors, having a KB of approximately 45 nM. Consistent with these findings (−)‐(S)‐carvedilol (0.1 mg/kg, i.v.) produced a 25‐fold rightward shift in the β1‐adrenoceptor‐mediated positive chronotropic response to isoproterenol in pithed rats, whereas the (+)‐R‐enantiomer had no β1‐adrenoceptor blocking activity in vivo at this dose. In contrast to the marked degree of stereoselectivity observed at βl1‐adrenoceptors, both (−)‐(S)‐ and (+)‐(R)‐carvedilol produced equal antagonism of the α1‐‐‐‐adrenoceptor‐mediated vasoconstrictor response to norepinephrine in rabbit aorta, with KB values of 14 and 16 nM, respectively. Furthermore, in the pithed rat, the α1‐adrenoceptor‐mediated pressor dose–response curve to cirazoline was shifted approximately 6‐fold to the right by both the (+)‐R‐ and (−)‐S‐enantiomers of carvedilol at a dose of 1 mg/kg, i.v. In anesthetized spontaneously hypertensive rats, (−)‐(S)‐carvedilol was 6‐fold more potent as an antihypertensive than (+)‐(R)‐carvedilol. The vasodilator and acute antihypertensive activity of carvedilol results from α1‐andrenoceptor blockade produced by both enantiomers, and the concomitant β1‐adrenoceptor blockade produced by the (−)‐S‐enantiomer, which prevents reflex tachycardia that can offset the antihypertensive response, leading to greater overall antihypertensive potency of (−)‐(S)‐carvedilol relative to the (+)‐R‐enantiomer. These data also suggest that distinct regions of the carvedilol molecule are responsible for blocking α1‐ and β1‐adrenoceptors, with β1‐adrenoceptor blockade resulting from an area of the molecule containing the asymmetric carbon atom, specifically the carbazolyloxy propanolamine moiety, and α1‐adrenoceptor blockade resulting from a part of the molecule that does not contain the asymmetric carbon atom, most likely the phenoxyethylamine moiety.
Crystal structure and absolute configuration of (+)546‐[copy4Cl2]HDBT: An example of torsional isomerism
Authors: Payne N. C. , Thachuk M. E.
Published: January 2005

The crystal structure and absolute configuration of the (−)589‐dibenzoylmonohydrogentartrate salt of the cation [Co(pyridine)4Cl2]+ have been determined from a three‐dimensional X‐ray analysis. Single crystals were grown from dimethylsulfoxide: space group P212121, Z = 4, and cell dimensions a = 21.463(4), b = 23.112(3), and c = 7.490(1) Å. Full‐matrix least‐squares refinement on F converged at R = 0.075, 196 variables and 2029 observations. The cation has pseudotetragonal coordinate geometry, with axial Cl and equatorial N atoms. The dihedral angles between the pyridine ligands and the equatorial plane are 47(1), 39(1), 50(1), and 45(1)° and torsional isomerism is responsible for the solid‐state chiroptical properties of the cation. The preferential crystallization of the P atropisomer of the cation is attributed to a general electrostatic attraction between cation and anion.
Stereoisomeric flavour compounds XXXV: Chiral aroma compounds of sherry I. Optically pure stereoisomers of solerone and solerole
Authors: Mosandl Armin , Hollnagel Angelika
Published: January 2005

The enantioseparation of the sherry aroma components 5‐oxo‐4‐hydroxyhexanoic acid γ‐lactone (solerone) and 4,5‐dihydroxyhexanoic acid γ‐lactone (solerole) is achieved, using Chiraspher (Merck) as the chiral HPLC phase and the optical purity ascertained directly by HRGC with heptakis(3‐O‐acetyl‐2,6‐di‐O‐pentyl)‐β‐cyclodextrin (Lipodex D) as the chiral stationary phase. The absolute configurations of 4,5‐dihydroxyhexanoic acid γ‐lactones are assigned by 1H‐NMR spectral data of diastereomeric α‐methoxy‐α‐trifluoromethylphenylacetic acid (MTPA) esters, according to Mosher's model. Sensory qualities of the isomers are given.
Preparative resolutions of an α‐methyl carboxylic acid through selective transformations of readily epimerizable intermediates
Authors: Josef Kurt A. , D'Ambra Thomas E. , Rosi David , Philion Richard E.
Published: January 2005

Two preparations of the enantiomers of 2 are described. The first makes use of the chromatographic separation of the diastereomeric amides 6a and 6b. Standard hydrolysis of these amides caused racemization, so a milder sequence was developed which utilized carbonyldiimidazole and 1 equivalent of 1 N LiOH. The second preparation involved classical resolution of 9 with (−)‐cinchonidine. Subsequent transformations of this substrate involved ester formation, Friedel–Crafts acylation, and ester hydrolysis, all without racemization. The most notable of these reactions was the use of EtAlCl2 in the Friedel–Crafts step, which provided a mild acylation of 10. This second preparation affords a high yield, mild process for the potential preparation of kilogram quantities of (−)‐(R)‐2b.
Enantiomeric resolution of DNS‐amino acids by ligand exchange chromatography using l‐phenylalaninamide together with Cu(II) ions as chiral additives to the eluent
Authors: Carunchio V. , Girelli A. M. , Messina A. , Sinibaldi M.
Published: January 2005

Resolution of various α‐DNS DL‐amino acids by ligand exchange chromatography of L‐phenylalaninamide–copper(II) complexes on a conventional reversed‐phase packing is reported. Parameters of the mobile phase which control retention and enantioselectivity such as concentration of Cu(II) ion and L phenylalaninamide (PheNH2), pH, ionic strength, and acetonitrile content were examined. In order to obtain further information on the distribution and stability of the prevailing complex species formed between the metal ion and the chiral selector, spectrophotometric measurements in different media were also carried out.
Stereoselective pharmacokinetics of 3,4‐methylenedioxymethamphetamine in the rat
Authors: Fitzgerald Robert L. , Blanke Robert V. , Poklis Alphonse
Published: January 2005

Studies to characterize the pharmacokinetics of the enantiomers of MDMA were conducted in rats using the iliac arterial cannulation. Two routes of administration, intravenous and subcutaneous, were evaluated at two dose levels for each route [20 and 40 mg/kg (±)‐MDMA for subcutaneous, 10 and 20 mg/kg (±)‐MDMA for intravenous administrations]. The average half‐life (±SD) for all dosing groups was 2.5 ± 0.8 h for (−)‐(R)‐MDMA and 2.2 ±0.8 h for (+)‐(S)‐MDMA. The more rapid clearnace of (+)‐(S)‐MDMA compared with (−)‐(R)‐MDMA is consistent with the area under the curve (AUC) data of the parent drug and its primary metabolite MDA. The mean (±SD) AUC S/R ratios of MDMA and MDA were 0.70 ± 0.05 and 3.1 ± 0.8, respectively. Following a 20 mg/kg dose of racemic MDMA iv the mean (±SD) of the percent dose excreted as (−)‐(R)‐MDMA, (+)‐(S)‐MDMA, (−)‐(R)‐MDA, and (+)‐(S)‐MDA were 20 ± 10, 12 ± 6, 3 ± 1, and 6 ± 2, respectively.
Enantioselective binding of mephobarbital to plasma proteins
Authors: O'shea Nerida J. , Hooper Wayne D.
Published: January 2005

The enantioselective protein binding of mephobarbital (MPB) was investigated in human plasma and human serum albumin solutions by equilibrium dialysis. A small but statistically significant difference was observed in the in vitro plasma protein binding of the enantiomers; (S)‐MPB was ∼59% bound and (R)‐MPB ∼67% bound. The binding to albumin [(S)‐MPB: ∼29% bound, and (R)‐MPB: ∼41% bound] was less than to plasma proteins but showed somewhat greater enantioselectivity, suggesting that albumin binding is a major source of the enantioselectivity in plasma. The effects of MPB concentration, of varying enantiomeric concentration ratio, and of phenobarbital on the enantioselective binding of MPB were studied. The effect of age was also investigated by measuring the binding in plasma from 8 young (18–25 yr) and 8 elderly (>60 yr) male subjects who took single doses of MPB. The results were in close agreement with the in vitro binding data, and the binding of both enantiomers was marginally but significantly lower in the young compared with the elderly subjects. These differences in binding were consistent with previously observed pharmacokinetic differences between the two subject groups.
Optical resolution and absolute configuration of a nonsteroidal antiinflammatory drug, 2‐(10,11‐Dihydro‐10‐oxodibenzo‐[b,f]thiepin‐2‐yl)propionic acid
Authors: Yamamoto Masao , Nohira Hiroyuki , Masaki Mitsuo
Published: January 2005

The title compound (±)‐1 (CN‐100) was efficiently resolved into a pair of enantiomers by fractional crystallization of the diastereomeric salts of (−)‐and (+)‐1‐phenylethylamine. The purity of the enantiomers was determined using the chiral cellulose column (CHIRALCEL OJ®) which allowed direct separation of the enantiomers. A separation factor (α) of 1.73 was obtained. X‐Ray crystallographic analysis of the (+)‐isomer [salt of (−)‐1‐(4‐bromophenyl)ethylamine] showed that this enantiomer has S‐configuration. Biological studies have shown that only the (+)‐isomer has antiinflammatory activity. Racemization of (−)‐isomer was carried out by heating its propionic acid solution in the presence of mineral acid, such as HBr.
Relative configuration of thioridazine enantiomers
Authors: Patrick Kennerly S. , Singletary Joan L.
Published: January 2005

The relative configuration of the enantiomers of thioridazine was defined to explore the stereochemistry associated with the selective binding of (−)‐thioridazine to dopamine D‐1 receptors and (+)‐thioridazine to D‐2 receptors. Using a seven‐step stereoconservative synthesis, (−)‐(S)‐2‐piperidinecarboxylic acid was converted to (−)‐(S*)‐2‐(2‐chloroethyl)‐1‐methylpiperidine, a literature (−)‐thioridazine synthetic precursor. Accordingly, (−)‐ and (+)‐thioridazine are the (S)‐ and (R)‐enantiomers, respectively.
Helix‐sense‐selective polymerization of diphenyl‐2‐pyridylmethyl methacrylate with chiral anionic initiators
Authors: Okamoto Yoshio , Mohri Haruhiko , Nakano Tamaki , Hatada Koichi
Published: January 2005

Polymerization of diphenyl‐2‐pyridylmethyl methacrylate was carried out with the complexes of organolithium compounds with 22 chiral ligands. Helix‐sense‐selectivity of the polymerization was largely affected by a slight structural difference of chiral ligands. (+)‐(S)‐2‐(1‐Pyrrolidinylmethyl)pyrrolidine was the most effective ligand in producing a one‐handed helical polymer with narrow molecular weight distribution.
Iridium complexes of dehydroamino acids: The kinetic resolution of racemic diphosphines and their application in catalytic asymmetric hydrogenation
Authors: Brown John M. , Maddox Peter J.
Published: January 2005

The reaction of chiral diphosphines with a configurationally pure cationic bis‐enamide complex of iridium, bis(menthyl (Z)‐α‐benzamidocinnamate)‐iridium tetrafluoroborate, is described. When the reactant ligand is racemic then kinetic resolution occurs with high specificity under the appropriate conditions. Since the iridium diphosphine complex is catalytically inactive in homogeneous hydrogenation, the residual enantiomer may be reacted with bis(norbornadiene)‐rhodium tetrafluoroborate to produce an active catalyst. This effects the hydrogenation of methyl (Z)‐α‐acetamidocinnamate in optical yields comparable with those obtained separately with the enantiomerically pure ligand rhodium complex. The reaction of pure (+)‐ or (‐)‐enantiomer of bis(menthyl (Z)‐α‐benzamidocinnamate)‐iridium tetrafluoroborate with enantiomerically pure diphosphines has been studied. Invariably one hand of the diphosphine reacts rapidly with a given enantiomer of the iridium complex to give a stable diphosphine iridium enamide complex in which the original configuration of the coordinated olefin is maintained. The other combination of enantiomers reacts much more slowly, in keeping with the kinetic resolution work, and produces an enamide complex which is unstable in solution, isomerising to a second diastereomer. Since the absolute configuration of the iridium bis‐enamide complex has been established by X‐ray crystallography, this experiment affords a method of determining the configuration of rhodium enamide complexes in asymmetric hydrogenation (assuming structural homology between Rh and Ir). In all cases the disfavoured enamide complex was the one involved in the catalytic pathway.
Chiral aspects of drug action at ion channels: A commentary on the stereoselectivity of drug actions at voltage‐gated ion channels with particular reference to verapamil actions at the Ca2+ channel
Authors: Kwon Yong‐Wha , Triggle David J.
Published: January 2005

Ion channels may be considered as pharmacological receptors possessing specific drug binding sites with defined structure‐activity relationships. Accordingly drug binding to ion channels is stereoselective. Interpretation of this stereoselectivity may be complex because of the existence of differences in affinity and access to different channel states. Such state‐dependent interactions may give rise to quantitative and qualitative differences in stereoselectivity. The implications of such differences are reviewed for drug action at Na+, K+ and Ca2+ channels. Detailed attention is paid to the actions of verapamil enantiomers in the cardiovascular system where activities differ in vascular and cardiac tissues because of state‐dependent interactions and stereoselective first‐oass metabolism.
The kinetics of diastereomeric amino acids with o‐phthaldialdehyde
Authors: Meyer Marc W. , Meyer Veronika R. , Ramseyer Stephan
Published: January 2005

The kinetics of the reaction of the amino acid epimers L‐isoleucine, D‐alloisoleucine, L‐threonine, and D‐allo‐threonine with o‐phthaldialdehyde and mercaptoethanol were determined at 25°C. L‐Isoleucine reacts faster than its D‐epimer whereas L‐threonine reacts slightly slower than its D‐epimer. In the case of isoleucine, the consequence can be an allo/iso ratio which in the worst case is 25% too low if these amino acids are quantified by liquid chromatography and o‐phthaldialdehyde fluorescence detection. The effect on dating of fossils by amino acid racemization is discussed.
Chiral resolution of α,α′‐bis[3‐(N,N‐diethylcarbamoyl)piperidino]‐p‐xylene, a novel antiplatelet compound
Authors: Gollamudi Ramachander , Feng Zixia
Published: January 2005

α,α′‐Bis[3‐(N,N‐diethylcarbamoyl)piperidino]‐p‐xylene dihydrobromide, a novel antiplatelet agent, was resolved into three isomers A, B, and C, on a chiral α1‐acid glycoprotein analytical column using a mobile phase of 0.025 M phosphate buffer containing 0.025 M tetrabutylammonium hydrogen sulfate, at a pH of 6.5. The effect of molarity, temperature, pH, flow rate, and organic modifiers on the enantioselectivity was examined. Based on circular dichroic spectra at 220 nm, A and C appear to be the (−)‐ and (+)‐enantiomers, respectively, and B the meso diastereomer. Attempts at resolution using Pirkle type columns gave unsatisfactory results. It appears that both hydrophobic and polar interactions between the compound and the stationary phase are important determinants of resolution.
Some mechanistic aspects on chiral discrimination of organic acids by immobilized bovine serum albumin (BSA)
Authors: Allenmark Stig , Andersson Shalini
Published: January 2005

Although chiral anionic compounds, notably a large number of organic acids, have been found to be readily separated into enantiomers on BSA‐based columns, the structural requirements for an efficient enantiomer discrimination by the protein is still not very well known. Since it is often observed that very hydrophobic acids, like many of the antiinflammatory “profens,” can be resolved with large separation factors for the enantiomers, a systematic study of a series of racemic α‐substituted alkanoic acids was made. The series of analytes was prepared from α‐amino acids, RCH(NH2)CO2H (where R = C1‐C6), by reaction with N‐(chloroformyl)‐carbazole. A rapid increase in the capacity ratios of both enantiomers was found with increasing length of R. The effect, however, was larger for the last eluted enantiomer, leading to a substantial increase in the separation factor; this being 7.3 for R = C6 in 20 mM phosphate buffer (pH 8.0) with 30% of acetonitrile. Further, the separation factor also increased with decreasing organic modifier content. Thus when the R = C6‐analyte was run at a mobile phase concentration of 20% acetonitrile and a flow rate of 1.5 ml/min, the time difference between the two eluted enantiomers exceeded 20 hr.

A reasonable interpretation of our results seems to be that enantioselectivity is promoted by increased hydrophobic interaction. Since the anionic charge of the analyte is also taking part in the retention mechanism, a tight binding of the analyte will result from simultaneous electrostatic and hydrophobic interaction. When the latter is increased, less conformational freedom will be left for the analyte and the steric configuration at the α‐carbon atom will become more and more important. Steric hindrance by the α‐substituent in the first eluted enantiomer will counteract the tight binding caused by the combined binding interactions and lead to a smaller increase in the capacity ratio.
Enantioselective chromatography of the antimalarial agents chloroquine, mefloquine, and enpiroline on a α1 ‐acid glycoprotein chiral stationary phase: Evidence for a multiple‐site chiral recognition mechanism
Authors: Aubry Anne‐FrançCoise , Gimenez FrançCois , Farinotti Robert , Wainer Irving W.
Published: January 2005

The effect of mobile phase pH and dimethyloctylamine (DMOA) on the retention (k') and stereoselectivity (α) of antimalarial agents mefloquine, enpiroline, and chloroquine on the α1‐acid glycoprotein chiral stationary phase (AGP‐CSP) was investigated. An increase of k' with increasing pH was observed while the effect on α was a function of the solute. The magnitude and direction of changes induced by DMOA depended on pH and the structure of the solute.

The results of this study are consistent with a change of the conformation of the AGP between pH 5 and 7. At pH 7, the effect of DMOA on mefloquine was relatively well described by a competitive displacement from one enantioselective site. The effect on chloroquine and enpiroline suggests a multiple‐site mechanism in which both competitive and allosteric interactions are involved.
4',6‐Dichloroflavan (BW683C): Enantiomeric separation by hplc/dad and antirhinovirus activity
Authors: Quaglia M.G. , Desideri N. , Bossù E. , Sestili I. , Conti C.
Published: January 2005

Racemic 4',6‐dichloroflavan (BW683C), a highly effective inhibitor of rhinovirus serotype 1B in vitro, was resolved by high‐performance liquid chromatography on a chiral stationary phase. The enantiomers were separately collected and circular dichroism curves were obtained, in order to determine the absolute configuration of the two enantiomers. The activity of the isomers was studied on human rhinovirus serotype 1B multiplication in HeLa cell cultures, by means of the plaque reduction assay. Both enantiomers were potent inhibitors of virus replication; by comparing the IC50 values, the S form was 3.5 times more effective than the R form.
The effect of the enantiomers of ibuprofen and flurbiprofen on the β‐oxidation of palmitate in the rat
Authors: Zhao Bin , Geisslinger Gerd , Hall Iris , Day Richard O. , Williams Kenneth M.
Published: January 2005

The effects of the enantiomers of ibuprofen (0.25 and 0.50 mmol/kg b.w.) and flurbiprofen (0.01, 0.03, and 0.06 mmol/kg b.w.) on the β‐oxidation of palmitate were investigated in the rat. The mean cumulative exhalation of 14CO2 after ip administration of [U‐14C]palmitic acid was significantly reduced over 6 h by ibuprofen at the higher dose but not at the lower dose for either enantiomer. There was no difference between the enantiomers, the reduction over 6 h being 31.3 and 33.0% for (R)‐ and (S)‐ibuprofen, respectively. There was also a significant inhibition of β‐oxidation by flurbiprofen at all 3 doses. Again, there was no stereoselectivity evident in this inhibition. Flurbiprofen was much more potent than ibuprofen in eliciting this effect, the 0.01mmol/kg dose giving a similar reduction in β‐oxidation as observed for the 0.50 mmol/kg dose of ibuprofen. The data support the hypothesis that inhibition of the in vivo β‐oxidation of palmitate by ibuprofen and flurbiprofen is primarily via a nonstereoselective noncoenzyme A‐dependent mechanism. © 1992 Wiley‐Liss, Inc.
Enantio‐ and regioselectivity in the epoxide‐hydrolase‐catalyzed ring opening of aliphatic oxiranes: Part II: Dialkyl‐ and trialkylsubstituted oxiranes
Authors: Wistuba D. , Träger O. , Schurig V.
Published: January 2005

The extent of substrate enantioselectivity and regioselectivity of a series of aliphatic 2,3‐dialkyl‐ and trialkylsubstituted oxiranes in their in vitro epoxide‐hydrolase‐catalyzed hydrolysis depends on the size of the alkyl residues and on the substitution pattern of the oxirane ring. The enzyme‐catalyzed hydrolysis of cis‐oxiranes, containing at least one methyl substituent, shows complete or nearly complete substrate enantioselectivity and regioselectivity with nucleophilic attack by water occurring with inversion of configuration at the methylsubstituted ring carbon atom of (S)‐configuration. In the hydrolysis of the isomeric trans‐oxiranes, both enantiomers are metabolized with a higher rate for the (2S;3S)‐enantiomer. The conversion of trimethyloxirane occurs with high substrate enantioselectivity in favor of the (S)‐enantiomer and with complete regioselectivity at the monomethylsubstituted ring carbon atom. The differentiation of the enantiotopic ring carbon atoms (product enantioselectivity) in the smallest aliphatic meso‐oxirane, cis‐2,3‐dimethyloxirane, leads to (2R;3R)‐butane‐2,3‐diol with ee = 86%. cis‐2‐Ethyl‐3‐propyloxirane, possessing alkyl residues larger than methyl, represents an extremely poor substrate in the epoxide‐hydrolase‐catalyzed hydrolysis process. © 1992 Wiley‐Liss, Inc.
Short and simple synthesis of (R)‐ and (S)‐4‐hydroxypentylaminoacetamide: both enantiomers of the (ω‐1)‐hydroxylated metabolite of milacemide
Authors: Gorissen Hugo J. , Van Hoeck Jean‐Pierre , Mockel Anne M. , Journée Guido H. , Delatour Claude , Libert Valéry R.
Published: January 2005

Both (R)‐ and (S)‐4‐hydroxypentylaminoacetamide have been synthesized by reductive amination of glycinamide on the γ‐valerolactols corresponding to (R)‐ and (S)‐γ‐valerolactone, respectively. These enantiomeric lactones were readily obtained in high enantiomeric excess (ee) by enzymic porcine pancreatic lipase (PPL) kinetic resolution of rac‐methyl γ‐hydroxyvalerate. © 1992 Wiley‐Liss, Inc.
Preparation of α‐substituted α‐amino acids of high enantiomeric purity
Authors: Pirkle William H. , Heire Richard , Hyun Myung Ho
Published: January 2005

Racemic 5,5‐dialkyl hydantoins derived from ketones are resolved by preparative liquid chromatography as the diastereomeric 1‐carboxamide derivatives afforded by the reaction with optically pure configurationally known α‐phenylethyl isocyanate. Hydrolysis of the resolved diastereomers affords α‐substituted α‐amino acids of high enantiomeric purity. The synthetic route is short, overall yields are high, and the absolute configuration of the amino acid enantiomers may be deduced from the chromatographic and NMR properties of the diastereomers. © 1992 Wiley‐Liss, Inc.
The influence of solute structure, temperature, and eluent composition on the chiral separation of 21 aminotetralins on a cellulose tris‐3,5‐dimethylcarbamate stationary phase in high‐performance liquid chromatography
Authors: Witte Dirk T. , Franke Jan‐Piet , Bruggeman Frank J. , Dijkstra Durk , De Zeeuw Rokus A.
Published: January 2005

In the present study 21 different chiral aminotetralins were used to investigate the mechanism behind their enantiomeric resolution (Rs) on a commercially available high‐performance liquid chromatography (HPLC) cellulose tris‐3,5‐dimethylcarbamate stationary phase. The differences in the chemical structures of the aminotetralins used were never directly located on the chiral carbon. Their chromatographic behavior was studied for two eluent compositions at six different temperatures. Hydrogen bonding and ππ interactions are two possible solute–chiral stationary phase (CSP) interactions. Differences between the enantiomers in their spatial arrangement of positions involved in solute–CSP interactions were the major forces behind enantiomeric separation.

Lowering the temperature increased the Rs for the aminotetralins having π‐electrons not directly bonded to that part of the molecule where the hydrogen bonding with the CSP is located. Primary amines and secondary amines, with a sufficiently short N‐alkyl substituent, showed a decrease of Rs with lower temperatures, all other aminotetralins yielding an increase of Rs with lower temperatures. © 1992 Wiley‐Liss, Inc.
Cytochrome p‐455 nm complex formation in the metabolism of phenylalkylamines. XII. Enantioselectivity and temperature dependence in microsomes and reconstituted cytochrome p‐450 systems from rat liver
Authors: Jönsson Karl‐Henrik , Lindeke Björn
Published: January 2005

Formation of metabolic intermediate (MI) complexes was studied with the enantiomers of amphetamine, 1‐phenyl‐2‐pentanamine, N‐hydroxyamphetamine, and 2‐nitroso‐1‐phenylpropane (the C‐nitroso analogue of amphetamine). Three different enzyme systems were used; liver microsomes from phenobarbital pretreated rats and two reconstituted systems containing the P450 2B1 and P450 2C11 forms of cytochrome P‐450. Enantioselective complex formation in microsomes was shown for the amines and the nitroso compound, but not for the hydroxylamine. The highly purified P450 2B1 system formed the MI complex with all substrates tested, and the enantioselectivity observed with the microsomal system was reproduced. In the P450 2C11 system the nitroso compounds were completely inactive, whereas the enantiomers of N‐hydroxyamphetamine still produced the complex at a high rate. Changes in temperature were shown to affect (R)‐2‐nitroso‐1‐phenylpropane more than its enantiomer. Both enantiomers showed biphasic Arrhenius plots for MI complex formation in microsomes (breaks around 22°C), but the activation energies of the (R)‐isomer were about five times higher than those of the (S)‐isomer. A theory is presented which suggests different modes of interaction with the active site of P‐450 to account for the different behaviour of the various substrates. © 1992 Wiley‐Liss, Inc.
Measurement of the (R)‐ and (S)‐isomers of warfarin in patients undergoing anticoagulant therapy
Authors: McAleer Sarah D. , Chrystyn Henry , Foondun Aboo S.
Published: January 2005

An achiral/chiral high‐performance liquid chromatographic system for the analysis of total warfarin together with the (R)‐ and (S)‐enantiomers in clinical samples has been developed. The achiral analysis is achieved using a C8 column, which is coupled to a chiral stationary phase, α1‐acid glycoprotein (AGP), thereby allowing for analysis of warfarin isomers without interfering serum peaks. A 0.015 M phosphate buffer mobile phase with 15% v/v propan‐2‐ol (pH 7.0) was used on the C8/AGP system. UV analysis at 308 nm was used for quantitation of total warfarin on the C8 column and fluorescence (excitation 300 nm, emission 390 nm) detection was employed for isomer quantitation on the AGP. Retention time of total warfarin on the C8 column was 5.95 min, while that of the (S)‐ and (R)‐warfarin on the AGP column was 10.38 and 12.69 min, respectively. Peak resolution of the warfarin isomers was 1.64. All serum samples were subjected to solid‐phase extraction. Data from two patients in a single dose study indicate that a two‐compartmental model could represent the warfarin concentration—time data with enterohepatic circulation. In some patients studied during steady state therapy, concentrations of (S)‐warfarin were greater than (R)‐warfarin indicating that the clearance of the former is slower in these patients. © 1992 Wiley‐Liss, Inc.
Indirect chiral separation and analyses in human biological fluids of the stereoisomers of a thienothiopyran‐2‐sulfonamide (TRUSOPT), a novel carbonic anhydrase inhibitor with two chiral centers in the molecule
Authors: Matuszewski B. K. , Constanzer M. L.
Published: January 2005

The indirect chiral separation of the four stereoisomers (1)‐‐(4) of a novel carbonic anhydrase inhibitor with two chiral centers in the molecule is reported. The method is based on chemical derivatization of the secondary amino group of the inhibitor with chiral isocyanate, formation of diastereomeric urea derivatives, each with three chiral centers in the molecule, and their separation under nonchiral HPLC conditions. The attempts to separate racemic mixture (1)+(2) from its diastereomeric counterpart (3)+(4) under nonchiral conditions, and to separate enantiomers (1) and (2) directly on a chiral stationary phase (CSP) are also reported. The indirect method was utilized for the assessment of an in vivo inversion of configuration at either one or both chiral centers of the molecule of (1). Analyses of selected whole blood and urine samples from human subjects after multiple bilateral topical ocular dosing with (1) did not reveal the presence of any of the three possible stereoisomers (2)‐‐(4) of (1) indicating that the inversion of configuration at neither one nor two chiral centers of (1) occurs in vivo. © 1992 Wiley‐Liss, Inc.
Absolute configuration of (+)‐cis‐2,3‐dihydro‐2‐[(methylamino)methyl]‐1‐ [4‐(trifluoromethyl)phenoxy]‐1H‐indene hydrochloride, a chiral serotonin uptake inhibitor
Authors: Michals Dawn R. , Smith Howard E.
Published: January 2005

The absolute configuration of (+)‐cis‐2,3‐dihydro‐2[(methylamino)methyl]‐1‐[4‐(trifluoromethyl)pheno<y]‐1H‐indene hydrochloride, the more active enantiomer of a new serotonin inhibitor, was established as 1S,2S. This assignment was based on the application of the benzene sector and chirality rules to the interpretation of the inhibitor's circular dichroism spectrum and the spectra of other related chiral 1‐substituted 2,3‐dihydro‐1H‐indenes. © 1993 Wiley‐Liss, Inc.
Synthesis of (+)‐(R)‐ and (−)‐(S)‐5‐hydroxy‐2‐methyl‐2‐dipropylaminotetralin: Effects on rat hippocampal output of 5‐HT, 5‐HIAA, and DOPAC as determined by in vivo microdialysis
Authors: Höök Berit Backlund , Johansson Anette M. , Hjorth Stephan , Sundell Staffan , Hacksell Uli
Published: January 2005

Racemic 5‐methoxy‐2‐methyl‐2‐dipropylaminotetralin (3) has been prepared by a short synthetic route, in which the N,N‐dipropyliminium perchlorate of 5‐methoxy‐2‐tetralone (4) is a key intermediate. Racemic 3 was resolved by crystallization of the corresponding diastereomeric di‐p‐toluoyltartrates. The enantiomeric excess (%ee) of the phenolic derivatives of (+)‐(R)‐ and (−)‐(S)‐3 [(+)‐(R)‐ and (−)‐(S)‐2] was determined by 1HNMR spectroscopic analysis of the corresponding diastereomeric (−)‐(R)‐1,1′‐binaphthyl‐2,2′‐diylphosphoric acid salts utilizing 13C satellites. X‐ray crystallography established the absolute configuration of (−)‐(S)‐2 · HCl. The enantiomers of 2 were tested for hippocampal output of 5‐hydroxytryptamine, 5‐hydroxyindoleacetic acid, and dihydroxyphenylacetic acid in rats by use of in vivo microdialysis. The (−)‐(S)‐enantiomer appeared to affect 5‐HT‐turnover, whereas (+)‐(R)‐2 was inactive. Results obtained provide support for the previously reported hypothesis that the inactivity of (−)‐(S)‐2 at central DA receptors is caused by the steric bulk of the C(2)‐methyl group. This makes it possible to define a “DA D2 receptor essential volume.” © 1993 Wiley‐Liss, Inc.
Stereoselectivity of the aliphatic hydroxylation of 6‐n‐propylchromone‐2‐carboxylic acid in rat and guinea pig
Authors: Darbyshire John F. , Caldwell John
Published: January 2005

Following administration of 6‐n‐propylchromone‐2‐carboxylic acid (6‐n‐PCCA) (500 μmol/kg) to male rats, three metabolic products were detected and isolated from the 0–24 h urine. All were identified as resulting from oxidation exclusively along the 6‐n‐propyl moiety. Some 66% of the dose was excreted in the 0–24 h urine, 55% of which was 6‐PCCA, with 15% as (6‐1′‐hydroxypropyl)chromone‐2‐carboxylic acid (6‐1′‐HPCCA), 22% as 6‐(2′‐hydroxypropyl)chromone‐2‐carboxylic acid (6‐2′‐HPCCA), and 4% as (6‐3′‐carboxypropyl)chromone‐2‐carboxylic acid (6‐3′‐CPCCA). Derivatization of the methyl esters of the hydroxylated metabolities with S‐α‐methoxy‐α‐(trifuloromethyl)‐phenylacetyl chloride (Mosher's reagent) allowed the evaluation of urinary enantiomeric composition by HPLC and assignment of their absolute configurations by NMR. This was found to be 90:10 (R/S) for 6‐2′‐HPCCA, and 7:93 (R/S) for 6‐1′‐HPCCA. When rats were dosed with the racemic 1′‐ and 2‐hydroxy metabolites; no stereoselective metabolism or excretion was observed. Administration of 6‐n‐PCCA to male guinea pigs revealed that this species was unable to metabolise this compound. © 1993 Wiley‐Liss, Inc.
Chiral discrimination by albumin: A mechanistic study of liquid chromatographic optical resolution of nonaromatic carboxylic acids
Authors: Allenmark Stig
Published: January 2005

In order to get further insight into the mechanism by which bovine serum albumin (BSA) discriminates between enantiomers of organic acids, some radioisotopically labeled, nonaromatic carboxylic acids were studied under varying mobile phase conditions. It was found for a series of N‐alkanoyl‐DL‐[3H]leucines that the D‐enantiomers were much more strongly retained and that the composition of the mobile phase could be adjusted to give very large (α > 20) enantiomeric separation factors. The elution order was consistent with what has been found earlier for other N‐acyl derivatives as well as for N‐arylcarbamoyl derivatives of simple aliphatic amino acids. A marked increase in the hydrophobic interaction of the D‐enantiomers with the chiral phase was found upon a lowering of the mobile phase strength, conditions under which the L‐form was only slightly influenced. These and other results are consistent with a chiral recognition model by which inclusion of the compound in a hydrophobic chiral cavity of BSA with simultaneous charge interaction is assumed to take place and whereby discrimination is determined by the steric bulk and orientation of the α‐substituent. © 1993 Wiley‐Liss, Inc.
HPLC separation of the enantiomers of nicotine and nicotine‐like compounds
Authors: Demetriou Demetrios , Rustemeier Klaus , Voncken Peter , Schepers Georg
Published: January 2005

A sensitive and reproducible HPLC method utilizing a commercially available chiral α1‐acid glycoprotein (AGP) phase has been developed to separate and quantify the enantiomers of nicotine. The method is suitable for routine use as indicated by column life. The quantification of (R/S:0.05/99.95)‐nicotine or (R/S:99/1)‐nicotine was possible. In addition, the separation or at least partial separation of the enantiomers of nornicotine and nornicotine‐derived compounds was achieved. © 1993 Wiley‐Liss, Inc.
Dissymmetric calix[4]arenes: Optical resolution of some conformationally fixed derivatives
Authors: Pickard Simeon T. , Pirkle William H. , Tabatabai Moniralsadat , Vogt Walter , Böhmer Volker
Published: January 2005

Various possibilities to obtain intrinsically chiral calix[4]arenes are discussed. The enantiomers of three 1,3‐dietheresters and one monoether compound derived from dissymmetric calix[4]arenes with C4 symmetry were separated by HPLC using chiral stationary phases and characterized by their CD spectra. © 1993 Wiley‐Liss, Inc.
D‐amino acid levels in human physiological fluids
Authors: Armstrong Daniel W. , Gasper Mary , Lee Sun Haing , Zukowski Janusz , Ercal Nuran
Published: January 2005

Plasma, urine, cerebrospinal fluid (CSF), and amniotic fluid were examined to determine whether free D‐amino acids were present and if so at what levels. It was found that D‐amino acids exist in all physiological fluids tested, but that their level varied, considerably. The lowest levels of D‐amino acids were usually found in amniotic fluid or CSF (almost always <1% of the corresponding L‐amino acid). The highest levels were found in urine (usually tenth percent to low percent levels). Pipecolic acid seemed to be different from the other amino acids tested in that it was excreted primarily as the D‐enantiomer (often >90%). Correspondingly high levels of D‐pipecolic acid were not found in plasma. Some of the trends found in this work seemed to be analogous to those found in a recent rodent study. © 1993 Wiley‐Liss, Inc.
Stereoselective and isozyme‐selective drug interactions
Authors: Gibaldi Milo
Published: January 2005

A surprisingly large number of marketed drugs are racemic mixtures. The pharmacokinetic literature on racemic drugs contains a vast amount of information on drug–drug interactions derived from the measurement of total drug concentrations in plasma and urine. The appreciation of the role of stereochemistry in drug interactions with racemic warfarin resulted in a long‐overdue scientific rigor being applied to the study of drug interactions. It also compelled us to recognize that much of the literature was uninterpretable. A better understanding of oxidative metabolism, particularly the complexity of the cytochrome P‐450 family of enzymes, has also strengthened the scientific basis of drug interactions. We now recognize that investigators and clinicians must consider both stereoselectivity and isozyme selectivity in the study of drug interactions to understand the nature of the interaction so as to more effectively use new and potent drugs. © 1993 Wiley‐Liss, Inc.
Tissue distribution of bupivacaine enantiomers in sheep
Authors: Rutten Albert J. , Mather Laurence E. , McLean Colin F. , Nancarrow Craig
Published: January 2005

rac‐Bupivacaine HCl was infused intravenously to constant arterial blood drug concentrations in sheep using a regimen of 4 mg/min for 15 min followed by 1 mg/min to 24 h. At 24 h, arterial blood was sampled, the animal was killed with a bolus of KCl solution, then rapidly dissected and samples were obtained from heart, brain, lung, kidney, liver, muscle, fat, gut, and rumen. Tissue:blood distribution coefficients for (+)‐(R)‐bupivacaine exceeded those of (−)‐(S)‐bupivacaine (P < 0.05) for heart, brain, lung, fat, gut, and rumen by an overall mean of 43%. Blood:plasma distribution coefficients of (−)‐(S)‐bupivacaine exceeded those of (+)‐(R)‐bupivacaine by a mean of 29% and this offset the tissue:blood distribution coefficients so that the previously significant enantioselective differences disappeared. It is concluded that although enantioselectivity of bupivacame distribution is shown by the measured tissue:blood distribution coefficients, it is not shown when tissue:plasma water distribution coefficients are calculated, suggesting that there is no intrinsic difference between the bupivacaine enantiomers in tissue affinity. Sheep given fatal intravenous bolus doses of rac‐bupivacaine had significantly greater concentrations of (+)‐(R)‐bupivacaine than (−)‐(S)‐bupivacaine in brain (P = 0.028) and ventricle (P = 0.036); these could augment the greater myocardial toxicity of this enantiomer found in vitro. © 1993 Wiley‐Liss, Inc.
Enantioselectivity of esterases in human brain
Authors: Yang Shen K. , Huang Amy , Huang Jin‐Ding
Published: January 2005

Subcellular fractions of three human brain specimens were found to contain esterase activities which hydrolyzed racemic oxazepam 3‐acetate (rac‐OXA). All three human brain preparations were highly selective toward the S‐enantiomer of rac‐OXA. © 1993 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America.
Chiral discrimination in nonracemic mixtures of methanephosphonic acid, N,N′‐bis(1‐phenylethyl)diamides
Authors: Ouryupin Andrei B. , Kadyko Mikhail I. , Petrovskii Pavel V. , Fedin Erlen I.
Published: January 2005

Enantiomeric (S,S)‐ and (R,R)‐bis(1‐phenylethyl)diamidomethylphosphonates, the phosphorus atom being prochiral, have been synthesized, starting from the methanephosphonic acid dichloride and corresponding chiral amines. The splitting observed in the 31P‐NMR spectra of their nonracemic mixtures may be accounted for the self‐discrimination of chiral species. This effect can be very useful for enantiomeric analysis of amines based on coupling reactions with methanephosphonic acid dichloride. © 1994 Wiley‐Liss, Inc.
Enantioselective separations using capillary electrophoresis
Authors: Rogan Manus M. , Altria Kevin D. , Goodall David M.
Published: January 2005

The preconditions are outlined for enantioselective separations in capillary electrophoresis (CE) with chiral selectors as additives to the background electrolyte. Free solution capillary electrophoresis conditions are characterised by a single solution phase. Chiral separations are reviewed by selector type (chiral ligand exchange, cyclodextrins, crown ethers, glycoproteins) with the extensive studies on cyclodextrins grouped into sections on amino acids, pharmaceuticals, and speciality chemicals, optimisation, biological fluids, and quantitative aspects. In micellar electrokinetic capillary chromatography, enantioselective discrimination occurs by partition in a two‐phase system, with a chiral micellar phase as selector. Optimum separation conditions can be readily predicted for a given selector–selectand combination, and absolute values of binding constants determined by CE. Advantages of CE in comparison with HPLC using a chiral stationary phase include robust, rapid assays and the use of small volumes of aqueous solutions; disadvantages include less favourable detection limits. © 1994 Wiley‐Liss, Inc.
HPLC with carbohydrate carbamate chiral phases: Influence of chiral phase structure on enantioselectivity
Authors: Matlin Stephen A. , Tiritan M. Elizabeth , Crawford Andrew J. , Cass Quezia B. , Boyd Derek R.
Published: January 2005

The enantioselective resolution of trans‐stilbene oxide and of 23 chiral sulfoxides was investigated on cellulose and amylose tris(arylcarbamate) stationary phases coated on aminopropylated 7 μm spherical silica with 500 Å diameter pores. Cellulose tris‐(3,5 dimethylphenylcarbamate) showed good resolving power for many of the sulfoxides and amylose tris‐(3,5 dimethoxyphenylcarbamate) showed advantages for the resolution of certain sulfoxides which were not separated on other phases. © 1994 Wiley‐Liss, Inc.
The origin of chirality in protein amino acids
Authors: Chela‐Flores Julian
Published: January 2005

We discuss the origin of the chirality of protein amino acids from the point of view of a phase transition from a racemic mixture into an optically pure state. We assume that Bose–Einstein condensation may act as an amplification mechanism. The original theory is due to Salam. We suggest a new role for the phase transition. Following Quack we distinguish parity violation of two kinds (de facto and de lege symmetry breaking). While the Salam phase transition corresponds to parity violation of the second kind (de lege), the phase transition we discuss in this work corresponds to parity violation of what we may call a third kind. This is suggested by recent experimental phenomena which correlate chiral symmetry breaking and pattern formation (spontaneous symmetry breaking that separates an initial racemic mixture into right‐ and left‐handed space domains by means of a substrate). Tentative comments are given on the eventual design of possible experiments that may test this new hypothesis. © 1994 Wiley‐Liss, Inc.
Racemisation of drug enantiomers by benzylic proton abstraction at physiological pH
Authors: Pepper Christopher , Smith H. John , Barrell Kevin J. , Nicholls Paul J. , Hewlins Michael J. E.
Published: January 2005

The enantiomers of the aromatase inhibitors 3‐(4‐aminophenyl)‐pyrrolidine‐2,5‐dione (WSP‐3, II), its N‐pentyl derivative (III), and the antifungal econazole (IV), all possessing a benzylic proton at the chiral centre, are rapidly racemised in vitro in phosphate buffer (0.01 M) at pH 7.4 and 23°C with t½ values of 7, 6, and 5 h respectively. In vivo studies in rats show that (+)‐econazole is racemised after intraperitoneal injection with t½ = 1.24h. The enantiomers of the antifungal 1‐[(benzofuran‐2‐yl)‐4‐chlorophenylmethyl] imidazole (V) were stable at pH 7.4, attributable to steric hindrance to carbanion formation in the racemisation step. © 1994 Wiley‐Liss, Inc.
Enantioselective disposition of oral amlodipine in healthy volunteers
Authors: Laufen Heinrich , Leitold Máagtyá Ags
Published: January 2005

Plasma concentrations of (R)‐ and (S)‐amlodipine were measured after single oral administrations to 18 healthy volunteers of 20 mg amlodipine racemate. The contribution of the pharmacologically active (S)‐enantiomer to the concentrations of total amlodipine (sum of enantiomers) was significantly higher than that of the inactive (R)‐enantiomer, with mean values of 47% R to 53% S for the Cmax and 41% R to 59% S for the AUC (range between 24% R:76% S and 50% R:50% S). The oral clearance of the active (S)‐form was subject to much less intersubject variation (25% CV) than that of the inactive (R)‐form (52% CV). (R)‐Amlodipine was more rapidly eliminated from plasma than (S)‐amlodipine, with mean terminal half‐lives of 34.9 h (R) and 49.6 h (S). The terminal half‐lives of total amlodipine (mean 44.2 h) were strongly correlated with—and thus highly predictive for—the half‐lives of the (S)‐enantiomer. It is proposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers. © 1994 Wiley‐Liss, Inc.