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  • 1995-1999  (824)
  • 1950-1954
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  • 1997  (824)
  • Organic Chemistry  (824)
  • 201
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 150-152 
    ISSN: 0899-0042
    Keywords: amino acid ; stereoconversion ; racemization ; liquid chromatography ; isomer ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A chiral liquid chromatographic method was validated to analyze the D-and L-enantiomers of five amino acids contained in a commercial solution: aspartic acid, leucine, lysine, phenylalanine, and valine. These 10 compounds were separated on a chiral crown ether column with a mobile phase composed of water adjusted to pH 1.5 with perchloric acid, with ultraviolet detection at 220 nm. The method was applied to the commercial amino acid solution before and after sterilization by 5 kGy irradiation; no stereoconversion was observed following sterilization. Chirality 9:150-152, 1997. © 1997 Wiley-Liss, Inc.
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  • 202
    ISSN: 0899-0042
    Keywords: high-performance liquid chromatography ; nonporous chiral stationary phase ; MICRA NPS ; tert-butyl carbamoylated quinine selector ; weak chiral anion exchanger ; N-protected α-amino acids ; DNP ; DNB ; DNZ ; mobile phase optimization ; DryLab ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: In this study, tert-butyl carbamoylated quinine as chiral selector was immobilized on nonporous silica (NPS) 1.5 μm particles developed by MICRA, and this new chiral stationary phase (CSP) was packed into a 3.3 cm column (4.6 mm ID). A series of various N-protected α-amino acids was chosen as chiral selectands, including 3.5-dinitrobenzyloxycarbonyl amino acids (DNZ-AAs). In order to optimize the chromatographic conditions with this novel CSP and to apply it to the resolution of acidic analytes the following parameters have been varied and studied: pH of the mobile phase, buffer concentration, and percentage of methanol or acetonitrile in the mobile phase. DryLabR software was applied to optimize enantioseparation by simulating chromatographic functions of experimental conditions for isocratic and/or gradient runs. Thus, we were able to resolve a set of test compounds within several minutes, whereby our attention was particularly drawn to the resolution of DNZ-AA derivatives. Chirality 9:157-161, 1997. © 1997 Wiley-Liss, Inc.
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  • 203
    ISSN: 0899-0042
    Keywords: stereoisomer separation ; cyclodextrin ; pesticide ; capillary electrophoresis ; high-performance liquid chromatography ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Micellar electrokinetic capillary chromatography (MECC) and high-performance liquid chromatography (HPLC) were used for the separation of stereoisomers of the lipophilic uncharged pyrethroids cypermethrin, alphamethrin, permethrin, and fenpropathrin. Different kinds of cyclodextrin (β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin, and γ-cyclodextrin), surfactants (sodium dodecyl sulphate [SDS] and cetyltrimethylammonium bromide [CTAB]), and cations of background electrolyte (sodium, ammonium, TRIS, and Ammediol) were tested. Optimized conditions (background electrolyte: 50 mmol/l sodium phosphate, pH ≈ 2.5, 150 mmol/l SDS, 150 mg/ml γ-cyclodextrin) allowed the separation of alphamethrin, the eight cypermethrin stereoisomers being eluted in seven peaks and the separation of two enantiomers of fenpropathrin with resolution Rs = 10 and with n ≃ 500,000 theoretical plates. Different experimental conditions, e.g., mobile phase composition, temperature, injected amount, and flow rate, were also optimized in HPLC experiments. The optimal conditions (stationary phase: ChiraDex, 5 μm; mobile phase: 150 mmol triethylamine/l with H2SO4 in water (pH = 3.5) with methanol or acetonitrile; flow rate: 0.8 or 0.6 ml/min; temperature: ambient or 30°, 20°, or 10°C; experimental conditions were modified according to the type of analysis) allow chiral discrimination of alphamethrin enantiomers and analysis of permethrin stereoisomers. MECC offers higher efficiency and shorter analysis time than HPLC, but under tested conditions it was shown that the methods complement each other. Chirality 9:162-166, 1997. © 1997 Wiley-Liss, Inc.
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  • 204
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 317-319 
    ISSN: 0899-0042
    Keywords: NSAID metabolism ; rat liver microsomes ; metabolic pathway ; He-Ne laser ; (+)-(R)-1-phenylethylamides ; HPLC separation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: This paper reports in vitro studies on the metabolic inversion of flurbiprofen (FL), an arylpropionic acid antiinflammatory agent (2-APA). The inversion was studied with both rac-FL and R-FL, by incubation with rat hepatic microsomes, in the presence of either CoASH and ATP or NADPH. The two isomers of the drug were separated as their (+)-(R)-1-phenylethylamides by direct phase high-performance liquid chromatography on a silica gel column with an achiral mobile phase. The inversion was more pronounced in the presence of CoASH and ATP for both the racemate and the R-isomer, which supports the key role of CoA thioesters in the metabolic inversion of profens. The inversion observed in the presence of NADPH suggests that, when the incubation is run with hepatic microsomes, a CYP450-mediated pathway is also active. In order to get more insight into the CYP450-mediated inversion pathway, we studied the effect of irradiating microsomes with a low dose of He-Ne laser radiation (0.2 J). Such irradiation caused a significant increase in inversion at all times studied and normalized the anomalous value of inversion observed at 15 min in his pathway. Chirality 9:317-319, 1997. © 1997 Wiley-Liss, Inc.
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  • 205
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 329-334 
    ISSN: 0899-0042
    Keywords: atenolol ; enantiomers ; liquid chromatography ; cellobiohydrolase I ; chiral CBH ; coupled-columns ; cellobiose ; peak compression ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Two different enantioselective chiral chromatographic methods were developed and validated to investigate the disposition of the β1-receptor antagonist atenolol in blood and in brain extracellular fluid of rats (tissue dialysates). System A for the plasma samples was a one-column chromatographic system with a Chiral CBH column with an aqueous buffer as mobile phase into which cellobiose was added for selective regulation of the retention of the internal standard, (S)-metoprolol. The plasma samples were analysed after a simple extraction procedure. The limit of quantitation was 0.2 μg/ml for the atenolol enantiomers. The repeatability of the medium concentration quality control plasma sample (6.0 μg rac-atenolol/ml) was 11-18% for the enantiomers. The dynamic linear range of the plasma samples was 0.5-20 μg/ml. For system B, since atenolol is an extremely hydrophilic drug, the tissue dialysate sample required a much more sensitive system as compared to the plasma samples. A coupled column system was used for peak compression of the enantiomers in the eluate after the separation on the Chiral CBH column, hence increasing the detection sensitivity. The limit of quantification was 0.045 μg/ml for the atenolol enantiomers in artificial CSF. The repeatability of the medium concentration quality control samples (0.1 and 4.0 μg rac-atenolol/ml in artificial CSF and Hepes Ringer, respectively) was 2.8-9.3% for the two enantiomers. The dynamic linear range of the brain samples was 0.05-1.0 and 0.5-20 μg/ml in artificial CSF and Hepes Ringer, respectively. Chirality 9:329-334, 1997. © 1997 Wiley-Liss, Inc.
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  • 206
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 350-353 
    ISSN: 0899-0042
    Keywords: xenobiotics ; pollutants ; non-planar aromatics ; chirality ; atropisomerism ; ab initio calculations ; electron correlation ; density functional theory ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The rotational barriers of overcrowded PCBs are predicted by ab initio methods including electron correlation, thus settling the controversy between theory and experiment. For 2,2′,3,3′,4,6′-hexachlorobiphenyl (PCB 132), an enantiomerization barrier of 185 kJ/mol is calculated by B3LYP/6-31G*, in excellent agreement with the experimental data. Chirality 9:350-353, 1997. © 1997 Wiley-Liss, Inc.
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  • 207
    ISSN: 0899-0042
    Keywords: ibuprofen ; enantiomers ; stereoselective ; interactions ; plasma protein binding ; rat ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Stereoselective pharmacokinetics of ibuprofen (IB) enantiomers were studied in rats. Unidirectional conversion from R-ibuprofen (R-IB) to S-ibuprofen (S-IB) was observed following intravenous administration. S-IB concentrations in plasma following racemate administration were simulated according to a conventional compartmental model using the parameters obtained after the administration of individual enantiomers, and resulted in overestimation of S-IB concentrations.Binding of IB enantiomers measured in rat plasma was stereoselective, the binding of R-IB being more favorable than that of S-IB. Moreover, there are interactions between IB enantiomers in binding, which may cause the increase of distribution volumes of IB enantiomers in the presence of their antipodes. Hence simulated S-IB concentrations according to a conventional compartment model were significantly greater than those observed. Indeed, when the enantiomer-enantiomer interactions were taken into account, simulation of S-IB concentrations in plasma following racemate administration was in good agreement with observed values. Therefore, interactions between stereoisomers as well as dispositional stereoselectivity have to be considered when pharmacokinetics of stereoisomers after administration of the racemate are compared to those after administration of individual isomers. Chirality 9:354-361, 1997. © 1997 Wiley-Liss, Inc.
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  • 208
    ISSN: 0899-0042
    Keywords: lipoic acid ; reduction ; dihydrolipoamide dehydrogenase ; antioxidant ; enantiomers ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: For the antioxidant effect of lipoic acid, reduction to dihydrolipoic acid is considered to be important. Dihydrolipoamide dehydrogenase (LipHD) preferentially reduces R-lipoic acid and in a subsequent reaction, the R-dihydrolipoic acid formed may non-enzymatically reduce S-lipoic acid. Using circular dichroism (CD) spectroscopy, the second order rate constant of the latter reaction was determined (k2 = 15 M-1 sec-1). In vitro, it was found that S-lipoic acid is reduced by LipDH using R-lipoic acid as a catalyst. The non-enzymatic dithiol-disulfide reaction leads to synergistic reduction of the enantiomers which can explain the higher antioxidant activity of racemic lipoic acid found in vivo (Maitra et al. Biochem. Biophys. Res. Commun. 221:422-429, 1996) in comparison to the enantiomers. Lipoic acid is therapeutically active in several diseases via antioxidant activity. These findings suggest that racemic lipoic acid can be therapeutically more active than the separate enantiomers. Chirality 9:362-366, 1997. © 1997 Wiley-Liss, Inc.
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  • 209
    ISSN: 0899-0042
    Keywords: protein-drug binding ; Hummel and Dreyer method ; column switching ; high performance liquid chromatography ; chiral separation ; BSA/HSA-bond silica gel ; polarimetric/chiroptical detection ; enantioselectivity ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The stereoselectivity of the reversible binding interactions between the D- and L-tryptophan enantiomers and serum albumins of different animal species and fragments of human serum albumin (HSA) was investigated by applying three novel high performance liquid chromatographic (HPLC) arrangements. The separations were performed by means of (1) an achiral (diol-bond), (2) a chiral (bovine serum albumin-bond) silica gel sorbent, and (3) a column switching technique which uses both the diol- and HSA-bond HPLC stationary phases. A polarimetric detector and/or an ultraviolet (UV) spectrophotometer were used to monitor the separation process. HPLC arrangement 3 allowed the evaluation of enantioselective binding for D- and L-tryptophan to different albumins and albumin fragments. At present, column switching can be considered the technique of the broadest applicability for investigating the reversible binding interactions between a protein and drug enantiomers. Chirality 9:373-379, 1997. © 1997 Wiley-Liss, Inc.
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  • 210
    ISSN: 0899-0042
    Keywords: optical resolution ; diastereomeric method ; molecular compound ; 2-chloro-3-phenylpropanoic acid ; 2-methylamino-3-phenylpropanoic acid ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: First, (RS)-2-chloro-3-phenylpropanoic acid [(RS)-CPP] was optically resolved using ethyl (S)-phenylalaninate as a resolving agent, aiming at preparation of optically active 2-methylamino-3-phenylpropanoic acid (MPP). The (R)-CPP obtained as the sodium salt monohydrate was reacted with methylamine to give (S)-2-methylamino-3-phenylpropanoic acid [(S)-MPP]. Next, the optical resolution of (RS)-MPP was also attempted via molecular compound formation with optically active mandelic acid (MAN). The molecular compound of (R)-MPP with (S)-MAN [(R)-MPP (S)-MAN] was obtained as the less soluble diastereomeric compound, while the (S)-MPP (S)-MAN compound was found to be the more soluble one. Recrystallization of (R)-MPP (S)-MAN compound from water, followed by treatment with acetone, gave optically pure (R)-MPP in 79% yield, based on a half amount of the starting (RS)-MPP. The (S)-MPP obtained from (S)-MPP (S)-MAN compound was again subjected to formation of molecular compound with (R)-MAN to give optically pure (S,)-MPP in 66% yield. Chirality 9:386-389, 1997. © 1997 Wiley-Liss, Inc.
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  • 211
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 643-649 
    ISSN: 0899-0042
    Keywords: ibuprofen ; stereoselective ; binding ; HSA ; interaction ; fluorescent ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Binding of ibuprofen (IB) enantiomers to human serum albumin (HSA) was studied using a chiral fluorescent derivatizing reagent, which enabled the measurement of IB enantiomers at a concentration as low as 5 × 10-8 M. Scatchard analyses revealed that there were two classes of binding sites for both enantiomers. For the high affinity site, the number of the binding sites was one for both enantiomers, and the binding constant of R-IB was 2.3-fold greater than that of S-IB. The difference in the affinity at the high affinity site may result in the stereoselective binding of IB enantiomers at therapeutic concentrations. It was confirmed that the high affinity site of IB enantiomers is Site II (diazepam binding site) by using site marker ligands. Also, significant enantiomer-enantiomer interactions were observed in the binding. The binding data were quantitatively analyzed and a binding model with an assumption of competitive interactions only at the high affinity site simulated the binding characteristics of IB enantiomers fairly well. Chirality 9:643-649, 1997. © 1997 Wiley-Liss, Inc.
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  • 212
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 661-666 
    ISSN: 0899-0042
    Keywords: esterase ; O-acyl-propranolol ; substrate specificity ; structure activity relationship ; in vitro degradation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Species differences and substrate specificities for the stereoselective hydrolysis of fifteen O-acyl propranolol (PL) prodrugs were investigated in pH 7.4 Tris-HCl buffer and rat and dog plasma and liver subfractions. The (R)-isomers were preferentially converted to propranolol (PL) in both rat and dog plasma with the exception of isovaleryl-PL in rat plasma, although the hydrolytic activities of prodrugs in rat plasma were 5-119-fold greater than those in dog plasma. The prodrugs with promoieties (C(=O)CH(R)CH3) based on propionic acid showed marked preference for hydrolysis of the (R)-enantiomers in plasma from both species (R/S ratio 2.5-18.2). On the other hand, the hepatic hydrolytic activities of prodrugs were greater in dog than rat, especially in cytosolic fractions. The hydrolytic activity was predominantly located in microsomes of the liver in rat, while the cytosol also contributed to hepatic hydrolysis in dog. Hepatic microsomal hydrolysis in dog showed a preference for the (R)-isomers except acetyl- and propionyl-PL. Interestingly, in rat liver all types of prodrugs with substituents of small carbon number showed (S)-preference for hydrolysis. The hydrolyses of (R)- and (S)-isomers of straight chain acyl esters in rat liver microsomes were linearly and parabolically related with the carbon number of substituents, respectively, while these relationships were linear for both isomers in dogs. Chirality 9:661-666, 1997. © 1997 Wiley-Liss, Inc.
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  • 213
    ISSN: 0899-0042
    Keywords: albendazole ; enantiomeric separation ; high performance liquid chromatography ; cellulose derived phase ; pharmacokinetic ; cysticercosis ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We present a method for the enantioselective analysis of albendazole sulfoxide (ABZSO) in plasma for application in clinical pharmacokinetic studies. ABZSO enantiomers were separated on a 5-μm Chiralcel OB-H® column (4.6 × 150 mm) using hexane:ethanol (93:7, v/v) as the mobile phase and fluorescence detection. ABZSO was extracted with chloroform:isopropanol (8:2, v/v) from 500-μl aliquots of acidified plasma, with full drug recovery. The proposed method presented quantitation limits of 20 ng/ml for (-)ABZSO and 50 ng/ml for (+)ABZSO and was linear up to a concentration of 5,000 ng/ml of each enantiomer. Chirality 9:722-726, 1997. © 1997 Wiley-Liss, Inc.
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  • 214
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 727-731 
    ISSN: 0899-0042
    Keywords: chiral HPLC ; amylose tris(3,5-dimethylphenylcarbamate) ; cellulose tris(3,5-dimethylphenylcarbamate) ; cellulose tris(4-methylbenzoate) ; imine enantiomers ; e.e. determination ; imine isomerization reaction ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A high-performance liquid chromatographic method has been developed for the analysis of the intermediate imines and end products in an asymmetric isomerization route toward optically active amines. Separation of the imine enantiomers was performed on commercially available Chiralcel OD-H, Chiralcel OJ, and Chiralpak AD chiral stationary phases. All substituted imine enantiomers could be readily resolved with selectivities (α) higher than 1.10 using the Chiralpak AD column. By derivatization with ring-substituted benzaldehydes, aromatic amines were converted into Schiff base derivatives and the enantiopurity of these amines was determined. Chirality 9:727-731, 1997. © 1997 Wiley-Liss, Inc.
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  • 215
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 395-406 
    ISSN: 0899-0042
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: No abstract.
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  • 216
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 407-423 
    ISSN: 0899-0042
    Keywords: helical twisting power ; chiral induction ; induced cholesteric phases ; intramolecular chirality transfer ; intermolecular chirality transfer ; circular dichroism ; sector and helicity rules ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The helical twisting power (HTP) of a chiral guest in a chiral or achiral mesophase as host system is a chirality observation and, therefore, should be a suitable quantity for determination of the absolute configuration. Rules correlating the sign of the HTP and the absolute configuration of the guest are not known or, as sometimes proposed, do not exist at all. The sign and size of the HTP of compounds with one or more chiral centers are determined by the effects of an intramolecular and an intermolecular chirality transfer. The intramolecular chirality transfer is a well known phenomena in the development of sector or helicity rules for circular dichroism spectroscopy. Due to the strong omisotrophy of the intermolecular chirality transfer in a liquid crystal phase the development of rules for the determination of the absolute configuration from the sign of the HTP is called in question. By analysis of the HTP and the circular dichroism (CD) of mono- and bis-aminoanthraquinones we now show that the development of rules in comparison to CD measurements does seem to be possible if some specialities of the anisotropic mesophases are taken into account. Chirality 9:407-423, 1997. © 1997 Wiley-Liss, Inc.
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  • 217
    ISSN: 0899-0042
    Keywords: diastereoselective deuteration ; (5′R)/(5′S)-2′-deoxy[5′-2H]ribonucleosides ; Bu3Sn2H-Et3B ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Diastereoselective syntheses of [5′-2H]thymidine (6-T) [(5′R)/(5′S) = 31:69], N4-benzoyl-2′-deoxy[5′-2H]cytidine (6-CBz) [(5′R)/(5′S) = 27:76], N6-benzoyl-2′-deoxy[5′-2H]adenosine (6-ABz [(5′R)/(5′S) = 39:61], and 2′-deoxy-N2-isobutyryl[5′-2H]guanosine (6-GiBu) [(5′R)/(5′S) = 20:80] were attained by a radical reductive deuteration reaction of the corresponding 5′-O-acetyl-3′-O-TBDMS-2′-deoxy-5′-phenylselenoribonucleosides (4) with a Bu3Sn2H-Et3B system at 〈-70°C to give 5 (87-98% yields), followed by unmasking (66-79% yields); 4 were synthesized in three steps of reactions from the corresponding 2′-deoxy-3′-O-TBDMS-5′-O-Ms-ribonucleosides (1) (88-93% yields) by a known method. Chirality 9:435-442, 1997. © 1997 Wiley-Liss, Inc.
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  • 218
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 454-458 
    ISSN: 0899-0042
    Keywords: biomimetic synthesis ; cyclopentenones ; reductive cyclisation ; kinetic resolution ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: An enantioselective route to the hydroxyfuran acetal substructure 36 of azadirachtin is described. The enantiopure key intermediate 29 was obtained in both absolute configurations by a kinetic resolution experiment, making use of an optical pure cyclopentadiene. After protection of the cyclopentenone double bond a highly diastereoselective reduction - cyclisation sequence, that may mimic the biogenetic pathway, afforded the tricyclic framework of the target molecule. Chirality 9:454-458, 1997. © 1997 Wiley-Liss, Inc.
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  • 219
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 9 (1997), S. 10-12 
    ISSN: 0899-0042
    Keywords: piperidine-2,6-dione ; chiral recognition ; enantioselectivity ; elution order ; cellulose based chiral stationary phase ; reversed phase mode ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A newly developed reversed phase cellulose tris(4-methyl benzoate) known as Chiralcel OJ-R was used to investigate the chiral recognition and enantiomeric separation of eight racemic piperidine-2,6-dione compounds - namely, aminoglutethimide and its major metabolite acetylaminoglutethimide, glutethimide, cyclohexylamino-glutethimide, pyridoglutethimide, thalidomide, phenglutarimide, and 3-phenylacetyl-amino-2,6-piperidinedione (antineoplaston A-10). Chiral separation of these compounds was achieved under varying ratios of the mobile phase, except for phenglutarimide and 3-phenylacetylamino-2,6-piperidinedione, for which separation was unsuccessful. Possible chiral recognition mechanisms are also presented. Chirality 9:10-12, 1997. © 1997 Wiley-Liss, Inc.
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  • 220
    ISSN: 0899-0042
    Keywords: proton pump inhibitor ; pantoprazole ; stereoselective pharmacokinetics ; genetic polymorphism ; human ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Pantoprazole (PAN) is a proton pump inhibitor that is administered as a racemic mixture. The pharmacokinetics of PAN enantiomers were investigated in extensive metabolizers (EMs) and apparent poor metabolizers (PMs) of PAN who received a single 40, 60, or 80 mg oral dose of racemic PAN as enteric-coated formulation. In the EMs, the serum concentrations of (-)-PAN were slightly higher than those of (+)-PAN at each dose level. The (+)/(-) ratios for the area under the concentration-time curve (AUC) and the half-life were 0.58-0.89 and 0.62-0.88, respectively. In the PMs, the serum concentrations of both enantiomers were much higher than those in the EMs at each dose level and significant differences in pharmacokinetics of (+)- and (-)-PAN were observed. The half-lives for (+)-PAN were 2.67-3.77 times longer than those for (-)-PAN. The AUCs for (+)-PAN were 2.65-3.45 times greater than those for (-)-PAN. Therefore, the metabolism of (+)-PAN is impaired to a greater extent than (-)-PAN in the PMs, which resulted in the stereoselective disposition of PAN in the PMs. It has been suggested that the EMs and the PMs of PAN could be differentiated by determining the (+)/(-) enantiomer ratio in serum at one time point, possibly 2-6 h after oral dosing, because the (+)/(-) enantiomer ratios in the PMs were opposite those in the EM subjects. Chirality 9:17-21, 1997 © 1997 Wiley-Liss, Inc.
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  • 221
    ISSN: 0899-0042
    Keywords: pharmacokinetics ; metabolism ; stereoselectivity ; protein binding ; binding site ; displacement ; metabolic chiral inversion ; chiral HPLC ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The present study was an attempt to elucidate the relationship between stereoselective pharmacokinetics and protein binding of KE-298 and its active metabolites, deacetyl-KE-298 (M-1) and S-methyl-KE-298 (M-2). Metabolic chiral inversion was also investigated. The levels of unchanged KE-298 in plasma after oral administration of (+)-(S)-KE-298 to rats were lower than those of (-)-(R)-KE-298, whereas the levels of M-1 and M-2 after administration of (+)-(S)-KE-298 were higher than after (-)-(R)-KE-298. In vitro, rat plasma protein binding of (+)-(S)-KE-298 was lower than that of (-)-(R)-KE-298. In contrast, the binding of (+)-(S)-M-1 and (+)-(S)-M-2 was higher than that of (-)-(R)-M-1 and (-)-(R)-M-2. Displacement studies revealed that the (+)-(S) and (-)-(R)-enantiomers of KE-298 and their metabolites bound to the warfarin binding site on rat serum albumin. These results suggest that the stereoselective plasma levels in KE-298 and its metabolites were closely related to enantiomeric differences in protein binding, attributed to quantitative differences in binding to albumin rather than to the different binding sites. Unidirectional chiral inversion was detected after oral administration of either (-)-(R)-KE-298 or (-)-(R)-M-2 to rats both yielding (+)-(S)-M-2. Chirality 9:22-28, 1997 © 1997 Wiley-Liss, Inc.
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  • 222
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    Chirality 9 (1997), S. 191-197 
    ISSN: 0899-0042
    Keywords: TADDOL ; titanium complexes ; chiral Lewis acid ; polymer-supported ; polystyrene-divinylbenzene ; enantioselective ; Diels-Alder ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The synthesis of the first polymer-supported TADDOL is reported. Its efficiency as chiral ligand of Ti(IV) was studied in the Diels-Alder cycloaddition of cyclopentadiene to 3-crotonoyl-1,3-oxazolidin-2-one, and was superior to that observed for its homogeneous equivalent. (4R,5R)-α,α,α′,α′-2-pentaphenyl-4,5-dimethanol-1,3-dioxolane. Recycling of the heterogeneous Ti(IV)-TADDOLate was also studied, being the most suitable method for the repreparation of the catalyst from the ligand after use. Chirality 9:191-197, 1997. © 1997 Wiley-Liss, Inc.
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  • 223
    ISSN: 0899-0042
    Keywords: rac-doxazosin ; doxazosin ; liquid chromatography ; chiral ; carboxymethyl-β-cyclodextrin ; optimisation ; central composite design ; mobile phase additive ; experimental design ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The chromatographic resolution of rac-doxazosin using reversed-phase high performance liquid chromatography (HPLC) with the chargeable chiral mobile phase additive, carboxymethyl-β-cyclodextrin (CM-β-CD), is described. The effects of different modifiers (acetonitrile, methanol and tetrahydrofuran), pH, temperature, and cyclodextrin concentration were investigated to (a) assess the key chromatographic parameters for subsequent chemometric optimisation, and (b) explore the enantioselective mechanism. Assuming a 1:1 complex between each doxazosin enantiomer and CM-β-CD, studies of the relationship between the capacity factors (k′) and functions of CM-β-CD concentration indicate that the mechanisms for retention and chiral selectivity are comparable with those proposed earlier by Sybilska et al.1 Stability constants (KG) calculated for rac-doxazosin complexed with CM-β-CD (647 ± 55 and 594 ± 45 M-1 for each enantiomer respectively) are significantly larger than those calculated for the barbiturates complexed with β-CD (ca. 101-108 M-1).1 Investigations on pH indicate an ionic or ion-pair interaction between the anionic CM-β-CD and the cationic doxazosin enantiomers.A central composite design was used to optimise the key chromatographic parameters: pH, methanol (v/v) and CM/β-CD concentration. The Kaiser peak separation index, Pi, was used for the response function. The predicted response for this chiral separation has been compared with that observed experimentally and samples of the four-dimensional response surface have been assessed for their value in showing robustness. Chirality 9:184-190, 1997. © 1997 Wiley-Liss, Inc.
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  • 224
    ISSN: 0899-0042
    Keywords: 1H NMR β-cyclodextrin ; heptakis(2,3-di-O-acetyl)β-cyclodextrin ; heptakis(6-O-acetyl)β-cyclodextrin ; ephedrine derivatives ; job technique ; ROESY ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: NMR spectroxcopy has been used to compare the interaction of ephedrine and N-methylephedrine with β-cyclodextrin, heptakis(2,3-di-O-acetyl)β-cyclodextrin, heptakis(6-O-acetyl)β-cyclodextrin. The stoichiometry of the complexes formed between all three cyclodextrins and N-methylephedrine was found to be 1:1 by UV spectroscopy by means of the Job technique. NMR spectra of the single enantiomers of ephedrine and N-methylephedrine in the presence of all three cyclodextrins gave information about the parts of the ligands which interact differently with the host molecules and may be responsible for the chiral discrimination. To quantify the complex stabilities, binding constants were calculated from the changes in the chemical shifts of the ligand signals upon complexation. Analyses of the coupling constants of both species showed that no significant conformational change occurs upon complexation. ROESY spectra of these optical isomers with all three cyclodextrins provided detailed information about the geometry of the complexes. Different intermolecular cross-peaks between the individual isomers of ephedrine and N-Methylephedrine were found for native β-cyclodextrin and its 2,3-diacetylated derivative but not for 6-acetyl cyclodextrin. Analyses of the intramolecular cross-signals of the ligands confirmed that no significant conformational change occurs upon complexation. Chirality 9:211-219, 1997. © 1997 Wiley-Liss, Inc.
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  • 225
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    Chirality 9 (1997), S. 233-237 
    ISSN: 0899-0042
    Keywords: non-covalent molecular imprinting ; Scatchard plot ; batch rebinding ; site specificity ; boc-amino acids ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A potential problem associated with molecularly imprinted polymer (MIP) sorbents is that of cross-reactivity. In this study three MIPs (imprinted with Boc-L-phenylalanine, Boc-L-alanine, Boc-L-glutamic acid) plus a non-imprinted control were prepared and examined for their ability to bind differentially the enantiomers of boc-protected phenylalanine in an effort to quantify cross-reactivity and to develop a predictive model. Batch rebinding studies showed a degree of predictability for a number of MIP-ligand pairs, but other combinations showed unexpectedly high levels of cross-reactivity. Despite the general acceptance of heterogeneity of MIP binding sites, many previous studies report linear Scatchard plots, which is indicative of binding site homogeneity. The data from this study produced curves, clearly demonstrating heterogeneity. The theoretical and practical implications of this heterogeneity are discussed. Chirality 9:233-237, 1997. © 1997 Wiley-Liss, Inc.
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  • 226
    ISSN: 0899-0042
    Keywords: 1,2-diacetoxycyclohexanes ; 1,3-diacetoxycyclohexanes ; 2,3-diacetoxynorbornanes ; 2,7-diacetoxynorbornane ; enantioselective hydrolysis ; biocatalyst ; cultured plant cells ; Marchantia polymorpha ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Very high enantioselectivities were observed in the hydrolysis of racemic 1,2- and 1,3-diacetoxycyclohexanes and their derivatives by cultured cells of Marchantia polymorpha in suspension. Asymmetry was also induced in the hydrolyses of meso-1,2- and 1,3-diacetates to the corresponding monoacetates. These findings indicate that these cultured cells hydrolyze the acetoxyl groups enantioselectively at the stereogenic center of R-configuration. Chirality 9:250-253, 1997. © 1997 Wiley-Liss, Inc.
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  • 227
    ISSN: 0899-0042
    Keywords: microbial chiral inversion ; 2-phenylpropionic acid ; kinetic isotope effect ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Previous investigations have described the development of nongrowing suspension of Verticillium lecanii as a microbial model of the mammalian chiral inversion of the 2-arylpropionic acids (2-APAs). Mechanistic studies in mammals have shown that inversion involves loss of the α-methine proton but retention of the original atoms at the β-methyl position, and a mechanism has been proposed involving enzymatic epimerisation of acyl-CoA thioester derivatives of the substrate. Inversion of the 2-APAs by V. lecanii exhibits extensive intersubstrate variation in the presence, rate, extent, and direction of inversion, which are different from those observed in mammalian systems, possibly indicating differences in the mechanism of inversion between mammalian and microbial cells. This study involved the investigation of proton/deuterium exchange by 1H-nuclear magnetic resonance following incubation of deuterated derivatives of 2-phenylpropionic acid (2-PPA), a model compound, in cell suspensions of V. lecanii and incubation of undeuterated 2-PPA in cell suspensions containing D2O. The results indicated that the inversion of 2-PPA by V. lecanii also involved exchange of the α-methine proton but complete retention on the original atoms at the β-methyl position. No kinetic deuterium isotope effect was observed, indicating that loss of the α-methine proton is not the rate-limiting step of the inversion process. This suggests that the observed differences between microbial and mammalian systems probably involve the stereoselective acyl-CoA thioester formation step and not the subsequent epimerisation of the resultant diastereomers. Chirality 9:254-260, 1997. © 1997 Wiley-Liss, Inc.
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  • 228
    ISSN: 0899-0042
    Keywords: enantioselective transport ; single two-phase liquid-liquid extraction ; N-protected α-amino acid derivatives ; quinine carbamate-type chiral selectors ; chiral anion-exchange carrier ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Two-phase liquid-liquid extraction experiments were undertaken to study the enantioselective transport of the chiral N-protected α-amino acid derivatives from an aqueous buffer solution into an organic phase employing highly lipophilic carbamoylated quinine as chiral selector and phase transfer carrier, respectively. The chiral separation, derived from enantioselective ion-pair formation and differential solubility in the aqueous and organic phases of diastereomeric associates thus formed has been shown to be primarily dependent on the structure of the selectand, the nature of the organic solvent, the molar ratio of a given chiral selector to selectand in the two phases, and the pH of the aqueous phase. Extracted enantiomers were recovered by back-extraction using a relatively polar acidic medium in which the selector is barely insoluble. Thus, the enantiomeric purity of N-(3,5-dinitrobenzoyl)-leucine exceeded 95% enantiomeric excess with 70% overall yield with a single extraction and back-extraction step. Chirality 9:268-273, 1997. © 1997 Wiley-Liss, Inc.
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  • 229
    ISSN: 0899-0042
    Keywords: Xenopus oocytes ; stereochemistry ; chiral chromatography ; chiral benzodiazepines ; enantioselective modulation of GABAA receptor ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Xenopus laevis oocytes injected with Poly(A)+-RNA isolated from neuronal tissue express membrane proteins peculiar to the origin of mRNA. The translation of gamma aminobutyric acid type A (GABAA) receptors has been shown by dose/ response behavior of GABA and the reversible blockade of the GABA-induced current by picrotoxin. This current was analyzed quantitatively under two electrode voltage-clamp conditions. This methodology has been applied for the first time to study the functional properties of the receptor as a function of the stereochemistry of the ligands. The (+)-S and (-)-R enantiomers of a water-soluble benzodiazepine derivative, 7-chloro-1,3-dihydro-3-hemisuccinyloxy-5-phenyl-1,4-benzodiazepin-2-one (OXHEM), obtained by preparative high performance liquid chromatographic (HPLC) resolution on chiral stationary phase, act as agonists in the in vitro modulation of the chloride channel. The (+)-S-OXHEM enantiomer was the more active. Chirality 9:286-290, 1997. © 1997 Wiley-Liss, Inc.
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  • 230
    ISSN: 0899-0042
    Keywords: capillary electrophoresis ; high-performance frontal analysis ; propranolol ; verapamil ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The function of sialic acid groups at the terminal of sugar chains of human α1-acid glycoprotein (AGP) was investigated with respect to chiral discrimination between optical isomers of basic drugs, using high-performance capillary electrophoresis/frontal analysis (HPCE/FA), a novel analytical method developed for the determination of unbound drug concentration with ultramicrosample volume (100-200 nl). Native human AGP and desialylated AGP were used as test proteins, and propranolol (PRO) and verapamil (VER) were used as model drugs. The unbound concentration of (S)-VER was 1.31 times higher than that of (R)-VER in native AGP solution. This selectivity was not affected by desialylation. Further, enzymatic elimination of galactose residues, which neighbored sialic acid groups, did not change the binding of either isomer of VER. On the other hand, the unbound concentration of (R)-PRO was 1.27 times higher than that of (S)-PRO in native AGP solution. Desialylation caused the unbound concentration of (S)-PRO to rise to the same level of (R)-PRO, resulting in loss of enantioselectivity. Thus, it follows that sialic acid groups of AGP, as a whole, are not responsible for chiral recognition between enantiomers of VER but are involved in enantioselectivity toward the isomers of PRO. Chirality 9:291-296, 1997. © 1997 Wiley-Liss, Inc.
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  • 231
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    Chirality 9 (1997), S. 303-306 
    ISSN: 0899-0042
    Keywords: reboxetine ; enantiomers ; dog ; pharmacokinetics ; HPLC determination ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Reboxetine, (RS)-2-[(RS)-α-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week washout period: 10 mg/kg reboxetine, 5 mg/kg (R,R)- and 5 mg/kg (S,S)-. Plasma and urinary levels of the reboxetine enantiomers were monitored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After reboxetine administration mean tmax was about 1 h for both enantiomers. Cmax and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values ± SD being 704 ± 330 and 427 ± 175 ng/ml for Cmax and 2,876 ± 1,354 and 1,998 ± 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t½ (3.9 h). Total recovery of the two enantiomers in urine was similar, the Ae (0-48 h) being 1.3 ± 0.7 and 1.1 ± 0.7% of the enantiomer dose for the (R,R)- and the (S,S)-enantiomers, respectively. No marked differences in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans. Chirality 9:303-306, 1997. © 1997 Wiley-Liss, Inc.
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  • 232
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    Chirality 9 (1997), S. 307-312 
    ISSN: 0899-0042
    Keywords: stereoselective release ; stereoselective dissolution ; propranolol ; enantiomers ; cellulose derivatives ; tablet matrices ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The dissolution characteristics of propranolol enantiomers from tablet formulations containing cellulose, or one of eight cellulose derivatives, were determined under a range of conditions. The derivatives examined were: cellulose tris(phenylcarbamate) (1), cellulose tris(2,3-dichlorophenylcarbamate) (2), cellulose tris 2,4-dichlorophenylcarbamate (3), cellulose tris(2,6-dichlorophenylcarbamate) (4), cellulose tris(2,3-dimethylphenylcarbamate) (5), cellulose tris(3,4-dichlorophenylcarbamate) (6), cellulose tris (3,5-dichlorophenylcarbamate) (7), cellulose tris(3,5-dimethylphenylcarbamate) (8). In water at 25°C, the release rates of (-)R-propranolol were generally greater than those of (-)-S-propranolol, although these differences were not always statistically significant; only compounds 5 and 8 demonstrated significant enantioselectivity. Using compound 8 in further experiments, statistically significant stereoselective dissolution of propranolol HCl was observed in buffer pH 7.4 at 25°C (intrinsic dissolution rates: 0.41 ± 0.01 mgcm2min-1 for R-propranolol and 0.30 ± 0.02 mgcm2min-1 for S-propranolol; P = 0.003). The cumulative amounts of enantiomers released at every time point were also found to be statistically significant (mean ratio R:S 1.25 ± 0.05). The observed low stereoselectivity of 8 with propranolol base was probably attributable to low solubility in pH 7.4 buffer, although stereoselective release did increase with time. This suggested that there is a relationship between stereoselectivity and contact time in an aqueous environment. Results also suggested that increased temperature may affect the release process as well as stereoselective interactions of 8 with individual enantiomers. To conclude, differential release of rac-propranolol from cellulose derivative matrices has been demonstrated, which supports the principle of stereoselective retardation as a potential means of stereoselective drug delivery for solid dosage forms. Chirality 9:307-312, 1997. © 1997 Wiley-Liss, Inc.
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  • 233
    ISSN: 0899-0042
    Keywords: flavour ; biosynthesis ; peach-like aroma ; enantiomeric ratio ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Sporidiobolus salmonicolor is an aroma-producing yeast which gives a peach-like smell to the culture media. The enantiomeric ratios of the five γ-lactones produced by this yeast cultivated in two different media were determined by multidimensional gas chromatography (MDGC) on a fused silica capillary column coupled to a modified β-cyclodextrin column.These ratios remain constant during growth and are not affected by the composition of the medium. The (R)-enantiomer is highly predominant (99%) for γ-decalactone and predominant (68-88%) for γ-octalactone, γ-nonalactone, and (Z6)-γ-dodecenolactone. A ratio close to racemic was found for γ-dodecalactone. A discussion on the metabolic origin of these lactones is based on the analysis of the enantiomeric ratios obtained. With respect to consumers' preference for products considered as “natural,” microbial lactone production may represent a valuable alternative to fruit flavors. The enantiomeric lactone ratios produced by Sporidiobolus salmonicolor are compared with those reported from some fruits. Chirality 9:667-671, 1997. © 1997 Wiley-Liss, Inc.
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  • 234
    ISSN: 0899-0042
    Keywords: absolute configuration ; muscarinic ; agonists ; chemical resolution ; capillary electrophoresis ; receptor binding ; enantioselectivity ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Methods for the synthesis of each of the four stereoisomers of 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane (10, 11, 12, and 13) and 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.1]heptane (18, 19, 20, and 21), and the two stereoisomers of 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane (27 and 28) were developed. The relative configuration of the compounds was determined on the basis of previously described 1H NOE experiments, and the absolute configuration of 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octanes (10, 11, 12, and 13) and 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane (27 and 28) was determined by single crystal X-ray crystallography. Optical purity was determined by capillary electrophoresis (CE) using chiral selectors as trimethyl-β-cyclodextrin and heparin dissolved in the running buffer. All the 3-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles had low nanomolar affinity for muscarinic receptors as determined by displacement of radiolabelled oxotremorine-M (3H-Oxo-M) and pirenzepine (3H-Pz) from cortical rat brain homogenates. The binding assay discriminated between diastereomers, but only a minor degree of enantioselectivity was observed in the binding assays. Chirality 9:739-749, 1997. © 1997 Wiley-Liss, Inc.
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  • 235
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    Chirality 9 (1997), S. 424-427 
    ISSN: 0899-0042
    Keywords: polymers ; chiral amplification ; Italy ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The fact that stereoregular polymers produced by Ziegler-Natta polymerization methods could be crystallized and studied by X-ray diffraction methods lead to the discovery that these polymers adopted helical conformations in the crystalline solid. In addition to the nearly perfect asymmetric synthesis demonstrated by the highly isotactic stereoregularity produced by the catalyst, the conformation adopted in the crystalline state also involves chirality. The large number of units polymerized produced though gives rise to a cryptochiral material in which the mirror helical conformations are necessarily equally populated and therefore the measurement of optical activity can never be a consideration in these experiments. At that time though Natta's students began to prepare stereoregular vinyl polymers with chiral nonracemic pendant groups and discovered that the optical activities of such materials in solution showed nonlinear relationships between enantiomeric content and optical activity. This phenomenon arising from the effect of the chiral pendants on the population of the helical senses of the polymer backbone, acted to demonstrate that these stereoregular polymers adopted helical conformations in solution comparable to those investigated in the solid state. In recent times this effect has reached an extreme in the polyisocyanates which show a much larger sensitivity to chiral effects than found for the vinyl polymers although the underlying forces at work are identical to those studied earlier by the Italian School. Chirality 9:424-427, 1997. © 1997 Wiley-Liss, Inc.
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  • 236
    ISSN: 0899-0042
    Keywords: (R)-dihydrohaloperidol ; (S)-dihydrohaloperidol ; (R)-dihydrobromo-peridol ; (S)-dihydrobromoperidol ; catalepsy ; dyskinesia ; motor deficit ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Optically active dihydrohaloperidols and dihydrobromoperidols, the major metabolites of haloperidol and bromoperidol, clinically used as neuroleptic drugs in humans, were asymmetrically synthesized by Jaen's method. The motor effects of all the reduced haloperidol and bromoperidol metabolites were evaluated by the mouse catalepsy test. The results indicate that administration of the optically active dihydrohaloperidols and dihydrobromoperidols as well as haloperidol and bromoperidol can cause significant motor deficits in mice. Chirality 9:443-445, 1997. © 1997 Wiley-Liss, Inc.
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  • 237
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    Chirality 9 (1997), S. 604-615 
    ISSN: 0899-0042
    Keywords: circular dichroism ; mesobilirubins ; conformation ; ridge-tile shape ; molecular helicity ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Bilirubin, the yellow pigment of jaundice, is a bichromophoric tetrapyrrole that readily adopts either of two enantiomeric, folded conformations shaped like ridge-tiles and stabilized by a network of six intramolecular hydrogen bonds. Interconversion of these M and P helical chirality conformational enantiomers is rapid at room temperature but may be displaced toward either enantiomer by intramolecular nonbonded steric interactions. Introduction of a methyl group at the β and β′ carbons of the propionic acid chains on the symmetric bilirubin analog, mesobilirubin-XIIIα, shifts the conformational equilibrium toward the M or the P-chirality intramolecularly hydrogen-bonded conformer, depending only on the S or R stereochemistry at β and β′, resulting in pigments with intense exciton coupling circular dichroism (CD) for the ∼430 nm transition(s). Optically active synthetic analogs of bilirubin with propionic acid groups lengthened systematically to heptanoic acid (1-5) were synthesized and examined by spectroscopy to explore the influence of alkanoic acid chain length on conformation and intramolecular hydrogen bonding. In these diacids and their dimethyl esters (6-10), strong exciton chirality CD spectra are observed, and the data are correlated with molecular helicity. Chirality 9:604-615, 1997. © 1997 Wiley-Liss, Inc.
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  • 238
    ISSN: 0899-0042
    Keywords: terbium(III) ; mandelic acid ; circularly polarized luminescence ; 1,2-propanediaminetetraacetic acid ; phenyllactic acid ; stereoselectivity ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: It has been found that the binding of mandelic acid (MAN) at the inner coordination sphere of Tb(propanediaminetetraacetate) is profoundly affected by the enantiomeric identity of the MAN ligand, but that such stereoselective effects are absent in the formation of analogous ternary complexes containing phenyllactic acid (PLA). For Tb(PDTA)(MAN) complex species, the largest formation constants were obtained when the PDTA and MAN ligands were of the opposite absolute configuration, and the smallest were obtained when the two bound ligands were of the same configuration. The formation constants of all Tb(PDTA)(PLA) complexes were found to be equivalent to within experimental error, indicating no stereoselectivity in the formation of these ternary complexes.The circularly polarized luminescence within the Tb(III) emission bands indicated that steric interactions accompanied the binding of MAN by a Tb(PDTA) complex, which were deduced to be associated with perturbations in ligand conformations. No such effects were noted between bound PDTA and PLA ligands, where the observed CPL intensities of the ternary complexes could be calculated by a simple addition of PDTA and PLA contributions. Determinations of metal ion hydration revealed that the fully formed Tb(PDTA)(MAN) complexes were essentially anhydrous, while the fully formed Tb(PDTA)(PLA) to complexes still contained residual water. This finding indicated that the binding of MAN a Tb(PDTA) complex is accompanied by a total expulsion of all coordinated water molecules, implying the existence of a tight fit by the MAN ligand in the residual inner coordination sphere of a Tb(PDTA) complex. The lack of any demonstrable steric interactions between bound PDTA and PLA ligands implies that the PLA ligand has a smaller steric requirements than does the MAN ligand. This is thought to be due to the additional methylene group of PLA, which provides an additional spacing between the coordinating hydroxycarboxylate group and the sterically demanding phenyl group, and which appears to be sufficient to move the phenyl group out to a distance which does not require its interaction with the PDTA functionality. Chirality 9:583-592, 1997. © 1997 Wiley-Liss, Inc.
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  • 239
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    Chirality 9 (1997), S. 601-603 
    ISSN: 0899-0042
    Keywords: Mosher's acid ; 1H NMR ; epoxides ; chiral recognition ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: It was found that the oxirane ring is a functional group amenable to chiral discrimination by dirhodium-MTPA complexes. Considerable signal shifts up to 0.7 ppm are observed for 1H nuclei close to the rhodium atoms in the complex. In analogy to previously reported olefins, this method appears to be comparable to the use of chiral lanthanoid shift reagents. Chirality 9: 601-603, 1997. ©1997 Wiley-Liss, Inc.
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  • 240
    ISSN: 0899-0042
    Keywords: polyphenylacetylene ; rhodium catalyst ; chiral discrimination ; circular dichroism ; induced circular dichroism ; absolute configuration ; helix ; acid-base ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Five phenylacetylenes bearing an amino group such as 4-amino (1), 3-amino (2), 4-N,N-dimethylamino (3), 4-aminomethyl (4), and 4-N,N-diisopropylamino-methyl (5) group on the phenyl group, 4-pyridylacetylene (6), and 2-pyridylacetylene (7) were synthesized and polymerized with [Rh(nbd)Cl]2 (nbd: norbornadiene). Monomer 5 showed the highest polymerizability and afforded quantitatively a fibrous polymer, whereas the other monomers showed lower reactivity and the resulting polymers were powdery. Although most polymers were not soluble in common organic solvents such as tetrahydrofuran (THF), chloroform, acetonitrile, and dimethyl sulfoxide, some polymers were soluble in the presence of carboxylic acids. Among the polyphenylacetylene derivatives, only poly-5 having a stable, highly cis-transoidal stereoregular structure exhibited an induced circular dichroism (ICD) in the UV-visible region, probably due to a prevailing one-handed helical conformation upon complexation with optically active carboxylic and α-hydroxy acids such as mandelic acid, lactic acid, and 2-phenylbutyric acid in THF, the sign of which reflected the absolute configuration of the acids. Therefore, poly-5 can be used as a novel probe for determining the chirality of acids. The α-hydroxy acids of the same configuration gave the same sign in induced Cotton effect in THF. However, carboxylic acids used in the present study showed the opposite signs to those of the α-hydroxy acids when their absolute configurations were same. The magnitude of the ICDs seems to depend on the bulkiness of the α-hydroxy acids. On the contrary, other poly(phenylacetylenes) bearing an amino group and poly(pyridylacetylenes) did not show any ICD in the presence of optically active acids, probably because of either low basicity for the acid-base complexation or low stereoregularity of the polymers. Chirality 9:593-600, 1997. © 1997 Wiley-Liss, Inc.
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  • 241
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    Chirality 9 (1997), S. 616-622 
    ISSN: 0899-0042
    Keywords: exciton coupling ; chiral coordination complex ; C3-symmetry ; tripodal ligand ; absolute stereochemistry ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The solution configuration of labile coordination complexes may be difficult to determine, even in cases in which the solid state structure is known. We have previously synthesized a series of chiral ligands which form pseudo-C3-symmetric complexes with ZnII and CuII salts that possess an available electrophilic coordination site. Molecular modeling of ZnII complexes of the chiral ligand N,N-bis[(2-quinolyl)methyl]-1-(2-pyridyl)ethanamine (α-MeBQPA) showed that the spatial arrangement of the heterocyclic arms is controlled by a substituent on one methylene arm, resulting in the adoption of an enantiomeric conformation displaying a propeller-like asymmetry. In this paper we report the application of the exciton chirality method to the determination of the conformation of asymmetric metal-ligand complexes in solution. There is a good correlation between the predicted and the observed Cotton effects, demonstrating that the geometry in solution closely resembles that predicted by computational simulations and those obtained by X-ray crystallographic studies of metal complexes with racemic and enantiomerically pure ligands. The X-ray crystallographic structure of the first optically pure complex in this series is reported. Chirality 9:616-622, 1997. © 1997 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
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  • 242
    ISSN: 0899-0042
    Keywords: bacterial lipopolysaccharides ; bichromophoric ; acyclic polyols ; 2-anthroate ; heptose side chains ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The absolute configuration of the acyclic side chain of heptopyranosides and heptofuranosides was determined by exciton coupled CD, employing the strongly fluorescent 2-anthroate chromophore. The usage of this chromophore offers significant improvements over previous chemical and spectroscopic procedures since its intense fluorescence greatly facilitates the isolation and HPLC purification at the nanogram scale. The large amplitudes of the bisignate spectra allow CD manipulations in the 1 × 10-7 M range. Chirality 9:699-712, 1997. © 1997 Wiley-Liss, Inc.
    Additional Material: 13 Ill.
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  • 243
    ISSN: 0899-0042
    Keywords: chiral solvating agents ; enantiomers ; enantiomeric excess ; chiral sulfoxides ; chiral amines ; chiral alcohols ; chiral carboxylic acids ; optical purity ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Esters of 1-(1-naphthly)ethylurea derivatives of L-valine, L-leucine, L-tert-leucine, and L-proline are examined as organic-soluble chiral nuclear magnetic resonance (NMR) resolving agents. The reagents are useful for resolving the spectra of chiral sulfoxides, amines, alcohols, and carboxylic acids. Enantiomeric resolution is caused by a combination of diastereomeric effects and the different association constants of the substrates with the resolving agents. Organic-soluble lanthanide species are added to resolving agent-substrate mixtures and often enhance the enantiomeric resolution. The enhancement occurs because the substrate that exhibits weaker binding with the resolving agent is more available to bond to the lanthanide. Broadening in the spectra with lanthanides is reduced at 50°C. Enantiomeric resolution is still observed at elevated temperatures. Chirality 9:1-9, 1997. © 1997 Wiley-Liss, Inc.
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  • 244
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    Chirality 9 (1997), S. 13-16 
    ISSN: 0899-0042
    Keywords: R-warfarin ; S-warfarin ; steady-state clearance ; patients ; AUC data ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Previous studies to identify the pharmacokinetics of R- and S-warfarin have not used steady-state area under the curve (AUC) data during therapeutic doses of racemic warfarin. Instead they have used high single doses of either racemic warfarin or a single enantiomer in volunteers or have taken a single blood sample from anticoagulated patients and assumed full compliance and a steady-state status. In this study, a series of steady-state racemic warfarin, R-warfarin, and S-warfarin serum concentrations, during a 24 h dosage interval, was measured in 10 compliant patients (5 females and 5 males) taking racemic warfarin. The anticoagulation status of all 10 patients according to the International Normalised Ratio (INR) was stable. Their mean (SD) age and weight were 67.0 (9.9) yr and 63.9 (15.4) kg. The mean (SD) clearances derived from steady-state AUC values, following therapeutic dosing, for racemic warfarin, R-warfarin, and S-warfarin were 2.40 (0.82), 2.30 (0.65), and 2.80 (1.17) ml/h/kg, respectively. The mean (SD) ratio of S-:R-warfarin clearance was 1.24 (0.40). Comparison of the clearance measured from the AUC, of these patients, to one point determinations assuming steady state for the samples drawn at either 6, 15, or 20 h after dosage (during the dosing interval) showed some statistical differences. Most single point determinations of warfarin clearance assume that a sample 12 h postdose is equivalent to that of the steady-state concentration, but in this study the steady-state concentration of only 6 patients occurred between 6 and 15 h postdose. This could explain why these studies demonstrate differences in the clearance of R- and S-warfarin compared to the values we have derived from steady-state AUC data using patients with proven compliance and therapeutic doses. Chirality 9:13-16, 1997. © 1997 Wiley-Liss, Inc.
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  • 245
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    Chirality 9 (1997), S. 52-58 
    ISSN: 0899-0042
    Keywords: famprofazone ; stereoselective metabolism ; N-dealkylation ; β-hydroxylation ; p-hydroxylation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Following administration of famprofazone to humans, the stereoselective metabolism from the drug to its known metabolites (+,-)-ephedrine, (+,-)-pseudoephedrine, (+,-)-norephedrine, (+,-)-norpseudoephedrine, (+,-)-p-hydroxy-amphetamine, (+,-)-p-hydroxymethamphetamine, and (+,-)-p-hydroxynorephedrine was studied. The enantiomers of the metabolites were derivatized with α-methoxy-α-(trifluoromethyl)-phenylacetyl chloride (MTPA.Cl) as the chiral derivatizing agent for amino groups and N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA) or N-methyl-N-triethylsilyl trifluoroacetamide (MTESTFA) as protecting agents of the hydroxyl groups. The diastereomeric derivatives were well separated by capillary gas-liquid chromatography and determined by mass spectrometry with selected-ion monitoring (SIM). (-)-Methamphetamine, (-)-amphetamine, (-)-p-hydroxyamphetamine, and-(-)-hydroxymethamphetamine were excreted in greater amounts than their enantiomers after administration of racemic famprofazone; and (-)-ephedrine, (-)-pseudoephedrine, (-)-norephedrine, and (-)-norpseudoephedrine were found in higher concentration than their enantiomers. Famprofazone was metabolized by product and substrate stereoselective N-dealkylation, β-hydroxylation, and p-hydroxylation, metabolites of which may be predominantly responsible for the side effects of famprofazone. Chirality 9:52-58, 1997. © 1997 Wiley-Liss, Inc.
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  • 246
    ISSN: 0899-0042
    Keywords: stereoselectivity ; fatty-acyl CoA oxidase ; H4IIEC3 cells ; CV-1 cells ; structure-activity relationships ; absolute configuration assignment ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Enantiomers of a series of substituted analogs of 2-(4-chloronhenoxy)-acetic acid (CPAA) were synthesized and used to examine the influence of steric and structural parameters on peroxisome proliferation. The effects of these compounds were studied on the activation of the peroxisome proliferator-activated receptor α (PPARα) in CV-1 cells using an in vitro co-transfection assay. Selected sets of isomers were tested for their ability to increase peroxisomal fatty acyl-CoA oxidase (ACO) activity in H4IIEC3 (rat Reuber hepatoma) cells. Of the series of 2-substituted analogs studied, the isomers of the n-propyl and phenyl derivatives of CPAA showed a high degree of stereoselectivity [(S)-isomer ≫ (R)-isomer]. In general, the potency of the compound to activate the receptor increased with the size of the 2-alkyl substituent. Among the 4-chlorobenzyloxy- and 4-(4′-chlorophenyl)benzyloxy- analogs studied, 2-[4-(4′-chlorophenyl)-benzyloxy]-propanoic acid exhibited a high degree of stereoselectivity in both the biological systems studied [(R) ≫ (S)]. The congeners of 2-methyl substituted CPAA showed a reverse stereoselectivity [(R) 〉 (S)] as compared to the other 2-substituted analogs [(S) 〉 (R)]. Our results indicate that (1) both structural and steric characteristics of CPAA analogs play an important role in the activation of rPPARα and on stimulation of peroxisomal ACO activities, and (2) clofibric acid and analogs exert their peroxisome proliferative effects by interaction with a specific site on a protein. The enantiomers of the 2-n-propyl and the 2-phenyl CPAA analogs may be useful as mechanistic probes in elucidating the nature of this binding site. Chirality 9:37-47, 1997. © 1997 Wiley-Liss, Inc.
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  • 247
    ISSN: 0899-0042
    Keywords: enantioseparation ; chiral stationary phase ; HPLC ; amylose phenylcarbamate ; chiral discrimination ; resolution ; enantiomer ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Four 4-halogen-substituted phenylcarbamate derivatives of amylose were prepared and their chiral recognition abilities as chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) were evaluated and compared with those of the corresponding cellulose derivatives. The amylose derivatives with fluoro, chloro, bromo, or iodo group at the four-position on the phenyl group were found to show higher chiral resolving ability than the corresponding cellulose derivatives. Among four amylose derivatives 4-fluoro- and 4-chlorophenylcarbamates showed an excellent chiral recognition ability. Especially, amylose tris(4-chlorophenylcarbamate) resolved (±)-1,2,2,2-tetraphenylethanol with a very high α value (α = 8.29). In order to obtain useful information concerning the chiral recognition mechanism of this resolution, we also performed enantioseparation of a variety of analogous racemic alcohols, and found that both the hydroxy and bulky triphenylmethyl groups of the racemate are essential for the effective chiral recognition. Chirality 9:63-68, 1997. © 1997 Wiley-Liss, Inc.
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  • 248
    ISSN: 0899-0042
    Keywords: stereoselective synthesis ; carboxyibuprofen diastereoisomers ; circular dichroism ; chiral LC separation ; ibuprofen ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The chromatographic resolution of the four stereoisomers of carboxyibuprofen, a major metabolite of ibuprofen in man, was achieved using a Chiralpak AD chiral stationary phase (CSP) (J.T. Baker, Milton, Keynes, UK). The elution order of the stereoisomers was determined to be 2′S,2R; 2′R,2R; 2′R,2S; 2′S,2S by a combination of stereoselective synthesis of diastereoisomeric mixtures and analysis of the two diastereoisomers isolated from human urine following the administration of (S)-ibuprofen. The individual stereoisomers were isolated by semipreparative chiral phase chromatography and characterized by circular dichroism spectroscopy. Chirality 9:75-87, 1997. © 1997 Wiley-Liss, Inc.
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  • 249
    ISSN: 0899-0042
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: In the article listed above, the caption for Figure 5 should read as“Ionspray mass spectra of the negatively charged [DPB-CHF 1024] (A) and [DPB-CHF 1024 urea derivative] (B) complexes. The m/z values referred to the normal masses of ions.” rather than “Collision-activated dissociation spectrum of….”.The authors apologize for the error.
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  • 250
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    Chirality 9 (1997), S. 103-103 
    ISSN: 0899-0042
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: No abstract.
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  • 251
    ISSN: 0899-0042
    Keywords: capillary electrophoresis ; HPLC, α-phosphonosulfonic acid ; enantiomers, β-cyclodextrin ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The enantiomers of α-phosphonosulfonic acids were completely resolved by capillary electrophoresis using β-cyclodextrin as a chiral selector in a borate electrolyte and HPLC using a chiral AGP column. The methods were used to quantitate the R-enantiomer present as an impurity in the S-enantiomer, a potential cardiovascular drug candiate. Chirality 9:104-108, 1997. © 1997 Wiley-Liss, Inc.
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  • 252
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    Chirality 9 (1997), S. 122-125 
    ISSN: 0899-0042
    Keywords: enantiomeric excess determination ; polarimetry ; HPLC ; enantiomers ; solvent effects ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Investigations into the parameters affecting the sensitivity of polarimetric detectors for the determination of enantiomeric excess by achiral HPLC are presented. The results obtained showed that the specific optical rotation of an analyte was highly sensitive to the methanol content of the mobile phase. The purpose of this short communication is to demonstrate that “off-line” optical rotation measurements are a necessary part of the method development process for successful use of polarimetric detectors. Chirality 9:122-125, 1997, © 1997 Wiley-Liss, Inc.
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  • 253
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    Chirality 9 (1997), S. 113-121 
    ISSN: 0899-0042
    Keywords: 1,3,5-triazine ; chiral discrimination ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: 2-Hexylamino-4-[(S)-1-(1-naphthyl)ethylamino]-6-L-valyl-L-valyl-L-valine isopropylester-1,3,5-triazine (1), a molecule characterized by two different chiral selectors, and 2-hexylamino-4,6-bis-L-valyl-L-valyl-L-valine isopropylester-1,3,5-triazine (2) and 2-ethoxy-4-hexylamino-6-[(S)-1-(1-naphthyl) ethylamino]-1,3,5-triazine (3), systems in which a single kind of chiral selector is present, have been prepared. The enantiodiscriminating ability in solution of the three compounds toward the N-3,5-dinitrobenzoyl derivatives of 1-phenylethylamine (4) or valine methylester (5) has been investigated by 1H nuclear magnetic resonance (NMR) spectroscopy: 1 shows an improved versatility, relative to 2 and 3, as a chiral solvating agent for NMR spectroscopy. On the basis of the indications obtained, the usefulness of 2-chloro-4-[(S)-1-(1-naphthyl)ethylamino]-6-L-val-L-val-L-valine isopropylester-1,3,5-triazine (1a), a direct precursor of 1, as chiral solvating agent for the determination by NMR of the enantiomeric compositions of derivatives of amines, amino alcohols, amino acids, and carboxyl acids bearing a 3,5-dinitrophenyl moiety, has been demonstrated. Chirality 9:113-121, 1997. © 1997 Wiley-Liss, Inc.
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  • 254
    ISSN: 0899-0042
    Keywords: anti-ischemic agent ; gerbil ; enantiomeric resolution ; column switching ; chiral crown ether ; HPLC ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A sensitive and selective high performance liquid chromatographic method using an automated column switching technique for the determination of FCE 28833 enantiomers in gerbil plasma was developed. After solid-liquid extraction using a Supelcosil C18 cartridge FCE 28833 was eluted on a clean-up column (Spherisorb CN) and the enantiomers were separated using an analytical chiral column (Crownpack CR(+)). The mobile phase (15% methanol in HClO4 1 mM) was directed through the columns at a flow rate of 1 ml/min and the fraction eluted between 13 and 40 min was transferred from the clean-up column into the analytical column. FCE 28833 enantiomers were monitored at 257 nm. The limit of quantitation of the method was 20 ng/ml plasma for both enantiomers and proved to be linear, precise, and accurate for the assay of both enantiomers in the 20-6,000 ng/ml concentration range. No interference from the blank gerbil plasma sample was observed. The suitability of the method was assessed using plasma samples obtained from male gerbils treated with a single oral dose (400 mg/kg) of FCE 28833. Chirality 9:133-138, 1997. © 1997 Wiley-Liss, Inc.
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  • 255
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    Chirality 9 (1997), S. 139-144 
    ISSN: 0899-0042
    Keywords: thin-layer chromatography ; propranolol ; bupranolol ; enantiomers ; cellulose derivatives ; chiral stationary phase ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Cellulose triphenylcarbamate derivatives have been used as stationary phases for resolution of the enantiomers of the β-blockers propranolol and bupranolol by TLC. The derivatives examined were: cellulose trisphenylacarbamate (1), cellulose tris(2,3-dichlorophenyl carbamate) (2), cellulose tris(2,4-dichlorophenyl carbamate) (3), cellulose tris(2,6-dichlorophenyl carbamate) (4), cellulose tris (2,3-dimethylphenyl carbamate) (5), cellulose tris(3,4-dichlorophenyl carbamate) (6), cellulose tris(3,5-dichlorophenyl carbamate) (7), and cellulose tris(3,5-dimethylphenyl carbamate) (8). A variety of mobile phases were used to achieve useful separations and the effects of solvent polarity are also discussed. The best resolution of rac-propranolol was obtained on CSP 8 (RfR = 0.26, RfS = 0.06, α = 4.33) in mobile phase hexane:propan-2-ol (80:20 v/v). The best resolution of rac-bupranolol was obtained on CSP 5 (RfR = 0.29, RfS = 0.09, α = 3.22) in mobile phase hexane:propan-2-ol (80:20 v/v). These results demonstrated the potential of cellulose triphenylcarbamates as chiral stationary phases in TLC and indicate that this is potentially a useful method for the direct, simple, and rapid (within 30 min) resolution of racemates in the analytical control of enantiomeric purity. Physical aspects such as problems in cracking of the CSP, adhesion to plate, and interference of spot detection due to triphenylcarbamate chromphores are also discussed, along with the method employed to overcome them. Chirality 9:139-144, 1997. © 1997 Wiley-Liss, Inc.
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  • 256
    ISSN: 0899-0042
    Keywords: chiral separation ; β-cyclodextrin derivatives ; capillary electrophoresis ; vicinal diols ; borate complexation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Capillary electrophoretic enantioseparation of compounds containing vicinal diol groups have been investigated using different β-cyclodextrin (CD) derivatives and borate as a background electrolyte. Both native β-CD and several β-CD derivatives are examined. Chiral recognition is attributed to both enantioselective inclusion of the analyte into the chiral cavity of the CD and complexation with borate. The influence of concentration of the chiral selector, pH, and organic modifiers on the resolution was studied. Four diols were baseline separated. Chirality 9:153-156, 1997. © 1997 Wiley-Liss, Inc.
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  • 257
    ISSN: 0899-0042
    Keywords: chromatographic resolution ; enantiomers ; sulfoximide ; sulfoximine ; sulfoxide ; hydrogen bonding ; DATD-based CSP ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Two O,O′-diaroyl derivatives of an N,N′-diallyl-L-tartardiamide-based CSP, 3,5-dimethylbenzoyl (CSP I) and 4-tert-butylbenzoyl (CSP II), have been investigated and compared with respect to retention behaviour and resolving capabilities of a series of endocyclic sulfoximides of the 1-R-3-oxo-benzo[d]-isothia (IV)-azole 1-oxide type (R = methyl, octyl, 2′-carboxyphenyl, and 2′-carbethoxyphenyl) and their corresponding sulfoxide precursors. For the sulfoximides, selectivities of 1.44, 1.27, 1.28, and 1.20, respectively, were found on CSP II when eluted with 15% 2-propanol in hexane. Both the sulfoximide compounds and their sulfoxide precursors are well resolved by CSPs I and II. The retention was larger on the former phase, indicating that the molecular skeletons of the analytes studied interact, through hydrogen bonding, more strongly with CSP I than CSP II. Chirality 9:167-172, 1997. © 1997 Wiley-Liss, Inc.
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  • 258
    ISSN: 0899-0042
    Keywords: chiral high-performance liquid chromatography ; polysaccharides ; structure-retention relationships ; amides ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A series of enantiomeric amides have been chromatographed on three amylose-based chiral stationary phases (CSPs): amylose tris(3,5-dimethylphenylcarbamate) (AD-CSP), amylose tris (S-phenylethylcarbamate) (AS-CSP), and amylose tris(R-phenylethyl-carbamate) (AR-CSP). The relative retentions and enantioselectives of the solutes on the three CSPs were compared and basic structure-retention relationships developed to describe the chromatographic results. The data indicate that for these solutes the observed elution order was a function of the chirality of the amylose backbone, while the magnitude of the enantioselective separations was affected by the chirality of the carbamate side chain. Chirality 9:173-177, 1997. © 1997 Wiley-Liss, Inc.
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  • 259
    ISSN: 0899-0042
    Keywords: chiral recognition mechanisms ; quantitative structure ; enantioselective retention relationships ; chiral chromatography ; enantioselective separations ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A series of 12 chiral arylcarboxylic acids were chromatographed on an immobilized human serum albumin chiral stationary phase (HSA-CSP). The effects of solute structure on chromatographic retentions and enantioselective separations were examined by linear regression analysis and the construction of quantitative structure-enantioselective retention relationships. Competitive displacement studies were also conducted using R-ibuprofen as the displacing agent. The results indicate that the enantioselective retention of the solutes takes place at the indole-benzodiazepine site (site II) on the HSA molecule and that chiral recognition is affected by the hydrophobicity and steric volume of the solutes. The displacement studies also identified a cooperative allosteric interaction induced by the binding of R-ibuprofen to site II. Chirality 9:178-183, 1997. © 1997 Wiley-Liss, Inc.
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  • 260
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    Chirality 9 (1997), S. 198-202 
    ISSN: 0899-0042
    Keywords: oligopeptide ; amino acid N-carboxyanhydride ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: This article describes improvements in the Juliá asymmetric epoxidation reaction. The oligopeptides needed for the study were synthesised from N-carboxyanhydrides (NCAs) employing various initiators, such as water, 1,3-diaminopropane (DAP), and cross-linked aminomethylpolystyrene (CLAMPS) 1. Chirality 9:198-202, 1997. © 1997 Wiley-Liss, Inc.
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  • 261
    ISSN: 0899-0042
    Keywords: chiral selectors ; natural product derived hosts ; optically active hosts ; clathrate hosts ; bulky diols ; inclusion compounds ; host-guest complexes ; chiroselective cocrystallization ; crystal packing analysis ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: New chiral host molecules 1 and 2 involving a bulky terpenoid unit and aromatic ethyne spacer groups were synthesized using Pd-catalyzed cross-coupling reactions of (+)-2α-ethynyl-2β-hydroxybornane (4) or (+)-2α-ethynyl-2β-hydroxyfenchane (5) with 9,10-dibromoanthracene. Host compounds 1 and 2 from crystalline inclusions with 1-methoxy-2-propanol (3) in 1:1 and 1:2 stoichiometry, respectively. In the case of 1, complete enantiomer resolution (ee 〉 99%) of 3 is effected in one cocrystallization step. However, constitutional isomer 2 failed in the enantiomer separation of 3, which might be explained due to the different crystal lattice buildup of these cocrystals. Chirality 9:203-210, 1997. © 1997 Wiley-Liss, Inc.
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  • 262
    ISSN: 0899-0042
    Keywords: quartz crystal microbalance ; electronic nose ; fragrance ; odour ; detection ; chemical sensor ; cyclodextrin ; chiral discrimination ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Quartz crystal microbalances (QCMB) have been constructed using 10 MHz AT cut quartz crystals coated with heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(6-O-methyl-2,3-di-O-pentyl)-β-cyclodextrin, and octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin as 50% and 20% (w/w) solutions in OV1701. The reduction in frequency seen on exposure of each coated QCMB to pure enantiomeric forms of α- and β-pinene and cis- and trans-pinane show that statistically significant (P = 0.05, n = 7) differences are observed between the enantiomeric pairs. The apparent preferential binding shown by the QCMB for enanciomers of α- and β-pinene and cis- and trans-pinane have been compared with the elution order observed on the corresponding gas chromatographic stationary phase. The magnitude of the observed separation factor (calculated as the ratio of the OV1701 normalised frequency shift) is seen to be dependent upon the chiral stationary phase concentration. These results indicate that on-line determination of enantiomeric excess and concentration of certain monoterpenes is possible at room temperature using QCMB in conjunction with chiral gas chromatographic stationary phases. Chirality 9:225-232, 1997. © 1997 Wiley-Liss, Inc.
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  • 263
    ISSN: 0899-0042
    Keywords: racemic compound crystal ; mixed crystal of (+) and (-) enantiomers ; enantiomeric enrichment in solution ; reversal of chirality ; X-ray powder diffraction ; chiral sulfonium sulfonate ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A new example of a racemate showing unusual enantiomeric resolution phenomenon, in which simple recrystallization of the racemate leads to remarkable enantiomeric enrichment of either enantiomer up to 100% ee in the mother liquor, has been found. This compound is (±)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]-ethyl]dimethylsulfonium p-nitrobenzenesulfonate [EtOCH2CH(OH)CH2OC6H4NHCOCH2CH2SMe2+O2NC6H4SO3-] [(±)-SN]. By repeating recrystallization of (±)-SN and the resulting deposited crystals successively and collecting the resulting enantiomerically enriched mother liquors with the same chirality sense, highly efficient enantiomeric resolution of the racemate into its separate enantiomers has been accomplished. The relationship between the occurrence of this enantiomeric resolution phenomenon and the crystal properties has been investigated with respect to SN and its aryl- and alkylsulfonate derivatives. The mode of enantiomeric resolution of (±)-SN was similar to that of para-substituted benzenesulfonate derivatives (±)-ST (4-MeC6H4SO3-) and (±)-SC (4-ClC6H4SO3-) previously reported, whereas the unsubstituted derivative (±)-SB (C6H5SO3-) and alkysulfonate derivatives (±)-SO (n-C8H17SO3-) and (±)-SM (CH3SO3-) did not show such an enantiomeric resolution phenomenon. The crystalline form of the former racemates that underwent the enantiomeric resolution was racemic compounds, while the latter were mixed crystals (solid solutions) composed of the respective optical antipodes. Chirality 9:220-224, 1997. © 1997 Wiley-Liss, Inc.
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  • 264
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    Chirality 9 (1997), S. 243-249 
    ISSN: 0899-0042
    Keywords: chiral polymethine dyes ; circular dichroism ; helicity ; helicity rules ; cis-peak ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Synthesis, chiroptical properties, and quantum-mechanical calculations of the monomethine dye 3 and of the trimethine dyes 7 and 11 are reported. In 3 and 11, the chromophore is forced into a twisted all-Z-conformation by steric interaction of the end groups in the former and the presence of a t-butyl group in the mesoposition of the latter, which is manifest in the UV/Vis spectra not only in the reduced intensity of the longest wavelength absorption, but also in the occurrence, at shorter wavelength, of a “cis-peak.” Chiral substitution of the end groups serves as chiral anchor to discriminate between otherwise enantiomeric forms and makes them amenable to chiroptical investigation. The results are in agreement with theoretically calculated chiroptical data based on helically twisted cyanine chromophores. They support the contention that not only the sense of the helix, but also its length determines the sign of the associated Cotton effect. Chirality 9:243-249, 1997. © 1997 Wiley-Liss, Inc.
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  • 265
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    Chirality 9 (1997), S. 238-242 
    ISSN: 0899-0042
    Keywords: non-covalent molecular imprinting ; hydrogen bonding parameters ; solvent properties ; chiral separation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The aim of this study was to rationalise retention behaviour of a chiral solute on molecularly imprinted polymer (MIP) HPLC stationary phases in terms of variation of the mobile phase. It is generally held that the most important interaction governing the separation of enantiomers on such materials is H-bonding, and that retention times increase with decreasing H-bonding potential of the mobile phase. Previous studies have largely concerned mobile phases containing chloroform with acetic acid as a polar modifier. Boc-L-Phenylalanine (Boc-L-Phe-OH) MIPs were prepared, processed, and packed into HPLC columns, which were then used to investigate the retention characteristics of Boc-L-Phe-OH and Boc-D-Phe-OH with a range of mobile phases. The main observations were as follows: (1) in chloroform-based mobile phases there was generally a linear relationship between the H-bond donator factor of the polar modifier and capacity (K′). Results also indicated a hydrogen bond donor parameter value for a polar modifier at which retention became concentration independent; (2) For given values of K′L, K′D varied depending on the polar modifier, indicating that enantiomer resolution was solvent dependent; (3) Using mobile phases based on solvents of lower polarity/H-bonding potential than chloroform, substantial increases in K′ were observed, although enantioselectivity was greatly reduced. Chirality 9:238-242, 1997. © 1997 Wiley-Liss, Inc.
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  • 266
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    Chirality 9 (1997), S. 261-267 
    ISSN: 0899-0042
    Keywords: industrial scale ; phenylalanine ; enhancing enantioselectivity ; membrane solvent ; chiral extraction ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We describe the use of emulsion liquid membrane technology to perform chiral separations on low molecular weight species. We have reviewed liquid membrane technology in the context of existing process scale chiral separations. We illustrate the potential of this new technique by presenting our results on the selective extraction of phenylalanine enantiomers, using copper (II) N-decyl-(L)-hydroxyproline as a chiral selector in an emulsion liquid membrane configuration. This is compared with an analogous batch solvent extraction system. Initial batch enantiomeric excesses of greater than 40% were observed with the emulsion liquid membrane system compared with around 25% for the solvent extraction system. It was also noted that the system is not limited by the equilibrium capacity constraints of the solvent extraction system. We have shown that kinetic chiral liquid membrane technology offers high productivity and flexibility compared with analogous process scale chiral technologies. Recent transfer of highly specific chiral reversed-phase high-performance liquid chromatographic chemistries have shown that “one-stop” enantiomeric excesses of commercial interest (〉95%) are achievable using kinetic chiral liquid membrane systems. Solvent and temperature selection strategies also have been outlined as means of increasing the enantioselectivity of existing liquid membrane extraction chemistries. Chirality 9:261-267, 1997. © 1997 Wiley-Liss, Inc.
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  • 267
    ISSN: 0899-0042
    Keywords: chiral HPLC ; resolution ; enantiomeric purity ; configurational assignment ; circular dichroism ; AMPA receptor affinity ; electrophysiology ; AMPA receptor agonism ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA) shows the characteristics of a partial agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, (S)-APPA is a full AMPA receptor agonist and (R)-APPA a weak competitive AMPA receptor antagonist. This observation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue of APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl)isoxazol-4-yl]propionic acid (2-Py-AMPA), is a potent and apparently full AMPA receptor agonist, and this compound has now been resolved into (+)- and (-)-2-Py-AMPA (ee ≥ 99.0%) by chiral HPLC using a Chirobiotic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis of comparative studies of the circular dichroism spectra of the enantiomers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the (S)- and (R)-configuration, respectively. In a series of receptor binding studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid receptor sites or different sites at the N-methyl-D-aspartic acid (NMDA) receptor complex. (+)-(S)-2-Py-AMPA was an effective inhibitor of [3H]AMPA binding (IC50 = 0.19 ± 0.06 μM) and a potent AMPA receptor agonist in the rat cortical wedge preparation (EC50 = 4.5 ± 0.3 μM) comparable with AMPA (IC50 = 0.040 ± 0.01 μM; EC50 = 3.5 ± 0.2 μM), but much more potent than (+)-(S)-APPA (IC50 = 5.5 ± 2.2 μM; EC50 = 230 ± 12 μM). Like (-)-(R)-APPA (IC50 〉 100 μM), (-)-(R)-2-Py-AMPA (IC50 〉 100 μM) did not significantly affect [3H]AMPA binding, and both compounds were week AMPA receptor antagonists (Ki = 270 ± 50 and 290 ± 20 μM, respectively). Chirality 9:274-280, 1997. © 1997 Wiley-Liss, Inc.
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  • 268
    ISSN: 0899-0042
    Keywords: dexketoprofen ; enantiomer ; stereoselectivity ; brain ; cyclooxygenase ; rat ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Although it has been assumed that the effects of nonsteroidal antiinflammatory drugs (NSAIDs) are mainly the result of their action on local synthesis of prostaglandins, there is growing evidence to suggest that they may also exert a central analgesic action. Some authors have suggested that inhibition of prostaglandin synthesis in the brain could contribute to the analgesic action. The effect of dexketoprofen trometamol (tromethamine salt of the enantiomer (+)-S-ketoprofen) on prostaglandin synthesis was investigated in rat brain fragments and in cyclooxygenase preparations from rat brain microsomes. Effects of the (-)-R-enantiomer and the racemic mixture were also evaluated. Significant levels of prostaglandin F2α (PGF2α) were synthesized in rat brain fragments after 10 min of incubation at 37°C. Dexketoprofen was found to be a potent inhibitor of this PGF2α production in rat brain (IC50 = 6.2 nM), and it completely suppressed PGF2α production at 1 μM concentration. In addition, inhibition of PGF2α synthesis by dexketoprofen was highly stereoselective since the enantiomer (-)-R-ketoprofen was significantly less potent (IC50 = 294 nM); with this enantiomer, even at high concentrations such as 1 μM, less than 60% inhibition was achieved. These results correlated with those obtained in the study of racemic ketoprofen and its enantiomers on cyclooxygenase activity of rat brain microsomes, where dexketoprofen also inhibited enzymatic activity stereoselectively. IC50 values obtained for dexketoprofen, (-)-R-ketoprofen, and rac-ketoprofen were 3.5 μM, 45.3 μM, and 5.8 μM, respectively. The above results could be related to the potent analgesic effect of dexketoprofen observed in vivo, which was also stereoselective. Taken together, these findings suggest that prostaglandin synthesis inhibition in rat brain by dexketoprofen could be associated, at least in part, with the analgesic effect of this NSAID. Chirality 9:281-285, 1997. © 1997 Wiley-Liss, Inc.
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  • 269
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    Chirality 9 (1997), S. 313-316 
    ISSN: 0899-0042
    Keywords: ibuprofen ; topical administration ; chromatography ; skin metabolism ; percutaneous penetration ; chiral ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: In vitro experiments to investigate possible stereoselective aspects of the topical administration of ibuprofen have been conducted. Incubation of ibuprofen with rat skin homogenates in the presence of coenzyme A, ATP, and magnesium provided no evidence for the formation of ibuprofenyl coenzyme A (the initial intermediate in the metabolic inversion of [R]- to [S]-ibuprofen). Similar incubation studies gave no indication of a change in the enantiomeric ratios of ibuprofen over the time course of the experiments. Percutaneous penetration studies of ibuprofen gel through porcine skin indicated that the ibuprofen enantiomer levels in the reservoir solutions were consistent with racemic ibuprofen having traversed the skin with no metabolic inversion. These results suggest that, in the models studied, skin metabolism does not result in the chiral inversion of (R)- to (S)-ibuprofen and that the topical administration of ibuprofen will result in the delivery of 50% “isomeric ballast.” Chirality 9:313-316, 1997. © 1997 Wiley-Liss, Inc.
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  • 270
    ISSN: 0899-0042
    Keywords: anti-inflammatory drugs ; ibuprofen ; clinical pharmacokinetics ; bioinversion ; enantiomers ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The pharmacokinetics of ibuprofen enantiomers were investigated in a crossover study in which seven healthy male volunteers received single oral doses of 800 mg racemic ibuprofen as a soluble granular formulation (sachet) containing L-arginine (designated trade name: Spedifen®), 400 mg (-)R-ibuprofen arginine or 400 mg (+)S-ibuprofen arginine.Plasma levels of both enantiomers were monitored up to 480 minutes after drug intake using an enantioselective analytical method (HPLC with ultraviolet detection) with a quantitation limit of 0.25 mg/l.Substantial inter-subject variability in the evaluated pharmacokinetic parameters was observed in the present study. After (+)S-ibuprofen arginine, the following mean pharmacokinetic parameters ±SD were calculated for (+)S-ibuprofen: tmax 28.6 ± 28.4 min; Cmax 36.2 ± 7.7 mg/l; AUC 86.4 ± 14.9 mg · h/l; t½ 105.2 ± 20.4 min. After (-)R-ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S-ibuprofen and (-)R-ibuprofen, respectively: tmax 90.0 ± 17.3 and 50.5 ± 20.5 min; Cmax 9.7 ± 3.0 and 35.3 ± 5.0 mg/l; AUC 47.0 ± 17.2 and 104.7 ± 27.7 mg · h/l; t½ 148.1 ± 63.6 and 97.7 ± 23.3 min. After racemic ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S- and (-)R-ibuprofen, respectively: tmax 30.7 ± 29.1 and 22.9 ± 29.8 min.; Cmax 29.9 ± 5.6 and 25.6 ± 4.4 mg/l; AUC 105.1 ± 23.0 and 65.3 ± 15.0 mg · h/l; t½ 136.6 ± 20.7 and 128.6 ± 45.0 min. Tmax values of S(+)- and (-)R-ibuprofen after a single dose of 400 mg of each enantiomer did not differ significantly from the corresponding parameters obtained after a single dose of 800 mg of racemic ibuprofen arginine, indicating that the absorption rate of (-)R- and (+)S-ibuprofen is not different when the two enantiomers are administered alone or as a racemic compound. An average of 49.3 ± 9.0% of a dose of the (-)R-ibuprofen arginine was bioinverted into its antipode during the study period (480 minutes post-dosing). The percent bioinversion during the first 30 minutes after (-)R-ibuprofen arginine intake averaged 8.1 ± 3.9%. The mean AUC of (+)S-ibuprofen calculated after 800 mg racemic ibuprofen arginine (105.1 ± 23.0 mg · h/l) was lower than the mean AUC value obtained by summing the AUCs of (+)S-ibuprofen after administration of 400 mg (+)S-ibuprofen arginine and 400 mg (-)R-ibuprofen arginine (133.4 ± 26.6 mg · h/l).In conclusion, the administration of Spedifen® resulted in very rapid absorption of the (+)S-isomer (eutomer) with tmax values much lower than those observed for this isomer when conventional oral solid formulations such as capsules or tablets of racemic ibuprofen are administered. This characteristic is particularly favourable in those conditions in which a very rapid analgesic effect is required. Chirality 9:297-302, 1997. © 1997 Wiley-Liss, Inc.
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  • 271
    ISSN: 0899-0042
    Keywords: Saccharomyces cerevisiae ; asymmetric β-keto-ester reduction ; enzymatic kinetic resolution ; chiral 2-allyl-2-carboethoxy-cyclopentanol ; chiral high resolution gas chromatography ; chiral stationary phase ; β-cyclodextrin derivative ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The improvement of the biocatalytic reduction of 2-allyl-carboethoxy-cyclopentanone (2) to the corresponding cyclopentanol derivative (+)-(1R,2R)-(1) was accomplished employing baker's yeast in organic media. This chiral cyclopentanol derivative (1), analyzed by high resolution gas chromatography performed over β-cyclodextrin stationary phase, was obtained in 38% yield (〉99% e.e.). Chirality 9:321-324, 1997. © 1997 Wiley-Liss, Inc.
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  • 272
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    Chirality 9 (1997), S. 325-328 
    ISSN: 0899-0042
    Keywords: enthalpy ; heat of fusion ; chiral recognition ; crystalline state ; polymorphism ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Heats of solution in dimethyl sulfoxide (DMSO) have been determined for the diastereomeric salts (-)-(R)-methamphetammonium (+)-(RR)-bitartrate and (-)-(R)-methamphetammonium (-)-(SS)-bitartrate, (+)-(R)-α-phenethylammonium (-)-(R)-2-phenylbutyrate and (-)-(S)-α-phenethylammonium (-)-(R)-2-phenylbutyrate, and of a new polymorph of (+)-(1S2R)-ephedrinium (-)-(R)-mandelate. The heats of solution for these salts were found to be 11.4 and 10.0 kcal/mol, 15.6 and 14.0 kcal/mol, and 7.4 kcal/mol, respectively.Differential enthalpy contributions to chiral discrimination computed from these numbers are 1.4, 1.6, and 2.1 kcal/mol for the methamphetammonium bitartrates, α-phenethylammonium (-)-2-phenylbutyrates, and ephedrinium mandelates, respectively. The new and previously observed (Zingg et al. J Am Chem Soc 110:1565-1580, 1988) polymorphs of the (+)-(1S2R)-ephedrinium (-)-(R)-mandelate are separated by nearly 1 kcal/mol.Comparison of differential heats of solution with the corresponding differential heats of fusion suggests that heats of fusion differences do not properly represent the energy differences useful for diastereomeric salt separations. Chirality 9:325-328, 1997. © 1997 Wiley-Liss, Inc.
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  • 273
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    Chirality 9 (1997), S. 335-340 
    ISSN: 0899-0042
    Keywords: chiral chromatography ; cys34 modified human serum albumin ; ethacrynic acid ; protein binding ; enantioselectivity ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Derivatization of the free cys34 in human serum albumin (HSA) anchored to a silica matrix has been performed by in situ reaction with ethacrynic acid. This modification, which is reported to occur under physiological conditions, gives rise in practice to a new column with different binding properties with respect to the column based on the native protein. Significant differences were observed in the binding of drugs known to bind to site I, (R)-(S)-warfarin and phenylbutazone, and to site II, 1,4-benzodiazepin-2-ones and nonsteroidal anti-inflammatory agents. In particular, the chromatographic retentions markedly decreased for most of the drugs, and, in the case of chiral compounds, significant differences were often observed in the behavior of the two enantiomers, with higher values of enantioselectivity obtained for some of the examined compounds. Furthermore, the noncovalent binding of ethacrynic acid to the protein modifies the binding properties of the albumin. Chirality 9:335-340, 1997. © 1997 Wiley-Liss, Inc.
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  • 274
    ISSN: 0899-0042
    Keywords: chiral recognition ; amino acids ; ternary copper(II) complexes ; stability constants ; EPR ; circular dichroism ; fluorescence ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A modified β-cyclodextrin bearing a 2-aminomethylpyridine binding site for copper(II) (6-deoxy-6-[N-(2-methylamino)pyridine)]-β-cyclodextrin, CDampy was synthesized by C6-monofunctionalization. The acid-base properties of the new ligand in aqueous solution were investigated by potentiometry and calorimetry, and its conformations as a function of pH were studied by NMR and circular dichroism (c.d.). The formation of binary copper(II) complexes was studied by potentiometry, EPR, and c.d. The copper(II) complex was used as chiral selector for the HPLC enantiomeric separation of underivatized aromatic amino acids. Enantioselectivity in the overall stability constants of the ternary complexes with D- or L-Trp was detected by potentiometry, whereas the complexes of the Ala enantiomers did not show any difference in stability. These results were consistent with a preferred cis coordination of the amino group of the ligand and of the amino acid in the ternary complexes (“cis effect”), which leads to the inclusion of the aromatic side chain of D-Trp, but not of that of L-Trp. In Trp-containing ternary complexes, the two enantiomers showed differences in the fluorescence lifetime distribution, consistent with only one conformer of D-Trp and two conformers of L-Trp, and the latter were found to be more accessible to fluorescence quenching by acrylamide and KI. Chirality 9:341-349, 1997. © 1997 Wiley-Liss, Inc.
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  • 275
    ISSN: 0899-0042
    Keywords: enantiomers ; salsolinol ; dopamine ; catechol-O-methyltransferase ; high-performance liquid chromatography ; electrochemical detection ; brain ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: (+)-(R)- and (-)-(S)-salsolinol, dopamine-derived tetrahydroisoquinolines, were tested as substrates of pig brain soluble and membrane-bound catechol-O-methyltransferase (COMT) and as inhibitors of O-methylation of dopamine by soluble COMT in vitro. Methylation products were separated by high-performance liquid chromatography with electrochemical detection. Quantification of the products showed that O-methylation of (+)-(R)-salsolinol by soluble COMT afforded the 7-O-methylated product salsoline preferentially, whereas (-)-(S)-salsolinol yielded almost equivalent amounts of the 6- and 7-methyl ethers. Unlike O-methylation by soluble COMT, 7-O/6-O-methylation ratio produced by membrane-bound COMT varied with (+)-(R)-salsolinol concentration. As to the O-methylation of dopamine by soluble COMT, comparable competitive inhibition was observed with both (+)-(R)- and (-)-(S)-salsolinol. Chirality 9:367-372, 1997. © 1997 Wiley-Liss, Inc.
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  • 276
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    Chirality 9 (1997), S. 380-385 
    ISSN: 0899-0042
    Keywords: asymmetric synthesis ; campholene aldehyde derivatives ; fragrance compounds ; sandalwood odor ; santalum album L ; structure-odor-relationships ; molecular similarity ; molecular modeling ; computer-aided fragrance design ; molecular surface comparison ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The asymmetric syntheses of the enantiomers of Madrol® (1) are described and their odor properties evaluated. (1S)-(-)-1 exerts a powerful sandalwood odor with some animalic undertones, whereas its antipode smells sweet and flowery rather than like sandalwood. Molecular surface comparisons show remarkable deviations in the hydrophobic parts of the two enantiomers. Chirality 9:380-385, 1997. © 1997 Wiley-Liss, Inc.
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    Chirality 9 (1997), S. 390-390 
    ISSN: 0899-0042
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: No abstract.
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  • 278
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    Chirality 9 (1997), S. 391-391 
    ISSN: 0899-0042
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: No abstract.
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  • 279
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    Chirality 9 (1997), S. 650-655 
    ISSN: 0899-0042
    Keywords: direct separation ; chiral ion-pair chromatography ; di-anionic N-derivatized dipeptides ; aminoalcohols ; column temperature ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: This paper describes the synthesis of two new N-derivatized dipeptides. The two compounds, N-benzyloxycarbonyl-L-glutamyl-L-proline (Z-L-glu-L-pro) and N-benzyloxycarbonyl-L-glutamyl-D-proline (Z-L-glu-D-pro), were tested as chiral counter ions for the enantiomeric resolution of amino alcohols. The chiral counter ions were dissolved in a polar solvent, e.g., methanol and porous graphitic carbon, Hypercarb, were used as the achiral solid phase. The enantiomers of several of the tested compounds were baseline separated using Z-L-glu-L-pro as the chiral counter ion but no enantioselective retention was obtained using its diastereoisomer Z-L-glu-D-pro. The influence of solute structure as well as the importance of converting the chiral counter ion to its dianionic form will be described together with the effect of column temperature on enantioselective retention. Chirality 9:650-655, 1997. © 1997 Wiley-Liss, Inc.
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  • 280
    ISSN: 0899-0042
    Keywords: β-chloro-α-amino acid ; conglomerate ; successive optical resolution ; racemic structure ; (2RS,3SR)-ACB · HCl ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: (2RS,3SR)-2-Amino-3-chlorobutanoic acid hydrochloride [(2RS,3SR)-ACB · HCl] was found to exist as a conglomerate based on the melting point, infrared spectrum, and solubility. Optical resolution by preferential crystallization of (2RS,3SR)-ACB · HCl was achieved to yield both (2R,3S)- and (2S,3R)-ACB · HCl of 80-100% optical purities. The obtained (2R,3S)- and (2S,3R)-ACB · HCl were recrystallized, taking into account the solubility of (2RS,3SR)-ACB · HCl, to give efficiently optically pure (2R,3S)- and (2S,3R)-ACB · HCl. Treatment of the purified (2R,3S)- and (2S,3R)-ACB · HCl with triethylamine gave optically pure (2R,3S)- and (2S,3R)-2-amino-3-chlorobutanoic acid, respectively. Chirality 9:656-660, 1997. © 1997 Wiley-Liss, Inc.
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  • 281
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    Chirality 9 (1997), S. 678-680 
    ISSN: 0899-0042
    Keywords: methanopterin ; absolute stereochemistry ; 2-hydroxyglutaric acid ; sarcinopterin ; folates ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The absolute stereochemistry of the 2-hydroxyglutaric acid present in methanopterin and its α-glutamyl derivative, sarcinapterin, has been determined to be (S). Thus, the absolute stereochemistry of the 2-hydroxyglutaric acid present in the side chain of these modified folates is the same as the L-glutamic acid present in the side chain of folates. Chirality 9:678-680, 1997. © 1997 Wiley-Liss, Inc.
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  • 282
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    Chirality 9 (1997), S. 672-677 
    ISSN: 0899-0042
    Keywords: chiral SFC ; SubFC ; SFC ; methanol modified CO2 ; efficiency ; selectivity ; retention ; packed column SFC ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Optimization of chiral resolution, using carbon dioxide based mobile phases, must take into consideration the individual contributions of analyte retention, selectivity, and efficiency. Each of these factors may be independently affected by changes in pressure, temperature, or state of the mobile phase. The ability to control retention by different means reflects an advantage of carbon dioxide based mobile phases over conventional HPLC mobile phases. Utilization of this advantage requires that the effects of each of these factors on each contributor to resolution be known. The cumulative effect that each of these variables has on retention, selectivity and efficiency suggests that maximum resolution is obtained using low pressures and temperatures. Maximum resolution (at fixed k′) results from low temperatures and high pressures. The latter may be of more practical importance when speed of analyses and detection limits are considered. Chirality 9:672-677, 1997. © 1997 Wiley-Liss, Inc.
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  • 283
    ISSN: 0899-0042
    Keywords: 5-acetyl-2-methyl-4-methylsulfinyl-6-phenyl-3(2H)-pyridazinone ; chromatographic chiral resolution ; absolute configuration ; X-ray crystallographic analysis ; antiplatelet activity ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: In a series of 5-acyl-6-phenyl-2,4-substituted-3(2H)-pyridazinones the derivative 1a, with a sulfur stereogenic center, had the most potent activity as human platelet aggregation inhibitor. The resolution of rac-1a was successfully performed by chiral chromatography on Chiralcel OD-R, OD-H, and Chiralpak AD columns and scaled up to a preparative level. The absolute configuration of (-)-(S)-1a was determined by X-ray crystallographic analysis. In vitro human platelet aggregation inhibitory activity was evaluated. Both the enantiomers showed IC50 values in the same micromolar range, but the (-)-(S) isomer was slightly more potent [(S)/(R) potency ratio was 4/1]. Chirality 9:681-685, 1997. © 1997 Wiley-Liss, Inc.
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  • 284
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    Chirality 9 (1997), S. 693-698 
    ISSN: 0899-0042
    Keywords: supercritical fluid chromatography ; subcritical fluid chromatography ; HFC-134a ; 1,1,1,2-tetrafluoroethane ; carbon dioxide ; chiral selectivity ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: As supercritical fluid chromatography becomes more accepted as a facile means for the separation of chiral compounds, the need for mobile phases that can readily solubilize these polar compounds grows. Prior studies suggest that HFC-134a may prove suitable due to its very high eluotropic strength compared to carbon dioxide-based mobile phases. A comparison is made between ethanol-modified carbon dioxide, HFC-134a, and decafluoropentane as to their relative eluotropic strength, selectivity, and efficiency for three chiral compounds using a Whelk O-1 chiral bonded phase. The bulk component of the mobile phase was found to have relatively little effect on chiral selectivity over the range of 5° to 95°C. Chirality 9:693-698, 1997. © 1997 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
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  • 285
    ISSN: 0899-0042
    Keywords: hydroxymethylmexiletine ; p-hydroxymexiletine ; circular dichroism ; diastereomer HPLC ; validation ; plasma ; pharmacokinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Pre-column derivatization with o-phthaldialdehyde and N-acetyl-l-cysteine was used for liquid-chromatographic diastereomeric resolution of p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), metabolites of mexiletine formed by aromatic and aliphatic hydroxylation, respectively. The resulting diastereomeric derivatives were resolved on a C18 column and monitored by fluorescence detection. The diastereomeric elution order for both metabolites was determined on the basis of the circular dichroism spectra of each eluted fraction. Plasma samples (500 μl) showed recoveries greater than 75% for both the metabolites. Calibration curves in plasma samples were linear over the concentration ranges 10-500 and 20-1,000 ng/ml for each enantiomer of PHM and HMM, respectively. The limits of quantitation were found to be 10.0 and 5.0 ng/ml for both enantiomers of PHM and HMM. The within-day and between-day coefficients of variation were less than 10%. The assay was shown to be suitable for a pharmacokinetic study performed in a patient with ventricular arrhythmias following the short-term oral treatment of 200 mg t.i.d. of racemic mexiletine hydrochloride. Chirality 9:732-738, 1997. © 1997 Wiley-Liss, Inc.
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  • 286
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    Chirality 9 (1997), S. 393-393 
    ISSN: 0899-0042
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: No abstract.
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  • 287
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    Chirality 9 (1997), S. 428-430 
    ISSN: 0899-0042
    Keywords: asymmetric synthesis ; chiral ; geometrical isomers ; homochiral ; optical isomers ; optical purity ; stereogenic center ; thalidomide ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Misuse of current stereochemical terms is discussed, including terms that should be avoided altogether and replaced by other, standard ones. The reasons for using the proper terms and avoiding the infelicitous ones are pointed out. Chirality 9:428-430, 1997. © 1997 Wiley-Liss, Inc.
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  • 288
    ISSN: 0899-0042
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: By use of an asymmetric Ullmann coupling involving chiral naphthalene oxazolines 1, the title compounds were prepared in good yields and with high diastereoselectivity. Hydrolysis of the binaphthyl oxazolines 2 led to the di-aldehydes 5, which were transformed into the azepine derivative, 6. The latter was treated with the appropriate phosphoryl halide to access the chiral HMPA systems 7 and 9. The CD spectra of the chiral azepine 6 and the chiral phosphoramides 7 and 9 were measured and showed a strong positive CD couplet near 225 nm, consistent with the P axial chirality (S configuration). Semi-empirical CNDO/S molecular orbital calculations of the CD spectrum of 6 satisfactorily reproduced the major features of the observed spectrum. Chirality 9:431-434, 1997. © 1997 Wiley-Liss, Inc.
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  • 289
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    Chirality 9 (1997), S. 446-453 
    ISSN: 0899-0042
    Keywords: cyclotriveratrylene ; cyclotriphenolene ; cryptophane ; thiovanillin ; resolution ; enantiomers ; diastereoisomers ; circular dichroism ; exciton chirality ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A new route to (+)-(M) and (-)-(P)-cyclotriphenolene (1) is described, starting from 4-mercapto-3-methoxybenzaldehyde (thiovanillin (7)), which was converted into rac-3-methoxy-4-[(1-carboxyethyl)thio]benzyl alcohol (9). The latter was resolved by crystallization of its cinchonidine salts to give (-)-9, to which (S) absolute configuration was assigned. On reaction with formic acid, (-)-(S)-9 afforded the C3-cyclotiveratrylene diastereomers (-)-(P)-11a and (-)-(M)-11b which were separated and submitted to Raney Ni desulfuration to give the (+) and (-)-cyclotrianisylene enantiomers (4), which in turn were converted to (+) and (-)-1 on demethylation. Finally, (-)-1 was transformed into (+)-cryptophane-C according to a previously described method. Chirality 9:446-453, 1997. © 1997 Wiley-Liss, Inc.
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  • 290
    ISSN: 0899-0042
    Keywords: citalopram ; metabolites ; enantiomer pharmacokinetics ; stereospecific HPLC analysis ; DCT ; DDCT ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The steady-state pharmacokinetics in serum and urine of the enantiomers of citalopram and its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), were investigated after multiple doses of rac-citalopram for 21 consecutive days (40 mg per day) to healthy human subjects who were extensive metabolisers of sparteine and mephenytoin. Comparable pharmacokinetic variability was noted for (+)-(S)-, (-)-(R)- and rac-citalopram. Enantiomeric (S/R) serum concentration ratios for citalopram were always less than unity and were constant during the steady-state dosing interval. A modest, but statistically significant, stereoselectivity in the disposition of citalopram and its two main metabolites was observed. Serum levels of the (+)-(S)-enantiomers of citalopram, DCT, and DDCT throughout the steady-state dosing interval investigated were 37 ± 6%, 42 ± 3% and 32 ± 3%, respectively, of their total racemic serum concentrations. The (+)-(S)-enantiomers of citalopram, DCT, and DDCT were eliminated faster than their antipodes. For (-)-(R)- and (+)-(S)-citalopram, respectively, the serum t½ averaged 47 ± 11 and 35 ± 4 h and AUCss averaged 4,193 ± 1,118 h · nmol/l and 2,562 ± 1,190 h · nmol/l. The observed enantiospecificities were apparently more related to clearance, rather than to distributional mechanisms. Chirality 9:686-692, 1997. © 1997 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
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  • 291
    ISSN: 0899-0042
    Keywords: muscarinic antagonist ; rociverine enantiomers ; chiral synthesis ; optical resolution ; absolute configuration ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The compound [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate 1 is a muscarinic antagonist characterized by the presence of three chiral atoms and eight possible stereoisomers. The binding affinities to the five cloned m1-m5 muscarinic receptors of the stereoisomers of 1 were previously investigated and proved to be related to the chirality of the molecules. The eight isomers are prepared through the synthesis of their racemates followed by chemical resolution as (+) and (-) tartrate or (+) and (-) dibenzoyltartrate salts. The isomers with cis-configuration of OH and COOH substituents of the cyclohexane are also obtained by coupling optically active (1S, 2S) or (1R,2R)-1-hydroxy-[1,1′-bicyclohexyl]-2-carboxylic acid with (S)- or (R)-1-diethylamino-2-propanol. Chiral GC and HPLC methods are used to determine their optical purity. The absolute configurations of the four cis- and four trans-isomers are established by stereospecific synthesis and X-ray crystallographic data. Chirality 9:713-721, 1997. © 1997 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
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  • 292
    ISSN: 0899-0042
    Keywords: diastereomeric salt resolution ; chiral HPLC ; enantiomeric purity ; absolute stereochemistry ; X-ray crystallography ; NMDA receptor antagonist ; AMPA receptor antagonist ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation using N-BOC protected ATAA and (R)- and (S)-phenylethylamine. Enantiomeric purities (ee 〉 98%) of (R)- and (S)-ATAA were determined using the Crownpak CR(-) and CR(+) columns, respectively. The absolute configuration of (R)-ATAA was established by an X-ray crystallographic analysis of the (R)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 〉 100 μM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 ± 5 μM and 57 ± 1 μM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation (Ki 〉 1,000 μM). Chirality 9:529-536, 1997. © 1997 Wiley-Liss, Inc.
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  • 293
    ISSN: 0899-0042
    Keywords: circular dichroism (CD) ; chiral crown ethers ; enantiomeric recognition ; heterochiral complexing ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: CD studies were performed on the enantiomeric recognition of chiral aralkyl ammonium salts 1-3 by chiral pyridino-18-crown-6 ligands 4 and 6. Heterochiral complexing was found to result in larger spectral effects in both the 1Lb and 1La band regions of the chiral crown ethers. Based on the results reported herein, CD spectroscopy can be an efficient tool for discriminating between enantiomeric chiral aralkyl ammonium salts and determining the stoichiometry and relative stability of their complexes with chiral pyridino-18-crown-6 ligands. Chirality 9:545-549, 1997. © 1997 Wiley-Liss, Inc.
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  • 294
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    Chirality 9 (1997), S. 29-31 
    ISSN: 0899-0042
    Keywords: 2-arylpropionate ; reversible chiral inversion ; NSAIDs ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The R enantiomers of some of the 2-arylpropionic acid non-steroidal antiinflammatory drugs (NSAIDs) are known to undergo metabolic chiral inversion to their more pharmacologically active antipodes. This process is drug and species dependent and usually unidirectional. The S to R chiral inversion, on the other hand, is rare and has been observed, in substantial extents, only for ibuprofen in guinea pigs and 2-phenylpropionic acid in dogs. After i.p. administration of single doses of racemic ketoprofen or its optically pure enantiomers to male CD-1 mice and subsequent study of the concentration time-course of the enantiomers, we noticed substantial chiral inversion in both directions. Following racemic doses, no stereoselectivity in the plasma-concentration time courses was observed. After dosing with optically pure enantiomer, the concentration of the administered enantiomer predominated during the absorption phase. During the terminal elimination phase, however, the enantiomers had the same concentrations. Our observation is suggestive of a rapid and reversible chiral inversion for ketoprofen enantiomers in mice. Chirality 9:29-31, 1997. © 1997 Wiley-Liss, Inc.
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  • 295
    ISSN: 0899-0042
    Keywords: chiral thiol derivatisation ; diastereomeric derivative ; reversed phase HPLC ; fluorescence detection ; assay validation ; enantiomer pharmacokinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A specific plasma level assay for the enantiomers of α-lipoic acid is described. It makes use of liquid-liquid extraction, chemical reduction to the dithiol enantiomers, and their precolumn chiral derivatisation with o-phthalaldehyde in the presence of D-phenylalanine. The two diastereomeric derivatives are separated by reversed-phase HPLC with fluorescence detection. The working range of the assay is between 15 ng/ml (lower limit of quantitation) and 1,000 ng/ml for either enantiomer. Chirality 9:32-36, 1997. © 1997 Wiley-Liss, Inc.
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  • 296
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    Journal für Praktische Chemie/Chemiker-Zeitung 339 (1997), S. 575-577 
    ISSN: 0941-1216
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
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  • 297
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    Journal für Praktische Chemie/Chemiker-Zeitung 339 (1997), S. 590-593 
    ISSN: 0941-1216
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
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  • 298
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    Journal für Praktische Chemie/Chemiker-Zeitung 339 (1997), S. 763-764 
    ISSN: 0941-1216
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
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  • 299
    ISSN: 0941-1216
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
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  • 300
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    Journal für Praktische Chemie/Chemiker-Zeitung 339 (1997), S. 646-649 
    ISSN: 0941-1216
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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