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1. |
Determination of the enantiomers of citalopram, its demethylated and propionic acid metabolites in human plasma by chiral HPLC |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 389-395
B. Rochat,
M. Amey,
H. Van Gelderen,
B. Testa,
P. Baumann,
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摘要:
AbstractA stereoselective HPLC assay has been developed to analyze the enantiomers of citalopram and of its three main metabolites in plasma after their separation on a Chiracel OD column. Using a fluorescence detector, the limit of quantification in plasma samples was 15, 4, 5, and 2 ng/ml for the enantiomers of citalopram (CIT), desmethylcitalopram (DCIT), didesmethylcitalopram (DDCIT), and for the citalopram propionic acid derivative (CIT‐PROP), respectively. Except for CIT, all metabolites were derivatized with achiral reagents. Identification of the enantiomers was realized with an optical rotation detector which showed that the enantiomers invert their rotation depending on the polarity and nature of the solvent. Under varying conditions, a racemization study has shown that the pure enantiomers of CIT and its demethylated metabolites are configurationally stable. Preliminary results obtained with five patients treated with CIT show a mean S/R ratio of 0.7 for both CIT and its active metabolite DCIT and of 3.6 for CIT‐PROP in plasma. This suggests that the pharmacologically relevant (+)‐(S)‐isomers of CIT and DCIT could be preferentially and steroselectively metabolized to CIT‐PROP. © 1995 Wiley
ISSN:0899-0042
DOI:10.1002/chir.530070602
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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2. |
Racemization, enantiomerization, diastereomerization, and epimerization: Their meaning and pharmacological significance |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 396-400
Marianne Reist,
Bernard Testa,
Pierre‐Alain Carrupt,
Martin Jung,
Volker Schurig,
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摘要:
AbstractThe configurational lability of enantiomers can be characterized by different terms, each defining a specific process. Racemization relates to the macroscopic and statistical process of the irreversible transformation of one of the enantiomers into the racemic mixture. Enantiomerization refers to the microscopic and molecule process of the reversible conversion of one enantiomer into the other. Methods allowing the experimental determination of rate constants of racemization (krac) and enantiomerization (kenant) are discussed, and it is shown thatkenant= 1/2krac. Neglect of this fact is a source of some confusion in the literature. When two or more elements of chirality are present in a molecule and one of them is configurationally labile, epimerization occurs, a particular case of diastereomerization. These processes of interconversion between diastereomers are kinetically more complicated than racemization and enantiomerization since the rate constants of the forward and reverse reactions are always different (kdiast/A‐to‐B≠ kdiast/B‐to‐A), however small the difference. An important aspect of the configurational lability of stereoisomeric drugs is the time scale of the phenomenon. When interconversion occurs to a significant extent during the residence time of a drug in the body, a pharmacological time scale is implied. In contrast, the pharmaceutical time scale refers to slower rates of interconversion that affect the configurational purity of a drug during its shelf‐life. © 1995 Wil
ISSN:0899-0042
DOI:10.1002/chir.530070603
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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3. |
Mechanisms of enantiomeric resolution in cyclodextrin‐modified capillary electrophoretic separations of binaphthyl compounds |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 401-408
Christine L. Copper,
Joe B. Davis,
Michael J. Sepaniak,
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摘要:
AbstractThe enantiomers of 1,1′‐bi‐2‐naphthol, 1,1′‐binaphthyl diyl hydrogen phosphate, and 1,1′‐binaphthyldicarboxylic acid are separated using capillary electrophoresis with cyclodextrins added to the running buffer. It is demonstrated that the type and concentration of cyclodextrin employed are critical for maximum enantiomeric resolution. A modified version of a previously described model of enantiomeric separations in capillary electrophoresis is shown to support the observed separation behavior. Molecular modeling is employed to calculate interaction energies between the various enantiomers and cyclodextrins. A reasonable correlation between these computationally derived interaction energies and separation behavior resulted from a statistical mechanical treatment of the molecular modeling data. The importance of hydrogen bonding in inclusion complex formation was probed and the effects of minimization and solvation in molecular modeling calculations are also discussed. © 1995
ISSN:0899-0042
DOI:10.1002/chir.530070604
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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4. |
Rapid chiral separation methods development by cyclodextrin‐mediated capillary electrophoresis for acidic and basic compounds |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 409-414
András Guttman,
Sandra Brunet,
Caroline Jurado,
Nelson Cooke,
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摘要:
AbstractChiral separation methods development using conventional techniques such as GC or HPLC requires a lot of experience, effort, and expense, due to the wide diversity of the optically active solutes and their possible chiral selectors. Capillary electrophoresis has received increased attention as an alternative technique for chiral separation due to its inherent high efficiencies and ease of methods development. However, due to the wide variety of chiral selectors available in CE, the benefits of this technique might be diminished without an appropriate methods development scheme. In this paper detailed examples are shown for fast, efficient, and predictable chiral capillary electrophoresis separation methods development based on a new and systematic theory. Optimized separations and their parameters are presented for several enantiomeric acids and bases. All the three possible cases, such as the use of low and high pH, as well as pH = pKbuffer systems are thoroughly discussed. © 1995 Wiley‐Liss, I
ISSN:0899-0042
DOI:10.1002/chir.530070605
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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5. |
Chiral separation based on immobilized intact and fragmented cellobiohydrolase II (CBH II): A comparison with cellobiohydrolase I (CBH I) |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 415-424
Hongbin Henriksson,
Stefan Jönsson,
Roland Isaksson,
Göran Pettersson,
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摘要:
AbstractIntact and fragmented cellobiohydrolase II (CBH II) were immobilized to silica and used as chiral stationary phases (CSPs) for liquid chromatographic separations of enantiomers. Both acidic and basic chiral compounds could be resolved into their enantiomers on these phases. The enantioselectivities obtained on intact CBH II and its core were almost equivalent. Comparisons were also made with CBH I silica. It was found that the new materials show quite different chiral and chromatographic properties. The enzymatic activity of the CBH II in free solution was influenced by alprenolol and mexiletine, both separated on the corresponding CSP. It indicates that the sites for catalysis and for chiral recognition overlap. © 1995 Wiley‐Liss, I
ISSN:0899-0042
DOI:10.1002/chir.530070606
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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6. |
Chromatographic properties of composite chiral stationary phases based on cellulose derivatives |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 425-433
Tong Zhang,
Eric Francotte,
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摘要:
AbstractChiral stationary phases (CSPs) prepared by mixing together two different cellulose derivatives, before or after being coated on macroporous silica gel, were developed in order to determine the mutual influence of two different polymers on global chiral recognition capacity. The chromatographic properties of these CSPs were evaluated using a wide range of racemic test solutes. The mixing method does not significantly affect the enantioselectivities. The composite CSPs obtained by cocoating of two different cellulose derivatives on silica generally exhibit chiral recognition capacities intermediate between those of the two individual phases, and thus broadening the application range of a single column. These results indicate that the simultaneous coating of two different cellulose derivatives does not significantly alter the optical resolution power of each chiral material and are discussed in relationship with the supramolecular structure of the polymeric stationary phases. © 1995 Wiley‐Liss, I
ISSN:0899-0042
DOI:10.1002/chir.530070607
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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7. |
GABAAagonists: Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 434-438
Bente Frølund,
Lone Jeppesen,
Povl Krogsgaard‐Larsen,
Jan J. Hansen,
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摘要:
Abstract(3SR,4RS)‐3,4‐Epoxypiperidine‐4‐carboxylic acid (isoguvacine oxide) is a potent and specific GABAAreceptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAAreceptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)‐1‐(benzyloxycarbonyl)‐3,4‐epoxypiperidine‐4‐carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of1(ee ≥ 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABABreceptor sites (IC50>100 μM), (+)‐isoguvacine oxide (IC50= 0.20 ± 0.03 μM) and (−)‐isoguvacine oxide (IC50= 0.32 ± 0.05 μM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAAreceptor sites. Furthermore, (+)‐isoguvacine oxide (EC50= 6 μM; 33% relative efficacy) and (−)‐isoguvacine oxide (EC50= 5 μM; 38% efficacy relative to 10 μMmuscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAAreceptor‐associated benzodiazepine site. This latter effect is an in vitro estimate of GABAAagonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAArecognition site(s), derived from extensive structure—activity studies on GABAAagonists. Thus, the model of the GABAArecognition site(s) comprising a narrow cleft or pocket, in which the anionic moiety of the zwitterionic GABAAagonists is assumed to be embedded during receptor activation, m
ISSN:0899-0042
DOI:10.1002/chir.530070608
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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8. |
Preparation of (+)‐ and (−)‐1,2‐dimethyl‐3‐pyrrolidone and stability studies |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 439-445
Simona Collina,
Anna Gamba,
Victor Ghislandi,
Ornella Azzolina,
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摘要:
Abstract1,2‐Dimethyl‐3‐pyrrolidone is an important intermediate in the synthesis of cycloalkylaminonaphthalenic analgesics. The optical resolution of this compound with L‐ and D‐tartaric acids is described and the behaviour of the diastereomeric tartrates and of the enantiomers in solution was investigated by NMR spectroscopy and polarimetric analysis. Tautomeric equilibria involving C4 and C2 atoms, which are responsible for the instability of the compound, are demonstrated. Theoretical studies of conformational analysis were also made in order to define the relationships between the stability of the conformers of 1,2‐dimethyl‐3‐pyrrolidone and its structural features. © 1995
ISSN:0899-0042
DOI:10.1002/chir.530070609
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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9. |
Circular dichroism of ketoprofen complexed to serum albumins: Conformational selection by the protein: A novel optical purity determination technique |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 446-451
Maurizio Zandomeneghi,
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摘要:
AbstractComplexation of 2‐(3′‐benzoylphenyl)propionic acid (ketoprofen),1, to bovine serum albumin (BSA) results in an intense negative circular dichroism in the ketonic n → π* band of the benzoylphenyl moiety. This high CD contrasts with the weak CD of1‐enantiomers dissolved in common solvents. Furthermore, a number of chiral and achiral molecules containing the benzophenone moiety are easily complexed to BSA: all these complexes show an intense CD at the same transition. To account for the observed CD intensities of the above molecules, it appears that BSA complexation markedly shifts the equilibrium between strongly asymmetric, antipodic conformers. Dissymmetry of these conformers is connected to the instability of a structure with phenyl rings coplanar to the carbonyl chromophore, as also indicated by molecular mechanics calculations. The magnification of the Cotton effects of the1‐antipodes, due to the protein, can be used to measure the optical purity of1‐samples with excellent precision. In contrast with BSA, human SA is unable to recognize the chirality of1‐antipodes; oleic acid cocomplexation modifies this fact as well as other features of the binding. © 199
ISSN:0899-0042
DOI:10.1002/chir.530070610
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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10. |
Synthesis of (+)‐(R)‐ and (−)‐(S)‐trans‐8‐hydroxy‐2‐[N‐n‐propyl‐N‐(3′‐iodo‐2′‐propenyl)] aminotetralin: New 5‐HT1Areceptor ligands |
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Chirality,
Volume 7,
Issue 6,
1995,
Page 452-458
Zhi‐Ping Zhuang,
Mei‐Ping Kung,
William Clarke,
Saul Maayani,
Mu Mu,
Hank F. Kung,
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摘要:
Abstract(R,S)‐trans‐8‐Hydroxy‐2‐[N‐n‐propyl‐N‐(3′‐iodo‐2′‐propenyl)amino]tetralin7, a new radioiodinated ligand based on 8‐OH‐DPAT, was reported as a potential ligand for 5‐HT1Areceptors. The optically active (+)‐(R)‐ and (−)‐(S)‐7were prepared to investigate the stereoselectivity of (R,S)‐7. Racemic intermediate 8‐methoxy‐2‐N‐n‐propyltetralin was reacted with the acyl chloride of (−)‐(R)‐O‐methylmandelic acid to form a mixture of (S,R)‐ and (R,R)‐diastereoisomers, which were separated by flash column chromatography. After removing theN‐acyl group from the diastereoisomers, the desired (+)‐(R)‐or (−)‐(S)‐7was obtained by adding anN‐iodopropenyl group. In vitro homogenate binding studies showed the stereoselectivity of this new compound for 5‐HT1Areceptors. (+)‐(R)‐7isomer displayed 100‐fold higher affinity than the (−)‐(S)‐7isomer. Biochemical study indicated that (+)‐(R)‐7potently inhibited forskolin‐stimulated adenylyl cyclase activity in hippocampal membranes (Emaxand EC50were 24.5% and 5.4 nM, respectively), while (−)‐(S)‐7showed no effect at 1 μM.The radioiodinated (+)‐(R)‐ and (−)‐(S)‐[125I]7were confirmed by coelution with the resolved unlabeled compound on HPLC (reverse phase column PRP‐1, acetonitrile/pH 7.0 buffer, 80/20). The active isomer, (+)‐(R)‐[125I]7, displayed high binding affinity to 5‐HT1Areceptors (Kd= 0.09 ± 0.02 nM). In contrast, the (−)‐(S)‐7isomer displayed a significantly lower affinity to the 5‐HT1Areceptor (Kd>10 nM). Thus, (+)‐(R)‐[125I]trans‐8‐OH‐PIPAT, (+)‐(R)‐7, an iodinated stereoselective 5‐HT1Areceptor agonist, is
ISSN:0899-0042
DOI:10.1002/chir.530070611
出版商:Alan R. Liss, Inc.
年代:1995
数据来源: WILEY
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