bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct resolution of some phenylglycines by liquid chromatography on a chiral crown ether phase
Authors: Udvarhelyi Peter M. , Watkins J. C. 
Published: January 2005

AbstractThe optical resolution of a series of 12 amino acids of the phenylglycine family was studied using a chiral crown ether column. The effects of pH, temperature, and mobile phase additive were investigated. In three examples it was confirmed that the R enantiomer eluted prior to the S enantiomer. Most phenylglycines were resolved with large separation factors; those with two functional groups substituents on opposing sides of the phenyl ring, however, were not well separated.
Quantitation of the criticality of chiral centers toward stereoselective recognition: Epimeric eudismic analysis of 1,3‐oxathiolane muscarinic agonists and antagonists
Authors: Lehmann F. Pedro A. 
Published: January 2005

AbstractRecently published data1 on the aftinities of 14 pairs of chiral ligands, (1,3‐oxathiolanes) for muscarinic receptors in three different tissues were subjected to eudismic analysesThe enantiomeric eudismic‐affinity correlations (EACs) found by Gualtieri et al.1 were confirmed and extended to the submolecular level: (1) regressions of the eudismic index (log affinity ratio; EI) against eutomer potency of the average affinities were highly significant, indicating that the binding sites in all three tissues are identical; (2) for the five agonists the EAC was shifted to lower affinities and had a small slope (EAQ), in agreement with previous observations in other systems; (3) of the nine antagonists, six gave an excellent regression with unit slope, practically superimposable on that previously obtained for 10 structurally different oxotremorine derivatives, while two others (1,3‐oxathiolanes) could be plotted on a separate line with the same EAQ, but shifted to higher affinities; (4) the aberrant low EI of the last antagonist could be explained in terms of its structureFurthermore, an epimeric EAC (EEAC) revealed additional important information for quantitative stereo‐structure–activity relationships (QSSAR): the 25 possible epimeric comparisons were found to group into 6 different EACs in accord with differences in their structure: (1) the agonists fell on three separate lines of nearly identical (unitary) slope, which grouped cleanly in terms of the center of epimerization (positions 2, 3, and 5); (2) the antagonists of lower affinity fell on three lines with a common X‐intercept but with different slopes corresponding to epimerization at the different centers of chirality, indicating that these display quantitative differences in their criticality toward stereoselective recognition; (3) the remaining two antagonists of higher affinity fell on a separate line, again of unit slope.The significance of these correlations is discussed in relation to receptor speciation and in regard to other stereoselectivity data available on muscarinic receptorsThe quantitation of the criticality of different chiral centers, made possible here by the very high binding energies involved, should also be applicable to other stereoselective recognition processes (e.g., in enantioselective chromatography). Finally, a fundamental assumption of molecular pharmacology and QSAR, i.e., that a given structural feature always contributes a constant amount to the overall binding energy, is questioned in view of the above findings, which indicate that the contribution increases with the overall affinity, a feature which might be applicable to all pharmaca, not just to those containing chiral molecules.
Excavations in drug chirality: 1. Cyclothiazide
Authors: Nusser Elfriede , Banerjee Anirban , Gal Joseph 
Published: January 2005

AbstractThere is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of “several stereoisomers.” Inspection of the chemical structure of the drug, 6‐chloro‐3,4‐dihydro‐3‐(5‐norbornen‐2‐yl)‐2H‐l,2,4‐benzothiadiazine‐7‐sulfonamide 1,1‐dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast‐atom‐bombardment mass spectrometry, gas–liquid chromatography, chiral and nonchiral high‐performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered.
Comparative effects of the diastereoisomers, quinine and quinidine in producing phenocopy debrisoquine poor metabolisers (PMs) in healthy volunteers
Authors: Ayesh R. , Dawling S. , Hayler A. , Oates N. S. , Cholerton S. , Widdop B. , Idle J. R. , Smith R. L. 
Published: January 2005

Abstract
A single oral dose (50 mg) of quinidine significantly increased the debrisoquine metabolic ratio in six healthy volunteers. For four of the volunteers the metabolic ratio changed to that typical of the poor metaboliser (PM) phenotype.
The effect of quinidine in producing debrisoquine oxidation “poor metaboliser” phenocopies persisted for at least 3 days but had disappeared by 1 week.
The debrisoquine metabolic ratios for the same six subjects were not significantly altered by the oral administration of quinine (200 or 400 mg), the dia‐stereoisomer of quinidine.
The plasma pharmacokinetic parameters of both nortriptyline and desipramine in healthy volunteers were all changed to those more typical of the debrisoquine PM phenotype following the concomitant administration of quinidine (50 mg).
It is concluded that quinidine, but not its diastereoisomer quinine, is a potent selective inhibitor of the in vivo oxidation of debrisoquine and can produce an artifactual PM phenocopy in persons who are phenotypically extensive metaboliser (EM) phenotype status. The clinical implications of this observation are discussed.
Benzoyl cellulose beads in the pure polymeric form as a new powerful sorbent for the chromatographic resolution of racemates
Authors: Francotte Eric , Wolf Romain M. 
Published: January 2005

AbstractCellulose‐based stationary phases are known to be very efficient and versatile chiral sorbents for the chromatographic resolution of racemates. Except for microcrystalline cellulose triacetate (CTA I), basically all other cellulose‐based phases have been prepared by coating of ca. 20% weight polymer on a wide pore silica gel used as a carrier. In this work we describe the preparation of benzoylcellulose (TBC) beads in the pure polymeric form (without inorganic carrier) from an emulsion of the organic polymer. The new material has been fully characterized and used as a chiral stationary phase for the resolution of various classes of racemic compounds such as benzylic alcohols or acetate derivatives of aliphatic alcohols and diols. The structural variety of the separated solutes as well as the irrational influence of the aromatic substituent in different classes of aryl compounds suggest that multiple interaction sites are involved in the complexation, making a prediction of the separation difficult. The benzoyl cellulose beads exhibit a very high loading capacity, which is particularly useful for preparative purposes as demonstrated for selected examples.
Chirality of isomers of aldosterone formed in dilute alkali
Authors: Duax William L. , Griffin Jane F. 
Published: January 2005

AbstractIn the presence of dilute alkali at room temperature aldosterone undergoes rearrangement to form 11β,18:18,21‐diepoxy‐20,21‐dihydroxy‐4‐pregnen‐3‐one (V). X‐Ray crystallographic analysis demonstrates that isomers of both 18R, 20S, 21S and 18R, 20S, 21R configuration are formed rather than the 18R, 20R, 21R isomer postulated on the basis of examination of 1H‐NMR spectra. The spectra appears to be consistent with the major component of the mixture. The 20S configuration observed is in agreement with the chirality assigned to the degradation product obtained when the same alkaline solution of aldosterone is subjected to reflux. The crystals of (V) are monoclinic P21, Z = 4 with a = 20.891(2), b = 6.3848(5), c = 16.067(2)Å, β = 122.09°(1) with two molecules in the asymmetric unit. Molecule A has the 20S,21S configuration and the molecules in the second site are a mixture of the 20S, 21S and 20S, 21R configuration in the ratio of 3:2.
Stereoisomeric flavour compounds XLV: Structure analysis of 2‐alkoxy‐5‐alkyl‐tetrahydrofurans
Authors: Palm Ursula , Mosandl Armin , Bensch Wolfgang 
Published: January 2005

AbstractThe synthesis of several 2‐alkoxy‐5‐alkyl‐tetrahydrofurans is of interest in our investigations of structure–function relationships of chiral flavour compounds. For the preparation of the enantiomeric acetals the unambiguous configurational assignment of the cis and trans series of these compounds is indispensable. By means of crystalline acetal derivatives the absolute structure of a model compound in the cis and the trans configuration is revealed by X‐ray measurement and correlated with the corresponding cis and trans configurated aroma compounds. The first complete structure elucidation of the class of 2‐alkoxy‐5‐alkyltetrahydrofurans has been carried out.
A convenient synthesis of (2R,8R)‐8‐methyl‐2‐decanol and its 2S epimer, the parent alcohols of rootworm pheromones
Authors: Chattopadhyay S. , Mamdapur V. R. , Chadha M. S. 
Published: January 2005

AbstractA highly stereospecific synthesis of the title compound (2R,8R)‐8‐methyl‐2‐decanol (I) has been devised via 16 simple steps. The required chirons (5 and 11) were prepared from easily accessible templates viz. (R)‐methyl citronel‐late and (S)‐glutamic acid. This on Grignard coupling furnished the ketal (12) which was converted to the desired epoxide (14) and subsequently reduced to furnish the alcohol (2R,8R)‐I. Its corresponding (2S)‐epimer was prepared by total stereoselective inversion of its C‐2 center. The title compounds are the parent alcohols of the pheromone components of the female rootworms.
Fluorometric and liquid chromatographic study of the binding of two coumarins to β‐cyclodextrin
Authors: Karnik N. A. , Prankerd R. J. , Perrin J. H. 
Published: January 2005

AbstractThe fluorescences of warfarin and phenprocoumon are enhanced following complexation with β‐cyclodextrin; (+)‐(R)‐ and (−)‐(S)‐phenprocoumons have different affinities for this cyclodextrin, whereas the corresponding enantiomers of warfarin have similar binding constants. Apparently, hemiketal formation in the case of warfarin minimizes chiral discrimination. This is confirmed using a β‐cyclodextrin bonded chromatography column on which the phenprocoumon enantiomers are separated, whereas those of warfarin are not.
Stereospecific HPLC method for the quantitation of the enantiomers of MK‐0571, a potent leukotriene D4 receptor antagonist, in biological specimens
Authors: Lee Ling L. , Zacchei Anthony G. 
Published: January 2005

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

AbstractInversion of inactive (R)‐ibuprofen to active (S)‐ibuprofen has been suggested to occur presystemically only. In order to investigate the site of inversion in dogs we administered both enantiomers either intravenously or intraduodenally (10 mg/kg) to adult, male beagle dogs (n = 3) in a crossover design. Plasma, urine, and bile were collected for up to 6 h and analyzed stereospecifically by HPLC, according to a previously published method. Pharmacokinetic parameters were calculated using a linear computer program. Absorption after intraduodenal administration occurred rapidly, resulting in maximum plasma concentrations 0.2 h after giving the enantiomer. Approximately 70% of the (R)‐enantiomer (according to AUC) was inverted to the S‐enantiomer independent of route of administration. No R‐ibuprofen could be detected in plasma after (S)‐ibuprofen administration. Mean residence time was found to be 2 to 3 times longer for (S)‐than for (R)‐ibuprofen. Total systemic clearance from plasma was twice as high for (R)‐ than for (S)‐ibuprofen. There were no differences between plasma clearances after intravenous and intraduodenal administration. Between 8 and 17% of dose was recovered in bile [especially as free and conjugated (S)‐ibuprofen] and 3–12% in urine [as (S)‐ibuprofen, hydroxy‐ and carboxyibuprofen, free and conjugated forms]. Small amounts of (R)‐ibuprofen were detected in bile after intraduodenal administration of (R)‐ibuprofen only (1.8% of dose). In short, the unidirectional inversion of R‐ibuprofen appears to occur systemically rather than presystemically in dogs.
Absolute configuration of feroxidin: An experimental support to snatzke's helicity rules for tetralins
Authors: Speranza Giovanna , Manitto Paolo , Pezzuto Donata , Monti Diego 
Published: January 2005

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

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

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

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

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

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

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

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