bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and effects on peripheral thyroid hormone conversion of (R)‐4‐hydroxypropranolol, a main metabolite of (R)‐propranolol
Authors: Buchinger Wolfgang , Eber Otto , Uray Georg , Lind Peter , Lindner Wolfgang
Published: January 2005

The inhibiting effect of (R,S)‐propranolol on peripheral T4/T3 conversion can be related to the (R)‐isomer. The intention of this study is to clarify if (R)‐4‐hydroxypropranolol, a main metabolite of (R)‐propranolol, develops the same or even a stronger effect on peripheral thyroxine metabolism as the parent drug. (R)‐4‐hydroxypropranolol was synthesized via (R)‐4‐methoxypropranolol and their optical purity was checked chromatographically. Twenty patients suffering from hyperthyroidism were divided into five groups and treated with (R)‐4‐hydroxypropranolol · HCl in dosages from 12 to 75 mg per day in a placebo controlled study over a period of 5 days. The serum hormone levels and resting pulse rate were measured. No significant changes of thyroid parameter could be observed but a significant decrease of resting pulse rate under treatment with 75 mg (R)‐4‐hydroxypropranolol occurred. It could be concluded that (R)‐4‐hydroxypropranolol possesses negative chronotropic effects but develops no changes in thyroid hormone metabolism in hyperthyroid patients.
Fast liquid chromatography for the resolution of chiral compounds
Authors: Perrin Scott R.
Published: January 2005

A Pirkle‐concept chiral stationary phase (CSP) derived from N‐(1‐naphthyl)leucine was evaluated for developing methods to reduce analysis times and investigating techniques in the rapid screening of a variety of chiral compounds over a given chiral selector. The effects of reduced column lengths and elevated temperatures were studied to shorten analysis times.
N,N‐dimethylcarbamyl derivatives of oxazepam
Authors: Yang Shen K. , Lu Xiang‐Lin
Published: January 2005

Three N,N‐dimethylcarbamyl derivatives of oxazepam {1‐(N,N‐dimethylcarbamyl)oxazepam, 3‐O‐(N,N‐dimethylcarbamyl)oxazepam, and 1,3‐O‐bis(N,N‐dimethylcarbamyl)oxazepam} and a 3‐O‐acyl‐1‐(N,N‐dimethylcarbamyl)‐oxazepam were synthesized from either oxazepam or demoxepam. Enantiomeric pairs of these derivatives and of camazepam were resolved by high‐performance liquid chromatography on at least two of three commercially available chiral stationary phase columns employed. Absolute configurations of resolved enantiomers were established by comparing their circular dichroism spectra to those of enantiomeric oxazepams with known absolute stereochemistry. Similar to those of oxazepam, enantiomers of 1‐(N,N‐dimethylcarbamyl)oxazepam undergo rapid racemization (t½ 1.9 min at 23°C and 0.9 min at 37°C) in an aqueous solution at pH 7.5. The (R)‐enantiomer of rac‐3‐O‐acyl‐1‐(N,N‐dimethylcarbamyl)oxazepam was hydrolyzed ∼4.6‐fold faster than the (S)‐enantiomer by esterases in rat liver microsomes, whereas the (S)‐enantiomer was hydrolyzed ∼43‐fold faster than the (R)‐enantiomer by esterases in rat brain S9 fraction.
Chirality of reverse micelles
Authors: Colombo Luca M. , Thomas Richard M. , Luisi P. L.
Published: January 2005

Four chiral analogues of the surfactant Aerosol‐OT (AOT) have been synthesized and characterized. All of them form reverse micelles in apolar solvents in the w0 range 0–30 (w0 = [water]/[tenside]). Reverse micellar solutions have been investigated by UV absorption and circular dichroism spectroscopies with the aim of clarifying whether the formation of the macromolecular micellar structure induces the appearance of new chromophoric bands or perturbs the existing ones. Methanolic solutions of the surfactants, in which no micellar aggregates are formed, were taken as references. One of the products 1(S),1′(S)‐dimethylbisheptylsulphosuccinate sodium salt (MH‐AOT) was capable of forming reverse micelles of relatively high water content (w0 up to 40) and this process was accompanied by a specific increase in the intensity of the circular dichroism band associated with the ester absorbance of the molecule. As no concomitant changes were seen in the UV absorbance spectrum, it was concluded that this observation reflected conformational events occurring within the surfactant rather than chromophoric perturbation. These results are qualitatively similar to those found recently for lecithin reverse micelles which, however, form gels at sufficiently high water contents. The chiroptical properties of these supramolecular aggregates are compared with those of covalent macromolecular systems such as polypeptides.
Control of asymmetric induction in the organometallic synthesis of 3‐methyl‐(E)‐4‐hexen‐2‐one
Authors: Bartik T. , Markó L. , Gerdes I. , Heimbach P. , Knott W. , Schulte H.‐G.
Published: January 2005

Bis(μ‐methyl‐1,3‐dimethyl‐η3‐allylnickel) reacts in the presence of phosphorus(III) ligands (phosphines, phosphites) with CO to give 3‐methyl‐(E)‐4‐hexen‐2‐one. Systematic experiments were performed using chiral ligands containing menthyl or menthoxy groups and different achiral groups on the P atom to determine the influence of ligand structure and concentration on the direction and extent of chiral induction in this ketone synthesis. It could be shown that reversion of enantioselectivity can be obtained not only by the obvious method of reversing the absolute configuration of the ligand (“parity control”) but also by modifying the nonchiral substituents of the phosphorus ligand (“complementarity control”). The synthesis, physical, and spectroscopic properties of several new menthyl phosphines and phosphites are reported.
A highly enantioselective rhodium catalyst for the hydrogenation of aliphatic α‐keto esters
Authors: Spindler Felix , Pittelkow Ulrich , Blaser Hans‐Ulrich
Published: January 2005

The enantioselective hydrogenation of several α‐keto acid derivatives with rhodium diphosphine catalysts has been investigated using a random screening approach. The neutral rhodium catalyst prepared in situ from bis(2,5‐norbornadiene rhodium chloride) and NORPHOS has been found to be an excellent catalyst for preparing aliphatic α‐hydroxy esters in high optical purities. The reaction parameters for the hydrogenation of ethyl 2‐oxo‐4‐phenyl‐butyrate, an intermediate for the ACE inhibitor Benazepril, were optimized and the best optical yields obtained were 96%.
Steric hindrance influence on the enantiorecognition ability of tyrosine‐derived chiral stationary phases
Authors: Siret L. , Tambuté A. , Bégos A. , Rouden J. , Caude M.
Published: January 2005

Four chiral stationary phases (CSPs) derived from N‐(3,5‐dinitrobenzoyl)tyrosine have been synthesized. They differ by the substituent nature (methyl, ethyl, isopropyl, tert‐butyl) of the aliphatic amide function. The enantiorecognition ability of these CSPs was evaluated with 10 racemates. For the majority of them, the stereoselectivity increases with the steric hindrance of the substituent. The chiral selector enantiomeric separation on the resulting CSPs has evidenced a reversal of elution order only for CS 4 on CSP 4 (tert‐butyl substituent), suggesting a change in its conformation.
Cyclodextrin derivatives in GC separation of racemic mixtures of volatiles: Part III
Authors: Bicchi Carlo , Artuffo Giuseppe , D'Amato Angela , Galli Anna , Galli Mario
Published: January 2005

The gas chromatographic performance of differently derivatized α‐, β‐, and γ‐cyclodextrins in the separation of racemic mixtures of volatiles is investigated. The performances of 2,3,6‐permethylated α‐, β‐, and γ;‐cyclodextrins and 2,6‐dimethyl‐3‐trifluoro‐acetyl α‐, β‐, and γ‐cyclodextrins mixed with different ratios of OV‐1701 or OV‐1701‐OH terminated were tested with racemates with widely differing structures. The influence of the percentage of cyclodextrins in polysiloxane, of film thickness of the stationary phase, of the length of the column, of column conditioning, and of the operating temperatures in the separations of different racemates has been evaluated.
Stereoselective disposition and tissue distribution of carvedilol enantiomers in rats
Authors: Fujimaki Masayoshi
Published: January 2005

After intravenous bolus injection of rac‐carvedilol at 2 mg/kg to the rat, the (+)‐(R)‐ and (—)‐(S)‐enantiomer levels in the blood and tissues (liver, kidney, heart, muscle, spleen, and aorta) were measured by stereospecific HPLC assay. As compared with the (+)‐(R), the (—)‐(S) had a larger Vdss (3.32 vs. 2.21 liter/kg), MRT (33.4 vs. 25.6 min), and CLtot (96.1 vs. 83.8 ml/min/kg). AUC comparison after iv and po administration showed systemic bioavailability of the (—)‐(S) to be about half that of its antipode, explained by the fact that the free fraction of the (—)‐(S) in blood was 1.65‐fold greater than that of the (+)‐(R). Tissue‐to‐blood partition coefficient values for the (—)‐(S) were 1.6‐ to 2.1‐fold greater than those for the (+)‐(R) in all tissues, showing that the (—)‐(S) accumulates more extensively in the tissues. These results were consistent with the greater Vdss for the (—)‐(S) estimated from systemic blood data. The stereoselective tissue distribution of carvedilol enantiomers results from an enantiomeric difference in plasma protein binding rather than in tissue binding. © 1992 Wiley‐Liss, Inc.
Chiral hplc‐cd studies of the antituberculosis drug (+)‐ethambutol
Authors: Blessington B. , Beiraghi A. , Lo T.W. , Drake A. , Jonas G.
Published: January 2005

Long standing errors in major pharmacopoeiae (BP,USP, and Eu.Ph.) concerning the absolute stereochemistry of the widely used antituberculosis drug (+)‐ethambutol have been clarified by unambiguous synthesis and chiral HPLC. on a Pirkle, covalent D‐phenylglycine column of perbenzoyl derivatives of each stereomer; the enantiomeric (−)‐(R,R) and (+)‐(S,S)‐ethambutols together with the optically inactive (meso)‐(R,S)‐ethambutol. This paper describes how circular dichroism (CD) alone and combined with HPLC is used to demonstrate this chiral separation and also to confirm the absolute stereochemistry of each stereomer of ethambutol and its synthetic precursor 2‐aminobutan‐1‐ol from studies of „exciton coupling.”︁ The strengths and weaknesses of these chiral techniques are discussed.
Effects of the stereochemical orientation of phenethylamines and imidazolines on α‐adrenergic receptor‐mediated dna synthesis in primary cultured rat hepatocytes
Authors: Esbenshade Timothy A. , Hamada Akihiko , Miller Duane D. , Feller Dennis R.
Published: January 2005

The hepatic α1‐adrenergic receptor mediates a variety of hepatic functions including respiration, glycogenolysis, gluconeogenesis, and growth. We have utilized a rat primary hepatocyte culture system to show that the α1‐adrenergic receptor can be activated in a stereoselective manner by a series of phenethylamines and catecholimidazolines resulting in the stimulation of DNA synthesis as determined by [3H]thymidine incorporation. The phenethylamines adhered to the Easson–Stedman hypothesis with a rank order of potency of (–)‐(R)‐norepinephrine (NE) > (+)‐(S)‐NE > the desoxy analog dopamine (DA) for the stimulation of DNA synthesis. However, the 2‐substituted catecholimidazolines did not follow this trend and demonstrated an order of potency of the desoxy analog 3,4‐dihydroxybenzyl imidazoline (DHT) ≥ (–)‐(R)‐2‐(3,4,α‐trihydroxybenzyl)imidazoline (TBI) > (+)‐(S)‐TBI. 4‐Substituted catecholimidazolines were less potent as inducers of DNA synthesis than the corresponding 2‐substituted analogs with an order of potency of (+)‐(R)‐4‐(3,4‐dihydroxybenzyl)imidazoline (DBI) > (+, –)‐(R,S)‐DBI > (–)‐(S)‐DBI. When the β‐hydroxyl moiety of NE is replaced with an amino group as in 3,4‐dihydroxyphenylethylenediamine, the isomers are less active than the β‐hydroxylated analogs and also demonstrate no stereoselectivity for the stimulation of DNA synthesis. These results demonstrate that the hepatic α1‐adrenergic receptor can recognize various isomeric forms of these compounds and that hepatocellular growth can be modulated in a stereoselective manner by phenethylamines and imidazolines. © 1992 Wiley‐Liss, Inc.
An improved synthesis of the enantiomers of bm‐5 and their effects on the central in vivo release of acetylcholine
Authors: Nilsson Björn M. , De Boer Peter , Grol Cor. J. , Hacksell Uli
Published: January 2005

Racemic N‐methyl‐N‐(1‐methyl‐4‐pyrrolidino‐2‐butynyl)acetamide (BM‐5), a putative postsynaptic agonist and presynaptic antagonist at muscarinic receptors, was resolved into the enantiomers by a new method suitable for large scale preparation. The method involves a chemoselective N‐debenzylation as the key step. The enantiomers of BM‐5 were obtained after six separate steps in 25% overall yield. The ability of the enantiomers to release acetylcholine was evaluated in vivo by use of brain dialysis. (R)‐BM‐5 was the more potent enantiomer in this assay. © 1992 Wiley‐Liss, Inc.
Absolute configuration and conformation of the pure opioid antagonist (+)‐2,9α‐dimethyl‐5‐(m‐hydroxyphenyl)morphan
Authors: Froimowitz Mark , Pangborn Walter , Cody Vivian
Published: January 2005

(+)‐2,9α‐Dimethyl‐5‐(m‐hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid K‐receptors is greater than its affinity for opioid κ‐receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X‐ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (–)‐phenylmorphan while the weak atypical agonist (–)‐2,9α‐dimethyl‐5‐(m‐hydroxyphenyl)morphan corresponds to the potent morphine‐like (+)‐phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2‐87 and found to vary from that of the two parent compounds. The atypical properties of the two 9α‐methyl analogs is consistent with an opioid ligand model which proposes that morphine‐like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X‐ray crystallography and computed with the MM2‐87 program. © 1992 Wiley‐Liss, Inc.
Resolution and stability of oxazepam enantiomers
Authors: Yang Shen K. , Lu Xiang‐Lin
Published: January 2005

A solvent mixture containing dioxane, acetonitrile, and hexane was found to be suitable as a mobile phase to resolve oxazepam enantiomers by chiral stationary phase high performance liquid chromatography using covalent Pirkle columns. The resolved oxazepam enantiomers in this solvent mixture had a racemization half‐life greater than 3 days at 23°C. When desiccated at 0°C as dried residue, OX enantiomers were stable for at least 50 days with less than 2% racemization. The conditions which stabilized OX enantiomers significantly facilitated the determination of racemization half‐lives of OX enantiomers in a variety of aqueous and nonaqueous solvents and at different temperatures. © 1992 Wiley‐Liss, Inc.
Enantioselectivity in the induction of peroxisome proliferation by 2‐ethylhexanoic acid
Authors: Macherey Anne Christine , Grégoire Stéphane , Tainturier Gérard , Lhuguenot Jean Claude
Published: January 2005

The stereoselectivity of the peroxisome proliferation potency of 2‐ethylhexanoic acid (2‐EHA), a metabolite of the plasticizer di‐(2‐ethylhexyl) adipate, was investigated in vitro. The enantiomers of 2‐EHA were prepared via the semipreparative HPLC resolution of their diastereoisomeric (+)‐(R)‐1‐phenylethylamine derivatives and the subsequent hydrolytic cleavage. Monolayers of hepatocytes were incubated 3 days with solutions of (—)‐(R), (+)‐(S), and (±)‐2‐EHA. The peroxisome proliferation potency was measured by means of determination of the peroxisomal palmitoyl coenzyme A oxidation. The theoretical induction component due to each enantiomer were calculated from the experimental data considering the enantiomeric purities of the acids. The (+)‐(S)‐enantiomer was found to be the most potent inducer, e.g., the eutomer, while the (—)‐(R) was the distomer. The eudismic ratio was about 1.6 and the racemic mixture exhibited an intermediary potency. These results, obtained in vitro in conditions avoiding confounding factors such as pharmacokinetics, suggest that the peroxisome proliferation induced by 2‐ethylhexanoic acid is a stereoselective phenomenon. © 1992 Wiley‐Liss, Inc.
Discrimination in resolving systems: Ephedrine‐mandelic acid
Authors: Valente Edward J. , Zubkowski Jeffrey , Eggleston Drake S.
Published: January 2005

Resolution of mandelic acid with (—)‐(1R,2S)‐ephedrine in water and ethanol produces intermediate diastereomeric salts with greatly disparate solubilities and melting points. Single crystal X‐ray analysis of the less (L) and more (M) soluble (—)‐ephedrinium mandelates (I, II) shows crystal structures which are isosteric, each crystallizing in the monoclinic system, space group C2. Protonated ephedrines occupy the same relative positions in the L‐ and M‐salts, and mandelates are in the same general locations. Hydrogen bonds link alternating protonated ephedrine nitrogens and mandelate carboxylate oxygens in each salt forming columns of ions. The helical H‐bonded chain winds down the crystallographic 2‐fold screw axis. Additional H‐bonds form between 2‐fold related mandelates in the L‐salt. Mixed crystals, containing both mandelate isomers, (2R)‐ and (2S)‐mandelates, are obtained from the resolving system partly depleted of the L‐salt. A specimen with nearly equal amounts of the mandelates (III) is also isosteric with the commensurate structures. I (294K), L‐salt: a = 18.160(7), b = 6.538(2), c = 13.898(4) Å, β = 92.02(3)°, V = 1649.1(9) Å3; IIa (294K), M‐salt: a = 17.978(11), b = 7.164(4), c = 13.574(6)Å, β = 96.41(4)°, V = 1737.3(16) Å3; IIb (223K), M‐salt: a = 17.805(8), b = 7.115(2), c = 13.50(5) Å, β = 96.89(3)°, V = 1697.9(15) Å3; III (294K), mixed‐salt: a = 18.184(22), b = 6.792(7), c = 13.808(19) Å, β = 93.74(10)°, V = 1701.7(35) Å3. © 1992 Wiley‐Liss, Inc.
Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: Application to carvedilol stereopharmacokinetics
Authors: Stahl Elke , Baumgartner Ulrich , Henke Dorit , Schölmerich Jürgen , Mutschler Ernst , Spahn‐Langguth Hildegard
Published: January 2005

As an experimental model for reduced liver function rats with surgical portacaval shunts (pcs) may be used. Carvedilol, a nonselective β‐adrenoceptor antagonist with vasodilating activity, is extensively metabolised by phase I as well as phase II pathways. In order to study the stereoselective pharmacokinetics of carvedilol in liver disease, pcs and control rats were given rac‐carvedilol intravenously and p.o. The carvedilol enantiomers and their conjugates were assayed in plasma, urine, and bile. Carvedilol was highly bound to plasma proteins; binding was reduced by pcs. In all groups, the plasma concentrations of (R)‐carvedilol exceeded those of (S)‐carvedilol significantly. In comparison to the control group the plasma concentrations of both enantiomers increased after pcs, while the difference between the stereoisomers decreased. The total clearance decreased proportionally to the decrease in liver weight (30%). Both the apparent oral clearance, as well as its stereoselectivity were reduced, by up to 90 and 43%, respectively. The biliary clearance of the parent drug after i.v. dosage increased in rats with pcs due to the reduced hepatic metabolism. © 1993 Wiley‐Liss, Inc.
The effects of (±)‐, (+)‐, and (−)‐atenolol, sotalol, and amosulalol on the rat left atria and portal vein
Authors: Doggrell Sheila A.
Published: January 2005

The effects of (±)‐, (+)‐, and (−)‐atenolol, sotalol, and amosulalol alone on the rat left atria and portal vein and on the respective β1‐ and β2‐adrenoceptor‐mediated responses to isoprenaline have been determined. (±)‐Atenolol at 10−6 M had no effect whereas high concentrations of (+)‐ and (−)‐sotalol, 10−5–10−4 M, and (±)‐, (+)‐, and (−)‐amosulalol depressed the response of the rat left atria to cardiac stimulation which indicates membrane stabilizing activity. None of the drugs tested had any effect alone on the rat portal vein. The order of potency as antagonists was (±)‐amosulalol > (±)‐atenolol > (±)‐sotalol at β1‐adrenoceptors and (±)‐amosulalol > (±)‐sotalol > (±)‐atenolol at β2‐adrenoceptors. (±)‐Atenolol and (±)‐amosulalol are β1‐selective whereas (±)‐sotalol is β2‐selective. For each of the racemic β‐blockers, the β1‐ and β2‐adrenoceptor blocking activity was predominantly due to the (−)‐enantiomer. © 1993 Wiley‐Liss, Inc.
Ciliotoxicity of intranasal formulations: Menthol enantiomers
Authors: Su Xiang‐Yao , Po Alain Li Wan , Millership Jeffrey S.
Published: January 2005

It is shown, using in vitro measurements of beat frequency of rat tracheal cilia, that (+)‐(1S, 2R, 5S)‐menthol and (−)−(1R, 2S, 5R)−menthol have equipotent ciliotoxicities despite the fact that inhalation of menthol vapours from the crystals of the pure enantiomers show clearly that the (−)−(1R, 2S, 5R)‐menthol produces a more potent cooling sensation. Differential scanning calorimetry demonstrates the formation of a racemic compound when equimolar amounts of the two enantiomers are admixed. © 1993 Wiley‐Liss, Inc.
Diastereomeric phosphonate ester adducts of chymotrypsin: 31P‐NMR measurements
Authors: Kovach Ildiko M. , McKay Linda , Velde David Vander
Published: January 2005

Generation of diastereomeric phosphonate ester adducts of chymotrypsin was evidenced for the first time by 31P NMR and spectrophotometric kinetic measurements. 31P NMR signals were recorded for 4‐nitrophenyl 2‐propyl methylphosphonate (IMN) at 32.2 ppm and for its hydrolysis product at 26.3 ppm downfield from phosphoric acid. The inhibition of α‐chymotrypsin at pH > 8.0 by the faster reacting enantiomer of IMN or 2‐propyl methylphosphonochloridate (IMCl), or other phosphonate ester analogs of these compounds, all caused a ∼6.0 ppm downfield shift of the 31P signal to the 39–40 ppm region. IMN, when applied below the stoichiometric amount of chymotrypsin, under the same conditions, generated two signals, at 39.0 and at 37.4 ppm. Scans accumulated in hourly intervals showed the decomposition of both diastereomers, with approximate half‐lives of 12 h at pH 8.0 and 22°C, into a species with a resonance at 35.5 ppm. The most likely reaction to account for the appearance of this new peak is the enzymic dealkylation of the isopropyl group from the covalently bound phosphonate ester. We base this conclusion mostly on the similarity of the upfield shift to the hydrolysis of phosphonate esters. Contrary to experience with phosphate ester adducts of serine proteases, no signal was detected higher than 25.0 ppm downfield from phosphoric acid for several phosphonate ester adducts of chymotrypsin and in no case did the resonance for the adduct shift further downfield in the course of the experiments. © 1993 Wiley‐Liss, Inc.
N‐Acetyl‐D and L‐esters of 5′‐AMP hydrolyze at different rates
Authors: Wickramasinghe Nalinie S. M. D. , Lacey James C.
Published: January 2005

Studies of the properties of aminoacyl derivatives of 5′‐AMP are aimed at understanding the origin of the process of protein synthesis. Aminoacyl (2′,3′) esters of 5′‐AMP can serve as models of the 3′‐terminus of aminoacyl tRNA. We report here on the relative rates of hydrolysis of AC‐D‐ and L‐Phe AMP esters as a function of pH. At all pHs above 3, the rate constant of hydrolysis of the AC‐L‐Phe ester is 1.7 to 2.1 times that of AC‐D‐Phe ester. The D‐isomer seems partially protected from hydrolysis by a stronger association with the adenine ring of the 5′‐AMP. © 1993 Wiley‐Liss, Inc.
Direct high‐performance liquid chromatography (HPLC) separation of etodolac enantiomers using chiral stationary phases
Authors: Caccamese Salvatore
Published: January 2005

The enantiomers of the antiinflammatory drug Etodolac were separated without derivatization on Chiralcel OD and Pirkle (R)‐DNBPG columns. Enantiomeric purity can be determined in less than 10 min. Optimization of separation was evaluated using various concentrations of 2‐propanol (doped with TFA) in hexane as the mobile phase. © 1993 Wiley‐Liss, Inc.
Use of chiral β‐lactones for the synthesis of chiral LC phases
Authors: Lohmann Dieter , Däppen Richard
Published: January 2005

Chiral β‐lactones offer an easy and economic approach to novel chiral R‐ or S‐configurated LC phases. The preferred method for their preparation is based on conventional ready‐to‐use aminopropyl‐functionalized silicas, e.g., aminopropyl HPLC columns. The new stationary phases can be used for analytical and preparative separations and are particularly suitable for the resolution of rotatory and heterocyclic stereoisomers. Applications in the LC, SFC, and TLC mode are possible, including the use of β‐lactone‐based mobile phase additives in a “push–pull” combination. A large variety of organic solvents can be used as eluents. © 1993 Wiley‐Liss, Inc.
Resolution of 7‐chloro‐4(4′‐diethylamino‐1′methylbutyl)aminoquinoline (chloroquine) into its enantiomers
Authors: Craiga J. Cymerman , Ansari Aslam M.
Published: January 2005

Evidence is accumulating that 7‐chloro‐4‐[4‐diethylamino‐1‐methylbutyl] amino quinoline (chloroquine) displays considerable stereoselectivity in its metabolism, pharmacokinetics, macromolecular interactions, and biological activity. The availability of the enantiomers has been hampered by the failure of direct methods of resolution. We now describe a successful resolution in which the atropisomeric 1,1′‐binaphthyl‐2,2′‐diyl hydrogen phosphate is used in a 1:1 ratio to form stereoselectively the 2:1 diastereomeric salt from one enantiomer of the base, leaving the other in solution. By this means both enantiomers of chloroquine may be readily isolated. © 1993 Wiley‐Liss, Inc.
Enzymatic and chromatographic chiral discrimination of racemic (thio)glycidyl esters: Part II. Optical resolution of racemic (thio)glycidyl esters on modified cellulose chiral stationary phases
Authors: Wagner Jürgen , Offhauss Ulrike , Martin Arnim A.
Published: January 2005

Chiral chromatography on cellulose tris(3,5‐dimethylphenyl carbamate) (Chiralcel OD) and cellulose tribenzoate (Chiralcel OB) coated stationary phases has been successfully used for the optical resolution of rac‐(thio)glycidyl esters (acetate, propionate, butyrate). Glycidyl esters could sufficiently be resolved on the OD column whereas for the thio analogues baseline resolution is obtained on CSP OB using hexane/2‐propanol mobile phases. The separation factor (α) and resolution (RS) depend on column temperature, eluent composition, and flow rate, respectively. Best results were obtained for the butyrates and at low temperatures in general. © 1993 Wiley‐Liss, Inc.
Chiral recognition by 1H‐NMR, EPR, and ENDOR spectroscopy
Authors: Stegmann Hartmut B. , Mäurer Manfred , Höfler Ulrike , Scheffler Klaus , Hewgill Frank
Published: January 2005

Chiral recognition with magnetic methods requires the formation of diastereomers. Due to the variety of appropriate reactions, hydrogen bond formation, esterification, and acetalization as well as host–guest interactions were chosen for basic investigations. The results obtained indicate that in the case of diamagnetic compounds the chemical shifts and for paramagnetic compounds the β‐proton coupling constants are the most useful parameters. By combination of both pieces of information, assignment of the absolute configuration was achieved. © 1993 Wiley‐Liss, Inc.
Resolution of rac‐ketoprofen esters by enzymatic reactions in organic media
Authors: Palomer Albert , Cabré Marta , Ginesta Joan , Mauleón David , Carganico Germano
Published: January 2005

Enzyme‐catalyzed reactions in organic media of rac‐ketoprofen esters with different nucleophiles such as alcohols, amines, and water have been studied. Among the parameters optimized are the enzyme, the activated substrate, and the solvent. With the enzymes used in this study the preferred substrate was the trifluoroethyl ester of rac‐ketoprofen (rac‐2), whose (R)‐enantiomer reacted preferentially. The enzyme of choice was the lipase M‐AP‐10 from Mucor miehei and best results were obtained with diisopropyl ether as solvent. Three different methods have been scaled‐up for the resolution of 75–150 g of substrate: transesterification with 1‐butanol (90% yield of (S)‐ketoprofen, 88% ee), transesterification with 2‐(2‐pyridyl)ethanol (94% yield, 92% ee), and hydrolysis in wet organic solvent (93% yield, 97% ee). Despite the comparable chemical and optical yields obtained with these three methods, the use of 2‐(2‐pyridyl)ethanol and the hydrolysis allowed a much easier work‐up and isolation of the desired (+)‐(S)‐ketoprofen. © 1993 Wiley‐Liss, Inc.
Preparative and analytical separation of the zopiclone enantiomers and determination of their affinity to the benzodiazepine receptor binding site
Authors: Blaschke Gottfried , Hempel Georg , Müller Walter E.
Published: January 2005

We report the preparative separation of rac‐zopiclone using malic acid as the resolving agent. Furthermore, two different methods for the analytical determination of zopiclone enantiomers by HPLC on chiral stationary phases are described. The benzodiazepine receptor binding of the isolated enantiomers was investigated. Half‐maximal inhibitory concentrations of (+)‐ and (−)‐zopiclone were 21 or 1,130 nmol/liter, respectively, indicating a more than 50 times higher affinity of the (+)‐enantiomer toward the receptor. © 1993 Wiley‐Liss, Inc.
Stereospecific determination of the in vitro dissolution of modified release formulations of (±)‐verapamil
Authors: Carr Robert A. , Pasutto Franco M. , Longstreth James A. , Foster Robert T.
Published: January 2005

The determination of the in vitro dissolution profiles of three different modified‐release formulations of (±)‐verapamil were determined and compared to a reference (Calan SR). The determination of (±)‐verapamil utilized a microwave‐facilitated derivatization reaction with an enantiomerically pure reagent followed by measurement of drug by reversed‐phase high‐performance liquid chromatography (HPLC). The dissolution profile of each of the four modified‐release formulations was followed for the first hour in simulated gastric fluid (pH 1.2) and then in simulated intestinal fluid (pH 7.5) for up to a total of 12 h. The resulting dissolution profiles of each modified‐release formulation suggested that only one of the three test formulations had a similar dissolution to the Calan SR reference. Interestingly, the (S:R)‐enantiomer ratios of two of the test products were significantly different from unity, and the third test product was also significantly different from unity if 4 out of 5 outliers were omitted. It is suggested that dissolution testing of modified‐release formulations containing chiral active ingredients must be stereospecific in order to discern whether a drug‐excipient interaction occurs. Additionally, it may be suggested that dissolution techniques relying more upon diffusion of medium through the tablet matrix, rather than erosion of the tablet, may accentuate enantiomeric differences in release rates. © 1993 Wiley‐Liss, Inc.
Chromatographic resolution of chiral intermediates in β‐adrenergic blocker synthesis on chiral stationary phases
Authors: Ader Ulrich , Muschalek Volker , Schneider Manfred P.
Published: January 2005

The enantiomeric purities of optically active intermediates for β‐adrenergic blocking agents prepared via enzyme‐assisted processes can be determined rapidly and with high accuracy using HPLC on commercially available columns with chiral supports [Chiralcel OD, OB; Chiralpak OT(+)]. The dependence of the resolution parameters on the substitution pattern of both hydroxy compounds and their esters is reported. © 1993 Wiley‐Liss, Inc.
Use of isotopically chiral [4′‐13C]famciclovir and 13C NMR to identify the chiral monoacetylated intermediates in the conversion of famciclovir to penciclovir by human intestinal wall extract
Authors: Hodge R. Anthony Vere , Darlison Sarah J. , Readshaw Simon A.
Published: January 2005

Famciclovir is the oral form of the potent antiherpesvirus agent, penciclovir. Hydrolysis of one of the acetyl ester groups of famciclovir creates a chiral centre leading to the possible formation of (R)‐ and (S)‐enantiomers. During its conversion to penciclovir, famciclovir forms two chiral metabolites, namely monoacetyl‐6‐deoxy‐penciclovir and monoacetyl‐penciclovir. The absolute configuration and stereospecificity of the monoacetyl metabolites of famciclovir, produced in human intestinal wall extract, were determined using isotopically chiral famciclovir and 13C NMR spectroscopy of the isolated metabolites. 13C NMR showed that the esterase(s), in human intestinal wall extract, hydrolysed the acetyl group preferentially from the pro‐(S)‐acetoxymethyl group of famciclovir. The specificity of esterase action in forming monoacetyl‐6‐deoxy‐penciclovir and monoacetyl‐penciclovir was about 77 and 72%, respectively. © 1993 Wiley‐Liss, Inc.
Diagnosis and monitoring of disseminated candidiasis based on serum/urine D/L‐arabinitol ratios
Authors: Roboz John
Published: January 2005

Disseminated candidiasis, a devastating disease with high morbidity and mortality in immunosuppressed patients, is difficult to diagnose because of the protean nature of symptoms and the lack of rapid and reliable laboratory diagnostic procedures. The subject of this review is the status of gas chromatographic–mass spectrometric techniques for the determination of D‐arabitinol, a unique metabolite of pathogenic Candida species, in serum and urine. The enantiomers are separated by chiral chromatography followed by specific and sensitive detection using chemical ionization and selected ion monitoring. Using D/L‐arabinitol ratios, instead of individual concentrations, eliminates the need for knowing the volume of samples and for calibration curves. A new filter paper technique requires only an unmeasured drop of whole blood (venous or finger/heel puncture) or urine; paper spots are mailable. Parallel determinations of D/L‐arabinitol ratios in serum and urine in normal subjects and cancer patients with both normal and increased D/L‐arabitinol ratios revealed constant (1.2–1.3 range) ratios of serum D/L‐arabitinol/urine D/L‐arabinitol for all populations studied. Analyzing two body fluids taken at the same time increases reliability by reducing false positives. © 1994 Wiley‐Liss, Inc.
(1′R,2′S,5′R)‐Menthyl‐(5R)‐acetoxy‐1,3‐oxathiolan‐(2R)‐carboxylate: Synthesis and isomeric purity determination by HPLC
Authors: Siddiqui M. Arshad , Jin Haolun , Evans Colleen A. , Dimarco Marika P. , Tse H. L. Allan , Mansour Tarek S.
Published: January 2005

Chemoselective reduction of one isomer of the 1‐menthylester of 1,3‐oxathiolan‐5‐one‐2‐carboxylic acid produces a mixture of four lactol diastereomers from which the title compound was isolated after acylation. The isomeric purity and absolute stereochemistry were determined by spectroscopic methods, chiral HPLC techniques, and conversion to (−)‐2′‐deoxy‐3′‐thiacytidine (Lamivudine, 3TCTM). © 1994 Wiley‐Liss, Inc.
Single dose pharmacokinetics of (S)‐atenolol administered orally as a single enantiomer formulation and as a racemic mixture (tenormin™)
Authors: Clementi William A. , Garvey Thomas Q. , Clifton G. Dennis , McCoy Randall A. , Brandt Steven , Schwartz Sheldon
Published: January 2005

The purpose of this study was to describe the pharmacokinetics of and heart rate and blood pressure responses to (S)‐atenolol (SATN) and (R)‐atenolol (RATN) after oral administration of (S)‐atenolol and (R,S)‐atenolol (Tenormin™) in man. Eight male subjects were given single oral doses of 50 mg of SATN as a single enantiomer formulation (SEF) and 100 mg of Tenormin™ (TMN) using a randomized, double‐blind, 2‐period, complete crossover study design. Subjects performed exercise tolerance tests (Bruce Protocol) before and 2, 4, 6, 8, 12, and 24 h after drug administration. Plasma samples were obtained 2 min before and 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after dosing. Urine was collected for the first 48 h after dosing. Plasma and urine samples were analyzed for SATN and RATN by an enantioselective HPLC method. SEF and Tenormin™ attenuated exercise‐induced increases in heart rate and systolic blood pressure. Mean changes in exercise heart rates 4 h after dosing were −38 ± 3 bpm and −37 ± 3 bpm for SEF and TMN, respectively, P = 0.792. Mean changes in exercise systolic blood pressure were −42 ± 12 mm Hg and −55 ± 14 mm Hg for SEF and TMN, respectively, P = 0.484. Mean area under the plasma level time curve (AUC0–24) and mean Cmax for SATN for SEF were significantly lower than for SATN after TMN. Mean SATN AUCs0–24 were 1867 ± 261 and 2543 ± 223 ng · h/ml (P = 0.005) and mean Cmaxs were 225 ± 29 and 333 ± 30 ng/ml, for SEF and TMN, respectively (P = 0.011). Mean Tmax for SATN occurred significantly earlier after SEF than after TMN (2.9 ± 0.3 and 3.3 ± 0.3 h, P = 0.028). The amount of SATN excreted in urine was significantly lower after SEF than after TMN (18.7 ± 2.7 and 24.2 ± 2.0 mg, P = 0.017). AUC, Cmax, and amount excreted in urine (Au) were significantly higher for RATN than SATN after TMN. Mean AUCs, Cmaxs, and Aus for RATN compared to SATN were 2806 ± 239 vs 2543 ± 223 ng ± h/ml (P < 0.0001), 360 ± 31 vs 333 ± 30 ng/ml (P < 0.0001), and 25 ± 2.1 vs 24 ± 2 mg (P = 0.004), respectively. SEF and TMN are equieffective in attenuating exercise‐induced increases in heart rate and systolic blood pressure. The SEF has lower bioavailability compared to TMN and RATN plasma levels are higher than SATN after TMN administration. © 1994 Wiley‐Liss, Inc.
Optical resolution by preferential crystallization of 4‐methylpiperidinium hydrogen (RS)‐phenylsuccinate
Authors: Shiraiwa Tadashi , Ohki Yasunobu , Sado Yujin , Miyazaki Hideya , Kurokawa Hidemoto
Published: January 2005

Gibbs energy of racemate formation, binary melting point diagram, and ternary solubility diagram suggested that 4‐piperidinium hydrogen (RS)‐phenylsuccinate [(RS)‐4‐MP salt] exists in a conglomerate. Appropriate conditions were explored on the basis of free energy of critical nucleation in a supersaturated solution to resolve efficiently (RS)‐4‐MP salt by preferential crystallization. Successive preferential crystallization of (RS)‐4‐MP salt in ethanol at 20°C gave (R)‐ and (S)‐4‐MP salts of 90–94% optical purities. Optically pure (R)‐ and (S)‐phenylsuccinic acids were obtained by recrystallization of the (R)‐ and (S)‐4‐MP salts, followed by treatment of the salts purified with hydrochloric acid. © 1994 Wiley‐Liss, Inc.
Investigation of enantioselective ligand–protein binding and displacement interactions using capillary electrophoresis
Authors: Lloyd David K. , Li Song , Ryan Patricia
Published: January 2005

When a protein such as human serum albumin is added to the separation buffer in capillary electrophoresis, the mobility of solutes which bind to that protein may be altered. The change in mobility of the solute is a function both of the strength of the binding interaction, and the difference in mobility between the free solute and protein additive. By adding other ligands which themselves bind to the protein, the strength of the solute–protein binding may be modified, leading to a measurable change in the mobility of the solute. These effects are particularly striking for chiral compounds, where enantioselectivity may be completely lost on addition of a competitive ligand. Capillary electrophoresis with human serum ablumin as a buffer additive was used to separate the enantiomers of benzoin and three phenothiazine derivatives. A comparison of the binding of (S)‐benzoin to human serum albumin as determined by capillary electrophoresis and by ultrafiltration was made. A variety of other ligands were then added to the buffer along with the protein, and the effects on mobility and enantioselectivity were studied. The displacers included (R)‐ and (S)‐oxazepam hemisuccinate, (R)‐ and (S)‐warfarin, nitrazepam, phenylbutazone, and octanoic acid. From the results obtained, it seems that capillary electrophoresis may be a useful, rapid method to screen for drug–drug interactions. There are some advantages of using this technique to study protein–ligand interactions: Only very small amounts of ligand are needed (useful when dealing with metabolites); for chiral compounds, if protein binding is stereoselective, then the method is also stereoselective, so single enantiomers are not needed; finally, measurements are obtained in solution, without the need for immobilization of the protein. A disadvantage is that the ligand and protein must have significantly different electrophoretic mobilities. © 1994 Wiley‐Liss, Inc.
Assignment of absolute configuration and optical purity determination of (R)‐ and (S)‐econazole nitrate by enantioselective HPLC: Method development and application
Authors: Lämmerhofer Michael , Lindner Wolfgang
Published: January 2005

A method is described for the synthesis and optical purity determination of (−)‐(R)‐ and (+)‐(S)‐econazole via the optically pure intermediates, (R)‐ and (S)‐imidazolylethanol, which are available by chromatographic resolution or by fractional crystallization of diastereomeric O,O′‐disubstituted (R*;R*)‐ or (S*;S*)‐tartaric acid monoesters of the parent imidazolylethanol racemate. Furthermore, this method allows the chromatographic assignment of the absolute configuration of the chiral center of the imidazolylethanol enantiomers and consequently of econazole enantiomers. In addition, a direct liquid chromatographic enantioseparation method for the determination of the optical purity of (R)‐ and (S)‐econazole and other chiral imidazoles on a protein type CSP (OVM) is described and applied to confirm chromatographically the absolute configuration evaluations. © 1994 Wiley‐Liss, Inc.
Effect of cytochrome P‐450 1A induction on enantioselective metabolism and pharmacokinetics of an aryltrifluoromethyl sulfide in the rat
Authors: Benoît Etienne , Buronfosse Thierry , Delatour Paul
Published: January 2005

The pharmacokinetics of the antiparasitic drug toltrazuril (1‐methyl‐3‐[3‐methyl‐4‐[4‐[trifluoromethyl]thio]phenoxy]phenyl‐1,3,5‐ triazine‐2,4,6(1H,3H,5H)‐trione) were studied in the rat following pretreatment with 3‐methylcholanthrene, an inducer of rat liver cytochrome P‐450 1A. The induction markedly modified the pharmacokinetics of the compound, leading to a decrease in the AUC value for toltrazuril sulfoxide. The results were explained on the basis of previous results from our laboratory relating to the product enantioselectivity of the formation of the sulfoxide and the substrate enantioselectivity of the subsequent formation of the sulfone. © 1994 Wiley‐Liss, Inc.
Influence of endotoxin on the stereoselective pharmacokinetics of oxprenolol, propranolol, and verapamil in the rat
Authors: Laethem Martine E. , Belpaire Frans M. , Wijnant Pascal , Rosseel Marie‐Thérèse , Bogaert Marc G.
Published: January 2005

The influence of endotoxin‐induced inflammation on the enantioselective pharmacokinetics of propranolol, oxprenolol, and verapamil, which bind to α1‐acid glycoprotein, was studied in the rat. The racemic mixtures were given orally. In the control animals, for propranolol and oxprenolol, the plasma concentrations of the (R)‐enantiomer were higher than those of the (S)‐enantiomer, while for verapamil the reverse was true. Protein binding and intrinsic clearance are the main factors responsible for this enantioselectivity. After endotoxin treatment, for the three drugs tested the plasma concentrations and the plasma binding of both enantiomers were significantly increased. This effect was more pronounced for (R)‐propranolol, (R)‐oxprenolol, and (S)‐verapamil than for their respective antipodes. The enantioselective effect of endotoxin on the plasma concentrations of the drugs studied seems mainly due to the enantioselective increase in binding to α1‐acid glycoprotein. © 1994 Wiley‐Liss, Inc.
The chemical and thermal stability of the acetamido group of (R)‐ and (S)‐atenolol: Synthetic and chromatographic studies
Authors: Kleidernigg Oliver P. , Maier Norbert M. , Uray Georg , Lindner Wolfgang
Published: January 2005

The chemical stability of the acetamido moiety of the β‐blocker atenolol toward possible dehydration causing a nitrile formation during an acid‐catalyzed chiral derivatization procedure with O,O′‐(R,R)‐diacylated tartaric acid anhydrides was elucidated. All the necessary reference compounds including the oxazolidine‐2‐one derivatives of the respective aminopropanols were synthesized, their structures confirmed by various spectroscopic methods, and chromatographically compared using HPLC and GC‐MS. In the course of this work it was shown that the acetamido moiety of atenolol is quite stable toward dehydrating agents but shows a significant thermolability, e.g., in the injection system of a GC, which leads to the dehydrated form of atenolol namely, “nitriloatenolol.” © 1994 Wiley‐Liss, Inc.
Effects of catechol ring fluorination on cardiovascular and renal activities of fenoldopam enantiomers
Authors: Kinter Lewis B. , Mann William A. , Weinstock Joseph , Ruffolo Robert R.
Published: January 2005

SK&F 87516 is a potent DA1 receptor agonist with demonstrated renal vasodilator activity. SK&F 87516 is the 6‐fluoro analog of another DA1 agonist/renal vasodilator agent, fenoldopam. SK&F 87516 is a racemic mixture of two enantiomers, SK&F(R)‐87516 and SK&F(S)‐87516, and like fenoldopam, the (R)‐enantiomer is responsible for the biological activities of the racemate. SK&F(R)‐87516 is diuretic in spontaneously hypertensive rats and in dogs, whereas its enantiomer, SK&F(S)‐87516 is inactive. SK&F(R)‐87516 increases glomerular filtration rate, an effect which may account, in part, for its diuretic activity. Unlike fenoldopam, SK&F(R)‐87516 is not associated with acute hypotensive activity, tachycardia, or stimulation of the renin‐angiotensin‐aldosterone system. The activity differences between SK&F(R)‐87516 and fenoldopam are not related to differences in DA1 agonist potency. The activity differences may be due to the differing effects of fluorine and chlorine on the electron distribution in the catechol ring, resulting in an enhanced effect of SK&F(R)‐87516 at α2‐adrenoceptors. © 1994 Wiley‐Liss, Inc.
Chiral pharmacokinetics of rac‐flurbiprofen and pharmacodynamics of anabolic bone response in the normal rat
Authors: Wechter William J. , Bigornia Annette E. , Murray E. David , Jee Webster S. S.
Published: January 2005

The route of administration of the NSAID, flurbiprofen (sq vs. po) resulted in positive and negative results respectively with regard to enhanced cancellous and cortical bone accumulation in the immature rat. This pharmacokinetic study was an effort to understand the pharmacodynamic difference between the two routes of administration observed when the same dose range of drug, given as single daily doses, had been employed in both studies. Conventional chiral pharmacokinetics were evaluated in young rats. A significant difference was observed in the Tmax of the active (S)‐enantiomer by both administration routes (sq 4 h and po 1 h). The bioavailability, as evaluated by AUCs favored the sq route as expected. The plasma concentrations over 18 h, at steady state, for one po dose group (0.5 mg/kg/day) fell well within the therapeutic window described by the 0.1 and 0.5 mg/kg sq doses which had demonstrated anabolic bone activity. Oral dosing had exhibited no significant bone activity. We conclude that the pharmacodynamic difference between routes of administration cannot be simply explained on a pahrmacokinetic basis. Consequently, experiments detailing the pharmacodynamics and pharmacokinetics of single and multiple dose administration of aryl‐propionic acids in normal and osteopenic states need further pharmacologic study. © 1994 Wiley‐Liss, Inc.