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  • 1
    Electronic Resource
    Electronic Resource
    Metabolism of halazepam by rat liver microsomes: Stereoselective formation and n-dealkylation of 3-hydroxyhalazepam (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 2 (1990), S. 1-9 
    Details
    ISSN: 0899-0042
    Keywords: halazepam ; 3-hydroxyhalazepam ; diazepam ; N-desmethyldiazepam ; oxazepam ; enantiomers ; rat liver microsomes ; stereoselectivity ; enantioselectivity ; hydroxylation ; enantioselective N-dealkylation ; kinetics of racemization ; circular dichroism spectra ; chiral stationary phase ; high-performance liquid chromatography ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Metabolism of halazepam [7-chloro-1,3-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-2H-1,4-benzodi epin-2-one, HZ] was studied by incubation with liver microsomes prepared from untreated, phenobarbital (PB)-treated, and 3-methylcholanthrene (3MC)-treated male Sprague-Dawley rats. Metabolites of HZ were separated by normal-phase HPLC. Relative rates of HZ metabolism by liver microsomes prepared from untreated and treated rats were PB-treated ≫ untreated 〉 3MC-treated at low concentration of microsomal enzymes (0.25 mg protein per ml of incubation mixture) and PB-treated ≫ 3MC-treated ≈ untreated at high concentration of microsomal enzymes (2 mg protein per ml of incubation mixture). The relative amounts of major metabolites were found to be 3-hydroxy-HZ (3-OH-HZ) 〉 N-desalkylhalazepam (NDZ, also known as N-desmethyldiazepam and nordiazepam) ≫ oxazepam (OX) for all three rat liver microsomal preparations and the distribution of metabolites was independent of microsomal enzyme concentrations. Enantiomers of 3-OH-HZ were resolved by HPLC on a Chiralcel OC column (cellulose trisphenylcarbamate coated on silica gel, particle size 10 μm). 3-OH-HZ enantiomeres have racemization half-lives of ∼ 150 min in pH 4,7.5, and 10 aqueous solutions. 3-OH-HZ formed in the metabolism of HZ by liver microsomes prepared from untreated and treated rats were found to have 3R/3S enantiomer rations of 37/63 (untreated), 55/45 (PB-treated), and 36/64 (3MC-treated), respectively. N-dealkylation of 3-OH-HZ by liver microsomes from PB-treated rats was substrate enantioselective; the 3R-enantiomer was N-dealkylated faster than 3S-enantiomer. The results indicated that the stereoselective C3-hydroxylation of HZ is dependent on the cytochromes P-450 present in the rat liver microsomal preparations; pro-R in liver microsomes from PB-treated rats and pro-S in liver microsomes from untreated and 3MC-treated rats, respectively.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530020102
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  • 2
    Electronic Resource
    Electronic Resource
    Enantioselective aliphatic hydroxylations of racemic 1-hydroxy-3-methylcholanthrene by rat liver microsomes (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 2 (1990), S. 141-149 
    Details
    ISSN: 0899-0042
    Keywords: 3-methylcholanthrene ; 1-hydroxy-3-methylcholanthrene ; 1-hydroxy-3-hydroxymethylcholanthrene ; 3-methylcholanthrene trans-1,2-diol ; 3-methylcholanthrene cis-1,2-diol ; high-performance liquid chromatography ; chiral stationary phase ; resolution of enantiomers ; absolute configuration ; circular dichroism spectra ; enantioselective hydroxylation ; rat liver microsomes ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Enantiomeric pairs of 1-hydroxy-3-hydroxymethylcholanthrene (1-OH-3-OHMC), 3-methylcholanthrene (3MC) trans- and cis-1,2-diols, and 1-hydroxy-3-methylcholanthrene (1-OH-3MC) were resolved by HPLC using a covalently bonded (R)-N-(3,5-dinitrobenzoyl)phenylglycine chiral stationary phase (Pirkle type 1A) column. The absolute configuration of an enantiomeric 3MC trans-1,2-diol was established by the exciton chirality CD method following conversion to a bis-p-N,N-dimethylaminobenzoate. Incubation of an enantiomeric 1-OH-3MC with rat liver microsomes resulted in the formation of enantiomeric 3MC trans- and cis-1,2-diols; the absolute configurations of the enantiomeric 1-OH-3MC and 3MC cis-1,2-diol were established on the basis of the absolute configuration of an enantiomeric 3MC trans-1,2-diol. Absolute configurations of enantiomeric 1-OH-3-OHMC were determined by comparing their CD spectra with those of enantiomeric 1-OH-3MC. The relative amount of three aliphatic hydroxylation products formed by rat liver microsomal metabolism of racemic 1-OH-3MC was 1-OH-3-OHMC 〉 3MC cis-1,2-diol 〉 3MC trans-1,2-diol. Enzymatic hydroxylation at C2 of racemic 1-OH-3MC was enantioselective toward the 1S-enantiomer over the 1R-enantiomer (∼3/1); hydroxylation at the C3-methyl group was enantioselective toward the 1R-enantiomer over the 1S-enantiomer (∼58/42). Rat liver microsomal C2-hydroxylation of racemic 1-OH-3MC resulted in a 3MC trans-1,2-diol with a (1S,2S)/(1R,2R) ratio of 63/37 and a 3MC cis-1,2-diol with a (1S,2R)/(1R,2S) ratio of 12/88, respectively.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530020304
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  • 3
    Electronic Resource
    Electronic Resource
    N,N-dimethylcarbamyl derivatives of oxazepam (1991)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 3 (1991), S. 212-219 
    Details
    ISSN: 0899-0042
    Keywords: oxazepam ; demoxepam ; 3-O-acyl-1-(N,N-dimethylcarbamyl)oxazepam ; 1-(N,N-dimethylcarbamyl)oxazepam ; 3-O-(N,N-dimethylcarbamyl)oxazepam ; camazepam ; norcamazepam ; 1,3-O-bis(N,N-dimethylcarbamyl)oxazepam ; kinetics of racemization ; enantioselectivity of esterases ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Three N,N-dimethylcarbamyl derivatives of oxazepam {1-(N,N-dimethylcarbamyl)oxazepam, 3-O-(N,N-dimethylcarbamyl)oxazepam, and 1,3-O-bis(N,N-dimethylcarbamyl)oxazepam} and a 3-O-acyl-1-(N,N-dimethylcarbamyl)-oxazepam were synthesized from either oxazepam or demoxepam. Enantiomeric pairs of these derivatives and of camazepam were resolved by high-performance liquid chromatography on at least two of three commercially available chiral stationary phase columns employed. Absolute configurations of resolved enantiomers were established by comparing their circular dichroism spectra to those of enantiomeric oxazepams with known absolute stereochemistry. Similar to those of oxazepam, enantiomers of 1-(N,N-dimethylcarbamyl)oxazepam undergo rapid racemization (t½ 1.9 min at 23°C and 0.9 min at 37°C) in an aqueous solution at pH 7.5. The (R)-enantiomer of rac-3-O-acyl-1-(N,N-dimethylcarbamyl)oxazepam was hydrolyzed ∼4.6-fold faster than the (S)-enantiomer by esterases in rat liver microsomes, whereas the (S)-enantiomer was hydrolyzed ∼43-fold faster than the (R)-enantiomer by esterases in rat brain S9 fraction.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530030313
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  • 4
    Electronic Resource
    Electronic Resource
    Resolution and stability of oxazepam enantiomers (1992)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 4 (1992), S. 443-446 
    Details
    ISSN: 0899-0042
    Keywords: oxazepam ; chiral stationary phases ; high-performance liquid chromatography ; enantiomer separation ; enantiomer stability ; racemization ; kinetics of racemization ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A solvent mixture containing dioxane, acetonitrile, and hexane was found to be suitable as a mobile phase to resolve oxazepam enantiomers by chiral stationary phase high performance liquid chromatography using covalent Pirkle columns. The resolved oxazepam enantiomers in this solvent mixture had a racemization half-life greater than 3 days at 23°C. When desiccated at 0°C as dried residue, OX enantiomers were stable for at least 50 days with less than 2% racemization. The conditions which stabilized OX enantiomers significantly facilitated the determination of racemization half-lives of OX enantiomers in a variety of aqueous and nonaqueous solvents and at different temperatures. © 1992 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530040708
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  • 5
    Electronic Resource
    Electronic Resource
    Acid-catalyzed stereoselective heteronucleophilic substitution and racemization of 3-O-methyloxazepam and 3-O-ethyloxazepam (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 6 (1994), S. 175-184 
    Details
    ISSN: 0899-0042
    Keywords: 1,4-benzodiazepines ; oxazepam ; 3-O-methyloxazepam ; 3-O-ethyloxazepam ; stereoselective nucleophilic substitution ; kinetics of racemization ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Enantiomers of 3-O-methyloxazepam (MeOX) and 3-O-ethyloxazepam (EtOX) were resolved by chiral stationary phase high-performance liquid chromatography (CSP-HPLC). Reaction kinetics and deuterium isotope effects of acid-catalyzed racemization of enantiomeric MeOX in ethanol and enantiomeric EtOX in methanol were studied by spectropolarimetry. The acid-catalyzed heteronucleophilic substitution reactions of racemic MeOX in ethanol and racemic EtOX in methanol were studied by reversed-phase HPLC. Thermodynamic parameters involved in the reactions were obtained by temperature-dependent reaction rates. The effects of solvent's dielectric constant on the heteronucleophilic substitution reactions were also determined. A nucleophilically solvated and transient C3 carbocation intermediate resulting from an N4-protonated enantiomer, derived from a 1,4-benzodiazcpine either in M (minus) or P (plus) conformation, is proposed to be an intermediate and responsible for the acid-catalyzed stereoselective nucleophilic substitution and the resulting racemization. © 1994 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530060304
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  • 6
    Electronic Resource
    Electronic Resource
    Enantioselective hydrolysis of oxazepam 3-acetate by esterases in human and rat liver microsomes and rat brain s9 fraction (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 2 (1990), S. 150-155 
    Details
    ISSN: 0899-0042
    Keywords: oxazepam ; 3-O-acyloxazepam (oxazepam 3-acetate) ; diazepam ; N-desmethyldiazepam ; enantiomers ; esterases ; rat brain S9 fraction ; rat liver microsomes ; human liver microsomes ; enantioselective hydrolysis ; chiral stationary phase ; high-performance liquid chromatography ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Rates of hydrolysis of racemic and enantiomeric oxazepam 3-acetates (OXA) by esterases in human and rat liver microsomes and rat brain S9 fraction were compared. When rac-OXA was the substrate, esterases in human and rat liver microsomes were highly enantioselective toward (R)-OXA. In contrast, esterases in rat brain S9 fraction were highly enantioselective toward (S)-OXA. Hydrolysis rates of rac-OXA were highly dependent on the amount of esterases used. At 0.05 mg protein equivalent of esterases and 150 nmol of rac-OXA per ml of incubation mixture, the (R)-OXA was hydrolyzed 3.6-fold and 18.5-fold faster than (S)-OXA by rat and human liver microsomes, respectively. The specific activities (nmol of OXA hydrolyzed/mg microsomal protein/min) of liver microsomes in the hydrolysis of enantiomerically pure (R)-OXA were approximately 120 (rat) and 1,980 (human), and in the hydrolysis of enantiomerically pure (S)-OXA were 4 (rat) and 7 (human), respectively. In the incubation of rac-OXA with rat brain S9 fraction, (S)-OXA was hydrolyzed ∼6-fold faster than (R)-OXA. Results also indicated an enantiomeric interaction in the hydrolysis of rac-OXA by esterases in rat and human liver microsomes; the presence of (R)-OXA stimulated the hydrolysis of (S)-OXA, whereas the presence of (S)-OXA inhibited the hydrolysis of (R)-OXA. In rat brain S9 fraction, the presence of (R)-OXA inhibited the hydrolysis of (S)-OXA, whereas the presence of (S)-OXA appeared to have stimulated the hydrolysis of (R)-OXA.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530020305
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  • 7
    Electronic Resource
    Electronic Resource
    Acid-Catalyzed nucleophilic substitution and racemization of 3-methoxy-N-desmethyldiazepam enantiomers in methanol (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 5 (1993), S. 91-96 
    Details
    ISSN: 0899-0042
    Keywords: 1,4-benzodiazepines ; oxazepam ; 3-O-methyloxazepam ; stereoselective nucleophilic substitution ; kinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: pKa1 values of 3-methoxy-N-desmethyldiazepam in acetonitrile and methanol containing various acid concentrations were determined by spectrophotometry to be 3.5 and 1.3, respectively. Temperature-dependent racemization of enantiomeric 3-methoxy-N-desmethyldiazepam in methanol containing 0.5 M H2SO4 was studied by circular dichroism spectropolorimetry and the racemization reactions were found to follow apparent first-order kinetics. Thermodynamic parameters of the racemization reaction were found to be: Eact = 18.8 kcal/mol, and at 25°C: ΔH
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530050209
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  • 8
    Electronic Resource
    Electronic Resource
    Absolute configuration ofcis-5,6-dihydrodiol enantiomers derived from helical conformers of 1,12-dimethylbenz[a]anthracene (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 2 (1990), S. 58-64 
    Details
    ISSN: 0899-0042
    Keywords: 1,12-dimethylbenz[α]anthracene ; helical conformers ; cis-5,6-dihydrodiol ; high-performance liquid chromatography ; chiral stationary phase ; optical isomers ; resolution of enantiomers ; absolute configuration ; circular dichroism spectra ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: 1,12-Dimethylbenz[α]anthracene (1,12-DMBA) cis-5,6-dihydrodiol was synthesized by oxidation of 1,12-DMBA with osmium tetroxide in pyridine in low yield (≤3%) and was purified by sequential use of reversed-phase and normal-phase HPLC. Two pairs of 1,12-DMBA cis-5,6-dihydrodiol enantiomers, derived from P (right-handed helix) and M (left-handed helix) conformers, were eluted as a single chromatographic peak on both reversed-phase and normal-phase HPLC. However, these four enantiomers were resolved by sequential use of two chiral stationary phase (CSP) HPLC columns. CSP (Pirkle type I) columns were packed with either (R)-N-(3,5-dinitrobenzoyl)phenylglycine or (S)-N-(3,5-dinitrobenzoyl)leucine, which is ionically bonded to γ-aminopropylsilanized silica. Absolute configurations of enantiomers were determined by comparing their circular dichroism spectra with those of conformationally similar cis-5,6-dihydrodiol enantiomers of 4-methylbenz[α]anthracene and 7,12-dimethylbenz[α]-anthracene with known absolute stereochemistry.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530020109
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  • 9
    Electronic Resource
    Electronic Resource
    Enantiomeric analysis of terfenadine in rat plasma by HPLC (1991)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 3 (1991), S. 467-470 
    Details
    ISSN: 0899-0042
    Keywords: antihistamines ; chromatography ; stereoisomers ; chiral HPLC ; ovomucoid ; HI blockers ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Enantiomeric pairs of the antihistaminic drug terfenadine and its carboxylic acid derivative were directly separated by HPLC using an ovomucoid protein column. Absolute configurations of terfenadine enantiomers were assigned by comparing their circular dichroism spectra with those of 1-phenyl-1-butanol enantiomers of known absolute stereochemistry. Terfenadine and its major carboxylic acid metabolite extracted from blood plasma following an oral administration of a racemic terfenadine to rats were found to be enriched in the (S)- and (R)-enantiomers, respectively. The results indicated that the (R)-enantiomer of an orally administered racemic terfenadine was preferentially oxidized in rats to form a carboxylic acid metabolite enriched in the (R)-enantiomer.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530030610
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  • 10
    Electronic Resource
    Electronic Resource
    Enantioselectivity of esterases in human brain (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 5 (1993), S. 565-568 
    Details
    ISSN: 0899-0042
    Keywords: oxazepam ; oxazepam 3-acetate ; hydrolysis ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Subcellular fractions of three human brain specimens were found to contain esterase activities which hydrolyzed racemic oxazepam 3-acetate (rac-OXA). All three human brain preparations were highly selective toward the S-enantiomer of rac-OXA. © 1993 Wiley-Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530050714
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