摘要:

AbstractThe individual enantiomers of cimetidine sulfoxide were resolved by preparative chromatography using a Chiralcel OC stationary phase and were characterized by the determination of optical rotation and circular dichroism spectra. Cimetidine sulfoxide was isolated from the urine of two healthy male volunteers following oral administration of cimetidine (400 mg). Urine was collected every 2 h for 12 h postdosing, after which time HPLC analysis indicated negligible recovery of the drug as the sulfoxide. Some 7% of the dose was recovered as cimetidine sulfoxide over this period. The enantiomeric composition of cimetidine sulfoxide was determined by sequential achiral—chiral chromatography using the OC phase. Over the collection period the enantiomeric ratio was found to be constant in all samples at (+/−) of 71 ± 2.5:29 ± 2.5. The enantiomeric composition of cimetidine sulfoxide was also determined in rat urine (24 h) following the administration of cimetidine (30 mg/kg po) to male Wistar rats (n= 7). The enantiomeric ratio in this case was found to be (+/−) 57 ± 2.3:43 ± 2.3. These preliminary data indicate that sulfoxidation of cimetidine is stereoselective with respect to the (+)‐enantiomer and that species variation in enantiomeric composition occurs. © 1994 Wil

ISSN:0899-0042    

DOI:10.1002/chir.530060802

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractAssignment of absolute configuration to a recently developed chiral selector useful in the separation of the underivatized enantiomers of naproxen and other nonsteroidal anti‐inflammatory drugs (NSAIDs) is described. Circular dichroism,1H NMR, and X‐ray diffraction have been used to confirm the original assignment which was based solely upon elution orders from HPLC chiral stationary phases. All of these techniques agree in the assignment of the (S,S) absolute configuration to the enantiomer of the chiral selector which associates preferentially with (S)‐naproxen. © 1994 Wiley‐L

ISSN:0899-0042    

DOI:10.1002/chir.530060803

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe in vitro aromatase activity in microsomal fractions from rat ovary and its inhibition by enantiomers of aminoglutethimide (AG), rogletimide (RG), and cyclohexylaminoglutethimide (ChAG) were studied by analysing the [3H]H2O released when [1β‐3H]androstenedione was converted to estrone. Maximum velocity (Vmax) and the Michaelis‐Menten constant (Km) of the microsomal aromatase enzyme were 17.40 ± 0.45 pmol/ml/mg protein/min and 1.02 ± 0.06 μM, respectively. The IC50s for the enantiomers were similar for (+)‐R‐AG and (−)‐R‐ChAG (0.86 ± 0.06 and 0.89 ± 0.15 μM, respectively). (+)S‐ChA'G was most potent with IC50of 0.075 ± 0.003 μM. The IC50s for (−)‐S‐AG, (+)‐R‐RG, and (−)‐S‐RG were in the same range (23.15 ± 2.74, 24.58 ± 2.46, and 24.43 ± 2.2

ISSN:0899-0042    

DOI:10.1002/chir.530060804

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe determination of enantiomeric purity of (R)‐ and (S)‐2‐hydroxy‐4‐phenylbutyric acid by chiral HPLC is described. Good resolution has been obtained on covalently bonded L‐hydroxyproline saturated with Cu(II) ions. The method makes possible the determination of enantiomeric purity in media containing growing cells. © 1994 Wil

ISSN:0899-0042    

DOI:10.1002/chir.530060805

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractA series of optically active analogues of the H1‐antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (−)‐isomer of 4‐methylebastine (6d) showed more than 10‐fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of6dfor histamine H1‐receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S)‐isomers showed slightly but unanimously higher antihistaminic activity than the (R)‐isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H1‐antagonists has been described. © 19

ISSN:0899-0042    

DOI:10.1002/chir.530060806

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe protein binding of the enantiomers of the nonopiate analgesic, ketorolac, was investigated in vitro using human plasma and solutions of human serum albumin (HSA) at physiological pH and temperature. In order to detect the very low levels of unbound enantiomers in protein solutions, tritium‐labelledrac‐ketorolac was synthesised by regiospecific isotopic exchange of the parent drug with tritiated water as the isotope donor. Radio‐chemical purification of this compound by reversed‐phase HPLC followed by direct resolution using a chiral α1‐acid glycoprotein (Chiral‐AGP) HPLC column afforded labelled enantiomers of high specific activity. The in vitro use of (R)‐ and (S)‐[3H4]ketorolac enabled reproducible radiometric detection of enantiomers in protein solution ultrafiltrate. The unbound fractions of (R)‐ and (S)‐ketorolac [fu(R) andfu(S), respectively] were determined when drug was added to various plasma or albumin solutions as either the separate enantiomers or as the racemate. Over an enantiomeric plasma concentration range of 2.0—15.0 μg/ml,fu(S) (mean range: 1.572—1.795%) was more than 2‐fold greater (P0.05). At a concentration of 2.0 μg/ml in 40.0 g/liter fatty acid‐free HSA,fu(R) andfu(S) were approximately 0.5 and 1.1%, respectively, and both values declined with increasing concentrations of the long chain fatty acid, oleic acid. We have previously shown that the pharmacokinetics of ketorolac in humans are markedly enantioselective and suggest in this report that these differences are largely the result of substantial differences in the protein binding of ketorolac enantiomers. These findings stress the importance of monitoring the unbound concentrations of the enantiomers of chiral drugs if correct interpretations are to be made of enantioselective pharmacokine

ISSN:0899-0042    

DOI:10.1002/chir.530060807

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractChromobacterium viscosumlipase (c.v. lipase) was immobilized in microemulsion‐based órganogels and successfully utilized for the enantioselective esterification of (+/−)‐2‐methylbutynic acid to preferentially form ethyl‐(+)‐2‐methylbutyrate. The reaction time course and enantioselectivity obtained with the organogel—lipase system was compared and contrasted to that achieved in a reversed micellar solution system that contained lipase solubilized in its inner water core as well as that in which powdered lipases were directly dispersed in an organic solvent. The unique properties and potential benefits of the organogel system are discussed. © 199

ISSN:0899-0042    

DOI:10.1002/chir.530060808

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractDL‐Threonine [DL‐Thr; (2RS,3SR)‐2‐amino‐3‐hydroxybutanoic acid] was optically resolved by replacing crystallization usingL‐serine (L‐Ser) and 4‐hydroxy‐L‐proline (L‐Hyp) as optically active cosolutes.D‐Thr was allowed to crystallize preferentially from racemic aqueous solutions in the presence of theseL‐α‐amino acids. The optical resolution ofDL‐Thr was more successfully achieved by usingL‐Ser, whose structure is more similar to that ofDL‐Thr thanL‐Hyp, and successively gaveD‐ andL‐Thr of 87—92% optical purities. TheD‐ andL‐Thr obtained were then recrystallized from water to give o

ISSN:0899-0042    

DOI:10.1002/chir.530060809

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe effect of substituent groups on asymmetric induction by β‐cyclodextrin (β‐CD) was investigated in the reduction of a series ofo‐,m‐, andp‐substituted acetophenones (X = H, Br, Cl, CH3, NO2, OCH3) with aqueous NaBH4. The inclusion of the ketones studied in β‐CD led to water‐insoluble compounds so that the reaction proceeded in the solid state. The substitutions resulted generally in higher enantioselectivities than that obtained for acetophenone indicating stronger host—guest interactions. Acetophenone and itsm‐ andp‐derivatives gave preponderantly the (−)‐alcohol while the prevailing enantiomer was the (+)‐alcohol in the case of theo‐derivatives. The enantioface selectivity was found to be mainly governed by steric demands imposed by the size and the shape of the β‐CD cavity in the case of theo‐substituted acetophenones and by hydrophobic interactions in the case of them‐derivatives. A more complicated situation arose from the asymmetic reduction ofp‐derivatives where a combination of these factors with hydrogen bonding of the carbonyl group to the hydroxyls of β‐CD are responsible for the

ISSN:0899-0042    

DOI:10.1002/chir.530060810

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractCircular dichroism (CD) spectroscopy has been used to evaluate the ability of 21 different solvents to influence the aggregation state of amphotericin B. Using the relative donor/acceptor tendencies known for each solvent system, it was possible to deduce information as to the factors which goven the self‐association of amphotericin B. It was concluded that in the absence of strong solvent interaction, amphotericin B prefers to self‐associate into oligomeric species. This intrinsic driving force can be overcome through the use of solvents which function as strong electron pair donors, probably forming specific solvent—solute species. © 1994 Wiley‐L

ISSN:0899-0042    

DOI:10.1002/chir.530060811

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY