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1.
J Chromatogr A ; 992(1-2): 151-7, 2003 Apr 11.
Article in English | MEDLINE | ID: mdl-12735471

ABSTRACT

For a broad spectrum of simple chiral alcohols, incorporating a (substituted) (het)aryl building block, enantiomer separation characteristics are reported for both gas chromatography on a Chirasil-DEX phase, and liquid chromatography on an (S,S)-ULMO phase. On this chiral Pirkle-type phase, homochiral enantiomers (mostly R) are eluted first without exception. The elution order R before S appears conserved as a rule also for gas chromatographic separations on Chirasil-DEX, though with some remarkable exceptions indicating a change in the dominant discriminative mechanism. This was shown in the homologous series 1-phenylethanol to 1-phenylhexanol having the point of reversal at C4, while the o-methoxy analogues elute from C1 to C4 already in the reversed order.


Subject(s)
Chromatography, Gas/instrumentation , Chromatography, High Pressure Liquid/methods , Methanol/isolation & purification , Methanol/chemistry , Spectrophotometry, Ultraviolet , Stereoisomerism
2.
Chirality ; 13(10): 657-67, 2001.
Article in English | MEDLINE | ID: mdl-11746798

ABSTRACT

Several brush-type chiral stationary phases (CSPs) based on undecanoyl- or butanoyl-bound (R,R)-1,2-diphenylethane-1,2-diamine (DPEDA) as chiral selector were prepared by an innovative, fast, and less expensive kind of preparation. The key to this method is the immobilization of the enantiomeric pure diamine with only one amino function in a simple substitution reaction on hydroxysuccinimide ester-activated silica. No excess chiral material is lost. Loading can be easily monitored analyzing the filtrate. The free second amino function can subsequently be acylated with different acyl halogenides. Examples with benzoyl- and 3,5-dinitrobenzoyl (DNB) amides show that, based on our new approach, a library of differently acylated Pirkle-type CSPs can easily be obtained. A benzoylated analog of the commercially available ULMO CSP is shown to be very effective in separating enantiomers of N-acyl amino acids.

3.
J Org Chem ; 66(20): 6685-94, 2001 Oct 05.
Article in English | MEDLINE | ID: mdl-11578222

ABSTRACT

Structural features (orientation of the carboxyl group, ring puckering), electronic absorption, and circular dichroism spectra of 4-alkyl- and 4-aryl-dihydropyrimidones 1-5 are calculated by semiempirical (AM1, INDO/S), ab initio (HF/6-31G, CIS/6-31G, RPA/6-31G), and density functional theory (B3LYP/6-31G) methods. These calculations allow an assignment of the absolute configuration by comparison of simulated and experimental CD spectra. Although the ab initio methods greatly overestimate electronic transition energies, the general appearance of the experimental CD spectra is quite nicely reproduced by these calculations. Thus, comparison of experimental with calculated CD spectra is a reliable tool for the assignment of the absolute configuration. For 4-methyl derivatives 1, the first enantiopure DHPM examples with no additional aromatic substituent, the stereochemistry at C4 provided by the theoretical results is confirmed by X-ray structure determination of the diastereomeric salt 6. Additional support is the consistent HPLC elution order found for all investigated DHPMs on a cellulose-derived chiral stationary phase.


Subject(s)
Models, Molecular , Pyrimidinones/chemistry , Calcium Channel Agonists/chemistry , Calcium Channel Blockers/chemistry , Circular Dichroism , Spectrophotometry, Ultraviolet , Stereoisomerism , Thermodynamics
4.
J Chromatogr A ; 922(1-2): 13-23, 2001 Jul 13.
Article in English | MEDLINE | ID: mdl-11486858

ABSTRACT

Quantitative structure-retention (QSRR, retention factors log k1 and log k2 for the first and second eluted enantiomer) as well as enantioselective retention relationships (QSERR, separation factor log a) for a series of 42 chiral arylalkylcarbinols on four brush-type chiral stationary phases are derived by multiple linear regression analyses and artificial neuronal network calculations using 2D and 3D molecular descriptors including those obtained by quantum chemical calculations. Separation factors are in addition modeled by the 3D-QSAR method of comparative molecular field analysis (CoMFA). For the retention factors the LUMO energy turns out to be the most important descriptor, whereas for log a it is the hydrophobicity of the analytes. With CoMFA both the steric and electrostatic field are found to be of almost comparable significance.


Subject(s)
Chromatography, Liquid/methods , Methanol/isolation & purification , Chromatography, Liquid/instrumentation , Structure-Activity Relationship
5.
J Chromatogr A ; 911(2): 295-8, 2001 Mar 16.
Article in English | MEDLINE | ID: mdl-11293591

ABSTRACT

Simultaneous HPLC separation of the enantiomers of 3-benzyloxy-2-methyl-1,2-propanediol and the corresponding 3-benzyloxy-2-methyl-1,2-propene oxide could be accomplished on amylose derived Chiralpak AD switching between 10% 2-propanol and 3% 1,2-dimethoxyethane as polar modifier in n-heptane.


Subject(s)
Chromatography, High Pressure Liquid/methods , Phenyl Ethers/isolation & purification , Chromatography, Gas/methods , Stereoisomerism
6.
Enantiomer ; 5(3-4): 329-32, 2000.
Article in English | MEDLINE | ID: mdl-11126874

ABSTRACT

Using normal-phase HPLC, the enantiomers of 4-(2',4'-difluorobiphenyl-4-yl)-4-oxo-2-methylbutanoic acid (flobufen) could be separated on Whelk-O1 (alpha = 1.34), ULMO (alpha = 1.08) and Chiralcel ODH (alpha = 1.33) chiral stationary phases. (R,R/S,S)- and (R,S/S,R)-5-(2',4'-difluorobiphenyl-4-yl)-3-methylfuran-2-one, the lactone of the 4-hydroxy metabolite could be completely separated on ULMO only. On the same CSP this 4-(2',4'-difluorobiphenyl-4-yl)-4-hydroxy-2-methylbutanoic acid could be separated in part (alpha = 1.06 and 1.12). Absolute configuration of the metabolites was established by NOE experiments.

7.
Chirality ; 11(8): 659-62, 1999.
Article in English | MEDLINE | ID: mdl-10467318

ABSTRACT

The absolute configuration of three 4-aryl-3, 4-dihydro-2(1H)-pyrimidones (Biginelli compounds, DHPMs) was established by comparison of the typical circular dichroism (CD) spectra of individual enantiomers with reference samples of known absolute configuration. The enantiomers were obtained by semipreparative separation of racemic mixtures on a Chiralcel OD-H chiral stationary phase. The method was used to establish the enantiopreference of various lipases in biocatalytic kinetic resolution experiments employing activated DHPM esters.


Subject(s)
Pyrimidinones/chemistry , Chromatography, High Pressure Liquid , Circular Dichroism
8.
Chirality ; 8(7): 490-93, 1996.
Article in English | MEDLINE | ID: mdl-8970746

ABSTRACT

Fast and efficient baseline separation of asymmetrically substituted diarylmethanols and 1,1-diarylethanols was achieved on an endcapped, amide-linked N-3,5-dinitrobenzoylated, (R,R)-1,2-diphenyl-1,2-ethanediamine-derived chiral stationary phase (CSP). Optimal enantioselectivities on this CSP were obtained using 1% 2-propanol in n-heptane as the mobile phase. Enantiorecognition was found to be governed by pi-basicity and the substitution pattern of the aromatic substituents.


Subject(s)
Chromatography, High Pressure Liquid/methods , Ethylenediamines/chemistry , Methanol/analogs & derivatives , Binding Sites , Dinitrobenzenes/chemistry , Methanol/chemistry , Methanol/isolation & purification , Molecular Structure , Stereoisomerism
9.
J Biol Chem ; 268(20): 14781-7, 1993 Jul 15.
Article in English | MEDLINE | ID: mdl-7686905

ABSTRACT

Brain NO (nitric oxide) synthase contains FAD, FMN, heme, and tetrahydrobiopterin as prosthetic groups and represents a multi-functional oxidoreductase catalyzing oxidation of L-arginine to NO and L-citrulline, formation of H2O2, and reduction of cytochrome c. We show that substrate analogues and inhibitors interacting with the heme block both the reductive activation of oxygen and the oxidation of L-arginine without affecting cytochrome c reduction. We further demonstrate that N omega-hydroxy-L-arginine is an intermediate in enzymatic NO synthesis. The ratio of L-citrulline to free N omega-hydroxy-L-arginine was > or = 50 under various assay conditions, but could markedly be reduced down to 4 by redox active inhibitors. Brain NO synthase is shown to utilize both L-arginine and N omega-hydroxy-L-arginine for the formation of stoichiometric amounts of NO and L-citrulline. Tetrahydrobiopterin equally enhanced reaction rates from either substrate (approximately 5-fold), but its rate accelerating effects were only observed at NADPH concentrations > or = 3 microM. In the absence of L-arginine or tetrahydrobiopterin, brain NO synthase catalyzes the generation of H2O2. We now show that, in contrast to L-arginine, N omega-hydroxy-L-arginine fully blocked H2O2 formation in the absence of exogenous tetrahydrobiopterin, indicating that N omega-hydroxy-L-arginine is a direct inhibitor of enzymatic oxygen activation. Based on these data, a hypothetical mechanism of enzymatic NO formation is discussed.


Subject(s)
Amino Acid Oxidoreductases/metabolism , Arginine/analogs & derivatives , Brain/enzymology , Amino Acid Oxidoreductases/antagonists & inhibitors , Animals , Arginine/metabolism , Biopterins/analogs & derivatives , Biopterins/metabolism , Catalysis , Coenzymes/metabolism , Heme/metabolism , Hydrolysis , Kinetics , NADP/metabolism , Nitric Oxide Synthase , Oxidation-Reduction , Substrate Specificity , Swine
10.
Talanta ; 40(3): 453-7, 1993 Mar.
Article in English | MEDLINE | ID: mdl-18965650

ABSTRACT

We report on the first penicillin-sensitive fluorosensor not based on the use of an enzyme. Rather, the recognition process relies on the use of an anion carrier (which carries the penicillin anion from the aqueous sample into the membrane), a proton receptor (lipophilic nile blue which accepts the proton, thereby undergoing a change in fluorescence intensity), and a new lipophilic hydroxylic plasticizer material (which facilitates ion transport). All materials are contained in a dyed poly(vinyl chloride) membrane whose fluorescence is monitored. The optical sensor fully reversibly responds to penicillin V over the 0.01-10mM concentration range, and to penicillin G from 0.03 to 10mM. Potential interferences by about 20 other anions have been investigated. Nitrate, salicylate, and ascorbate were found to interfere significantly. These species are, however, usually not present in penicillin bioreactors or drug formulations where penicillin sensing is most important. The sensor does not respond to penicillins containing an aliphatic amino group (such as amoxicillin). The method has been applied for determination of penicillin G in pharmaceutical formulations.

11.
Naunyn Schmiedebergs Arch Pharmacol ; 339(4): 474-8, 1989 Apr.
Article in English | MEDLINE | ID: mdl-2739756

ABSTRACT

In a randomized, double-blind, placebo-controlled, cross-over study 24 healthy volunteers were examined before and 2 h after oral administration of 80 mg (R,S)-, 40 mg (R)- and 40 mg (S)-propranolol.HCl; 8 of them received placebo in an additional run. During exercise on a bicycle ergometer and a rest period the rate pressure product was decreased by 80 mg (R,S)-propranolol.HCl (-32.8% p less than 0.0001) and 40 mg (S)-propranolol.HCl (-32.3%; p less than 0.0001), whereas 40 mg (R)-propranolol.HCl as well as placebo showed no effect. Corresponding binding inhibition experiments using (-)-(125I)iodocyanopindolol in a sarcolemma-enriched cardiac membrane preparation yielded a eudismic ratio of 179 for (S)- over (R)-propranolol. 2 h after oral application, stereospecific HPLC analysis revealed different individual concentrations in plasma of (R)- 22.3 +/- 21.7 ng/ml) and (S)-propranolol (30.4 +/- 26.9 ng/ml) when 80 mg of (R,S)-propranolol.HCl was administered. The plasma levels were similar when 40 mg of the pure enantiomer of (R)- (22.7 +/- 20.3 ng/ml) or (S)-propranolol.HCl (28.7 +/- 22.5 ng/ml) was applied. (R)- and (S)-propranolol are two substances with different pharmacodynamic and pharmacokinetic properties. As there are methods available to produce the optically pure enantiomers, they should be used rather than the racemic mixture.


Subject(s)
Hemodynamics/drug effects , Propranolol/pharmacology , Adult , Blood Pressure/drug effects , Double-Blind Method , Female , Heart Rate/drug effects , Humans , Iodocyanopindolol , Male , Membranes/metabolism , Pindolol/analogs & derivatives , Random Allocation , Sarcolemma/metabolism , Stereoisomerism
12.
J Chromatogr ; 487(2): 375-83, 1989 Feb 24.
Article in English | MEDLINE | ID: mdl-2723004

ABSTRACT

A sensitive high-performance liquid chromatographic method was developed for the stereoselective assay of (R)- and (S)-propranolol in human plasma. The method involves diethyl ether extraction of the drugs and a racemic internal standard, N-tert.-butylpropranolol, followed by derivatization of the compounds with the chiral reagent (R,R)-O,O-diacetyl tartaric acid anhydride. The resulting diastereomeric derivatives were separated isocratically on a reversed-phase column. Quantitation was achieved by the peak-height ratio method with reference to the internal standard. The assay was accurate and reproducible in the concentration range 1-100 ng of (R)- and (S)-propranolol per ml plasma, using fluorescence detection at lambda ex 290 nm and lambda em 335 nm. The applicability of this method was demonstrated for the determination of concentration-time profiles of propranolol enantiomers in the course of comparative pharmacokinetic studies.


Subject(s)
Propranolol/blood , Administration, Oral , Anhydrides , Female , Humans , Indicators and Reagents , Male , Propranolol/administration & dosage , Propranolol/pharmacokinetics , Stereoisomerism , Tartrates
13.
Acta Chem Scand B ; 42(8): 524-9, 1988 Sep.
Article in English | MEDLINE | ID: mdl-3227742

ABSTRACT

A new synthesis of 4-methoxy-2,3,5-trimethylpyridine (2), an important building block for the preparation of gastric-acid inhibiting compounds, is described. Condensation of ethyl 3-amino-2-methyl-2-butenoate (3) and diethyl 2-methylmalonate (4) gives 4-hydroxy-3,5,6-trimethyl-2(1H)-pyridone 5. Reaction of 5 with phosphoryl chloride affords 2,4-dichloro-3,5,6-trimethylpyridine (9a), which, upon hydrogenolysis with palladium on charcoal, gives 2,3,5-trimethylpyridine (10). However, selective hydrogenolysis in acidic solution yields 4-chloro-2-3-5-trimethylpyridine (11). Substitution of the chlorine in 11 with methoxide ion gives 4-methoxy-2,3,5-trimethylpyridine (2), which can be oxidized to the corresponding N-oxide (13). This constitutes a new and efficient route to compound 2 in an overall yield of 43%.


Subject(s)
Anti-Ulcer Agents/chemical synthesis , Pyridines/chemical synthesis , Chemical Phenomena , Chemistry
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