摘要:

AbstractPasteur's conjecture (1860) that biomolecular homochirality arose from a chiral natural force as yet inaccessible in the laboratory was supplanted by Fischer's (1894) “key and lock” hypothesis of stereoselection in enantiomer to diastereomer conversions, whether in the laboratory or in living organisms. Elaborations of the “key and lock” hypothesis by Haldane (1930) and Pauling (1948) have been illustrated and supported with modification by X‐ray diffraction crystal structures of enzyme–substrate complexes over the past quarter century.Two types of mechanism for the product diastereoselectivity in the reactions of an enantiomer with an achiral reagent, early proposed, have recent support: one proposes a quasidiastereomeric structure for the enantiomer attacked in the ground state, the other for the corresponding transition state of the reaction. Approaches to the differential biological activity of two enantiomers postulate either the complete binding of each isomer to a chiral receptor site, resulting in diastereomeric complexes with inequivalent bioactivities, or the differential binding of the two isomers to a set of three sites, with which only one isomer is sterically congruent.Biochemical homochirality, based on the chiral stereoselectivity of both biosynthetic and metabolic reactions, derives from the evolutionary pressure for a progressive enhancement of the kinetic efficiency and economy of those reactions. Recently Pasteur has been vindicated in part, and the problem of the original prebiotic enantiomeric excess left outstanding by Fischer has been solved. The unification of the electromagnetic with the weak interaction provided a universal chiral natural force, the electroweak interaction, which favours the chiral series selected during the course of biochemical evolution, both theD‐sugars and the

ISSN:0899-0042    

DOI:10.1002/chir.530010302

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractOnly limited information is available on the stereochemistry of the in vivo distribution of β‐receptor‐blocking drugs. In this study we determined the levels of the propranolol enantiomers in plasma, cerebrospinal fluid (CSF) and central nervous system (CNS), and peripheral tissues in the dog following an intravenous dose of a deuterium‐labeled pseudoracemate. The appearance of the propranolol enantiomers in the CSF was rapid and nonstereoselective, with maximum concentrations reached at 15 min after dosing. The levels of the enantiomers in both CSF and plasma then declined in a parallel biphasic fashion, with a terminalt1/2of about 125 min. Except for an early high CSF/plasma concentration ratio of 0.35, the CSF propranolol levels corresponded to the unbound concentration in plasma, CSF/plasma 0.20. All areas of the brain showed a similar uptake of propranolol, with a tissue concentration exceeding that in plasma about 10‐fold during the terminal phase of elimination. The uptake of propranolol by peripheral tissues varied widely, ranging from a 50‐fold accumulation by the lungs compared to plasma to no accumulation by adipose tissue. However, as for the CSF, there was no evidence of stereoselective uptake of propranolol by any CNS or peripheral tissue except for the liver. A significantly higher level of (+)‐ vs. (–)‐propranolol in liver tissue presumably was a reflection of stereoselective hepatic metabolism of (–)‐propranolol by this tissue. The slight stereoselectivity in plasma binding of propranolol known to exist in the dog had no significant influence on tissue

ISSN:0899-0042    

DOI:10.1002/chir.530010303

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe prochiral carbonyl group of fenofibrate (isopropyl 2‐[4‐(4‐chlorobenzoyl)phenoxy]‐2‐methyl propionate) is reduced during its metabolism giving rise to a chiral secondary alcohol, “reduced fenofibric acid.” Chiral and diastereomeric HPLC methods have been developed for the determination of its enantiomeric composition and these have been applied to the measurement of the “reduced fenofibric acid” enantiomers in urine of rats, guinea pigs, dogs, and human volunteers given [14C]fenofibrate. In the three animal species, the reduction is markedly enantioselective for the (–)‐isomer, the enantiomeric ratios (–/ +) being 95:5. This was not due to differences in the excretion of the enantiomers, since when racemic “reduced fenofibric acid” was given to rats it was recovered in the urine with the same enantiomeric composition as the dose form. In humans the ratio was 52:48 showing the lack of stereoselectivity o

ISSN:0899-0042    

DOI:10.1002/chir.530010304

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe synthesis and stereochemistry (configuration and preferred solute conformation) of some 4‐alkyl (methyl,n‐propyl, isobutyl)‐4‐(3‐hydrxyphenyl)‐1‐methylpiperidines and corresponding 3‐methyl diastereoisomeric pairs are reported, together with their in vivo and in vitro activities as opioid ligands. All potent agonists exhibit a preference for axial 4‐aryl chair conformations when protonated, and stereochemical analogies with rigid opioids of the benzomorphan class are discussed. Antagonist properties are found in compounds with preference for equatorial 4‐aryl chairs, notably thecis3,4

ISSN:0899-0042    

DOI:10.1002/chir.530010305

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractA method for the determination of (R)‐ and (S)‐atenolol in human plasma and urine is described. The enantiomers of atenolol are extracted into dichloromethane containing 3% heptafluorobutanol followed by acetylation with acetic anhydride at 60°C for 2 h. The acetylated enantiomers were separated on a chiral α1‐AGP column. Quantitation was performed using fluorescence detection. A phosphate buffer pH 7.1 (0.01Mphosphate) containing 0.25% (v/v) acetonitrile was used as mobile phase. The described procedure allows the detection of less than 6 ng of each enantiomer in 1 ml plasma. The relative standard deviation is 4.4% at 30 ng/ml of each enantiomer in plasma. The plasma concentration of (R)‐ and (S)‐ atenolol did not differ significantly in two subjects who received a single tablet of racemic atenolol. The R/S ratio of atenolol in ur

ISSN:0899-0042    

DOI:10.1002/chir.530010306

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractSeparation and optical resolution of 6 diastereomers and 25 racemates of β‐lactams were examined by HPLC on chiral stationary phases composed of six cellulose and one amylose tris(phenylcarbamate) derivatives. Most β‐lactams were optically resolved at least by one of the derivatives. The absolute configuration of β‐lactams was estimated by CD spec

ISSN:0899-0042    

DOI:10.1002/chir.530010307

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe synthesis and analytical testing of two new fluorescent chiral derivatizing agents (−)‐(S)‐flunoxaprofen and (−)‐(S)‐naproxen isocyanate, is described. In a few simple steps the free carboxylic acids [(S)‐flunoxaprofen and (S)‐naproxen] are activated with ethyl chloroformate/sodium azide and transformed to the corresponding isocyanates. The crystalline reaction products display high enantiomeric and chemical purity and stability. The direction of the optical rotation of both substances is inverse to that of the corresponding carboxylic acids. At ambient temperature the reagents swiftly react with primary and secondary amines, yielding highly fluorescent ureas. The applicability of the two reagents for the resolution of racemic amines was tested with a number of pharmaceuticals (antiarrhythmics, β‐adrenergic antagonists, calcium channel blockers, centrally acting antidepressants). The diastereoisomeric derivatives were efficiently resolved and separated from side‐products by means of normal and reversed‐phase high‐performance liquid chromatography (HPLC). The use and sufficient sensitivity of the two reagents for pharmacokinetic studies were demonstrated with a determination of plasma levels of propranolol enantiomers after oral administration of the racemic drug [80 mg (R,S)‐propran

ISSN:0899-0042    

DOI:10.1002/chir.530010308

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractAn enantioselective gas chromatographic method has been developed and validated for the determination of the plasma concentration of the enantiomers of the anticancer drug ifosfamide (IFF). In this approach, the IFF enantiomers are separated from the plasma matrix by solid phase extraction, chromatographically resolved by gas chromatography on a chiral stationary phase, and detected by mass selective detection using selective ion monitoring. The assay has been validated for routine clinical and pharmacokinetic use and has a limit of detection in plasma of 250 ng/ml of each isomer.

ISSN:0899-0042    

DOI:10.1002/chir.530010309

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractDirect optical resolution of antiinflammatory drugs such as ibuprofen, ketoprofen, flurbiprofen, and tiaprofenic acid were attempted by high‐performance liquid chromatography using tris(3,5‐dimethylphenylcarbamate)s of cellulose and amylose as chiral stationary phases. Although ibuprofen was not sufficiently resolved, the other three 2‐arylpropionic acids were completely resolved by amylose tris(3,5‐dimethylphenylcarbamate). Ibuprofen was resolved as anilide der

ISSN:0899-0042    

DOI:10.1002/chir.530010310

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY

摘要:

AbstractDescribed is a direct enantioselective separation of the enantiomers of alfuzosin hydrochloride on the second generation α1‐AGP column which offers improved efficiency, shorter analysis, and improved stability with respect to the first generation columns. The method has been applied to the analysis of drug substance in rat plasma. This highly efficient extraction method and the use of fluorimetric detection result in selective and sensitive determination of the enantiomers. The analytical validation parameters demonstrate the applicability of this method to pharmacokinetic and metabolic studi

ISSN:0899-0042    

DOI:10.1002/chir.530010311

出版商:Alan R. Liss, Inc.    

年代:1989

数据来源: WILEY