bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preparation of chiral building blocks and auxiliaries by chromatography on cellulose triacetate (CTA I): Indications for the presence of multiple interaction sites in CTA I
Authors: Francotte Eric , Wolf Romain M. 
Published: January 2005

AbstractDue to the increasing demand for optically active compounds, the development of methods supplying optically pure isomers is intensively progressing. Among these methods the chromatographic resolution on chiral stationary phases is very promising, although only a limited number of preparative applications have been reported so far. In this work, we demonstrate that especially cellulose triacetate I (CTA I) as a chiral phase presents a number of advantages for this purpose. The broad applicability and the high loading capacity of CTA I are particularly important features for preparative chromatography. Nevertheless, slight structural modifications of the racemates to be resolved can often strongly improve the resolution. This strategy has been applied to numerous practical problems and is illustrated in this work taking as examples some chiral building blocks and auxiliaries. Moreover, a systematic investigation of the influence of a substituent in the para‐position of the phenyl ring for different series of aromatic compounds led to the conclusion that a large number of different interaction sites must be present in the chiral environment of CTA I.
Absolute configuration ofcis‐5,6‐dihydrodiol enantiomers derived from helical conformers of 1,12‐dimethylbenz[a]anthracene
Authors: Yang Shen K. , Mushtaq Mohammad , Fu Peter P. 
Published: January 2005

Abstract1,12‐Dimethylbenz[α]anthracene (1,12‐DMBA) cis‐5,6‐dihydrodiol was synthesized by oxidation of 1,12‐DMBA with osmium tetroxide in pyridine in low yield (⩽3%) and was purified by sequential use of reversed‐phase and normal‐phase HPLC. Two pairs of 1,12‐DMBA cis‐5,6‐dihydrodiol enantiomers, derived from P (right‐handed helix) and M (left‐handed helix) conformers, were eluted as a single chromatographic peak on both reversed‐phase and normal‐phase HPLC. However, these four enantiomers were resolved by sequential use of two chiral stationary phase (CSP) HPLC columns. CSP (Pirkle type I) columns were packed with either (R)‐N‐(3,5‐dinitrobenzoyl)phenylglycine or (S)‐N‐(3,5‐dinitrobenzoyl)leucine, which is ionically bonded to γ‐aminopropylsilanized silica. Absolute configurations of enantiomers were determined by comparing their circular dichroism spectra with those of conformationally similar cis‐5,6‐dihydrodiol enantiomers of 4‐methylbenz[α]anthracene and 7,12‐dimethylbenz[α]‐anthracene with known absolute stereochemistry.
Eudismic analysis of a series of muscarinic ligands carrying a 1,3‐oxathiolane nucleus
Authors: Gualtieri F. , Romanelli M. N. , Teodori E. 
Published: January 2005

AbstractEudismic analysis was performed on a set of 14 muscarinic ligands carrying a 1,3‐oxathiolane nucleus, in order to obtain information about both the existence of receptor subgroups and of agonist and competitive antagonist interaction sites. The results obtained were compared with those from a study of the enantioselectivity of the pairs of enantiomers. The two approaches do not appear to be completely equivalent and would seem to complement each other usefully.
2H‐NMR resolution of the methylenic isotopomers of ethanol applied to the study of stereospecific enzyme‐catalysed exchange
Authors: Rabiller Claude , Mesbahi Mahmoud , Martin Maryvonne L. 
Published: January 2005

AbstractWe have shown that site‐specific natural isotope fractionation of hydrogen studied by NMR (SNIF‐NMR) is an important source of information on the mechanistic and environmental effects which govern the photosynthesis of sugars and their fermentation into ethanol. Three isotope ratios associated with the methyl, methylene, and hydroxyl sites of ethanol are determined in achiral media. In this study we show that complementary information about possible stereospecific mechanisms involving the methylenic hydrogens is also rendered accessible by 2H‐NMR enantiomeric resolution. The synthesis of mandelate esters enables exchange between the pro‐R site of ethanol and water to be investigated. Simultaneous access to the three site‐specific isotope ratios of the ethyl group is obtained at isotopic dilutions close to the natural ones. Mediation of the exchange by the enzymic system alcohol dehydrogenase‐α‐lipoyldehydrogenase and by the yeast Saccharomyces cerevisiae are compared. The progress of the reaction can be followed quantitatively as a function of time and the occurrence of glycolytic metabolism of endogeneous materials by yeast can be substantiated in a one‐pot experiment.
Chemical synthesis, absolute configuration, and stereochemistry of formation of 10‐hydroxywarfarin: A major oxidative metabolite of (+)‐(r)‐warfarin from hepatic microsomal preparations
Authors: Lawrence Ross F. , Rettie Allan E. , Eddy A. Craig , Trager William F. 
Published: January 2005

AbstractThe synthesis of a diastereomerically pure 10‐hydroxywarfarin [4‐hydroxy‐3‐(2‐hydroxy‐3‐oxo‐1‐phenylbutyl)‐2H‐1‐benzopyran‐2‐one] was accomplished in three steps from racemic warfarin. The relative configuration of the synthetic product was established by conversion to a cyclic derivative followed by NMR and X‐ray diffraction analysis. Absolute stereochemistry was determined by enzymatic conversion of either of the pure enantiomers of warfarin to a 10‐hydroxy metabolite of known relative configuration. Metabolic formation of 10‐hydroxywarfarin was studied using hepatic microsomal preparations from female rats and man. The formation of 10‐hydroxywarfarin catalyzed by hepatic microsomes from both dexamethasone‐treated rats and man was highly stereoselective [(R)/(S): 3.4–9.0] for (R)‐warfarin. In contrast, little stereoselectivity was observed in reactions catalyzed by untreated rat liver microsomes. The resultant stereochemistry at the site of oxidation was also found to be highly dependent on substrate stereochemistry. (R)‐Warfarin gave (9R;10S)‐10‐hydroxywarfarin with only a trace of the (9R;10R) isomer irrespective of which enzyme preparation was used for catalysis, while (S)‐warfarin gave (9S;10R)‐10‐hydroxywarfarin with only a trace of the (9S;10S) isomer, again irrespective of which enzyme preparation was used for catalysis.
Reversal of elution order of urea and thiourea derivatives of propranolol enantiomers on ionically versus covalently bound pirkle phases
Authors: Dyas A. M. , Robinson M. L. , Fell A. F. 
Published: January 2005

AbstractThe chromatographic performance of a series of urea and thiourea derivatives of (±)‐propranolol has been evaluated on three different Pirkle stationary phases. Seven different isocyanate reagents were used to generate a range of both aliphatic and aromatic urea derivatives with the isothiocyanates yielding the corresponding thiourea analogues. The Pirkle phases employed consisted of 3,5‐dinitrobenzoylphenylglycine and 3,5‐dinitrobenzoylleucine, both ionically and covalently bound to aminopropyl silica as well as phenethylpropylurea (covalently attached only). The urea derivatives were consistently more strongly retained on covalently bound columns than their thiourea counterparts. This is in contrast to the situation observed for the ionic columns, where the thiourea derivatives were the more strongly retained on the phenylglycine column and the more strongly retained in four of seven instances on the leucine column. The underlying mechanisms giving rise to these differences in retention are as yet unidentified but appear to involve the urea group.
Calmodulin discriminates between the two enantiomers of the receptor‐operated calcium channel blocker sk&f 96365: A study using 1H‐NMR and chiral HPLC
Authors: Reid David G. , MacLachlan Lesley K. , Robinson Simon P. , Camilleri Patrick , Dyke Catherine A. , Thorpe Christopher J. 
Published: January 2005

Abstract1H nuclear magnetic resonance at 360 MHz shows that SK&F 96365 (1‐{β‐[3‐(p‐methoxyphenyl)‐propyloxy]‐p‐methoxyphenethyl}‐1H‐ imidazole hydrochloride), an antagonist of mammalian receptor‐operated calcium channels, interacts with the calcium‐binding regulatory protein calmodulin (CaM). This may be inferred by a number of chemical shift changes in the spectrum of the calcium‐saturated protein induced by addition of the compound. Moreover, two well‐resolved singlets corresponding to the 2‐proton of the SK&F 96365 imidazolium moiety are observed in the spectrum over a wide range of protein:compound ratios. Separation of rac SK&F 96365 into its two enantiomers by high‐performance liquid chromatography on a cellulose tris (4‐methylbenzoate) column enabled us to show that the doubling of this NMR signal in the presence of CaM is due to a propensity of the protein to distinguish between the two optical isomers of the compound.
Stereoselective inhibition of thromboxane‐induced coronary vasoconstriction by 1,4‐dihydropyridine calcium channel antagonists
Authors: Eltze Manfrid , Sanders Karl H. , Boss Hildegard , Boer Rainer , Ulrich Wolf‐Rüdiger , Flockerzi Dieter 
Published: January 2005

AbstractThe biological activity of the (+)‐S‐ and (−)‐R‐enantiomers of niguldipine, of the (−)‐S‐ and (+)‐R‐enantiomers of felodipine and nitrendipine, and of rac‐nisoldipine and rac‐nimodipine was investigated in vitro and in vivo. Inhibition of coronary vasoconstriction due to the thromboxane A2 (TxA2)‐mimetic U‐46619 in guinea pig Langendorff hearts, displacement of (+)‐[3H]isradipine from calcium channel binding sites of guinea pig skeletal muscle T‐tubule membranes, and blood pressure reduction in spontaneously hypertensive rats were determined. The enantiomers were obtained by stereoselective synthesis. Cross‐contamination was <0.5% for both S‐ and R‐enantiomers of niguldipine and nitrendipine and <1% for those of felodipine. From the doses necessary for a 50% inhibition of coronary vasoconstriction, stereoselectivity ratios for (+)‐(S)‐/(−)‐(R)‐niguldipine, (−)‐(S)‐/(+)‐(R)‐felodipine, and (−)‐(S)‐/(+)‐(R)‐nitrendipine of 28, 13, and 7, respectively, were calculated. The potency ratio racnisoldipine/rac‐nimodipine was 3.5. Ratios obtained from binding experiments and antihypertensive activity were (+)‐(S)‐/(−)‐(R)‐niguldipine = 45 and 35, (−)‐(S)‐/(+)‐(R)‐felodipine = 12 and 13, (−)‐(S)‐/(+)‐(R)‐nitrendipine = 8 and 8, and rac‐nisoldipine/rac‐nimodipine = 8 and 7, respectively. Highly significant correlations were found between the in vitro potency of the substances to prevent U‐46619‐induced coronary vasoconstriction and their affinity for calcium channel binding sites as well as their antihypertensive activity. The mechanism of TxA2‐induced coronary vasoconstriction in guinea pig Langendorff hearts can be readily explained by a transmembrane influx of extracellular Ca2+ susceptible to stereoselective blockade by 1,4‐dihydropyridine calcium channel antagonists.
Interindividual variability in the enantiomeric disposition of ibuprofen following the oral administration of the racemic drug to healthy volunteers
Authors: Avgerinos A. , Hutt A. J. 
Published: January 2005

AbstractThe plasma disposition of the enantiomers of ibuprofen has been investigated following the oral administration of the racemic drug (400 mg) to 24 healthy male volunteers. The plasma elimination of (R)‐ibuprofen was found to be more rapid than that of the S‐enantiomer [plasma half‐life: (R) 2.03 h; (S) 3.05 h; 2P < 0.001], resulting in a progressive enrichment in the plasma content of this isomer, some 64% of the total area under the plasma concentration time curves (AUC) being due to the pharmacologically active enantiomer. The influence of dose on the pharmacokinetic characteristics of the enantiomers of ibuprofen, over the range 200–800 mg, was investigated in three subjects. Examination of dosenormalized AUC values and oral clearance indicate the dose dependence of (R)‐ibuprofen disposition.
Immobilized serum albumin: Rapid HPLC probe of stereoselective protein‐binding interactions
Authors: Domenici Enrico , Bertucci Carlo , Salvadori Piero , Motellier Sylvie , Wainer Irving W. 
Published: January 2005

AbstractA human serum albumin‐based HPLC chiral stationary phase (HSA‐CSP) has been examined as a tool to investigate binding of chiral drugs to HSA and drug–drug protein‐binding interactions. Rac‐oxazepam hemisuccinate (OXH) was used as a model compound and the chromatographic retention (k′) of its enantiomers was determined after addition of displacers to the mobile phase. Compounds known to bind at the same site as OXH and at different sites were tested for their displacing capacities. Competitive binding interactions between the OXH enantiomers and displacers in the mobile phase were reflected by decreases in the k′s of (R)‐ and (S)‐OXH. The results indicate that retention on the HSA‐CSP accurately reflects binding to native HSA and the technique can determine enantioselective and competitive binding interactions at specific sites on HSA. The HSA‐CSP was also able to recognize separate binding areas for (S)‐ and (R)‐OXH.
An HPLC procedure for the enantiomeric purity of an optically active cytosine analogue using ligand exchange
Authors: Pack Edward J. , Bleiberg Bonnie , Rosenberg Ira E. 
Published: January 2005

AbstractAn acylonucleotide analogue, 1‐[3‐hydroxy‐2‐(phosphonyl‐methoxy)propyl]cytosine (HPMPC), has shown activity against herpes simplex Type I and Type II viruses. An HPLC separation of the R‐ and S‐enantiomers of HPMPC by ligand exchange using a mobile phase containing phenylalanine as the chiral modifier and copper(II) as the metal ion is reported.
Metabolic enantiomeric interactions: The inhibition of human (S)‐warfarin‐7‐hydroxylase by (R)‐warfarin
Authors: Kunze Kent L. , Eddy A. Craig , Gibaldi Milo , Trager William F. 
Published: January 2005

AbstractInhibition of the metabolism of (S)‐warfarin, the more pharmacologically active enantiomer of the racemic drug, by (R)‐warfarin was investigated in microsomes obtained from three human livers. In each case the production of both (S)‐6‐ and (S)‐7‐hydroxywarfarin was found to be competitively inhibited by (R)‐warfarin. The Kis for inhibition of (S)‐6‐ and (S)‐7‐hydroxylation by (R)‐warfarin ranged from 7.0 to 8.4 μM and from 6.0 to 6.9 μM, respectively, while the Kms for the 6‐ and 7‐hydroxylation of (S)‐warfarin ranged from 3.6 to 3.8 μM and from 3.3 to 3.9 μM, respectively. In contrast, except for the 4′‐hydroxylation pathway (S)‐warfarin was found to be a weak inhibitor of the metabolism of (R)‐warfarin. Possible implications of these findings include the following: (1) the kinetic parameters defining the interactions of two enantiomers of a racemic drug with the cytochrome P‐450s or other macromolecular systems in the living organism can only be properly defined from experiments with the pure enantiomers, (2) an enantiomer of a racemic drug may contribute significantly to biological effect not by its inherent activity but by altering the pharmacokinetics of the eutomer, and (3) enantiomeric interactions are not easily detected unless directly sought and may be relatively common.
Interaction of propafenone enantiomers with human α1‐acid glycoprotein
Authors: Oravcová Jana , Lindner Wolfgang , Szalay Peter , Boháčik Ľubor , Trnovec Tomáš 
Published: January 2005

AbstractThe interaction of propafenone enantiomers with human α1‐acid glycoprotein was studied using high‐performance liquid chromatography. Each of the two optical antipodes interacted with one class of high‐affinity binding sites characterized by Ka(R) = (6.18 ± 0.93) × 105 M−1, n(R) = 1.34 ± 0.09 for the (R)‐isomer and Ka(S) = (8.93 ± 1.82) × 105 M−1, n(S) = 0.99 ± 0.08 for the (S)‐isomer. Nonspecific binding to secondary low‐affinity high‐capacity binding site(s) was only slightly greater in the case of the (S)‐enantiomer (n′k′(S) = (1.06 ± 0.09) × 104 M−1) compared to the (R)‐enantiomer (n′k′(R) = (6.87 ± 0.72) × 103 M−1). It was concluded that both enantiomers interact with common single class of high‐affinity binding sites on AAG (along with nonspecific binding) exhibiting only slight stereoselectivity for propafenone.
Pharmacologic antagonism of thromboxane A2 receptors by trimetoquinol analogs in vitro and in vivo
Authors: Shin Yangmee , Romstedt Karl J. , Doyle Kathrine , Harrold Marc W. , Gerhardt Mark A. , Miller Duane D. , Patil Popat N. , Feller Dennis R. 
Published: January 2005

AbstractAlthough (−)‐(S)‐trimetoquinol [1‐(3,4,5‐trimethoxy‐benzyl)‐6,7‐dihydroxy‐1,2,3,4‐tetrahydroisoquinoline; TMQ] is recognized as a potent bronchodilator, (+)‐(R)‐TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of [3H]SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (−log IC50) values for U46619‐induced aggregation (r = 0.99, P < 0.01) and serotonin secretion (r = 0.99, P < 0.01) in human platelet‐rich plasma and for whole blood aggregation (r = 0.99, P < 0.01). In each system, the rank order of inhibitory potencies was rac‐iodoTMQ ⩾ (+)‐(R)‐TMQ > rac‐TMQ ≫ (−)‐(S)‐TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac‐iodoTMQ, (+)‐(R)‐TMQ and rac‐TMQ 15 min before the injection of U46619 (800 μg/kg, iv) protected mice against U46619‐induced sudden death. On the other hand, (−)‐(S)‐TMQ did not protect animals against death. Protection of U46619‐induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3–100 mg/kg. Our findings show that these TMQ analogs act as potent and highly stereospecific TXA2 receptor antagonists in vitro and in vivo.
Stereoselectivity of (R)‐ and (S)‐hexahydro‐difenidol binding to neuroblastoma M1, cardiac M2, pancreatic M3, and striatum M4 muscarinic receptors
Authors: Waelbroeck M. , Camus J. , Tastenoy M. , Mutschler E. , Strohmann C. , Tacke R. , Lambrecht G. , Christophe J. 
Published: January 2005

Abstract(R)‐Hexahydro‐difenidol has a higher affinity for M1 receptors in NB‐OK 1 cells, pancreas M3 and striatum M4 receptors (pKi 7.9 to 8.3) than for cardiac M2 receptors (pKi 7.0). (S)‐Hexahydro‐difenidol, by contrast, is nonselective (pKi 5.8 to 6.1). Our goal in the present study was to evaluate the importance of the hydrophobic phenyl, and cyclohexyl rings of hexahydro‐difenidol for the stereoselectivity and receptor selectivity of hexahydro‐difenidol binding to the four muscarinic receptors. Our results indicated that replacement of the phenyl ring of hexahydro‐difenidol by a cyclohexyl group (→ dicyclidol) and of the cyclohexyl ring by a phenyl moiety (→ difenidol) induced a large (4‐ to 80‐fold) decrease in binding affinity for all muscarinic receptors. Difenidol had a significant preference for M1, M3, and M4 over M2 receptors; dicyclidol, by contrast, had a greater affinity for M1 and M4 than for M2 and M3 receptors. The binding free energy decrease due to replacement of the phenyl and the cyclohexyl groups of (R)‐hexahydro‐difenidol by, respectively, a cyclohexyl and a phenyl moiety was almost additive in the case of M4 (striatum) binding sites. In the case of the cardiac M2, pancreatic M3, or NB‐OK 1 M1 receptors the respective binding free energies were not completely additive. These results suggest that the four (R)‐hexahydro‐difenidol “binding moieties” (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interactions with the M1, M2, and M3 muscarinic receptors. When each of the hydrophobic groups is modified, the position of the whole molecule, relative to the four subsites, was changed to allow an optimal overall interaction with the muscarinic receptor.
Synthesis of the [8] gingerol enantiomers
Authors: Martin Michel , Guibet Philippe 
Published: January 2005

Abstract(+)‐(S)‐5‐Hydroxy‐1‐(4‐hydroxy‐3‐methoxyphenyl)‐3‐dodecanone 1a commonly named (+)‐(S)‐[8] gingerol is a natural product known to have cardiotonic activity.1–5 A total synthesis of both enantiomers is described with details for the first time using a general synthetic scheme which was recently outlined in the literature.6 This synthesis relies both on the separation of the diastereoisomers 4a and 4b by simple column chromatography on silica gel and on an HPLC analysis on a chiral phase to determine the optical purity of the enantiomers 8a and 8b of protected [8] gingerol. The gingerol isomers were thus obtained in good chemical yields in greater than 96% enantiomeric excess.
Optical resolution of two isomeric naphthylalanines by immobilized enyzmes
Authors: Pugnière Martine , Castro Bertrand , Previero Aldo 
Published: January 2005

AbstractOptical resolution of β‐(1‐naphthyl)alanine and β‐(2‐naphthyl)alanine have been efficiently carried out through enzymatic hydrolysis of their methyl ester and/or N‐acetyl ester derivatives by immobilized enzymes. Difficulties related to the lipophilic character of these amino acids were overcome by using emulsions of n‐butyl acetate–water as reaction medium. The use of an automatic recirculating apparatus allowed reproducible and repetitive use of the immobilized biocatalysts.
N‐(n‐Butylamide) of (S)‐2‐(phenylcarbamoyloxy)propionic acid: A new chiral solvating agent, derived from L‐lactic acid, for the enantiomeric purity determination of derivatized amino acids
Authors: Pini Dario , Uccello‐Barretta Gloria , Rosini Carlo , Salvadori Piero 
Published: January 2005

AbstractThe N‐(n‐butylamide) of (S)‐2‐(phenylcarbamoyloxy)propionic acid, easily prepared starting from the inexpensive L‐ethyl lactate, can be used as convenient chiral solvating agent (CSA) to determine the enantiomeric composition of N‐(3,5‐dinitrobenzoyl)amino acid methyl esters.
New chiral fluoroanthryl derivatives: Resolution of the enantiomers by chromatography on cellulose esters and their evaluation as chiral solvating agents in NMR spectroscopy
Authors: Francotte Eric , Lang Robert W. , Winkler Tammo 
Published: January 2005

Abstract2,2,2‐Trifluoro‐1‐(9‐anthryl)ethanol (TFAE) has now been widely used as a powerful chiral solvating agent for NMR spectroscopy. In connection with the development of a new general synthesis of halogenoalkylalkanols, starting from the corresponding ketone or aldehyde, we synthesized some halogenoalkyl‐1‐(9‐anthryl)methanol derivatives liable to work as chiral solvating agents. The racemic anthryl derivatives were preparatively resolved into their corresponding enantiomers by chromatography on triacetyl cellulose (CTA I) or on meta‐methylbenzoyl cellulose beads as chiral stationary phases. Their effectiveness as chiral solvating agents was measured as the magnitude of the splitting induced in the 1H‐NMR spectra of 1‐phenylethylamine and of (1‐phenylethyl)methyl ether in comparison with splitting caused by TFAE. While TFAE induced the largest splitting for 1‐phenylethylamine, 2,2,3,3,3‐pentafluoro‐1‐(9‐anthryl)propanol 2 was more effective in the case of (1‐phenylethyl)methyl ether, pointing out that depending on the substrate, other derivatives of the TFAE type can be very useful as chiral solvating agents.
A chiral stationary phase which affords unusually high levels of enantioselectivity
Authors: Pirkle William H. , Deming Kris C. , Burke John A. 
Published: January 2005

AbstractA chiral stationary phase (CSP) derived from N‐(1‐naphthyl) leucine has been prepared. This CSP is conceptually similar to the CSP derived from N‐(2‐naphthyl)alanine and was expected to separate the enantiomers of the same clientele of analytes as does the latter. The magnitudes of the separation factors observed on the two CSPs may differ markedly for a given analyte, the new CSP often affording much greater enantioselectivity.