摘要:

AbstractThe inversion from R‐ to S‐enantiomer that occurs for some arylpropionic acids may have both toxicological and therapeutic implications. To characterize some properties of this inversion, arylpropionyl‐CoA thioester formation was studied in rat tissue homogenates and subcellular fractions for the enantiomers of fenoprofen, ibuprofen, and flurbiprofen. Thioesters were formed from (R)‐fenoprofen (64%) and (R)‐ibuprofen (33%) but not from the corresponding S‐enantiomers or the enantiomers of flurbiprofen. This correlates with the extensive inversion of fenoprofen and ibuprofen and lack of inversion of flurbiprofen in vivo. Subcellular fractions from rat liver showed thioester formation to occur in mitochondria and microsomes but not cytosol. Once formed, the thioesters were readily racemized by whole rat liver homogenate, mitochondria, and cytosol, but only partially inverted (S:R = 0.3) in microsomes. Thioester formation from fenoprofen and ibuprofen was studied in tissue homogenate obtained from liver, diaphragm, kidney, lung, skeletal muscle, smooth muscle, fat, caecum, and intestines. The liver was at least 50‐fold more efficient than the other tissues studied and would be expected to be a major organ of enantiomeric inversion. Our data support the hypothesis that R‐ to S‐enantiomeric inversion of arylpropionic acids proceeds via the stereoselective formation of CoA thioesters followed by enzymatic racemization and hydrolysis of the thioesters to reg

ISSN:0899-0042    

DOI:10.1002/chir.530020202

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractIbuprofen was used to demonstrate that isolated rat hepatocytes offer a suitable in vitro model to investigate the metabolic chiral inversion of anti‐inflammatory 2‐arylpropionic acids (profens). The inversion of the pharmacologically inactive (−)‐(R)‐ibuprofen to the active (+)‐(S)‐ibuprofen was shown to obey apparent first‐order kinetics during 5 h and to increase linearly with increasing hepatocyte concentration up to 4 × 105cells/ml. No elimination of (R)‐ibuprofen by routes other than inversion was seen, whereas the elimination of (S)‐ibuprofen appe

ISSN:0899-0042    

DOI:10.1002/chir.530020203

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractEudismic analysis was performed on a set of 14 muscarinic ligands carrying a 1,3‐oxathiolane nucleus, in order to obtain information about both the existence of receptor subgroups and of agonist and competitive antagonist interaction sites. The results obtained were compared with those from a study of the enantioselectivity of the pairs of enantiomers. The two approaches do not appear to be completely equivalent and would seem to complement each other usefull

ISSN:0899-0042    

DOI:10.1002/chir.530020204

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractWe have shown that site‐specific natural isotope fractionation of hydrogen studied by NMR (SNIF‐NMR) is an important source of information on the mechanistic and environmental effects which govern the photosynthesis of sugars and their fermentation into ethanol. Three isotope ratios associated with the methyl, methylene, and hydroxyl sites of ethanol are determined in achiral media. In this study we show that complementary information about possible stereospecific mechanisms involving the methylenic hydrogens is also rendered accessible by2H‐NMR enantiomeric resolution. The synthesis of mandelate esters enables exchange between the pro‐R site of ethanol and water to be investigated. Simultaneous access to the three site‐specific isotope ratios of the ethyl group is obtained at isotopic dilutions close to the natural ones. Mediation of the exchange by the enzymic system alcohol dehydrogenase‐α‐lipoyldehydrogenase and by the yeastSaccharomyces cerevisiaeare compared. The progress of the reaction can be followed quantitatively as a function of time and the occurrence of glycolytic metabolism of endogeneous materials by yeast can be substantiated in a one

ISSN:0899-0042    

DOI:10.1002/chir.530020205

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractRacemic 5‐hydroxy‐2‐(dipropylamino)tetralin (5‐OH DPAT), a potent and selective dopamine (DA) D2‐receptor agonist, was resolved into the enantiomers by a new method. The enantiomers of 5‐OH DPAT were determined by chiral ion‐pair chromatography usingN‐benzyloxycarbonylglycyl‐L‐proline as the counter ion. The enantiomeric purity of (R)‐5‐OH DPAT was found to be>99.7%. The ability of the enantiomers to change the rat brain DOPA levels was evaluated in vivo. The results indicate that (R)‐5‐OH DPAT is a weakly poten

ISSN:0899-0042    

DOI:10.1002/chir.530020206

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe synthesis of a diastereomerically pure 10‐hydroxywarfarin [4‐hydroxy‐3‐(2‐hydroxy‐3‐oxo‐1‐phenylbutyl)‐2H‐1‐benzopyran‐2‐one] was accomplished in three steps from racemic warfarin. The relative configuration of the synthetic product was established by conversion to a cyclic derivative followed by NMR and X‐ray diffraction analysis. Absolute stereochemistry was determined by enzymatic conversion of either of the pure enantiomers of warfarin to a 10‐hydroxy metabolite of known relative configuration. Metabolic formation of 10‐hydroxywarfarin was studied using hepatic microsomal preparations from female rats and man. The formation of 10‐hydroxywarfarin catalyzed by hepatic microsomes from both dexamethasone‐treated rats and man was highly stereoselective [(R)/(S): 3.4–9.0]for (R)‐warfarin. In contrast, little stereoselectivity was observed in reactions catalyzed by untreated rat liver microsomes. The resultant stereochemistry at the site of oxidation was also found to be highly dependent on substrate stereochemistry. (R)‐Warfarin gave (9R;10S)‐10‐hydroxywarfarin with only a trace of the (9R;10R) isomer irrespective of which enzyme preparation was used for catalysis, while (S)‐warfarin gave (9S;10R)‐10‐hydroxywarfarin with only a trace of the (9S;10S) isomer, again irrespecti

ISSN:0899-0042    

DOI:10.1002/chir.530020207

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe synthesis and chromatographic evaluation of two novel chiral stationary phases (CSPs) deriving from (S)‐tyrosine are reported. The chiral graft has been designed in order to bear both π‐acid and π‐basic sites, each one being connected to a distinct asymmetric centre. An intramolecular π‐π interaction may take place within these CSPs, leading to an energetically favoured conformation of the chiral selector (CS). The enantiorecognition ability of these CSPs was investigated for various classes of either π‐acid or π‐basic racemates. It is shown that these CSPs are able to separate simultaneously π‐acid and π‐basic racemates. Finally, chiral recognition mechanisms and mobile phase opt

ISSN:0899-0042    

DOI:10.1002/chir.530020208

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractThe chromatographic performance of a series of urea and thiourea derivatives of (±)‐propranolol has been evaluated on three different Pirkle stationary phases. Seven different isocyanate reagents were used to generate a range of both aliphatic and aromatic urea derivatives with the isothiocyanates yielding the corresponding thiourea analogues. The Pirkle phases employed consisted of 3,5‐dinitrobenzoylphenylglycine and 3,5‐dinitrobenzoylleucine, both ionically and covalently bound to aminopropyl silica as well as phenethylpropylurea (covalently attached only). The urea derivatives were consistently more strongly retained on covalently bound columns than their thiourea counterparts. This is in contrast to the situation observed for the ionic columns, where the thiourea derivatives were the more strongly retained on the phenylglycine column and the more strongly retained in four of seven instances on the leucine column. The underlying mechanisms giving rise to these differences in retention are as yet unidentified but appear to involve the urea

ISSN:0899-0042    

DOI:10.1002/chir.530020209

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

摘要:

AbstractA new urea‐bonded chiral stationary phase has been developed in our laboratory. This bonded phase has been shown to resolve N‐terminal substituted amino acids and the carboxyl derivatized anti‐inflammatory drugs. Typical α‐value for dinitrobenzoyl phenylglycine was 1.7. Values for derivatized ibuprofen, naproxen, and fenoprofen were 2, 1.84, and 1.6, respectively. Further application of these studies to biologically active compounds such as peptides and drugs is in

ISSN:0899-0042    

DOI:10.1002/chir.530020210

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY

ISSN:0899-0042    

DOI:10.1002/chir.530020211

出版商:Alan R. Liss, Inc.    

年代:1990

数据来源: WILEY