bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereoselective arylpropionyl‐CoA thioester formation in vitro
Authors: Knadler M. P. , Hall S. D. 
Published: January 2005

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 regenerate free acid.
Metabolic chiral inversion of ibuprofen in isolated rat hepatocytes
Authors: Müller Sylvia , Mayer Joachim M. , Etter Jean‐Claude , Testa Bernard 
Published: January 2005

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 × 105 cells/ml. No elimination of (R)‐ibuprofen by routes other than inversion was seen, whereas the elimination of (S)‐ibuprofen appeared to be saturable.
(R)‐ and (S)‐5‐hydroxy‐2‐(dipropylamino)tetralin (5‐OH DPAT): Assessment of optical purities and dopaminergic activities
Authors: Karlsson Anders , Pettersson Curt , Björk Lena , Andén Nils‐Erik , Hacksell Uli 
Published: January 2005

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 using N‐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 potent DA D2‐receptor antagonist.
Synthesis and evaluation of two novel “mixed” chiral stationary phases deriving from tyrosine: Csps designed for the resolution of either π‐acid or π‐basic racemates
Authors: Tambute A. , Begos A. , Siret L. , Caude M. , Rosset R. 
Published: January 2005

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 optimization are discussed.
Stereoselective disposition of ibuprofen and flurbiprofen in rats
Authors: Knihinicki Romualda D. , Day Richard O. , Graham Garry G. , Williams Kenneth M. 
Published: January 2005

Abstract(R)‐2‐Arylpropionates are often inverted to the pharmacologically active S‐enantiomers in vivo, although there is significant interspecies variability in inversion. In order to provide a basis for determining the biochemical consequences of this unique process using rats as a model, it was important to establish the pharmacokinetic disposition of the enantiomers of ibuprofen, a drug well inverted in man and flurbiprofen, a drug apparently poorly inverted in man. Rats were dosed i.v. with a single dose of (R)‐or (S)‐ibuprofen (20 mg/kg), (R,S)‐ibuprofen (40 mg/kg), (R)‐ or (S)‐flurbiprofen (10 mg/kg), or (R,S)‐flurbiprofen (20 mg/kg). Each treatment group consisted of six animals. Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen. These drugs were assayed in plasma by a stereospecific HPLC assay. The pharmacokinetics of the ibuprofen and flurbiprofen enantiomers were evaluated using a two‐compartment open model with conversion of the R‐ to S‐enantiomers in the central compartment. There was 50 ± 4% inversion of (R)‐ibuprofen, a figure similar to that observed in man and (R)‐ibuprofen had a higher clearance (12.6 ± 1.3 ml/min/kg) than (S)‐ibuprofen (7.7 ± 0.7 ml/min/kg; P < 0.01). The clearance of (R)‐ flurbiprofen after racemate (2.3 ± 0.1 ml/min/kg) was higher than its clearance when administered alone (1.7 ± 0.2 ml/min/kg; P < 0.01), indicating a pharmacokinetic interaction between the enantiomers (most probably at plasma protein binding sites). A corresponding difference was not observed for ibuprofen. There was a small amount of inversion of (R)‐flurbiprofen as determined by area analysis (4.5 ± 1.6%). However, this calculation may be in some error because of the interaction between the enantiomers. These data demonstrate quantitative similarities in the inversion of ibuprofen and flurbiprofen in rats and man, a useful basis for comparing the effects of these two drugs on fatty acid metabolism.
Stereoselective effect of warfarin and bilirubin on the binding of 5‐(o‐chlorophenyl)‐1,3‐dihydro‐3‐methyl‐7‐nitro‐2H‐1,4‐ benzodiazin‐2‐one enantiomers to human serum albumin
Authors: Fitos Ilona , Visy Julia , Magyar Anna , Simonyi MiklóS , Kajtár Judit 
Published: January 2005

AbstractThe binding of the title benzodiazepine enantiomers and its modulation by warfarin and bilirubin were studied by chromatography on human serum albumin (HSA) immobilized on Sepharose 4B, and also by a combination of ultrafiltration and circular dichroism (UF‐CD) methods. In the absence of warfarin and bilirubin the binding of the benzodiazepine was not stereoselective. (S)‐Benzodiazepine and (S)‐warfarin mutually increased the binding of each other, while the binding of (R)‐benzodiazepine was preferentially enhanced on HSA saturated with bilirubin.
Stereochemical features of 1,4‐benzodiazepin‐2‐ones bound to human serum albumin: Difference CD and UV studies
Authors: Bertucci Carlo , Domenici Enrico , Salvadori Piero 
Published: January 2005

AbstractThe stereochemistry of an achiral (Diazepam) and two chiral (3‐methyl and 3‐succinyloxy substituted) 1,4‐benzodiazepin‐2‐ones interacting with human serum albumin (HSA) has been investigated by making use of difference absorption (UV) and circular dichroism (CD) spectroscopies. Evidence is obtained for a higher affinity with HSA for one of the two possible conformations of the seven‐membered benzodiazepine ring. The red shift revealed by the absorption difference spectrum between the free and the bound drug accounts for the CD difference spectra observed.
Determination of the absolute configuration and enantiomeric purity of alcohols from the 13C‐NMR spectra of the corresponding MTPA esters
Authors: Lemière G. L. , Willaert J. J. , Dommisse R. A. , Lepoivre J. A. , Alderweireldt F. C. 
Published: January 2005

AbstractFrom a study of the 13C‐shift values of the MTPA esters of 3‐substituted cyclohexanols of known absolute configuration an empirical rule has been developed to determine the absolute configuration of chiral cyclohexanols. The method is based on the Dale–Mosher model, which was originally developed for 1H‐NMR spectra. The scope and limitations of this method are discussed. The enantiomeric purity of the alcohols can be determined simultaneously by integration of the signals in well‐resolved diastereotopic carbon pairs.
Characterization of the hemodynamic activities of fenoldopam and its enantiomers in the dog
Authors: Kinter Lewis B. , Horner Eugene , Mann William A. , Ruffolo Robert R. , Weinstock Joseph 
Published: January 2005

AbstractFenoldopam (SK&F 82526) is a potent and selective dopamine DA‐1 agonist with demonstrated renal vasodilator and antihypertensive activities in experimental animals and humans. Fenoldopam is a racemic mixture of two enantiomers, SK&F R‐82526 and SK&F S‐82526. The R‐enantiomer is uniformly reported to be more potent than the racemate; in contrast, there is controversy regarding potency of the S‐enantiomer. In these studies, the renal and systemic hemodynamic activities of fenoldopam and its enantiomers are characterized in anesthetized, phenoxybenzamine‐treated dogs. The results show that the renal and systemic vasodilator activities of fenoldopam are properties of the R‐enantiomer; the S‐enantiomer is essentially inactive. The renal and systemic vasodilator properties of SK&F R‐82526 are antagonized in a competitive fashion by the DA‐1 antagonist, SK&F R‐83566, but not the DA‐2 antagonist, domperidone. Ganglionic blockade did not attenuate renal vasodilation associated with SK&F R‐82526. Thus, the mechanism of SK&F R‐82526‐associated vasodilation, like that previously established for fenoldopam, is via stimulation of postganglionic DA‐1 receptors.
Pharmacokinetic studies with the lipid‐regulating agent beclobrate: Enantiospecific assay for beclobric acid using a new fluorescent chiral coupling component (S‐FLOPA)
Authors: Mayer Sascha , Mutschler Ernst , Spahn‐Langguth Hildegard 
Published: January 2005

AbstractThe major biotransformation pathway for the chiral lipid‐regulating agent beclobrate is conversion to the corresponding carboxylic acid, which is then metabolized to the acyl glucuronide. An enantiospecific assay for biological material was developed that is based on chiral derivatization with N‐ethyl‐N′‐(3‐dimethylaminopropyl)carbodiimide (EDAC) and the primary amine S‐FLOPA, a new chiral coupling component for carboxylic acids derived from the 2‐arylpropionic acid S‐flunoxaprofen. Conversion of beclobric acid to the acyl chloride prior to coupling with the amine is also feasible. From plasma or urine beclobric acid was extracted into n‐hexane/ethanol (9:1) at pH 4 after addition of sodium chloride. Clofibric acid was used as internal standard. Derivatization with EDAC/FLOPA was performed under addition of 1‐hydroxybenzotriazole in anhydrous dichloromethane containing trace amounts of pyridine (ambient temperature/2 h reaction time). The chromatographic separation was performed on a silica gel stationary phase (Zorbax Sil) using n‐hexane–chloroform–ethanol (100:10: 0.75, by vol) as mobile phase [flow rate, 2 ml/min; fluorescence detection, 305/355 nm; elution order of the derivatives, (−) before (+)]. Coefficients of variation were between 1.3 and 9.3% for both plasma and urine. Limit of quantification was 20–25 ng/ml for plasma based on a sample volume of 0.2 ml. Application of the assay in a pilot pharmacokinetic study showed significant differences between the kinetics of the two enantiomers. In plasma and urine, the concentrations of the dextrorotatory enantiomer exceeded those of the levorotatory enantiomer significantly.
A molecular dynamics investigation of chiral discrimination complexes as chiral stationary‐phase models: Methyl N‐(2‐naphthyl)alaninate with N‐(3,5‐dinitrobenzoyl)leucine n‐propylamide
Authors: Sabio Michael , Topiol Sid 
Published: January 2005

AbstractMolecular dynamics simulations were performed on complexes of (S)‐methyl N‐(2‐naphthyl)alaninate (NAP) with the enantiomers of N‐(3,5‐dinitrobenzoyl)leucine n‐propylamide (DNB), which are used as models for chiral stationary‐phase systems developed by Pirkle and co‐workers. These studies were undertaken to qualitatively examine (pictorially) the role of entropic effects in these systems. The results of the dynamics calculations were used to refine the search for low‐energy conformers. The structures were refined by the use of BioDesign's molecular mechanics method implemented in Biograf. The results of the structural refinements support our previous observation that the SR complex can achieve the same three primary interactions which are observed in the SS structure (i.e., two intermolecular hydrogen bonds and pi stacking) without a significant increase in energy. In addition, these primary interactions are conserved during molecular dynamics simulations with the occurrence of conformations which differ only in the rotational states of the alkyl side chains and ester group (which bears two potential hydrogen bond acceptors utilized in both the homo‐ and heterochiral complexes). The major difference in the two complexes is the relative position of the sec‐butyl group and hydrogen atom on DNB's chiral center, both of which are outside the primary interaction region. All other local minima which have different relative pi orientations (“front–back,” “back–back,” and “back–front” as defined herein) are not sufficiently populated to make more than a negligible contribution to the statistical (time‐ or energy‐averaged) analysis of the (SS)‐ and (SR)‐NAP–DNB complexes. Thus the entropic effects observed in this study (e.g., alkyl side chain or ester group rotations) do not show evidence of qualitative differential effects on the maintenance of the same three primary interactions by both the homo‐ and heterochiral complexes. The reliability of the present study, which provides pictorial representations of the entropic effects, is not sufficient to determine whether the entropic effects observed herein are sufficient to achieve enantiomeric discrimination alone or in conjunction with other factors (e.g., conformational strain energy). Thus, all of the computational studies we have performed to date (i.e., our previous studies, which include strain energy and through‐space field effects, and the present study, which includes entropic effects) show no evidence of any qualitative difference in the homo‐ and heterochiral complexes in terms of maintaining the same three “contact points”.
Benzylic alcohols as stereospecific substrates and inhibitors for aryl sulfotransferase
Authors: Rao Satish I. , Duffel Michael W. 
Published: January 2005

AbstractAryl sulfotransferase IV catalyzes the 3′‐phosphoadenosine‐5′‐phosphosulfate (PAPS)‐dependent formation of sulfuric acid esters of benzylic alcohols. Since the benzylic carbon bearing the hydroxyl group can be asymmetric, the possibility of stereochemical control of substrate specificity of the sulfotransferase was investigated with benzylic alcohols. Benzylic alcohols of known stereochemistry were examined as potential substrates and inhibitors for the homogeneous enzyme purified from rat liver. For 1‐phenylethanol, both the (+)‐(R)‐and (−)‐(S)‐enantiomers were substrates for the enzyme, and the kcat/Km value for the (−)‐(S)‐enantiomer was twice that of the (+)‐(R)‐enantiomer. The enzyme displayed an absolute stereospecificity with ephedrine and pseudoephedrine, and with 2‐methyl‐1‐phenyl‐1‐propanol; that is, only (−)‐(1R,2S)‐ephedrine, (−)‐(1R,2R)‐pseudoephedrine, and (−)‐(S)‐2‐methyl‐1‐phenyl‐1‐propanol were substrates for the sulfotransferase. In the case of 1,2,3,4‐tetrahydro‐1‐naphthol, only the (−)‐(R)‐enantiomer was a substrate for the enzyme. Both (+)‐(R)‐2‐methyl‐1‐phenyl‐1‐propanol and (+)‐(S)‐1,2,3,4‐tetrahydro‐1‐naphthol were competitive inhibitors of the aryl sulfotransferase‐catalyzed sulfation of 1‐naphthalenemethanol. Thus, the configuration of the benzylic carbon bearing the hydroxyl group determined whether these benzylic alcohols were substrates or inhibitors of the rat hepatic aryl sulfotransferase IV. Furthermore, benzylic alcohols such as (+)‐(S)‐1,2,3,4‐tetrahydro‐1‐naphthol represent a new class of inhibitors for the aryl sulfotransferase.
Prebiotic sources of biomolecular handedness
Authors: Mason Stephen F. 
Published: January 2005

AbstractFischer demonstrated (1890–1919) that functional biomolecules are composed specifically of the D‐sugars and the L‐amino acids, and that in the laboratory synthetic reactions of such molecules propagate with chiral stereoselectivity. Given a primordial enantiomer, biomolecular homochirality followed without the intervention of the chiral natural force conjectured by Pasteur (1860), except prebiotically. Polarized solar radiation and other classical chiral forces were proposed as agencies generating a prebiotic enantiomeric excess, but the forces then known were found to be evenhanded on a time and space average, exemplifying parity conservation (1927). The weak nuclear force, shown to violate parity (1956), was unified with electromagnetism in the electroweak force (1970). Ab initio estimations including the chiral electroweak force indicate that the L‐amino acids and the D‐sugars are more stable than the corresponding enantiomers. The small energy difference between these enantiomer pairs, with Darwinian reaction kinetics in a flow reactor, account for the choice of biomolecular handedness made when life began.
Solid angle as steric parameter of acyclic saturated groups
Authors: Chauvin R. , Kagan H. B. 
Published: January 2005

AbstractWith the early aim of quantifying steric consequences of chirality, efforts to define a nonempirical steric parameter of chemical groups are reported. Steric hindrance of a reacting center by any acyclic saturated R group has been characterized by a geometric “axial steric parameter”: the solid angle of R. When the group is a “symmetric top substituent” (i.e., when all the terminal atoms are equivalent), the solid angle matches the solid angle of a cone envelope of R. The definition of this cone is compared with Tolman's definition of a ligand cone in organometallic complexes. The chemical significance of this parameter is shown by an excellent correlation with the Dubois' experimental steric parameter E′s. Modeling steric repulsion by the cone of R, and correcting solid angles for conformational effects, only 3 empirical coefficients are needed to calculate 33 values of E′s with less than 10% error. The cone model is suggested to be relevant within the limits of random and independent free rotations about all the bonds in the C–R group. A separation between “axial cone steric hindrance” and other steric effects is proposed. The basic model and the corrections proposed allow the conformational features of esters to be discussed.
Cooperation in a deep helical energy well
Authors: Green Mark M. , Lifson Shneior , Teramoto Akio 
Published: January 2005

AbstractIn contrast to random coil polymers, polyisocyanates maintain a highly extended helical conformation in solution. This structural characteristic causes unusually large chiral optical properties to arise from copolymerization of tiny proportions of optically active monomer isocyanates with achiral isocyanates or even from stereospecific placement of deuterium in the side chain of poly(n‐hexyl isocyanate). These effects can be understood as phenomenologically related to the optical activity amplification properties of vinyl polymers studied by Pino and his co‐workers and ascribed to breaking the energetic degeneracy of the otherwise equally populated left‐ and right‐handed helical states of the backbone. Statistical thermodynamic calculations, based on this model, and analogous to those carried out earlier on the vinyl polymers, allow matching the temperature and molecular weight dependence of the optical activity in poly((R)‐1‐deuterio‐1‐hexyl isocyanate) to the approximate responsible energy terms.
A model for the homogeneous isospecific Ziegler–Natta polymerization of olefins: Enantioselectivity in the deuteration and deuteriooligomerization of 1‐alkenes
Authors: Cavallo Luigi , Guerra Gaetano , Vacatello Michele , Corradini Paolo 
Published: January 2005

AbstractThe enantioselectivity found in homogeneous isospecific Ziegler–Natta catalysts for the insertion of 1‐alkenes in metal–deuterium or in metalisobutyl bonds is discussed from a theoretical point of view. Nonbonded energy calculations, based on a model of the catalytic site previously proposed by us, indicate that the strong enantioselectivity found in the insertion of 1‐alkenes in a metal–isobutyl bond is drastically reduced in the presence of a metal–deuterium bond. In particular, a weak enantioselectivity in favour of a monomer coordinated with the opposite chirality (lower for the case of 1‐butene, higher for the case of styrene) is shown to occur in the latter case.
The asymmetric hydroformylation in the synthesis of pharmaceuticals
Authors: Botteghi Carlo , Paganelli Stefano , Schionato Alberto , Marchetti Mauro 
Published: January 2005

AbstractThe asymmetric hydroformylation reaction represents a potential powerful synthetic tool for the preparation of large number of different chiral products to be used as precursors of several organic compounds endowed with therapeutic activity. Essential and nonessential amino acids, 2‐arylpropanoic acids, aryloxypropyl‐ and β‐phenylpropylamines, modified β‐phenylethylamines, pheniramines, and other classes of pharmaceuticals are available through enantioselective oxo‐reaction of appropriate functionalized olefins; this process is catalyzed by rhodium or platinum complexes with chiral ligands, mainly chelating phosphines, and sometimes affords very high enantiomeric excesses. Furthermore, the application of many simple optically active aldehydes arising from asymmetric hydroformylation as chiral building blocks for the synthesis of complex pharmacologically active molecules such as antibiotics, peptides, antitumor macrocycle compounds, and prostaglandins is conveniently emphasized. The possibility of a future application of this asymmetric process for the production of many synthons to obtain other valuable pharmaceuticals is widely discussed too.
Circular dichroism detection in HPLC
Authors: Salvadori Piero , Bertucci Carlo , Rosini Carlo 
Published: January 2005

AbstractA circular dichroism‐based detection system presents several advantages in the HPLC analysis of chiral compounds because of the selective monitoring of optically active molecules. Its use allows reliable determination of enantiomeric excesses and elution order. To this end, the application of empirical, semiempirical, and nonempirical methods to get stereochemical information from the CD signal is reported. Furthermore, recording the CD spectra on line and evaluation of the dissymetry factor make the CD detection very powerful in characterizing the stereochemistry of chiral eluates.