bluuebunny/crossref_metadata_2025 huggingface dataset:
Separation and quantitation of (R)‐ and (S)‐atenolol in human plasma and urine using an α1‐AGP column
Authors: Enquist Märit , Hermansson Jörgen
Published: January 2005

A 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 (0.01 M phosphate) 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 urine was ∼ 1.
(−)‐(S)‐Flunoxaprofen and (−)‐(S)‐naproxen isocyanate: Two new fluorescent chiral derivatizing agents for an enantiospecific determination of primary and secondary amines
Authors: Martin E. , Quinke K. , Spahn H. , Mutschler E.
Published: January 2005

The 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)‐propranolol‐HCl] to two volunteers.
The role of configuration and conformation in the binding of 2,3‐benzodiazepines to human serum albumin
Authors: Visy Julia , Simonyi Miklós
Published: January 2005

2,3‐Benzodiazepines containing a centre of asymmetry at C‐5 possess both central and helical chiralities, and the solution of their racemates contains four molecular species. The binding of these compounds to human serum albumin (HSA) was studied by affinity chromatography. The binding strength depended both on the steric orientation of the 5‐ethyl substituent and on the conformation of the diazepine ring. Conformation P (defined by the positive sign of C‐1–N‐2‐N–3–C‐4 torsion angle) is favoured, while the quasiaxial orientation ‐of the 5‐ethyl substituent is not favoured by the albumin molecule.
Direct high‐performance liquid chromatographic separation of penbutolol enantiomers on a cellulose tris‐3,5‐dimethylphenyl carbamate chiral stationary phase
Authors: Aboul‐Enein Hassan Y. , Islam M. Rafiqul
Published: January 2005

Penbutolol is a β‐adrenoceptor blocking agent, and it contains the clinically relevant (−)‐S‐enantiomer. It was reported that the (+)‐R‐enantiomer of penbutolol is pharmacologically 50 times less active than the (−)‐S‐isomer in β‐sympatholysis and without intrinsic sympathomimetic activity and refractory period in the heart muscle. Furthermore, the (+)‐R‐enantiomer does possess mutagenic activity.

A high‐performance liquid chromatographic (HPLC) method is described for direct identification, stereochemical separation, and quantitation of (+)‐R‐enantiomer in the clinically used (−)‐S‐isomer. The method involves the use of cellulose tris‐3,5‐dimethylphenyl carbamate chiral stationary phase coated on silica gel (OD‐Chiralcel column). The capacity factors (k′) for the first eluted enantiomer and stereochemical separation factor (α) obtained were 1.32 and 1.98, respectively. The maximum stereochemical resolution factor (R) was 5.05. The method could be applied for optical purity determination of (−)‐(S)‐penbutolol in pharmaceutical formulation to detect for the presence of the undesirable (+)‐R‐enantiomer.
The stereochemical resolution of the enantiomers of aspartame on an immobilized α‐chymotrypsin hplc chiral stationary phase: The effect of mobile‐phase composition and enzyme activity
Authors: Jadaud Philippe , Wainer Irving W.
Published: January 2005

The enantioselective and diastereoselective resolutions of the stereoisomers of Nα‐aspartyl‐phenylalanine 1‐methyl ester (APME) have been accomplished on an HPLC chiral stationary phase based upon α‐chymotrypsin (the ACHT‐CSP) with observed enantioselectivities (α1) for the DL‐/LD‐enantiomers of as high as 29.17 and for the DD‐/LL‐enantiomers of as high as 28.97. In addition, the effect on the chromatographic retention of the APME stereoisomers of the activity of the ACHT and the composition of the mobile phase—structure of the anionic component, molarity, and pH—have been studied. The results of this study suggest that the aspartyl moiety and/or the aspartyl‐phenylalanine amide linkage play key roles in the observed enantioselectivity; the APME stereoisomers containing L‐phenylalanine, i.e., DL‐ and LL‐APME, bind at a different site in the ACHT molecule (the L‐Phe site) than the APME stereoisomers containing D‐phenylalanine (the D‐Phe site); and the observed enantioselectivity is a measure of the difference in the binding affinities at the two sites rather than the consequence of differential affinities at a single site.
Reversed‐Phase LC resolutions of chiral antiarrhythmic agents via derivatization with homochiral isothiocyanates
Authors: Gal Joseph , Meyer‐lehnert Sabine , Desai Daksha M.
Published: January 2005

The search for new antiarrhythmic agents has been intense, because the established drugs for the treatment of cardiac arrhythmias are neither uniformly effective nor well‐tolerated. Among the recently introduced new anti‐arrhythmic agents are tocainide (TOC), mexiletine (MEX), flecainide (FLE), and propafenone (PRO). Each of these drugs is a chiral amine used clinically as the racemic mixture. We have examined the high‐performance liquid chromatographic chiral resolution of the above four drugs via derivatization with homochiral derivatizing agents (HDAs). The amino functionality of the drugs was reacted with four homochiral isothiocyanates, 2,3,4,6‐tetra‐O‐acetyl‐β‐D‐glucopyranosyl isothiocyanate (TAGIT), (R)‐α‐methylbenzyl isothiocyanate (RAMBI), (S)‐1‐(1‐naphthyl)ethyl isothiocyanate (SNEIT), and (R)‐1‐(2‐naphthyl)ethyl isothiocyanate (RBEIT). Complete separation of the two peaks (resolution factor R = 1.5) was achieved with all four HDAs for TOC, with TAGIT, RBEIT, and RAMBI for MEX, with TAGIT and SNEIT for PRO, and only with TAGIT for FLE. SNEIT was used to develop analytical procedures for the determination of the enantiomeric composition of TOC in human urine and blood serum. The four HDAs offer several advantages over many other HDAs and should be useful in studies of enantioselective drug action and disposition.
Stereoselective arylpropionyl‐CoA thioester formation in vitro
Authors: Knadler M. P. , Hall S. D.
Published: January 2005

The 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

Ibuprofen 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

Racemic 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

The 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

(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

The 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

The 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

From 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

Fenoldopam (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

The 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

Molecular 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

Aryl 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

Fischer 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

With 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

In 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

The 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

The 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

A 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.
Interaction of pirprofen enantiomers with human serum albumin
Authors: Oravcová J. , Mlynárik V. , Bystrický S. , Šoltés L. , Szalay P. , Boháčik Ľ. , Trnovec T.
Published: January 2005

The interaction of pirprofen enantiomers with human serum albumin (HSA) was investigated by means of high‐performance liquid chromatography (HPLC), circular dichroism (CD), and 1H NMR spectroscopy. HPLC experiments indicated that both pirprofen enantiomers were bound to one class of high‐affinity binding sites (n(+) = 1.91 ± 0.13, K(+) = (4.09 ± 0.64) × 105 M−1, n(‐) = 2.07 ± 0.13, K(‐) = (6.56 ± 1.35) × 105 M−1) together with nonspecific binding (n′K′(+) = (1.51 ± 0.21) × 104 M−1, n′K′(‐) = (0.88 ± 0.13) × 104 M−1). Slight stereoselectivity in specific binding was demonstrated by the difference in product n(+)K(+) = (0.77 ± 0.08) × 106 M−1 vs. n(‐)K(‐) = (1.30 ± 0.21) × 106 M−1, i.e., the ratio n(‐)K(‐)/n(+)K(+) = 1.7. CD measurements showed changes in the binding sites located on the aromatic amino acid side chains (a small positive band at 315 nm and a pronounced negative extrinsic Cotton effect in the region 250–280 nm). The protein remains, however, in its predominantly alpha‐helical conformation. The 1H NMR difference spectra confirmed that both pirprofen enantiomers interacted with HSA specifically, most probably with site II on the albumin molecule.
Stereoselective accumulation of the β‐receptor blocking drug atenolol by human platelets
Authors: Walle T. , Webb J. G. , Walle U. K. , Bagwell E. E.
Published: January 2005

We have studied the stereochemistry of accumulation of the hydrophilic β‐adrenoceptor antagonist rac‐atenolol by human platelets in vitro. The accumulation was slow, not reaching equilibrium until 90 min at 37°C. The uptake was temperature dependent with the accumulation at 37°C being 3–4 times greater than at 4°C. The accumulation was also stereoselective at 37°C, favoring the active (−)‐enantiomer over the (+)‐enantiomer by 2.3‐fold. Reserpine, but not desipramine, inhibited the platelet accumulation of rac‐atenolol enantiospecifically. This uptake profile is different from the platelet uptake of lipophilic β‐blockers, which is characterized by nonspecific membrane binding, but similar to the carrier‐mediated accumulation of the neurotransmitter norepinephrine by storage granules within the platelet.
Production of a chiral polyester by Pseudomonas oleovorans grown with 5‐phenyl‐2,4‐pentadienoic acid
Authors: Antoun Safwat , Grizzi Ilaria , Lenz Robert W. , Fuller R. Clinton
Published: January 2005

Pseudomonas oleovorans has been previously shown to produce a polyester containing a phenyl pendant group when grown with 5‐phenylpentanoic acid under nutrient‐limiting conditions. The same polyester was produced when 5‐phenyl‐2,4‐pentadienoic acid was the only carbon source, and a mixture of two different polymers was produced when this bacterium was grown on a mixture of 5‐phenyl‐2,4‐pentadienoic acid and nonanoic acid. The polymer blend obtained was separated by fractional crystallization to yield poly(3‐hydroxy‐5‐phenylpentanoate) and the copolymer which is normally produced with nonanoic acid alone.
Improvement of the enantiorecognition ability of tyrosine‐derived chiral stationary phases: Direct resolution of 1,2‐amino‐alcohols (β‐blockers)
Authors: Tambute A. , Siret L. , Begos A. , Caude M.
Published: January 2005

A novel chiral stationary phase (CSP) derived from tyrosine is evaluated with regard to the first generation commercially available (S)‐ChyRoSine‐A CSP, under normalphase or reversed‐phase liquid chromatographic (NPLC or RPLC) and subcritical fluid chromatographic (SubFC) conditions. The complete scope of application of these CSPs is reviewed. The novel CSP, which bears a bulkier functional group, displays a higher enantiorecognition ability than previously described (S)‐ChyRoSine‐A toward about 15 families of racemates, whatever the mobile phase conditions.

The direct enantiomeric separation of 1,2‐amino‐alcohols (β‐blockers) is carried out on both CSPs. Facile separations are achieved within short analysis times using SubFC mode, whereas very poor separations are obtained using NPLC mode. These results disagree with previous theories (interchangeability between NPLC and SubFC modes).
The influence of aging on the stereoselective pharmacokinetics of propranolol in the rat
Authors: Vermeulen An M. , Belpaire Frans M. , Moerman Emmanuel , Smet Frits De , Bogaert Marc G.
Published: January 2005

The influence of aging on the pharmacokinetics and the tissue distribution of (R)‐ and of (S)‐propranolol was studied in 3‐, 12‐, and 24‐month‐old rats. After both iv and oral administration of rac‐propranolol, the plasma concentrations were higher for the (R)‐ than for the (S)‐enantiomer. For the tissue concentrations, the reverse was true. The free fraction of (S)‐propranolol in plasma was about 4 times larger than that of (R)‐propranolol, and this is the main factor responsible for the differences in kinetics between the two enantiomers. There was a suggestion for a difference in tissue binding between the two enantiomers. With aging, the plasma and tissue concentrations of both enantiomers increase, probably due to a decrease in blood clearance. Tissue binding did not change much with aging. Notwithstanding the marked differences between the kinetics of the propranolol enantiomers, the changes which occur with aging affect both enantiomers to the same degree.
Enantioselectivity of lipase‐catalyzed hydrolysis of some 2‐chloroethyl 2‐arylpropanoates studied by chiral reversed‐phase liquid chromatography
Authors: Allenmark Stig , Ohlsson Ann
Published: January 2005

A technique based exclusively on chiral reversed‐phase liquid chromatography has been shown to greatly facilitate studies of enantioselectivity in lipase‐catalyzed hydrolysis of chiral organic esters. Only two sets of experimental data are needed to calculate the enantioselectivity (E) of a kinetically controlled enantiomer‐differentiating reaction of this kind, viz. the enantiomeric excess of the product (eep) or substrate (ees), and the degree of substrate conversion (c). The product enantiomers are well separated on a BSA‐based column, giving eep directly. In addition, separation of the (unresolved) ester substrate from the enantiomeric products gives c by integration. Via an optimization of the mobile phase used in the chiral chromatographic system, both these parameters can often be determined in a single run. Highly precise and detailed kinetic studies of the enzymatic reaction can thus be performed. In this way, E‐values have been determined for a series of 2‐chloroethyl 2‐arylpropanoates hydrolyzed in the presence of a Candida cylindracea lipase at pH 6.0 and 7.1. Effects on the E‐values from a partial purification and further processing of the lipase have also been studied.
Plasma determination of the enantiomers of SL 84.0418, a new antihyperglycaemic drug, by HPLC on a chiral α1‐agp column
Authors: Guinebault Paul , McAnena‐Morice Deirdre , Colafranceschi Colette , Rouchouse Alain
Published: January 2005

SL 84.0418 is a new antihyperglycaemic drug. It is an orally active and selective α2‐adrenoceptor antagonist. This molecule, a pyrroloindole derivative, contains an asymmetric center yielding two enantiomers. In order to evaluate the pharmacokinetic profile of both enantiomers following oral administration of the racemate we have developed an HPLC method for their separation and quantification. The liquid—liquid extraction involved three steps with two salting‐out procedures at pH 11.5 before and after a back‐extraction with 0.005 M H2SO4. The enantiomers were separated by HPLC on a stainless‐steel column (100 x 4.0 mm) packed with a chiral α1 ‐acid. The UV response was linear from 1 to 250 ng/ml for both enantiomers. The relative standard deviation (RSD) for reproducibility was below 10.7%. Using quality control samples, precision was found below 7.8% and accuracy was 108%. Extraction recoveries were ca. 60% for both enantiomers and 94% for the internal standard. Column life was brought up to 2 months, which corresponds to about 1,000 injections of biological extract. No guard column was used, but a daily back‐flush was carried out. This method is suitable for routine analysis and 30 to 40 plasma samples a day can be processed. This method allows the definition of the pharmacokinetic profile of both enantiomers of SL 84.0418 in human plasma after single oral administration of doses as low as 20 mg of the racemic drug.
The resolution, isolation, and pharmacological characterization of the enantiomers of a benzamide containing a chiral sulfoxide
Authors: Butler Brent T. , Silvey Gary , Michael Houston D. , Borcherding David R. , Vaughn Valerie L. , McPhail Andrew T. , Radzik Donna M. , Wynberg Hans , Ten Hoeve W. , Van Echten E. , Ahmed Nahed K. , Linnik Matthew D.
Published: January 2005

Rac‐ML‐1035 (MDL 201,035: 4‐amino‐5‐chloro‐2‐[2‐(methylsulfinyl)ethoxy]— N‐[2‐(diethylamino)ethyl] benzamide hydrochloride) is a racemic gastroprokinetic with serotonergic (5‐hydroxytryptamine, 5‐HT) activity and a novel chiral sulfoxide substituent. Chromatographic and chemical methods have been developed to resolve the enantiomers of rac‐ML‐1035, and the absolute configuration of the (R)‐enantiomer has been determined. We also report pharmacological characterization of rac‐ML‐1035 and its respective isomers. Radioligand binding to rat cortical membranes revealed that (R)‐ML‐1035 (MDL 201,226) and (S)‐ML‐1035 (MDL 201,227) had equivalent activity at the 5‐HT3 receptor. However, in isolated tissue studies including field‐stimulated guinea pig ileum, field‐stimulated rat fundic strip, and nonstimulated guinea pig ileum, (S)‐ML‐1035 was equally potent yet had greater maximal activity than (R)‐ML‐1035 in eliciting or facilitating cholinergic contractions. Thus, enantiomers of rac‐ML‐1035 can be resolved, and the relative configuration of these isomers influences their pharmacological activity. © 1992 Wiley‐Liss, Inc.
Chiroptical detection during liquid chromatography: Applications to stereoanalysis and stereodynamics
Authors: Mannschreck Albrecht
Published: January 2005

Qualitative and quantitative use of polarimetry at one wavelength for detection during liquid chromatography is briefly reviewed. Acquisition of circular dichroism spectra by stopped‐flow and nonstop measurements has been further developed. Reasons are given why the angle of rotation, i.e., the polarimeter, is preferred for monochromatic use and differential absorbance, i.e., the dichrograph, for polychromatic requirements. Both methods are demonstrated by novel applications, mainly to enantiomers which interconvert thermally via intramolecular processes. © 1992 Wiley‐Liss, Inc.
Chromatographic resolution of the chiral isomers of several β‐blockers over cellulose tris(3,5‐dimethylphenylcarbamate) chiral stationary phase
Authors: Ching C.B. , Lim B.G. , Lee E.J.D. , Ng S.C.
Published: January 2005

The optical resolution of seven β‐blockers which have in common the N‐isopropyl‐3‐aryloxy‐2‐hydroxypropylamine moiety was carried out by HPLC using the cellulose tris(3,5‐dimethylphenylcarbamate) chiral stationary phase to quantitatively characterize the enantioselectivity of these compounds. The capacity factors and separation factors at different column temperature were determined with some qualitative trends derived. A compensation effect was observed for these compounds where there exists an approximately linear relationship between the enantiomeric differences in enthalpic and entropic energies. © 1992 Wiley‐Liss, Inc.
Optical stability of gossypol
Authors: Jaroszewski Jerzy W. , Strøm‐Hansen Thorbjørn , Hansen Lars Lindgaard
Published: January 2005

The optical stability of gossypol [1,1',6,6',7,7'‐hexahydroxy‐3,3'‐dimetyl‐5,5'‐bis(1‐methylethyl)‐2,2'‐binaphthalene‐8,8'‐dicarboxaldehyde], a natural product exhibiting profoundly enantiospecific antitumor and male antifertility action, was investigated by means of computational methods and thermal racemization experiments. The calculations on gossypol and several derivatives and model compounds were carried out using the MM2 force field; energies and geometries of minimum energy conformations, as well as structures along various inversion pathways, were calculated. According to the calculations, gossypol (the dialdehyde form) and its simple analogues are not thermally racemizable (energy barriers for rotational inversion above 50 kcal/mol). By contrast, the calculations suggest that the acetal tautomer of gossypol and its dehydration product (anhydrogossypol) are thermally racemizable, although the energy barriers are still relatively high (35–40 kcal/mol). Optically pure (+)‐anhydrogossypol was prepared and characterized; its racemization became rapid only at high temperatures (180–200°C). When dehydration of gossypol was hindered (in aqueous solution), no racemization of gossypol was observed after prolonged heating at 90°C. © 1992 Wiley‐Liss, Inc.
Computer‐Aided models for optimization of eluent parameters in chiral liquid chromatography
Authors: Tucker R.P. , Fell A.F. , Berridge J.C. , Coleman M.W.
Published: January 2005

The application of a central composite design to the enantiomeric separation of the antifungal drug tioconazole is investigated. The design involves application of a mathematical model to the data to model the response in regions of the factor space not investigated in the experimental design. The significance of the variable terms in the model is assessed statistically and those terms declared not significant are removed from the model. The statistical adequacy of these reduced models is discussed, together with an examination of the prediction errors of the models. Three‐dimensional predicted response surfaces for the complete models are presented and the predictive performance assessed. © 1992 Wiley‐Liss, Inc.
Formation of glycine conjugate and (–)‐(R)‐enantiomer from (+)‐(S)‐2‐phenylpropionic acid suggesting the formation of the coa thioester intermediate of (+)‐(S)‐enantiomer in dogs
Authors: Tanaka Y. , Shimomura Y. , Hirota T. , Nozaki A. , Ebata M. , Takasaki W. , Shigehara E. , Hayashi R. , Caldwell J.
Published: January 2005

It has been proposed that the chiral inversion of the 2‐arylpropionic acids is due to the stereospecific formation of the (–)‐R‐profenyl‐CoA thioesters which are putative intermediates in the inversion. Accordingly, amino acid conjugation, for which the CoA thioesters are obligate intermediates, should be restricted to those optical forms which give rise to the (–)‐R‐profenyl‐CoA, i.e., the racemates and the (–)‐(R)‐isomers. We have examined this problem in dogs with respect to 2‐phenylpropionic acid(2‐PPA). Regardless of the optical configuration of 2‐phenylpropionic acid administered, the glycine conjugate was the major urinary metabolite and this was shown to be exclusively the (+)‐(S)‐enantiomer by chiral HPLC. Both (–)‐(R)‐ and (+)‐(S)‐2‐phenylpropionic acid were present in plasma after the administration of either antipode, and further evidence of the chiral inversion of both enantiomers was provided by the presence of some 25% of the opposite enantiomer in the free 2‐phenylpropionic acid and its glucuronide excreted in urine after administration of (–)‐(R)‐ and (+)‐(S)‐2‐phenylpropionic acid. The (+)‐(S)‐enantiomer underwent chiral inversion to the (–)‐(R)‐antipode when incubated with dog hepatocytes. These data suggests that both enantiomers of 2‐phenylpropionic acid are substrates for canine hepatic acyl CoA ligase(s) and thus undergo chiral inversion, but that the CoA thioester of only (+)‐(S)‐2‐phenylpropionic acid is a substrate for the glycine N‐acyl transferase. These studies are presently being extended to the structure and species specificity of the reverse inversion and amino acid conjugation of profen NSAIDs. © 1992 Wiley‐Liss, Inc.
Optical isomers of a leukotriene b4 antagonist have differential effects on granulocyte diapedesis in the guinea pig dermis
Authors: Fretland Donald J. , Widomski Deborah L. , Anglin Charles P. , Yu Stella , Djuric Stevan W.
Published: January 2005

Leukotriene B4 (LTB4) is a proinflammatory product of arachidonic acid metabolism that has been implicated in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB4 has been shown to elicit a dose‐dependent infiltration of granulocytes as assessed by the level of the neutrophil marker enzyme myeloperoxidase. SC‐41930 [7‐[3‐(4‐acetyl‐3‐methoxy‐2‐propylphenoxy)propoxy]‐3,4‐dihydro‐8‐propyl‐2H‐1‐benzopyran‐2‐carboxylic acid] is a potent LTB4 receptor antagonist. When compounds were coadministered along with LTB4 (35 ng) into the dermal site, racemic SC‐41930, (+)‐SC‐41930, and (–)‐SC‐41930 each inhibited granulocyte accumulation with ED50 values of 340 ± 30, 98 ± 5.7, and 1000 ± 142 ng, respectively; when given intravenously inhibited with ED50 values of 0.5 ± 0.06, 0.3 ± 0.04, and 1.4 ± 0.19 mg/kg, respectively; and when given intragastrically inhibited with ED50 values of 1.7 ± 0.20, 1.4 ± 0.23, and 3.0 ± 0.41 mg/kg, respectively. © 1992 Wiley‐Liss, Inc.