bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the macrocyclic antibiotic vancomycin as a chiral selector for capillary electrophoresis
Authors: Armstrong Daniel W. , Rundlett Kimber L. , Chen Jing‐Ran
Published: January 2005

Vancomycin is one of a family of related macrocyclic glycopeptide antibiotics that were discovered by scientists at the Eli Lilly Company in the 1950s. It has been used to treat severe staphylococcal infections, particularly when bacterial resistance to other antibiotics has developed. Vancomycin is a naturally occurring chiral compound and has a number of stereogenic centers. Furthermore, it contains a variety of functionalities that are known to be useful for enantioselective interactions (e.g., hydrogen bonding groups, hydrophobic pockets, aromatic groups, amide linkages, etc.). The physicochemical properties of vancomycin, including its stability in solution, are discussed as they pertain to capillary electrophoresis. Over 100 racemates were resolved including many nonsteroidal antiinflammatory drugs, antineoplastic compounds and N‐derivatized amino acids. Many of these compounds had very high resolution factors. Optimization and the effect of different experimental parameters on the enantioselective separations are discussed. © 1994 Wiley‐Liss, Inc.
Enantioselective syntheses and calcium channel modulating effects of (+)‐ and (−)‐3‐isopropyl 5‐(4‐methylphenethyl) 1,4‐dihydro‐2,6‐dimethyl‐4‐(2‐pyridyl)‐3,5‐pyridinedicarboxylates
Authors: Iqbal Nadeem , Vo Dean , McEwen Carol‐Anne , Wolowyk Michael W. , Knaus Edward E.
Published: January 2005

The (+)‐ and (−)‐enantiomers of 3‐isopropyl 5‐(4‐methylphenethyl) 1,4‐dihydro‐2,6‐dimethyl‐4‐(2‐pyridyl)‐3,5‐pyridinedicarboxylate were synthesized using an efficient highly enantioselective (ee ≥ 96%) variant of the Hantzsch dihydropyridine synthesis. The key step in this procedure involved the asymmetric Michael addition of a metalated chiral aminocrotonate, derived from D‐valine or L‐valine, respectively, to the Knoevenagel acceptor (Z)‐2‐isopropoxycarbonyl‐1‐(2‐pyridyl)‐but‐1‐en‐3‐one. Both enantiomers exhibited a dual cardioselective partial calcium channel agonist (positive inotropic)/smooth muscle selective calcium channel antagonist effect. The relative in vitro smooth muscle calcium channel antagonist activities of the (−):(+) enantiomers was 26:1. In contrast, the (+)‐enantiomer exhibited a greater in vitro positive inotropic effect on guinea pig left atrium where the contractile force was maximally increased by 14.8% at a concentration of 1.63 × 10−8 M. © 1994 Wiley‐Liss, Inc.
Chiral copper(I)—thiolate clusters in metallothionein and glutathione
Authors: Presta Anthony , Stillman Martin J.
Published: January 2005

Metallothionein (MT) is a ubiquitous mammalian protein comprising 61 or 62 nonaromatic amino acids of which 20 are cysteine residues. The high sulfhydryl content imparts to this protein a unique and remarkable ability to bind multiple metal ions in structurally significant metal–thiolate clusters. MT can bind seven divalent metal ions per protein molecule in two domains with exclusive tetrahedral metal coordination. The domain stoichiometries for the M7S20 structure are M4(Scys)11 (α domain) and M3(Scys)9 (β domain). Up to 12 Cu(I) ions can displace the 7 Zn2+ ions bound per molecule in Zn7–MT. The incoming Cu(I) ions adopt a trigonal planar geometry with domain stoichiometries for the Cu12S20 structure of Cu6(Scys)11 and Cu6(Scys)9 for the α and β domains, respectively. The circular dichroism (CD) spectra recorded as Cu+ is added to Zn7–MT to form Cu12–MT directly report structural changes that take place in the metal binding region. The spectrum arises under charge transfer transitions between the cysteine S and the Cu(I); because the Cu(I)–thiolate cluster units are located within the chiral binding site, intensities in the CD spectrum are directly related to changes in the binding site. The CD technique clearly indicates stoichiometries of several Cu(I)–MT species. Model Cu(I)–thiolate complexes, using the tripeptide glutathione as the sulfhydryl source, were examined by CD spectroscopy to obtain transition energies and the Cu(I)–thiolate coordination geometries which correspond to these bands. Possible structures for the Cu(I)–thiolate clusters in the α and β domains of Cu12–MT are proposed. © 1994 Wiley‐Liss, Inc.
Pharmacokinetics of ketoprofen enantiomers in monkeys following single and multiple oral administration
Authors: Mauleon David , Mis Ricard , Ginesta Joan , Ortega Elvira , Vilageliu Jaime , Basi Nuria , Carganico Germano
Published: January 2005

Pharmacokinetic studies are reported after single oral administration of 3 mg/kg of stereochemically pure (S)‐ketoprofen [(S)‐KP] and (R)‐ketoprofen [(R)‐KP] to three male Cynomolgus monkeys and after repeated administration for 6 months of 3, 15 and 75 mg/kg/day of (S)‐KP to both male and female monkeys. A high‐performance liquid chromatographic (HPLC) analysis was performed without derivatization of the samples, using a chiral column. The pharmacokinetic parameters for (S)‐KP after administration of (S)‐KP and for (R)‐KP after administration of (R)‐KP were, respectively, elimination half‐life 2.32 ± 0.36 and 1.64 ± 0.40 h; oral clearance 3.50 ± 0.66 and 7.50 ± 3.20 ml/min/kg; apparent volume of distribution 0.74 ± 0.24 and 1.16 ± 0.76 liter/kg; mean residence time 1.79 ± 0.77 and 1.41 ± 0.65 h; area under the concentration/time curve 14.16 ± 2.93 and 7.31 ± 2.98 μg·h/ml. Forty‐nine percent unidirectional bioinversion of (R)‐KP to (S)‐KP was observed in this species and the pharmacokinetic parameters for the (S)‐KP resulting from this inversion were also calculated. In the study of 6‐month repeated administration of (S)‐KP, linear pharmacokinetic behavior and no evidence of drug accumulation were observed at the three dose levels. © 1994 Wiley‐Liss, Inc.
Chiral lumazines: Preparation, properties, enantiomeric separation
Authors: Klein Roger , Tatischeff Irene , Tham Gisele , Mano Nariyasu
Published: January 2005

Optically active lumazines (biolumazine, dictyolumazine, monalumazine, and neolumazine) are prepared from the corresponding pterins by enzymatic reaction, using pterin deaminase excreted by Dictyostelium discoideum. The fluorescence properties, circular dichroism spectra, and chromatographic behavior of these lumazines are studied. D‐ and L‐enantiomers of biolumazine, dictyolumazine, and monalumazine are separated using a chiral flavoprotein column. This column also separates the enantiomeric pterins of the threo form: monapterin and dictyopterin. However, the column does not separate the enantiomeric pterins of the erythro form: neopterin and biopterin. By coupling a reverse‐phase column to the flavoprotein column, the separation of pterins and lumazines in function of their hydrophobicity, as well as the separation of the diastereomers, is achieved. This coupled achiral/chiral high‐performance liquid chromatography method enables determination of the stereoconfiguration of natural lumazines by comparison with optically pure compounds. A lumazine derivative, present in the extracellular medium of Dictyostelium discoideum, is identified as D‐dictyolumazine, i.e., 6‐(D‐threo‐1,2‐dihydroxypropyl)‐lumazine. © 1994 Wiley‐Liss, Inc.
Marked enantioselective protein binding in humans of ketorolac in vitro: Elucidation of enantiomer unbound fractions following facile synthesis and direct chiral hplc resolution of tritium‐labelled ketorolac
Authors: Hayball Peter J. , Holman Jeffrey W. , Nation Roger L. , Massy‐Westropp Ralph A. , Hamon David P.G.
Published: January 2005

The protein binding of the enantiomers of the nonopiate analgesic, ketorolac, was investigated in vitro using human plasma and solutions of human serum albumin (HSA) at physiological pH and temperature. In order to detect the very low levels of unbound enantiomers in protein solutions, tritium‐labelled rac‐ketorolac was synthesised by regiospecific isotopic exchange of the parent drug with tritiated water as the isotope donor. Radio‐chemical purification of this compound by reversed‐phase HPLC followed by direct resolution using a chiral α1‐acid glycoprotein (Chiral‐AGP) HPLC column afforded labelled enantiomers of high specific activity. The in vitro use of (R)‐ and (S)‐[3H4]ketorolac enabled reproducible radiometric detection of enantiomers in protein solution ultrafiltrate. The unbound fractions of (R)‐ and (S)‐ketorolac [fu(R) and fu(S), respectively] were determined when drug was added to various plasma or albumin solutions as either the separate enantiomers or as the racemate. Over an enantiomeric plasma concentration range of 2.0—15.0 μg/ml, fu(S) (mean range: 1.572—1.795%) was more than 2‐fold greater (P < 0.001) than fu(R) (mean range: 0.565—0.674%). Both fu(R) and fu(S) were constant over this concentration range, and each was unaffected by the presence of the corresponding antipode (P > 0.05). At a concentration of 2.0 μg/ml in 40.0 g/liter fatty acid‐free HSA, fu(R) and fu(S) were approximately 0.5 and 1.1%, respectively, and both values declined with increasing concentrations of the long chain fatty acid, oleic acid. We have previously shown that the pharmacokinetics of ketorolac in humans are markedly enantioselective and suggest in this report that these differences are largely the result of substantial differences in the protein binding of ketorolac enantiomers. These findings stress the importance of monitoring the unbound concentrations of the enantiomers of chiral drugs if correct interpretations are to be made of enantioselective pharmacokinetic data. © 1994 Wiley‐Liss, Inc.
Enantioselectivity suggests a cytosolic origin for a commercial pig liver esterase preparation
Authors: Yang Shen K. , Chen Shu‐ju , Huang Jin‐ding
Published: January 2005

A widely utilized pig liver esterase preparation has been found to be derived essentially exclusively from the cytosolic fraction of pig livers. Esterases in cytosol and microsomes prepared from a fresh pig liver hydrolyzed the S‐ and R‐enantiomers of racemic oxazepam 3‐acetate (rac‐OXA) with specific activity ratios of approximately 2.3:1 and 1:62, respectively. Product formations were analyzed by chiral stationary phase high‐performance liquid chromatography. The commercial pig liver esterase preparation showed greater activity toward S‐OXA than did the esterases in the cytosolic fraction prepared from fresh pig liver. The results established that (i) esterases contained in microsomes and cytosol of pig liver have opposite enantioselectivity in the hydrolysis of rac‐OXA and (ii) the commercial pig liver esterase preparation has a cytosolic origin. © 1995 Wiley‐Liss, Inc.
Stereoselective binding of benzodiazepines and related compounds on calmodulin‐sepharose
Authors: Fitos Ilona , Visy Jüalia , Kardos Julianna , Simonyi Miklóas
Published: January 2005

A method has been presented to evaluate the Ca2+‐dependent binding affinity of ligands to calmodulin (CaM) from their chromatographic retentions obtained on a CaM‐Sepharose column. Enantiomers of benzodiazepines and related compounds could be separated. Among chiral calcium antagonists, verapamil showed stereoselectivity of binding. © 1995 Wiley‐Liss, Inc.
Chiral enamines derived from 2‐(2′‐pyrido)acetophenone and 2‐(2′‐quinolino)acetophenone as ligands in copper(I) catalyzed enantioselective cyclopropanations
Authors: Kirin srećko I. , Vinković Vladimir , Šunjić Vitomir
Published: January 2005

Optically active enamines of 2‐(2′‐pyrido)acetophenone or 2‐(2′‐quinolino)acetophenone with (R)‐1‐phenylethylamine, (R)‐1‐(1‐naphthyl)ethylamine, (R)‐cyclohexylethylamine, and (R)‐phenylglycinol were prepared and their copper(I) complexes used in the enantioselective cyclopropanation of styrene with ethyl‐ and menthyldiazoacetate. Enantioselectivities of up to 42% enantiomeric excess were obtained for cis/trans 2‐phenylcyclopropan‐1‐carboxylic acid ethyl esters, as determined by gas‐liquid chromatography (GLC) on chiral chromatographic columns. © 1995 Wiley‐Liss, Inc.
Asymmetric hydroformylation of mono‐ and sesquiterpenes
Authors: Kollár László , Bóadi Gábor
Published: January 2005

The hydroformylation of (+)‐(R)‐limonene (1), (+)‐(1R)‐isolimonene (2), camphene (3), and (+)‐β‐cedrene (4) resulted in the regiospecific formation of the corresponding linear aldehyde in the presence of homogeneous platinum and, in some cases, rhodium catalysts. The epimeric composition could be influenced slightly by optically active catalysts formed with chiral bidentate phosphines. The relative configurations of newly formed stereogenic centers were analyzed by1H and13C NMR. The primarily formed aldehydes of (+)‐8(15)‐cedren‐9‐ol (5) and γ‐gurjunene (6) underwent cyclization, giving a mixture of epimers of tetracyclic terpenes. Despite the moderate diastereoselection, the products are of practical importance due to their highly regioselective formation. © 1995 Wiley‐Liss, Inc.
Direct separation of albuterol enantiomers in biological fluids and pharmaceutical formulations using α1‐acid glycoprotein and pirkle urea type columns
Authors: Aboul‐enein Hassan Y. , Serignese Vince
Published: January 2005

A direct, isocratic, and simple chromatographic method is described for the resolution of racemic albuterol using the α1‐acid glycoprotein chiral stationary phase (AGP‐CSP) under reverse phase conditions. The effect of various organic modifiers, temperature, and phosphate buffer ionic strength on the separation factor (α) and stereochemical resolution factor (Rs) has been studied. The enantiomeric separation of albuterol was also achieved using a urea‐type CSP of (S)‐indoline‐2‐carboxylic acid and (R)‐1‐(α‐naphthyl)ethylamine, known as Chirex 3022, running in the normal phase mode. The effect of different organic acids added to the mobile phase was examined and the chiral recognition mechanism(s) is discussed. Solid phase extraction with C18 Sep‐Pak cartridges was applied as a clean‐up step to determine the enantiomeric ratio between (−)‐R and (+)‐S‐albuterol in pharmaceutical formulations and in human plasma. © 1995 Wiley‐Liss, Inc.
Aspects of chirality in overcrowded bistricyclic enes
Authors: Biedermann P. Ulrich , Levy Amalia , Stezowski John J. , Agranat Israel
Published: January 2005

Intramolecular overcrowding in bistricyclic enes (1) requires out‐of‐plane deformations in order to accommodate the sterically demanding tricyclic moieties without prohibitively close contacts of nonbonded atoms. The nonplanarity of 1 introduces the notion of chirality to the arena of overcrowded aromatic enes. Deviation from coplanarity occurs by twisting around the double bond and out‐of‐plane bending (hence pyramidalization). The bending is realized by folding of the tricyclic moieties. The conformations of homomerous (1, × = Y) and heteromerous (1, × ≠ Y) bistricyclic enes and their mono‐ and disubstituted derivatives are analyzed along with their point group symmetries and chirality. The implications are illustrated using the structures of characteristic examples calculated with the semiempirical method PM3. © 1995 Wiley‐Liss, Inc.
Synthesis of (+)‐(S)‐ibuproxam and preparation of some new complexes of racemic and (+)‐(S)‐ibuproxam with β‐cyclodextrin and its derivatives
Authors: Žmitek Janko , Verhnjak Katarina , Urleb Uroš , Kotnik Sonja
Published: January 2005

(+)‐(S)‐Ibuproxam, a prodrug of (+)‐(S)‐ibuprofen, the pharmacologically active component of ibuprofen, was synthesized in order to minimize side effects (especially gastric irritation) and reduce effective dose. The low water solubility of (+)‐(S)‐ibuproxam, which prevents rapid dissolution and absorption from the gastrointestinal tract, was overcome by complexation with β‐cyclodextrin and its derivatives. The inclusion complex formation was confirmed by differential scanning calorimetry (DSC), by 1H‐NMR spectroscopy, and X‐ray powder diffractometry. The physicochemical characteristics of ibuproxam were significantly improved by the complexation. © 1995 Wiley‐Liss, Inc.
Diastereoselective hydrogenations of unsymmetrically substituted aromatics
Authors: Exl Christina , Ferstl Eva , Hönig Helmut , Rogi‐Kohlenprath Renate
Published: January 2005

Attempts to induce enantioselectivity in the catalytic hydrogenation of unsymmetrically substituted aromatics using covalently bound, well known chiral auxiliaries are described. Marked differences in stereoselectivity and rate of hydrogenolysis are noted as a function of the auxiliary used. Enantioselectivities obtained in the resulting cyclohexyl derivatives are rather poor. © 1995 Wiley‐Liss, Inc.
Evaluation of the use of cyclodextrins in chiral separation of basic drug substances by capillary electrophoresis
Authors: Bjørnsdottir Inga , Hansen Steen Honoré
Published: January 2005

The influence of the choice of type and/or concentration of cyclodextrin, other additives, the temperature surrounding the capillary, and buffer pH on the separation of some chiral basic drug substances in capillary zone electrophoresis has been evaluated. It was found that pH of the buffer and type and concentration of cyclodextrin had a major influence on the separation. © 1995 Wiley‐Liss, Inc.
Central composite design for the rapid optimisation of ruggedness and chiral separation of amlodipine in capillary electrophoresis
Authors: Small Tracy S. , Fell Anthony F. , Coleman Michael W. , Berridge John C.
Published: January 2005

Systematic optimisation with central composite design offers an efficient route for rapid optimisation of resolution with multiple interacting parameters in chiral CE. This is illustrated by separations of amlodipine with α‐CD as chiral selector in the running buffer, for which the predicted performance of central composite design is assessed. The utility of response surface methodology for locating optimum ruggedness in CE is also described. © 1995 Wiley‐Liss, Inc.
Chiral derivatization for separation of racemic amino and thiol drugs by liquid chromatography and capillary electrophoresis
Authors: Leroy Pierre , Bellucci Luc , Nicolas Alain
Published: January 2005

Separation of racemic amino drugs (α‐methylbenzeneethanamine, 6‐amino‐2‐methyl‐2‐heptanol and 1‐aminoethyl‐benzenemethanol) and thiol drugs [N‐(2‐mercapto‐1‐oxopropyl) glycine, 2‐mercaptopropanoic acid, and N‐acetyl‐3‐mercaptovaline] has been evaluated after derivatization. ortho‐Phthalaldehyde (OPA) and naphthalene‐2,3‐dicarboxaldehyde (NDA) were used with either homochiral thiols (N‐acetyl‐L‐cysteine and N‐acetyl‐D‐penicillamine) or amines [(‐)‐(1R,2S)‐norephedrine, L‐phenylalanine, L‐tyrosine, and 3‐hydroxy‐L‐tyrosine] as chiral selectors according to the analyte reactive group. The resulting 36 diastereoisomeric derivatives were studied using reversed‐phase high‐performance liquid chromatography (RP‐HPLC) and capillary electrophoresis (CE). Of the CE modes, micellar electrokinetic chromatography (MEKC) using sodium dodecyl sulfate (SDS) as surfactant, β‐cyclodextrin (β‐CD)‐modified capillary zone electrophoresis (β‐CD‐CZE), and β‐CD‐MEKC were applied. Results highlight respective performance of the reagents and separative techniques. All OPA derivatives of racemic amino drugs were resolved either by MEKC or β‐CD‐MEKC. In the case of racemic thiol drugs, 10 of the 12 OPA derivatives were resolved in β‐CD‐CZE. © 1995 Wiley‐Liss, Inc.
Enantioselective assay of β‐receptor antagonists present in microdialysis and plasma samples of rats
Authors: Johansson Monika , Sjöberg Per , Hesselgren Ann‐Mari , Salmonson Thomas
Published: January 2005

The enantiomers of alprenolol, metoprolol, and propranolol have been separated on an enantioselective cellulase column and analysed using a fully automated HPLC system involving coupled column chromatography and fluorescence detection. The assays had sufficient selectivity and sensitivity to investigate the disposition of these β2‐receptor antagonists in blood and brain extracellular fluid of rats. A cellulase column was used as the first column to separate the enantiomers giving separation factors between 2.9 and 4.3. After the separation, the enantiomers were trapped on two small precolumns by the use of a switching valve and were then introduced on an achiral C18 analytical column by eluting the small columns backward. The enantiomers in blood and brain tissue dialysates were analysed by direct injection of 8 μl samples. The limit of quantitation was 0.025–0.4 μg/ml of the different enantiomers. Plasma samples were analysed after a simple extraction procedure. The intraassay precision of the lowest quality control plasma samples (0.2–0.8 μg rac drug/ml) was 4–8% for the different enantiomers. © 1995 Wiley‐Liss, Inc.
Stereoselective hydrolysis of xenobiotic esters by different cell lines from rat liver and hepatoma and its application to chiral prodrugs for designated growth suppression of cancer cells
Authors: Kageyama Yu‐Ichi , Yamazaki Yoshimitsu , Afify Adel S. , Ogawa Yoshikatsu , Okada Tomoko , Okuno Hiroaki
Published: January 2005

Stereoselectivity in the hydrolysis of racemic ethyl 2‐phenylacetate derivatives by cultured cells of noncancerous cell lines from rat liver (BRL, BRL 3A, Clone 9, and ARLJ301–3), spontaneously or oncogene transformed rat liver cell lines (ARLJ301–3TR1, Anr4, Anr9–1, and Anr13–1), and cancer cell lines from rat hepatoma (H4‐II‐E, McA‐RH7777, and MH1C1) and sarcoma (XC) was studied. A strong (R)‐enantiomer preference was found in the hydrolysis of ethyl 2‐hydroxy‐ (2c) and 2‐methoxy‐2‐phenylacetate (3c) by the noncancerous and oncogene‐transformed cells and an (S)‐enantiomer preference for ethyl N‐acylphenylalaninates with all the present cell lines. These inclinations were, however, not recognized with ethyl 2‐methoxy‐2‐phenylpropanoate and ethyl N‐difluoroacetyl‐or N‐trifluoroacetylphenylalaninate. Moreover, the R preference for 3c was reversed in the reaction by hepatoma cells. Thus, the stereoselectivity is influenced by both structure of acyl group and species of cell lines. The hepatoma cells were considerably different from the noncancerous or oncogene‐transformed cells in stereoselectivity. This fact was consistent with the order of colony formation in soft agar cultures (index of malignancy) and the resemblance in actively stained esterase patterns in gel electrophoresis. The stereoselective hydrolysis leads to cell‐specific activation of anticancer prodrugs. This has been confirmed for the first time by the stereoselectivity of Anr4 and H4‐II‐E cells in the hydrolysis of a chiral mustard ester, bis(2‐chloroethyl)aminophenyl 2‐methoxy‐2‐phenylacetate (14) and by the difference of IC50 values of (R)‐ and (S)‐14 against the two cell lines. © 1995 Wiley‐Liss, Inc.
A serious problem with computer processing of stereochemistry in chemical structure files: The need for standardisation
Authors: Blessington Bernard
Published: January 2005

Many computer programmes exist for drawing and modelling small and large molecules. Small molecules related to the antitubercular drug ethambutol are discussed. Some specific software problems, with stereochemical representations, are illustrated. Incompatibility of molecular structure files produced by different programmes and different hardware are shown. The need for a standardised file format is stressed. © 1995 Wiley‐Liss, Inc.
Chiral separation based on immobilized intact and fragmented cellobiohydrolase II (CBH II): A comparison with cellobiohydrolase I (CBH I)
Authors: Henriksson Hongbin , Jönsson Stefan , Isaksson Roland , Pettersson Göran
Published: January 2005

Intact and fragmented cellobiohydrolase II (CBH II) were immobilized to silica and used as chiral stationary phases (CSPs) for liquid chromatographic separations of enantiomers. Both acidic and basic chiral compounds could be resolved into their enantiomers on these phases. The enantioselectivities obtained on intact CBH II and its core were almost equivalent. Comparisons were also made with CBH I silica. It was found that the new materials show quite different chiral and chromatographic properties. The enzymatic activity of the CBH II in free solution was influenced by alprenolol and mexiletine, both separated on the corresponding CSP. It indicates that the sites for catalysis and for chiral recognition overlap. © 1995 Wiley‐Liss, Inc.
Chiral discrimination promoted by (1S,2S)‐1‐phenyl‐2‐amino‐1,3‐propanediol derivatives in the asymmetric Reformatsky reaction
Authors: Mastantuono Alberto , Pini Dario , Rolfini Chiara , Salvadori Piero
Published: January 2005

Some 3‐t‐butyldimethylsilyloxy derivatives, synthesized from the cheap commercially available (1S,2S)‐2‐amino‐1‐phenyl‐1,3‐propanediol [(1S,2S)‐1], have been successfully employed as new chiral ligands in the asymmetric Reformatsky reaction on aldehydic substrates. The influence both of the substrate and of the ligand on the stereochemical pathway has been investigated by varying the structure of the carbonyl substrate and of the optically active aminodiols. © 1995 Wiley‐Liss, Inc.
Absolute configurations and conformations of the opioid agonist and antagonist enantiomers of picenadol
Authors: Froimowitz Mark , Cody Vivian
Published: January 2005

The absolute configurations of the enantiomers of the opiod picenadol [cis‐1,3‐dimethyl‐4‐propyl‐4‐propyl‐4‐(3‐hydroxyphenyl)piperidine; cis‐3‐methyl, 4‐propyl] have been determined by an X‐ray crystallographic study of the chloride salt of the (+)‐enantiomer. The agonist (+)‐enantiomer and the antagonist (−)‐enantiomer were found to have the 3R, 4R and 3S, 4S absolute configurations, respectively. The conformational properties of the enantiomers were also examined with MM2–87 calculations. There was good agreement between the computed global minimum and the crystallographic structure with the phenyl ring approximately bisecting the piperidine ring by both methods. This orientation of the phenyl ring differs from that of related opioids such as the phenylmorphans, prodines, meperidine, and ketobemidone in which the phenyl ring tends to eclipse one edge of the piperidine ring. Because the phenyl ring bisects the piperidine ring in picenadol, there is little difference in the three‐dimensional orientations of the phenyl rings of the two enantiomers when one superimposes the piperidine rings. The agonist (+)‐enantiomer is ambiguous with respect to an opioid ligand model, which suggests that agonist activity requires a specific range of dihedral angles for the phenyl ring. While the global minimum of the agonist is not consistent with the model, a second conformer that is only 1.2 kcal/mol above the global minimum is consistent. An alternative explanation is that agonist or antagonist activity is solely due to the presence of the 3‐methyl group on the different edges of the piperidine ring. MM2–87 calculations were also performed on the opioid agonist des‐3‐methyl analog of picenadol and the closely related trans‐1,3,4‐trimethyl‐4‐(3‐hydroxyphenyl)piperidines (trans‐3‐methyl, 4‐methyl) in which both enantiomers are opioid antagonists. The conformational properties of these compounds are consistent with the ligand model. © 1995 Wiley‐Liss, Inc.
High‐Performance liquid chromatographic separation and molecular modelling of diastereomeric isoindole derivatives of amino compounds
Authors: Duchateau A. L. L. , Boesten J. M. M. , Coussens B. B.
Published: January 2005

A high‐performance liquid chromatography and molecular modelling study is presented for the diastereomeric adducts of a series of chiral thiol compounds and chiral amine compounds after reaction with o‐phthalaldehyde (OPA). It is shown that the possibility of hydrogen bonds forming between the thiol and amino residues in the diastereomeric adducts is an important factor for obtaining good selectivity. The experimental elution orders were explained on the basis of the strength of the interaction between the polar groups of the thiol and amine constituents; it was found that the diastereomeric form having the largest distance between these groups always eluted first. Moreover, within a series of OPA derivatives, the differences between the Boltzmann weighted averages of the distances between the polar groups of the two diastereomers show a good correlation with the experimental selectivities. © 1995 Wiley‐Liss, Inc.
Conversion of a racemate into a single enantiomer in one step by chiral liquid chromatography: Studies with rac‐2,2′‐diiodobiphenyl
Authors: Wolf Christian , Köunig Wilfried A. , Roussel Christian
Published: January 2005

The enantiomers of rac‐2,2′‐diiodobiphenyl were separated by liquid chromatography on microcrystalline triacetylcellulose. The conformational lability, a large separation factor α, and a suitable capacity factor k′(+) of this biphenyl allowed us to convert the racemate into 90% of enantiomerically pure (‐)‐2,2′‐diiodobiphenyl and 10% of pure (+)‐2,2′‐diiodobiphenyl, respectively, by a series of in situ racemization‐elution cycles. The much better retained (+)‐enantiomer was racemized on the chromatographic column at 50°C after the less retained (‐)‐enantiomer has already been eluted at 8°C. © 1995 Wiley‐Liss, Inc.
Three‐year recurrence‐free survival in a patient with recurrent medulloblastoma after resection, high‐dose chemotherapy, and intrathecal Yttrium‐90‐labeled DOTA0‐D‐Phe1‐Tyr3‐octreotide radiopeptide brachytherapy
Authors: Beutler Daniel , Avoledo Pierino , Reubi Jean‐Claude , Mäcke Helmut R. , Müller‐Brand Jan , Merlo Adrian , Kühne Thomas
Published: January 2005

BACKGROUND

Most medulloblastomas express high levels of somatostatin type 2 receptors (sst2). DOTA0‐D‐Phe1‐Tyr3‐octreotide (DOTATOC) specifically binds sst2 in the low nanomolar range. The cytotoxic effect is mediated by the chelated, β‐emitting, metallic radionuclide Yttrium 90 (90Y). The authors applied this innovative treatment option in a boy age 8 years who presented with a recurrent medulloblastoma of the cauda equina: a prognostically poor condition. Targeted radiotherapy was administered to treat minimal sst2‐expressing tumor remnants, which persisted despite conventional and high‐dose chemotherapy and intercurrent resection of the lesion.

METHODS

A medulloblastoma arising from the floor of the fourth ventricle had been removed surgically; then, the patient was treated with standard adjuvant chemotherapy and craniospinal irradiation according to the prospective HIT '91 protocol. Complete remission was achieved for 20 months, when a drop metastasis of the cauda equina manifested with sensorimotor lumbosacral deficits and urinary incontinence. After four cycles of neoadjuvant chemotherapy (which consisted of combined ifosfamide, carboplatinum and etoposide), two cycles of high‐dose chemotherapy and autologous stem cell transplantation were performed; in between, the responding residual tumor within the lumbosacral nerve fibers was microscopically removed. Thereafter, an Indium‐111‐DOTATOC test injection indicated sst2‐expressing tumor remnants within the cauda equina. Con‐ sequently, 4 cycles of [90Y]‐DOTATOC (4 × 562.5 megabecquerels) were injected directly into the cerebrospinal fluid in monthly intervals.

RESULTS

The consolidating intrathecal brachytherapy using [90Y]‐DOTATOC was tolerated well. A complete remission was achieved for a 3‐year period. The only remaining deficit was urinary incontinence.

CONCLUSIONS

Intrathecal administration of targeted radiopeptide brachytherapy in combination with conventional and high‐dose chemotherapy and surgical removal represents a promising new option to treat recurrent medulloblastoma and should be explored further. Cancer 2005. © 2005 American Cancer Society.
Residual tumor uptake of [99mTc]‐sestamibi after neoadjuvant chemotherapy for locally advanced breast carcinoma predicts survival
Authors: Dunnwald Lisa K. , Gralow Julie R. , Ellis Georgiana K. , Livingston Robert B. , Linden Hannah M. , Lawton Thomas J. , Barlow William E. , Schubert Erin K. , Mankoff David A.
Published: January 2005

BACKGROUND

Studies utilizing serial [99mTc]‐sestamibi (MIBI) scintimammography have reported accurate prediction of tumor response in patients with locally advanced breast carcinoma (LABC) undergoing neoadjuvant chemotherapy. The pathologic response of LABC to presurgical treatment regimens is a prognostic indicator of survival. The authors tested whether MIBI uptake posttherapy predicted survival.

METHODS

Sixty‐two patients with LABC underwent MIBI scintimammography just before chemotherapy and 2 months after treatment initiation. An additional MIBI scan was performed if treatment lasted > 3 months. The affected breast was imaged within 10 minutes after injection to reflect early uptake, which the authors have shown to be related to tumor blood flow. MIBI uptake was quantified using the lesion‐to‐normal breast (L:N) ratio. Most patients (93%) received weekly dose‐intensive doxorubicin‐based treatment. Disease‐free survival (DFS) and overall survival (OS) were compared with posttherapy primary MIBI uptake and with other established prognostic factors for neoadjuvantly treated LABC, namely, primary tumor pathologic response and posttherapy axillary lymph node status.

RESULTS

Patients with high uptake on the last observed MIBI scan (i.e., the L:N ratio was greater than the median value) had poorer DFS and OS (P < 0.01 and P = 0.01, respectively). Residual MIBI uptake retained independent prognostic significance in preliminary multivariate analysis that included other established prognostic markers.

CONCLUSIONS

High primary breast tumor MIBI uptake after neoadjuvant chemotherapy predicted poor survival, suggesting serial MIBI imaging may provide a useful quantitative surrogate end point for neoadjuvant chemotherapy trials. Given the association between MIBI uptake and tumor blood flow, this prognostic capability may be related to retained tumor vascularity after treatment. Cancer 2005. © 2005 American Cancer Society.
Abdominal computed tomography scans in the selection of patients with malignant peritoneal mesothelioma for comprehensive treatment with cytoreductive surgery and perioperative intraperitoneal chemotherapy
Authors: Yan Tristan D. , Haveric Namic , Carmignani Carlos P. , Chang David , Sugarbaker Paul H.
Published: January 2005

BACKGROUND

Malignant peritoneal mesothelioma is a rare and fatal disease. Until recently, the treatment options were very limited and ineffective. The new comprehensive approach of cytoreductive surgery with perioperative intraperitoneal chemotherapy offers improved survival rates at a cost of considerable morbidity and mortality as in other peritoneal surface malignancies. The outcome after these treatments is predominantly dependent on adequate cytoreduction. The aim of the current study was to identify computed tomography (CT) scan images that are useful in patient selection for this comprehensive approach.

METHODS

An analysis of the preoperative CT scans of 30 patients with peritoneal mesothelioma treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy at a single institution was performed. Based on the size of residual tumor nodules after cytoreductive surgery, patients were divided into 2 groups: those with residual lesions ≤ 2.5 cm (adequate cytoreduction) and those with residual lesions > 2.5 cm (suboptimal cytoreduction). The CT scans for each patient were evaluated by a standardized scoring system with the reader blinded to the operative findings. Thirty‐nine CT scan parameters were obtained and statistically analyzed to determine their association with the study outcome variables, namely, adequacy of cytoreduction.

RESULTS

Seven patients (64%) in the suboptimal cytoreduction group and 2 patients (11%) in the adequate cytoreduction group had a > 5‐cm tumor mass in the epigastric region (P = 0.004). Nine patients (82%) in the suboptimal group and 2 patients (11%) in the adequate cytoreduction group had CT scans that showed loss of normal architecture of the small bowel and its mesentery (P < 0.001). In a composite analysis of these 2 radiologic features, none of the patients with a > 5‐cm tumor mass in the epigastric region and loss of normal architecture of the small bowel and its mesentery had an adequate cytoreduction. Patients who lacked these two preoperative CT scan findings had a 94% probability of an adequate cytoreduction.

CONCLUSIONS

CT scans effectively identified large peritoneal mesothelioma tumors at crucial anatomic sites. Because adequate cytoreduction is necessary to achieve prolonged survival, CT scans became an accurate prognostic radiologic test for patient selection for comprehensive treatment. Cancer 2005. © 2005 American Cancer Society.
Evaluation of the CD34 and CD10 immunostains using a two‐color staining protocol in liver fine‐needle aspiration biopsies
Authors: Zimmerman Robert L. , Logani Sanjay , Baloch Zubair
Published: January 2005

Fine‐needle aspiration (FNA) biopsies of liver masses may need immunohistochemistry to resolve difficult cases. We examined liver FNAs with CD10 and CD34 using a two‐color staining protocol. Fifty‐one cases of hepatocellular carcinoma (HCC) and 23 cases of liver metastases were stained first with CD10 using diaminobenzidine as a chromogen and then with CD34 using Fast Red. All cases were reviewed in a blinded fashion by two of the authors (R.I.Z. and Z.B.). Diagnoses were unblinded and staining patterns evaluated. Forty‐eight of 51 cases of HCC stained for CD34 in a peripheral pattern and no cases of metastases stained for CD34 Seven of 23 cases of metastatic disease stained for CD10 in a diffuse cytoplasmic distribution and 29 of 51 HCCs stained in a canalicular pattern. Overall, the sensitivity of the CD10/CD34 combination was 98% and the specificity was 100% for HCC when appropriate staining patterns were observed. Two‐color immunostaining with CD10 and CD34 may prove useful in distinguishing HCC from metastases. Diagn. Cytopathol. 2005;32:88–91. © 2005 Wiley‐Liss, Inc.
Solvothermal Synthesis of NiS 3D Nanostructures
Authors: Zhang Wanqun , Xu Liqiang , Tang Kaibin , Li Fanqing , Qian Yitai
Published: January 2005

Highly uniform urchin‐like nanostructures (in the structures, nanoneedles or nanobelts grow radially from the core particles) of NiS (millerite) were successfully prepared by a solvothermal synthetic route using Ni(Ac)2·6H2O and dithizone as reagents and ethylenediamine as solvent in the temperature range of 220−240 °C. The prepared nickel sulfides with urchin‐like 3D architectures were characterized by X‐ray diffraction (XRD), field emission scanning electron microscopy (FE‐SEM) and high‐resolution transmission electron microscopy (HRTEM). The reaction temperature, sulfur sources, and solvent are of great importance on the final urchin‐like structures. On the basis of the experimental results, a possible growth mechanism of the urchin‐like NiS crystals is proposed, which is supported by the technical characterizations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Enhanced residual‐free bubble method for convection–diffusion problems
Authors: Cangiani A. , Süli E.
Published: January 2005

We analyse the performance of the enhanced residual‐free bubble (RFBe) method for the solution of elliptic convection‐dominated convection–diffusion problems in 2‐D, and compare the present method with the standard residual‐free bubble (RFB) method. The advantages of the RFBe method are two‐fold: it has better stability properties and it can be used to resolve boundary layers with high accuracy on globally coarse meshes. Copyright © 2005 John Wiley & Sons, Ltd.
(1‐Methoxyvinyl)boronic and (1‐chlorovinyl)boronic esters
Authors: Matteson Donald S. , Beedle Ellen C.
Published: January 2005

(s)‐Pinanediol (1‐methoxyvinyl)boronate (1) was prepared from (1‐methoxyvinyl)‐lithium and triisopropyl borate followed by (s)‐pinanediol. Attempted reaction with (dichloromethyl)lithium failed, and reaction with butylmagnesium chloride followed by acetic acid yielded a mixture of diastereomers of (s)‐pinanediol (1‐methoxy‐1‐methyl‐pentyl)boronate (2). (s)‐Pinanediol (1‐chlorovinyl)boronate (4) has been prepared by dehydrochlorination of (s)‐pinanediol 1,1‐dichloroethylboronate (3) with lithium chloride in dimethylformamide. Reaction of 4 with (dichloromethyl)lithium yielded (s)‐pinanediol (1S)‐(1,2‐dichloroallyl)boronate (5) in 92% diastereomeric excess. Reaction of 5 with RMgX resulted in a 3 : 1 ratio of displacement of the 1‐Cl from carbon by R to displacement of the entire 1,2‐dichloroallyl group from boron by R. With lithium benzyl oxide, displacement of the 1‐Cl from 5 failed entirely. Reaction of 4 with (dibromomethyl)lithium was inefficient and yielded a gross mixture of diastereomers.
Reactions involving selenium metal as an electrophile: Scope and limitations of the enolate‐selenolate transformation
Authors: Swiss Kevin , Choi Woo‐Baeg , Mohan Julie , Barnum Christopher , Saindane Manohar , Zima George , Liotta Dennis
Published: January 2005

When lithium enolates are allowed to react with selenium metal, selenolate (selenide) ions are formed. Alkylation of these selenolate ions produces the corresponding α‐alkylselenenyl carbonyl derivatives. These derivatives can then be converted to their unsaturated counterparts using the same type of protocols that are employed with arylselenenyl derivatives.
A facile method for generation of carbon oxide sulfide
Authors: Mizuno Takumi , Nishiguchi Ikuzo , Hirashima Tsuneaki , Sonoda Noboru
Published: January 2005

Carbon oxide sulfide was easily generated upon heating of amine salts of carbamothioic acids at 85°C which were produced in situ from amines, carbon monoxide, and elemental sulfur in the presence of a catalytic amount of selenium under mild conditions.
Some highly fluorinated acyclic, cyclic, and polycyclic derivatives of Cl2NCF2CF2NCl2 and Cl2CNCCl2CCl2NCCl2
Authors: Sarwar Ghulam , Kirchmeier Robert L. , Shreeve Jean'ne M.
Published: January 2005

When Cl2NCF2CF2NCl2 is heated with CF2CFX (X = Cl, F) ClXCFCF2N(Cl)CF2CF2N(Cl)CF2CXClF (X = Cl, 2; F, 3) is formed. Mercury extracts chlorine fluoride from 2 and 3 to form new polyfluorobisazomethines, ClXCFCF2NCFCFNCF2CXClF (X = Cl, 4; F, 5). Photolysis of the product obtained from CCl2NCCl2CCl2NCCl2 with ClF, CF2ClN(Cl)CF ClCFClN(Cl)CF2Cl (6) gives another bisazomethine, CF2ClNCFCFNCF2Cl (7) with concomitant loss of Cl2. At 25°C, in the presence of CsF, 4 and 5 are cyclized to give (X = Cl, 8; F, 9), and 7 forms a bicyclic derivative at 100°C, (1). Addition of chlorine fluoride to 8 and to 1 produces (10) and (14), respectively. Photolysis of 10 results in the loss of CFCl3 to form (11), and 14 loses Cl2 and dimerizes to the hydrazine (15). The further addition of ClF to 11 gives rise to (12) which when photolyzed at 3000 Å forms a second cyclic hydrazine, (13).
Phosphate‐phosphonate conversion: Nucleophilic displacement reactions involving phosphoric esters and methyllithium
Authors: Savignac Philippe , Teulade Marie‐Paule , Patois Carl
Published: January 2005

The alkylation‐metalation reaction of phosphoric esters depends on the way the lithium reagent has been prepared. With salt‐containing methyllithium (LiBr or LiI), the alkylation is never complete. On the contrary, with salt‐free methyllithium, the alkylation is completed at – 10°C. This reaction is performed independently of the substituents at the phosphoryl group.
Easy access to bismuth catecholates
Authors: Guilhaume Nolven , Postel Michèle
Published: January 2005

The reaction of catechols with bismuth (III) acetate in acetic acid solution provides an easy access to the polymeric bismuth catecholate acetate (1), 4‐tert ˙ butylcatecholate hydroxide (2), and 3,5‐di‐tert ˙ butylcatecholate hydroxide (3).
One‐Pot synthesis of (2E)‐ and (2E, 4E)‐ unsaturated carboxylic acid amides via organotellurium reagents
Authors: Xiao Wen‐Juan , Shi Li‐Lan , Chen Zheng‐Qing , Huang Yao‐Zeng , Lang S. A.
Published: January 2005

Di‐n‐butyl telluride, 2‐bromoacetylisobutylamide (or 2‐bromoacetylpiperidide) react directly with saturated or α,β‐unsaturated aldehydes at room temperature in the presence of potassium carbonate(s) to afford (2E)‐, or (2E, 4E)‐unsaturated carboxylic acid amides, respectively, in excellent yields with high E stereoselectivity.
Molecular modeling of oxaphosphetane intermediates of wittig olefination reactions
Authors: Marí Frank , Lahti Paul M. , McEwen William E.
Published: January 2005

The literature reveals that the structures of four unusual oxaphosphetanes have been established by x‐ray diffraction studies, and the structure of one mythical oxaphosphetane (6) has been deduced by theoretical calculations. We have used these known structures to calibrate the MMX87 force field, the only necessary modification being the stretching term for the P‐O bond. The bond length, 1o, was set at 1.80Å, which is an “average” of the P‐O axial bond distances of the stable oxaphosphetanes. The AMPAC (Ver. 1.0) molecular orbital package utilizing the MNDO hamiltonian was also applied to the same problem, starting with the minimized geometries of the modified MMX87 force field. Fixed bond lengths and full minimizations were performed. The computed geometries of the four‐member ring of each of the four oxaphosphetanes of known structures were found to be in very good agreement with the values obtained by x‐ray diffraction. Furthermore, the method was applied to the mythical oxaphosphetane, and the results of MMX87 and MNDO calculations were found to be in very good agreement with the results of ab initio calculations. The MMX force field and the MNDO semiempirical method have been used to calculate the geometries and the steric energies (or heats of formation) of diastereomeric oxaphosphetanes formed in a theoretically real Wittig reaction.
Second‐row anomeric interactions: The involvement of phosphorus
Authors: Juaristi Eusebio
Published: January 2005

Proton NMR spectroscopy and x‐ray crystallographic studies demonstrate the predominance of the axial conformer of 2‐(diphenylphosphinoyl)‐1,3‐dithiane (1). Chemical equilibration of anancomeric models (3 ⇌ 4) allows quantitative determination of the conformational free energy in 1, 1.0 kcal/mol, which corresponds to an anomeric effect of 2.64–3.74 kcal/mol, depending on the method used for estimating it. This value indicates that the anomeric effect operative in 1 may be among the largest yet measured.

Five distinct rationalizations are considered to account for such a strong S‐C‐P(O) anomeric effect: (a) dipole‐dipole interactions, (b) electrostatic, attractive interaction between the phosphoryl oxygen and the syn‐axial hydrogens in 1‐axial, (c) delocalization of the lone pair on the endocyclic heteroatom into the antiperiplanar (axial) adjacent polar C‐P bond, (d) through‐space 3p‐3d electron donation from sulfur to phosphorus, and (e) repulsive interaction between the lone pairs on sulfur and on the phosphoryl oxygen. All these hypotheses have some experimental and/or the‐oretical support, but evidence contrary to expectation can be found also to argue against each one of them.

The conformational preference of the diphenylthiophosphinoyl group in the 1,3‐dithian‐2‐yl ring was determined by nuclear magnetic resonance (NMR) analysis and by chemical equilibration of diastereomeric models. The slight predominance of axial 2‐(diphenylthiophosphinoyl)‐1,3‐dithiane (13‐ax) over 13‐eq reflects nonetheless the influence of a strong S‐C‐P anomeric interaction, worth ca. 2.3 kcal/mol.

Spectroscopic evidence for the predominance of the equatorial conformers in 2‐(diphenylphosphinoyl)‐1,3‐oxathiane (19) and 2‐(diphenylphosphinoyl)‐1,3‐dioxane (22) was confirmed by the study of derivatives containing counterpoise substitutents, or by chemical equilibration on anancomeric models. ΔD°27°C [P(O)Ph2] = ‐3.23 kcal/mol was determined for the dioxane (chloroform solution), and ΔG°C55°C [P(O)Ph2] = ‐1.42 kcal/mol for the oxathiane (ethanolic solution). Nevertheless, evaluation of the different steric requirements in 1, 13 and 22 reveals that the magnitude of the O‐C‐P(O) and S‐C‐P(O) anomeric effects in the heterocycles is, in fact, quite similar, close to kcal/mol.