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1. |
Editorial |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 1-1
Irving W. Wainer,
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ISSN:0899-0042
DOI:10.1002/chir.530030102
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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2. |
Excavations in drug chirality: 1. Cyclothiazide |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 2-13
Elfriede Nusser,
Anirban Banerjee,
Joseph Gal,
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摘要:
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 withendoconfiguration at the norbornene moiety predominate over theexoracemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs t
ISSN:0899-0042
DOI:10.1002/chir.530030103
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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3. |
Comparative effects of the diastereoisomers, quinine and quinidine in producing phenocopy debrisoquine poor metabolisers (PMs) in healthy volunteers |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 14-18
R. Ayesh,
S. Dawling,
A. Hayler,
N. S. Oates,
S. Cholerton,
B. Widdop,
J. R. Idle,
R. L. Smith,
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摘要:
Abstract1A 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.2The effect of quinidine in producing debrisoquine oxidation “poor metaboliser” phenocopies persisted for at least 3 days but had disappeared by 1 week.3The 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.4The 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).5It is concluded that quinidine, but not its diastereoisomer quinine, is a potent selective inhibitor of thein vivooxidation 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 disc
ISSN:0899-0042
DOI:10.1002/chir.530030104
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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4. |
Enantiomers of 11‐hydroxy‐10‐methylaporphine having opposing pharmacological effects at 5‐HT1Areceptors |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 19-23
Joseph G. Cannon,
Scott T. Moe,
John Paul Long,
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摘要:
AbstractThe two enantiomers of the title compound have been prepared by different synthetic routes. Both bind strongly to 5‐HT1Areceptors from rat forebrain membrane tissue. However, in a guinea pig ileum preparation, the (R)‐enantiomer exhibits properties consistent with its being an agonist, whereas the (S)‐enantiomer shows no agonist effect, but it blocks the actions of the (R)‐enantiomer and of 8‐hydroxy‐2‐di‐n‐propylaminotetralin (8‐OH‐DPAT), a 5‐HT1Aagonist. These data are presented as a rare example of enantiomers which demonstrate opposite pharmacological effec
ISSN:0899-0042
DOI:10.1002/chir.530030105
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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5. |
Metabolic enantiomeric interactions: The inhibition of human (S)‐warfarin‐7‐hydroxylase by (R)‐warfarin |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 24-29
Kent L. Kunze,
A. Craig Eddy,
Milo Gibaldi,
William F. Trager,
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摘要:
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. TheKis for inhibition of (S)‐6‐ and (S)‐7‐hydroxylation by (R)‐warfarin ranged from 7.0 to 8.4 μMand from 6.0 to 6.9 μM, respectively, while theKms for the 6‐ and 7‐hydroxylation of (S)‐warfarin ranged from 3.6 to 3.8 μMand 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 d
ISSN:0899-0042
DOI:10.1002/chir.530030106
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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6. |
Interaction of propafenone enantiomers with human α1‐acid glycoprotein |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 30-34
Jana Oravcová,
Wolfgang Lindner,
Peter Szalay,
Ľubor Boháčik,
Tomáš Trnovec,
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摘要:
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 byKa(R)= (6.18 ± 0.93) × 105M−1, n(R)= 1.34 ± 0.09 for the (R)‐isomer andKa(S)= (8.93 ± 1.82) × 105M−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) × 104M−1) compared to the (R)‐enantiomer (n′k′(R)= (6.87 ± 0.72) × 103M−1). It was concluded that both enantiomers interact with common single class of high‐affinity binding sites on AAG (along with nonspecific binding) exhibiting
ISSN:0899-0042
DOI:10.1002/chir.530030107
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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7. |
Pharmacokinetic studies with the lipid‐regulating agent beclobrate: Enantiospecific assay for beclobric acid using a new fluorescent chiral coupling component (S‐FLOPA) |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 35-42
Sascha Mayer,
Ernst Mutschler,
Hildegard Spahn‐Langguth,
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摘要:
AbstractThe major biotransformation pathway for the chiral lipid‐regulating agent beclobrate is conversion to the corresponding carboxylic acid, which is then metabolized to the acyl glucuronide. An enantiospecific assay for biological material was developed that is based on chiral derivatization withN‐ethyl‐N′‐(3‐dimethylaminopropyl)carbodiimide (EDAC) and the primary amine S‐FLOPA, a new chiral coupling component for carboxylic acids derived from the 2‐arylpropionic acid S‐flunoxaprofen. Conversion of beclobric acid to the acyl chloride prior to coupling with the amine is also feasible. From plasma or urine beclobric acid was extracted inton‐hexane/ethanol (9:1) at pH 4 after addition of sodium chloride. Clofibric acid was used as internal standard. Derivatization with EDAC/FLOPA was performed under addition of 1‐hydroxybenzotriazole in anhydrous dichloromethane containing trace amounts of pyridine (ambient temperature/2 h reaction time). The chromatographic separation was performed on a silica gel stationary phase (Zorbax Sil) usingn‐hexane–chloroform–ethanol (100:10: 0.75, by vol) as mobile phase [flow rate, 2 ml/min; fluorescence detection, 305/355 nm; elution order of the derivatives, (−) before (+)]. Coefficients of variation were between 1.3 and 9.3% for both plasma and urine. Limit of quantification was 20–25 ng/ml for plasma based on a sample volume of 0.2 ml. Application of the assay in a pilot pharmacokinetic study showed significant differences between the kinetics of the two enantiomers. In plasma and urine, the concentrations of the dextrorotatory enantiomer exceeded those of the levoro
ISSN:0899-0042
DOI:10.1002/chir.530030108
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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8. |
Benzoyl cellulose beads in the pure polymeric form as a new powerful sorbent for the chromatographic resolution of racemates |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 43-55
Eric Francotte,
Romain M. Wolf,
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摘要:
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 examp
ISSN:0899-0042
DOI:10.1002/chir.530030109
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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9. |
A molecular dynamics investigation of chiral discrimination complexes as chiral stationary‐phase models: MethylN‐(2‐naphthyl)alaninate withN‐(3,5‐dinitrobenzoyl)leucinen‐propylamide |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 56-66
Michael Sabio,
Sid Topiol,
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摘要:
AbstractMolecular dynamics simulations were performed on complexes of (S)‐methylN‐(2‐naphthyl)alaninate (NAP) with the enantiomers ofN‐(3,5‐dinitrobenzoyl)leucinen‐propylamide (DNB), which are used as models for chiral stationary‐phase systems developed by Pirkle and co‐workers. These studies were undertaken to qualitatively examine (pictorially) the role of entropic effects in these systems. The results of the dynamics calculations were used to refine the search for low‐energy conformers. The structures were refined by the use of BioDesign's molecular mechanics method implemented in Biograf. The results of the structural refinements support our previous observation that the SR complex can achieve the same three primary interactions which are observed in the SS structure (i.e., two intermolecular hydrogen bonds and pi stacking) without a significant increase in energy. In addition, these primary interactions are conserved during molecular dynamics simulations with the occurrence of conformations which differ only in the rotational states of the alkyl side chains and ester group (which bears two potential hydrogen bond acceptors utilized in both the homo‐ and heterochiral complexes). The major difference in the two complexes is the relative position of thesec‐butyl group and hydrogen atom on DNB's chiral center, both of which are outside the primary interaction region. All other local minima which have different relative pi orientations (“front–back,” “back–back,” and “back–front” as defined herein) are not sufficiently populated to make more than a negligible contribution to the statistical (time‐ or energy‐averaged) analysis of the (SS)‐ and (SR)‐NAP–DNB complexes. Thus the entropic effects observed in this study (e.g., alkyl side chain or ester group rotations) do not show evidence of qualitative differential effects on the maintenance of the same three primary interactions by both the homo‐ and heterochiral complexes. The reliability of the present study, which provides pictorial representations of the entropic effects, is not sufficient to determine whether the entropic effects observed herein are sufficient to achieve enantiomeric discrimination alone or in conjunction with other factors (e.g., conformational strain energy). Thus, all of the computational studies we have performed to date (i.e., our previous studies, which include strain energy and through‐space field effects, and the present study, which includes entropic effects) show no evidence of any qualitative difference in the homo‐ and heterochiral complexes
ISSN:0899-0042
DOI:10.1002/chir.530030110
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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10. |
Direct measurement of enantiomeric ratios of enzymatic resolution by chiral high‐performance liquid chromatography |
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Chirality,
Volume 3,
Issue 1,
1991,
Page 67-70
Shih‐Hsiung Wu,
Su‐Yuan Lai,
Shu‐Ling Lin,
Fei‐Ya Chu,
Kung‐Tsung Wang,
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摘要:
Abstract(R)‐ and (S)‐Methyl 2‐(phenoxy)propionate and their acids could be separated simultaneously by a Chiralcel OD or OK column, while (R)‐ and (S)‐methyl 2‐(4‐chlorophenoxy)propionate and their acids were separated concurrently only by an OK column. This is a novel and facile way to measure the enantiomeric excesses of the remaining substrate and product in the reaction of enzymatic resolution; enantiomeric ratios could then
ISSN:0899-0042
DOI:10.1002/chir.530030111
出版商:Wiley‐Liss, Inc.
年代:1991
数据来源: WILEY
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