bluuebunny/crossref_metadata_2025 huggingface dataset:
GABAB antagonists: Resolution, absolute stereochemistry, and pharmacology of (R)‐ and (S)‐phaclofen
Authors: Frydenvang Karla , Hansen Jan J. , Krogsgaard‐Larsen Povl , Mitrovic Ann , Tran Hue , Drew Colleen A. , Johnston Graham A. R.
Published: January 2005

Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)‐3‐(4‐chlorophenyl)‐4‐aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chromatographic techniques. The absolute stereochemistry of (−)‐(R)‐phaclofen was established by X‐ray crystallographic analysis. (−)‐(R)‐Phaclofen was shown to inhibit the binding of [3H]‐(R)‐baclofen to GABAB receptor sites on rat cerebellar membranes (IC50 = 76 ± 13 μM), whereas (+)‐(S)‐phaclofen was inactive in this binding assay (IC50 > 1000 μM). (−)‐(R)‐Phaclofen (200 μM) was equipotent with (RS)‐phaclofen (400 μM) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)‐(S)‐phaclofen (200 μM) was inactive. The structural similarity of the agonist (R)‐baclofen and the antagonist (−)‐(R)‐phaclofen suggests that these ligands interact with the GABAB receptor sites in a similar manner. Thus, it may be concluded that the different pharmacological effects of these compounds essentially result from the different spatial and proteolytic properties of their acid groups. © 1994 Wiley‐Liss, Inc.
Stereospecific synthesis and absolute configuration of mexiletine
Authors: Franchini Carlo , Cellucci Carla , Corbo Filomena , Lentini Giovanni , Scilimati Antonio , Tortorella Vincenzo , Stasi Francesca
Published: January 2005

Data on the absolute configuration of mexiletine (MEX) do not appear to have been published, although in several published reports the configuration is referred to as (−)‐(R) and (+)‐(S), based on information from manufactures providing the drug stereoisomers. We demonstrate that (−)‐MEX has the (R)‐configuration by mean of a new stereospecific synthesis. X‐Ray analysis of an optical active sample of (+)‐MEX as its hydrobromide salt, obtained from chemical resolution of the racemic mixture, was carried out in order to obtain precise information on bond lengths and angles, useful for studies on structure–activity relationships. We also report the NMR analysis in presence of Eu(hfc)3 as shift reagent, which represents a simple method for the determination of enantiomeric excess (ee) in addition to the well‐known chiral HPLC methods. © 1994 Wiley‐Liss, Inc.
Enantiomeric separation of tetrahydroisoquinoline alkaloids by high‐performance liquid chromatography with β‐cyclodextrin as chiral selector
Authors: Stammel Waltraud , Woesle Berthold , Thomas Helmut
Published: January 2005

Tetrahydroisoquinoline alkaloids, which are known to be present not only in plants but also in animals, including mammals, can be considered as condensation products of 2‐phenylethylamines (e.g., catecholamines) with aldehydes (e.g., acetaldehyde) or 2‐oxo acids (e.g., pyruvic acid). In this study the possibility of separating the optical isomers of several tetrahydroisoquinolines by high‐performance liquid chromatography was investigated. For isosalsoline, tetrahydropapaveroline and laudanosoline a good enantiomeric separation could be achieved by applying β‐cyclodextrin‐bonded silica as stationary phase in connection with various mobile phases. With respect to laudanosoline, the addition of β‐cyclodextrin as chiral selector to the mobile phase using a C18 reversed‐phase column as stationary phase revealed an even higher resolution when compared with the chiral columns. All tested tetrahydroisoquinolines which could be well separated into enantiomers bear a hydroxyl group at carbon atom 7 as a common structural feature. Those alkaloids substituted with a methoxy group on position 7 instead of a hydroxyl group (e.g., salsolidine) failed to be resolved into their optical isomers. Therefore, the presence of a hydroxyl group on C7 of the aromatic ring seems to be conducive to steric discrimination. However, the separation results for 1‐carboxysalsolinol were unsatisfactory although this molecule possesses a 7‐hydroxyl group. In this case the existence of a carboxyl group on C1 reduced the chiral recognition and thus the enantiomeric resolution. © 1995 Wiley‐Liss, Inc.
Enantiomeric separation and recognition mechanism of 2‐arylpropionic acid derivatives by high‐performance liquid chromatography using a chiral column
Authors: Asami Masato , Nakamura Kan‐ichi
Published: January 2005

An optical resolution of the amide derivatives of ibuprofen and the carbamate‐alkylester derivatives of the trans‐alcohol metabolite of loxoprofen and an analogous compound, CS‐670, was studied by chiral high‐performance liquid chromatography (HPLC). The chiral columns SUMIPAX OA‐4000 and OA‐4100 were used to investigate the enantiomeric separation behavior of these derivatives using both reversed and normal mobile phases. A better separation factor (α) of the amide and the carbamate ester derivatives was obtained in the normal mobile phase than in the reversed mobile phase HPLC. In addition, the recognition mechanisms of both amide and carbamate ester enantiomers were investigated by 1H‐nuclear magnetic resonance (NMR). It is suggested that the important driving forces for the enantiomeric separation are the formation of hydrogen bonding and the charge transfer complex between these derivatives and an active site of the chiral stationary phase. © 1995 Wiley‐Liss, Inc.
Studies in chiral symmetry breaking crystallization I: The effects of stirring and evaporation rates
Authors: Kondepudi Dilip K. , Digits Jennifer , Bullock Kimiley
Published: January 2005

Chiral symmetry breaking can be realized in stirred crystallization of Na‐ClO3. We present experimental and theoretical studies of the random distribution of crystal enantiomeric excess (cee) for various stirring and solvent evaporation rates. For a fixed solvent evaporation rate, as the stirring RPM is increased, the probability distribution of cee initially broadens and subsequently develops a sharp peak close to cee = 1. On further increase of stirring rate, the probability distribution once again broadens. This broad probability distribution becomes narrow, with a sharp peak near cee = 1, if the solvent evaporation rate is decreased. Thus we show some ways in which the probability distribution of cee can be controlled in stirred crystallization. In particular, our study shows that the stirring rate and the solvent evaporation rate can be adjusted to maximize crystal enantiomeric excess. © 1995 Wiley‐Liss, Inc.
Solubility phase diagram of praziquantel enantiomeric system
Authors: Lim Bee‐gim , Tan Reginald B. H. , Ng Siu‐choon , Ching Chi‐bun
Published: January 2005

The solubility behaviour of praziquantel enantiomeric system at −15°C, 4°C, and 15°C is presented. This system exhibits both a pseudoracemate behaviour and one which leads to the formation of enantiomerically pure crystals. For solutions with lower enantiomeric purity, the pseudoracemate behaviour is more prominent. Solid solutions are formed when the mixtures of the enantiomers are crystallised. The phase diagram shows a complete absence of a eutetic. For mixtures with higher enantiomeric purity, pure crystals of the excess enantiomer are obtained when the solution is crystallised. Temperature dependency of this polymorphism is not significant. With these phase diagrams, a method is suggested to obtain enantiomerically pure isomers of praziquantel from a partially resolved mixture. © 1995 Wiley‐Liss, Inc.
Circular dichroism spectroscopy of 2‐aminotetralins
Authors: Jansen Johanna M. , Johansson Anette M. , Karlén Anders , Hacksell Uli
Published: January 2005

The circular dichroism (CD) spectra of a series of oxygenated 2‐(dipropylamino)tetralin derivatives are reported. On the basis of known absolute configurations and conformational preferences of the compounds, the validity of published correlations between the sign of the 1Lb Cotton effect and the three‐dimensional structure was examined. Contrary to predictions, substitution in position 6 or 7 of the tetralin moiety did not change the sign of the 1Lb Cotton effect. An unexpected sign inversion was, however, observed in some of the compounds containing methyl substituents in the nonaromatic ring. The occurrence of this inversion was not correlated with a change in conformational behaviour and varied depending on the position and nature of the aromatic substituent. No correlations were obvious between the sign of the 1Lb Cotton effect and the absolute configuration and conformational preferences of the compounds. Therefore, at present, CD spectroscopy does not appear to be useful in assignments of the absolute configurations of 2‐(dipropylamino)tetralin derivatives. © 1995 Wiley‐Liss, Inc.
Synthesis of stereoisomers of antithrombotic nipecotamides
Authors: Zheng Xiaozhang , Day Cynthia , Gollamudi Ram
Published: January 2005

The stereoisomers of α,α′‐bis[3‐(N,N‐diethylcarbamoyl)‐piperidino]‐p‐xylene (1) were synthesized. Rac ethyl nipecotate was resolved by diastereomeric (‐)‐D‐ and (+)‐L‐tartrate salt formation. The enantiomeric esters were hydrolyzed to the corresponding nipecotic acids, which were then converted into t‐BOC derivatives. Treatment of the latter with diethylamine/isobutyl chloroformate and removal of the t‐BOC protecting group afforded (R)‐ and (S)‐N,N‐diethylnipecotamides. Condensation of the latter with α,α′‐dibromo‐p‐xylene gave (R,R)‐ and (S,S)‐1. The meso‐diastereomer was obtained by stereospecific synthesis in addition to our earlier procedure involving fractional crystallization of the diastereomeric mixture obtained by synthesis. The latter was resolved earlier into 1A,1B, and 1C using chiral high‐performance liquid chromatography (HPLC). Based on the stereospecific synthesis now achieved, 1A and 1B are assigned the configurations, (R,R) and (S,S) respectively, and 1C is assigned the meso configuration. The (R,S) structure of the latter is also confirmed by X‐ray crystallography. © 1995 Wiley‐Liss, Inc.
Chiral synthesis via organoboranes. 41. The utility of B‐chlorodiisopinocampheylborane for a general synthesis of enantiomerically pure drugs
Authors: Ramachandran P. Veeraraghavan , Gong Baoqing , Brown Herbert C.
Published: January 2005

A general approach to the synthesis of enantiomerically pure α‐phenyl amino alcohols via the asymmetric reduction of α‐phenyl haloalkyl ketones or α‐phenyl aminoalkyl ketones with B‐chlorodiisopinocampheylborane is described. Using this approach, an improved synthesis of a potential antipsychotic, α‐(4‐fluorophenyl)‐4‐(2‐pyrimidinyl)‐1‐piperazinebutanol in ⩾98% ee, and the broncholdilator 1‐(2‐methoxy‐2‐phenethyl)‐4‐(3‐hydroxy‐3‐phenylpropyl)piperazine (eprozinol) in ⩾99% ee is achieved. © 1995 Wiley‐Liss, Inc.
A comparison of LC and SFC for cellulose‐ and amylose‐derived chiral stationary phases
Authors: Bargmann‐Leyder Nathalie , Tambuté André , Caude Marcel
Published: January 2005

This paper presents a systematic comparison of liquid chromatography (LC) and supercritical fluid chromatography (SFC) for Chiralcel OD and Chiralpak AD chiral stationary phases (CSPs), performed using various chiral compounds having a known or potential pharmaceutical activity. The chiral recognition mechanisms involved in LC and SFC for the enantiomeric separation of β‐blockers have been studied more particularly. As a general rule, it appears that the presence of polar functions, like primary or secondary hydroxyl or amine functions, may result in marked discrepancies in selectivity between LC and SFC. This result is peculiar to cellulose‐ and amylose‐derived CSPs, for which the interactions involved in chiral recognition mechanism are not always well balanced, contrary to what happens for independent CSPs. In the case of chiral resolution of polar solutes or polymer‐type CSPs, the analyst should try both the LC and SFC techniques to be able to choose the more stereoselective one. © 1995 Wiley‐Liss, Inc.
NMR investigations of the enantiomeric excess effects in solutions with weak intermolecular association
Authors: Fedin Erlen I. , Davankov Vadim A.
Published: January 2005

The main features of statistically controlled associate diasteromerism (SCAD) in solution as measured by nuclear magnetic resonance (NMR) are discussed. In an achiral solvent, (R)‐ and (S)‐enantiomers can demonstrate distinct NMR signals, with the intensity ratio equal to the concentration ratio. The previous theory of SCADA (anisochronism of nuclear magnetic moments caused by SCAD) is supplemented by treatment of enantiomeric excess phenomena in relation with the hypothesis that a sample consists totally of short‐living diastereomeric dimers which are involved in fast (on the NMR time scale) exchange by enantiomers. Thermodynamic parameters of SCAD as well as limits for enantioselectivity phenomena are estimated. © 1995 Wiley‐Liss, Inc.
Chiral separation of unmodified α‐hydroxy acids by ligand exchange HPLC using chiral copper(II) complexes of (S)‐phenylalaninamide as additives to the eluent
Authors: Galaverna Gianni , Pantò Francesco , Dossena Arnaldo , Marchelli Rosangela , Bigi Franca
Published: January 2005

Copper(II) complexes of (S)‐phenylalaninamide have been successfully used for the direct enantiomeric separation of unmodified (R,S)‐α‐hydroxy acids in reversed phase high‐performance liquid chromatography (RP‐HPLC). The effect of various parameters (pH, eluent polarity, selector concentration) on enantioselectivity is discussed. Evidence is provided that a mechanism of ligand exchange is actually occurring during the chromatographic separation. The method is very convenient and easy to use, and the chiral selector is commercially available and can be recovered at the end of the analysis. A conventional achiral RP‐ODS‐2 column is used and no pretreatment of the samples is required. This method allows the accurate determination of the enantiomeric excess of α‐hydroxy acids in synthetic and biological samples. © 1995 Wiley‐Liss, Inc.
Enantioselectivity of aromatase inhibitors: Substituted 3‐(4‐aminophenyl)pyrrolidine‐2,5‐diones
Authors: Pepper Christopher , Smith H. John , Nicholls Paul J. , Barrell Kevin J. , Ahmadi Massoud
Published: January 2005

The (+)‐, (−)‐, and (±)‐forms of 1‐ and 1,3‐substituted 3‐(4‐aminophenyl)pyrrolidine‐2,5‐dione have been examined as inhibitors of P450AROM and P450CSCC. The inhibitory potency for P450AROM resided in the (+)‐enantiomers of (1), (2), and (4) and the (−)‐enantiomers of (3) and (5). These findings have been accommodated within a molecular graphics‐derived model for binding of P450AROM inhibitors to the substrate binding site. Crystallography showed that (+)‐(2) has the (R)‐configuration. Spectral binding studies with human placental P450AROM showed type II binding but although the KS values were in line with the IC50 values for individual compounds there was no overall correlation between KS and IC50 within the series. There was little difference in the inhibitory potency of the enantiomers and racemate of individual compounds toward P450CSCC. © 1995 Wiley‐Liss, Inc.
Chromatographic properties of composite chiral stationary phases based on cellulose derivatives
Authors: Zhang Tong , Francotte Eric
Published: January 2005

Chiral stationary phases (CSPs) prepared by mixing together two different cellulose derivatives, before or after being coated on macroporous silica gel, were developed in order to determine the mutual influence of two different polymers on global chiral recognition capacity. The chromatographic properties of these CSPs were evaluated using a wide range of racemic test solutes. The mixing method does not significantly affect the enantioselectivities. The composite CSPs obtained by cocoating of two different cellulose derivatives on silica generally exhibit chiral recognition capacities intermediate between those of the two individual phases, and thus broadening the application range of a single column. These results indicate that the simultaneous coating of two different cellulose derivatives does not significantly alter the optical resolution power of each chiral material and are discussed in relationship with the supramolecular structure of the polymeric stationary phases. © 1995 Wiley‐Liss, Inc.
GABAA agonists: Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide
Authors: Frølund Bente , Jeppesen Lone , Krogsgaard‐Larsen Povl , Hansen Jan J.
Published: January 2005

(3SR,4RS)‐3,4‐Epoxypiperidine‐4‐carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)‐1‐(benzyloxycarbonyl)‐3,4‐epoxypiperidine‐4‐carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee ≥ 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 > 100 μM), (+)‐isoguvacine oxide (IC50 = 0.20 ± 0.03 μM) and (−)‐isoguvacine oxide (IC50 = 0.32 ± 0.05 μM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)‐isoguvacine oxide (EC50 = 6 μM; 33% relative efficacy) and (−)‐isoguvacine oxide (EC50 = 5 μM; 38% efficacy relative to 10 μM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor‐associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure—activity studies on GABAA agonists. Thus, the model of the GABAA recognition site(s) comprising a narrow cleft or pocket, in which the anionic moiety of the zwitterionic GABAA agonists is assumed to be embedded during receptor activation, may have to be revised. © 1995 Wiley‐Liss, Inc.
Preparation of (+)‐ and (−)‐1,2‐dimethyl‐3‐pyrrolidone and stability studies
Authors: Collina Simona , Gamba Anna , Ghislandi Victor , Azzolina Ornella
Published: January 2005

1,2‐Dimethyl‐3‐pyrrolidone is an important intermediate in the synthesis of cycloalkylaminonaphthalenic analgesics. The optical resolution of this compound with L‐ and D‐tartaric acids is described and the behaviour of the diastereomeric tartrates and of the enantiomers in solution was investigated by NMR spectroscopy and polarimetric analysis. Tautomeric equilibria involving C4 and C2 atoms, which are responsible for the instability of the compound, are demonstrated. Theoretical studies of conformational analysis were also made in order to define the relationships between the stability of the conformers of 1,2‐dimethyl‐3‐pyrrolidone and its structural features. © 1995 Wiley‐Liss, Inc.
Synthesis of (+)‐(R)‐ and (−)‐(S)‐trans‐8‐hydroxy‐2‐[N‐n‐propyl‐N‐(3′‐iodo‐2′‐propenyl)] aminotetralin: New 5‐HT1A receptor ligands
Authors: Zhuang Zhi‐Ping , Kung Mei‐Ping , Clarke William , Maayani Saul , Mu Mu , Kung Hank F.
Published: January 2005

(R,S)‐trans‐8‐Hydroxy‐2‐[N‐n‐propyl‐N‐(3′‐iodo‐2′‐propenyl)amino]tetralin 7, a new radioiodinated ligand based on 8‐OH‐DPAT, was reported as a potential ligand for 5‐HT1A receptors. The optically active (+)‐(R)‐ and (−)‐(S)‐7 were prepared to investigate the stereoselectivity of (R,S)‐7. Racemic intermediate 8‐methoxy‐2‐N‐n‐propyltetralin was reacted with the acyl chloride of (−)‐(R)‐O‐methylmandelic acid to form a mixture of (S,R)‐ and (R,R)‐diastereoisomers, which were separated by flash column chromatography. After removing the N‐acyl group from the diastereoisomers, the desired (+)‐(R)‐or (−)‐(S)‐7 was obtained by adding an N‐iodopropenyl group. In vitro homogenate binding studies showed the stereoselectivity of this new compound for 5‐HT1A receptors. (+)‐(R)‐7 isomer displayed 100‐fold higher affinity than the (−)‐(S)‐7 isomer. Biochemical study indicated that (+)‐(R)‐7 potently inhibited forskolin‐stimulated adenylyl cyclase activity in hippocampal membranes (Emax and EC50 were 24.5% and 5.4 nM, respectively), while (−)‐(S)‐7 showed no effect at 1 μM. The radioiodinated (+)‐(R)‐ and (−)‐(S)‐[125I]7 were confirmed by coelution with the resolved unlabeled compound on HPLC (reverse phase column PRP‐1, acetonitrile/pH 7.0 buffer, 80/20). The active isomer, (+)‐(R)‐[125I]7, displayed high binding affinity to 5‐HT1A receptors (Kd = 0.09 ± 0.02 nM). In contrast, the (−)‐(S)‐7 isomer displayed a significantly lower affinity to the 5‐HT1A receptor (Kd > 10 nM). Thus, (+)‐(R)‐[125I]trans‐8‐OH‐PIPAT, (+)‐(R)‐7, an iodinated stereoselective 5‐HT1A receptor agonist, is potentially useful for study of in vivo and in vitro function and pharmacology of 5‐HT1A receptors in the central nervous system. © 1995 Wiley‐Liss, Inc.
A covalently bonded teicoplanin chiral stationary phase for HPLC enantioseparations
Authors: Armstrong Daniel W. , Liu Youbang , Ekborgott K. Helen
Published: January 2005

A macrocyclic glycopeptide antibiotic containing a hydrophobic “tail” is covalently attached to silica gel via linkage chains. This material is extensively evaluated as a chiral stationary phase (CSP) for HPLC. The relevant structural features of the teicoplanin molecule which make it an effective chiral selector are discussed. The teicoplanin CSP appears to have excellent enantioselectivity for native amino acids, peptides, α‐hydroxycarboxylic acids, and a variety of neutral analytes including cyclic amides and amines. Enantio‐separations can be achieved in the reversed phase, normal phase, and “polar‐organic” modes. This chiral selector is stable and the integrity of the CSP is excellent in all separation modes. Hence it can be considered a highly effective multimodal column. Optimization of these separations is discussed in terms of both selectivity and efficiency. Results indicate that the surface loading of the chiral selector affects all relevant separation parameters. A hypothesis is proposed to explain the enhanced efficiency obtained when using teicoplanin CSPs with higher surface coverage. It appears that teicoplanin is a widely applicable, highly effective chiral selector for HPLC enantioseparations. © 1995 Wiley‐Liss, Inc.
Lipase stereoselectivity and regioselectivity toward three isomers of dicaprin: A kinetic study by the monomolecular film technique
Authors: Rogalska Ewa , Nury Sylvie , Douchet Isabelle , Verger Robert
Published: January 2005

Here we present a kinetic study on the steroselectivity and regioselectivity of 23 purified lipases of animal and microbial origin. This work, concerning a general problem of the mechanism of lipase–substrate molecular recognition, was performed using pure dicaprin isomers: 1,2‐sn‐dicaprin, 2,3‐sn‐dicaprin, and 1,3‐sn‐dicaprin spread as monomolecular films at the air–water interface. The first two isomers are optically active antipodes (enantiomers), forming stable films up to 40 mN m−1, while the last is a prochiral compound, with a surface pressure of collapse of 32 mN m−1. To our knowledge, this is the first report on the use of three diglyceride isomers as lipase substrates under identical and controlled physicochemical conditions. The lipases tested display a typical behaviour, characteristic of each enzyme, which allowed us to classify the lipases in groups according to (1) the profiles of enzyme velocity as a function of surface pressure, (2) their preferences for a given diglyceride isomer, quantified using new parameters termed steroselectivity index (S.I.), vicinity index (V.I.), and surface pressure threshold (S.P.T.). The general observation, true for all the enzymes tested, is that the three substrates are well differentiated, and the differentiation is more pronounced at high interfacial energy (low surface pressure). This observation supports our hypothesis that lipase conformational changes, resulting from the enzymesurface interaction, affect the enzymes' specificities. Generally speaking, the stereopreference for either sn‐1 or sn‐3 position on glycerides is maintained both in the case of di‐ and tri‐glycerides. © 1995 Wiley‐Liss, Inc.
GABAB antagonists: Enantiopharmacology of 5‐amino‐4‐hydroxy‐2‐methylvaleric acid and X‐ray structure of the eutomer
Authors: Frydenvang Karla , Kristiansen Uffe , Frølund Bente , Herdeis Claus , Krogsgaard‐Larsen Povl
Published: January 2005

We have previously shown that (R)‐5‐amino‐4‐hydroxyvaleric acid [(R)‐4‐OH‐DAVA] and (S)‐2‐OH‐DAVA bind to GABAB receptor sites and antagonize GABAB receptor‐mediated function in a stereoselective manner. Furthermore, we have identified energy‐minimized superimposable conformations of (R)‐4‐OH‐ and (S)‐2‐OH‐DAVA which are assumed to reflect the receptor‐active conformations of these compounds. This paper describes the in vitro enantiopharmacology of 5‐amino‐4‐hydroxy‐2‐methylvaleric acid (2‐Me‐4‐OH‐DAVA). Whereas none of the four stereoisomers showed significant affinity for GABAA receptor sites or GABA uptake mechanisms in rat brain synaptic membranes, (2R,4R)‐2‐Me‐4‐OH‐DAVA was shown to inhibit stereoselectively the binding of [3H]GABA to rat brain GABAB receptor sites (IC50 = 14 ± 4 μM). (2R,4R)‐2‐Me‐4‐OH‐DAVA (Ki = 36 μM) and, with much lower potency, (2S,4R)‐2‐Me‐4‐OH‐DAVA (Ki = 370 μM) stereoselectively antagonized GABAB receptor‐mediated function in the isolated guinea pig ileum. The structure of the eutomer, (2R,4R)‐2‐Me‐4‐OH‐DAVA, was established by an X‐ray crystallographic analysis, and the solid‐state conformation of (2R,4R)‐2‐Me‐4‐OH‐DAVA was compared with the proposed receptor‐active conformations of (R)‐4‐OH‐DAVA and (S)‐2‐OH‐DAVA. © 1995 Wiley‐Liss, Inc.
Oxidation of 2‐(2‐bromoethyl)bromobenzene with toluene dioxygenase: Isolation and identification of new chiral synthons
Authors: Stabile Michele R. , Hudlicky Tomas , Meisels Meredith L. , Butora Gabor , Gum Andrew G. , Fearnley Stephen P. , Thorpe Andrew J. , Ellis Matthew R.
Published: January 2005

2(2‐Bromoethyl)bromobenzene was subjected to microbial oxidation by the whole cells of Pseudomonas putida 39/D and JM109(pDTG601) yielding (3R,4S)‐2‐(2‐bromoethyl)‐bromocyclohexa‐1,5‐diene‐3,4‐diol. © 1995 Wiley‐Liss, Inc.
Thermal behaviour, phase diagram, and spectroscopic properties of rac‐indobufen and its enantiomers
Authors: Vigevani Aristide , Zampieri Massimo
Published: January 2005

The binary phase diagram of the enantiomers of indobufen, 1 (Ibustrin), an antithrombotic drug, has been investigated by differential scanning calorimetry (DSC); 1 is a racemic compound (racemate) with melting point lower than that of the enantiomers. Its thermal behaviour (DSC) has been examined and is discussed in comparison with other physical methods (IR spectroscopy and X‐ray powder diffraction). Absolute configuration has been assigned to the enantiomers by 1H‐NMR correlations. © 1995 Wiley‐Liss, Inc.
Direct HPLC separation of enantiomers of pantoprazole and other benzimidazole sulfoxides using cellulose‐based chiral stationary phases in reversed‐phase mode
Authors: Tanaka Makoto , Yamazaki Hideki , Hakusui Hideo
Published: January 2005

A direct, isocratic, and simple reversed‐phase HPLC method was described for the separation of enantiomers of the proton pump inhibitor, rac‐pantoprazole (PAN) using cellulose‐based chiral stationary phases (Chiralcel OD‐R and Chiralcel OJ‐R). Some structurally related chiral benzimidazole sulfoxides, rac‐omeprazole (OME) and raclansoprazole (LAN), were also studied. Chiralcel OJ‐R was successful in the resolution of enantiomers of rac‐PAN and rac‐OME, while Chiralcel OD‐R was most suitable for resolving the enantiomers of rac‐LAN. Highest enantioselectivity to rac‐PAN and rac‐OME was achieved on Chiralcel OJ‐R by using acetonitrile as an organic modifier, whereas methanol afforded better resolution of rac‐LAN on Chiralcel OD‐R than acetonitrile. Increases in buffer concentration and column temperature decreased retention and did not improve the resolution of the enantiomers on both columns. Using a mixture of 50 mM sodium perchlorate solution and acetonitrile as a mobile phase at a flow rate of 0.5 ml/min, maximum separation factors of 1.26 and 1.13 were obtained for the enantiomers of rac‐PAN and rac‐OME using a Chiralcel OJ‐R column, while maximum separation factor of 1.16 was obtained for the enantiomers of rac‐LAN using a Chiralcel OD‐R column. © 1995 Wiley‐Liss, Inc.
Synthesis of one diastereomeric couple of the mucolytic drug domiodol [(4S, 2R,S)‐2‐iodomethyl‐4‐hydroxymethyl‐1,3‐dioxolane] from D‐mannitol as chiral starting material
Authors: Ferraboschi Patrizia , Grisenti Paride , Santaniello Enzo
Published: January 2005

The acid‐catalyzed reaction of D‐mannitol 4 with bromoacetaldehyde diethyl acetal followed by periodate cleavage of the corresponding diacetal 5 afforded (4S, 2R, S)‐2‐bromomethyl‐4‐hydroxymethyl‐1,3‐dioxolane 3c in good yields, from which the title compound 1 is obtained by displacement of the bromine with lithium iodide. © 1995 Wiley‐Liss, Inc.
Toxicokinetics of a single intravenous dose of rac‐propranolol versus optically pure propranolol in the rat
Authors: Bode Wilhelmina , Toet Arthur E. , Stolker Alida A. M. , Van Ginkel Leendert A. , Groen Kees , Wemer Johan , De Wildt Dick J.
Published: January 2005

Conscious male Wistar SPF Riv:TOX rats were dosed intravenously with 2.5, 5, or 10 mg/kg rac‐propranolol·HCl, or with 5 mg/kg of either (‐)‐(S)‐ or (+)‐(R)‐propranolol·HCl. Disposition of (‐)‐(S)‐ and (+)‐(R)‐propranolol after dosing of rac‐propranolol was linear in the dose range examined. Total plasma clearance was not changed in animals dosed with the individual enantiomers compared to the animals that were dosed with rac‐propranolol. However, for (‐)‐(S)‐propranolol both volume of distribution and elimination half‐life decreased, whereas for (+)‐(R)‐propranolol increases were observed for these characteristics, in animals dosed with the individual enantiomers. Our observations suggest that the (+)‐(R)‐enantiomer competes with (‐)‐(S)‐propranolol for plasma protein binding sites, resulting in lower plasma protein binding of the (‐)‐(S)‐enantiomer when the racemate is administered. From recent toxicological experiments, it was concluded that rac‐propranolol is more toxic than the individual enantiomers in the rat, when dosed iv at the same total mass. It is concluded that the observed potentiation of toxic effects of propranolol enantiomers when administered as a racemate can at least partly be explained by a pharmacokinetic interaction. © 1995 Wiley‐Liss, Inc.
Estimation of the rate and extent of chiral inversion using linear systems analysis
Authors: McLachlan Andrew J. , Williams Kenneth M.
Published: January 2005

An alternative method based on linear systems analysis is presented for the analysis of concentration‐time data for the enantiomers of the 2‐arylpropionic acids. This approach uses deconvolution to estimate the rate and extent of chiral inversion with respect to time, assuming linear pharmacokinetics and time invariance, without the need for complicated modelling procedures. Application to data for the chiral inversion of ibuprofen in the rat indicates that this approach provides a valid alternative to previous procedures for the analysis of chiral inversion data. © 1995 Wiley‐Liss, Inc.
Combined synthetic/CD strategy for the preparation and configurational assignments of model acyclic 1,3‐polyols with a 1,2‐diol terminal
Authors: Zhao Ning , Zhou Peng , Berova Nina , Nakanishi Koji
Published: January 2005

Acyclic 1,3‐polyols or skipped polyols are widely distributed in nature. Particularly skipped 1,3‐polyols with a terminal 1,2‐diol group are present in numerous antifungal polyene macrolides in various masked forms. Although over 200 polyene macrolides are known, the planar structures of only about 40 have been determined, while those for which the full stereochemistry has been elucidated is less than ten. No simple method exists for configurational assignments of the 1,3‐polyols moieties; moreover, this class of compounds are difficult to crystallize. In order to develop a general chiroptical method for structure determination of acyclic 1,3‐polyols, we have combined a divergent synthetic approach with CD to prepare all possible stereoisomers of 1,2,4‐triols, 1,2,4,6‐tetrols and 1,2,4,6,8‐pentols. The current set of reference polyols should be useful for setting up reference CD libraries and for model studies leading to a general method for configurational assignment of acyclic polyols. This strategy can be used to synthesize further extended members of acyclic 1,3‐polyols and mixed 1,2/1,3‐polyols which can be used for structural investigations of polyene macrolides and related compounds. © 1995 Wiley‐Liss, Inc.
Taxanes with anthracyclines as first‐line chemotherapy for metastatic breast carcinoma
Authors: Bria Emilio , Giannarelli Diana , Felici Alessandra , Peters William P. , Nisticò Cecilia , Vanni Barbara , Cuppone Federica , Cognetti Francesco , Terzoli Edmondo
Published: January 2005

BACKGROUND

The magnitude of the benefit of adding taxanes to anthracyclines in first‐line chemotherapy for metastatic breast carcinoma is still unclear. The authors performed a pooled analysis as well as a meta‐analysis of all Phase III trials, to determine whether the combination of anthracyclines plus taxanes provided an advantage over standard anthracyclines‐based regimens.

METHODS

All Phase III peer‐reviewed published or presented trials were considered eligible. A pooled analysis (Method A) and a literature‐based meta‐analysis (Method B) were accomplished, and event‐based relative risk ratios (RRA–B) with 95% confidence intervals were derived. Both analyses were performed to examine for significant differences in time to disease progression (TTP), overall response rate (ORR), overall survival (OS), complete response rate (CR), neutropenia, and febrile neutropenia (FN). For both analyses, a heterogeneity test was applied.

RESULTS

Seven trials (2805 patients) were gathered. When data were pooled and plotted, significant differences in favor of taxanes were seen for ORR (RRA–B 1.21, P < 0.001), CR (RRA 2.04; RRB 1.81, P < 0.001), even though they caused a significant increase in neutropenia (RRA 1.19; RRB 1.15, P < 0.001) and FN (RRA 2.82; RRB 3.44, P < 0.001). A borderline significance in favor of taxanes was seen in TTP (RRA 1.10, P = 0.05; RRB 1.06, P = 0.07). A nonsignificant trend for taxanes was found in OS. No significant heterogeneity (except for neutropenia, P < 0.01) was observed.

CONCLUSIONS

The adjunction of taxanes to anthracyclines in first‐line chemotherapy for metastatic breast carcinoma yielded a significant benefit in activity (ORR, CR), a slight advantage in TTP, and a trend in OS, although with a significant cost in hematologic toxicity. Cancer 2005. © 2005 American Cancer Society.
Serum vascular endothelial growth factor (VEGF) and VEGF‐C levels as tumor markers in patients with cervical carcinoma
Authors: Mitsuhashi Akira , Suzuka Kiyomi , Yamazawa Koji , Matsui Hideo , Seki Katsuyoshi , Sekiya Souei
Published: January 2005

BACKGROUND

Vascular endothelial growth factor (VEGF) and VEGF‐C play a crucial role in the regulation of tumor growth and metastasis. The current study examined the significance of serum VEGF and VEGF‐C levels in relation to conventional clinicopathologic parameters, response to treatment, and survival in patients with cervical carcinoma.

METHODS

Between December 1999 and March 2004, serum VEGF and VEGF‐C levels were analyzed in 78 patients with cervical carcinoma undergoing primary treatment (primary surgery [n = 40] and radiotherapy [n = 38]), as well as in 30 healthy controls. Serum VEGF and VEGF‐C levels were assessed by enzyme‐linked immunosorbent assay before and within 2 weeks after treatment.

RESULTS

Serum VEGF and VEGF‐C levels were higher in patients with cervical carcinoma than in the healthy control (P = 0.0002 and P = 0.0007, respectively). Both VEGF and VEGF‐C concentrations increased significantly in patients with squamous cell carcinoma (SCC vs. normal control: P < 0.0001 and P = 0.0001, respectively), but not in adenocarcinoma (vs. normal control: P = 0.2982 and P = 0.7766, respectively). In an analysis of SCC, the pretherapeutic serum levels of VEGF and VEGF‐C correlated significantly with advanced International Federation of Gynecology and Obstetrics stage and large tumor size, but not with lymph node metastasis. The pretherapeutic serum level of VEGF‐C also correlated significantly with disease recurrence or persistence after treatment. Both serum VEGF and VEGF‐C levels decreased significantly after treatment.

CONCLUSIONS

The serum levels of both VEGF and VEGF‐C have potential usefulness as biologic markers of SCC of the uterine cervix. Cancer 2005. © 2005 American Cancer Society.
Preradiation chemotherapy with methotrexate, cisplatin, 5‐fluorouracil, and leucovorin for pediatric nasopharyngeal carcinoma
Authors: Rodriguez‐Galindo Carlos , Wofford Marcia , Castleberry Robert P. , Swanson Gregory P. , London Wendy B. , Fontanesi James , Pappo Alberto S. , Douglass Edwin C.
Published: January 2005

BACKGROUND

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for < 1% of all cases. Treatment most commonly includes radiotherapy but long‐term side effects of such treatment can produce devastating cosmetic and functional sequelae in children. Chemotherapy may help to decrease the radiotherapy dose and limit the side effects of local therapies. However, little is known regarding the chemosensitivity of NPC tumors in pediatric patients.

METHODS

Patients with American Joint Committee on Cancer (AJCC) Stage I/II disease (Stratum 01) received irradiation only. Patients with AJCC Stage III/IV disease (Stratum 02) received 4 courses of preradiation chemotherapy comprising methotrexate (120 mg/m2) on Day 1, with cisplatin (100 mg/m2) 24 hours later, 5‐fluorouracil 1000 mg/m2 per day as a continuous infusion for 3 days, and leucovorin 25 mg/m2 every 6 hours for 6 doses. Irradiation was given after chemotherapy and consisted of 50.4 gray (Gy) to the upper neck and 45.0 Gy to the lower neck, with a boost to the primary tumor and positive lymph nodes for a total dose of 61.2 Gy.

RESULTS

One patient was enrolled in Stratum 01 and 16 evaluable patients were enrolled in Stratum 02. The median age of the patients was 13 years and 65% of the patients were black. All patients tested had evidence of Epstein–Barr virus infection. Two‐thirds of the patients developed Grade 3–4 mucositis during chemotherapy. The overall response rate to induction chemotherapy was 93.7%. The overall 4‐year event‐free and overall survival rates (± the standard error) were 77% ± 12% and 75% ± 12%, respectively.

CONCLUSIONS

The current study demonstrated that childhood NPC was sensitive to chemotherapy and that chemotherapy before irradiation was feasible. Future trials should investigate equivalent efficacy with a reduced radiotherapy dose. Cancer 2005. © 2005 American Cancer Society.
A phase II trial of continuous infusion of 5‐fluorouracil, mitoxantrone, and cisplatin for metastatic hepatocellular carcinoma
Authors: Ikeda Masafumi , Okusaka Takuji , Ueno Hideki , Takezako Yoriko , Morizane Chigusa
Published: January 2005

BACKGROUND

The aim of the current study was to evaluate the antitumor activity and toxicity of continuous infusion of 5‐fluorouracil, mitoxantrone, and cisplatin (FMP therapy) in chemotherapy‐naive patients with metastatic hepatocellular carcinoma (HCC).

METHODS

Fifty‐one patients with metastatic HCC who had not undergone previous systemic chemotherapy were enrolled. The therapy consisted of intravenous administration of 80 mg/m2 cisplatin and 6 mg/m2 mitoxantrone on Day 1 and continuous intravenous infusion of 450 mg/m2 5‐fluorouracil per day on Days 1–5. The treatment was repeated every 4 weeks for a maximum of 6 courses with dose adjustments based on the observed toxic effects if there was no evidence of tumor progression or unacceptable toxicity.

RESULTS

Of the 51 enrolled patients, 14 (27%) achieved a partial response (95% confidence interval, 16–42%) with a median duration of 7.6 months (range, 2.3–18.4 months). Twenty‐seven patients (53%) showed no change and 9 (18%) had progressive disease. The median survival time, 1‐year survival rate, and median progression‐free survival time for all patients were 11.6 months, 44.3%, and 4.0 months, respectively. The main Grade 3 and 4 toxicities were leukocytopenia (67%), neutropenia (71%), thrombocytopenia (27%), and elevated levels of aspartate aminotransferase (37%) and alanine aminotransferase (41%). These symptoms were generally brief and reversible, with the exception of one treatment‐related death due to acute hepatic failure.

CONCLUSIONS

FMP therapy had significant antitumor activity with acceptable toxicity in patients with metastatic HCC. Cancer 2005. © 2005 American Cancer Society.
Five‐day courses of irinotecan as palliative therapy for patients with neuroblastoma
Authors: Kushner Brian H. , Kramer Kim , Modak Shakeel , Cheung Nai‐Kong V.
Published: January 2005

BACKGROUND

The authors describe a large experience using short courses of irinotecan for palliative therapy in patients with neuroblastoma (NB). Quality of life was a major issue in choosing this regimen for patients whose disease was resistant to standard anti‐NB therapies.

METHODS

A retrospective review was conducted of all patients who were followed by the Department of Pediatrics at Memorial Sloan‐Kettering Cancer Center and treated for resistant NB with irinotecan at 50 mg/m2 per day for 5 days as a 1‐hour intravenous infusion. Treatment was outpatient, and there was a minimum 2‐week rest period between courses. Granulocyte colony‐stimulating factor was used to keep the absolute neutrophil count > 500–1000/mL.

RESULTS

Forty‐four patients had been treated aggressively and/or extensively before they received one or more five‐day courses of irinotecan. Emetogenic, diarrheal, and myelosuppressive effects were readily managed. Hospitalizations were limited to three patients with bacteremia. Twenty‐three patients had a change in therapy, although they did not have progressive disease (PD) after receiving 1 (n = 10), 2 (n = 3), 3 (n = 1), 4 (n = 6), 7 (n = 1 patient), 22 (n = 1 patient), or 24 (n = 1) courses. The most common reasons for changing treatment were to intensify retrieval therapy or to pursue immunotherapy. Of those 23 patients, 15 patients had stable disease, 7 were not evaluable for response because of concurrent radiotherapy, and 1 patient had a major response. Twenty‐one patients had PD after 1 (n = 3, 2 (n = 9), 4 (n = 2), 5 (n = 1), 6 (n = 3), 7 (n = 1), 9 (n = 1), and 11 (n = 1) courses.

CONCLUSIONS

In heavily treated patients, the regimen studied was well tolerated, allowed patients to continue most normal life activities, and produced anti‐NB effects. Its modest toxicity supported use with other antitumor agents. Cancer 2005. © 2005 American Cancer Society.
Structure and Electronic Properties of Fullerenes C52q+: Is C522+ an Exception to the Pentagon Adjacency Penalty Rule?
Authors: Díaz‐Tendero Sergio , Martín Fernando , Alcamí Manuel
Published: January 2005

The structure, vibrational spectra and electronic properties of the neutral, singly and doubly charged C52 fullerenes were studied by means of the Hartree–Fock method and density functional theory. Different isomers were considered, in particular those with the lowest possible number (five or six) of adjacent pentagons, and an isomer with a four‐atom ring. For neutral and singly charged species, the most stable isomer is that with the lowest number of adjacent pentagons, namely five. However, for C522+, the most stable structure has six adjacent pentagons. This finding, which contradicts the pentagon adjacency penalty rule, is a consequence of complete filling of the HOMO π shell and the near‐perfect sphericity of the most stable isomer. The simulated vibrational spectra show important differences in the positions and intensities of the vibrations for the different isomers.
Surface‐ and Resonance‐Enhanced Micro‐Raman Spectroscopy of Xanthene Dyes: From the Ensemble to Single Molecules
Authors: Vosgröne T. , Meixner A. J.
Published: January 2005

Surface‐enhanced resonance Raman scattering (SERRS) spectra of various rhodamine dyes, of pyronine G and thiopyronine adsorbed on isolated silver clusters were recorded at the ensemble level and at the single‐molecule level with a high‐resolution confocal laser microscope equipped with a spectrograph and a CCD‐detector. Comparing single‐molecule spectra with ensemble spectra, various inhomogeneous spectral features, such as line splitting, spectral wandering, spectral diffusion and abrupt spectral jumps between different metastable spectral states, are revealed in temporal sequences of spectra; these affect both the frequency positions and the relative intensities of the vibronic bands. Resonance enhancement is investigated with respect to single‐molecule surface‐enhanced Raman scattering (SERS) spectroscopy and is found to be responsible for approximately three orders of magnitude in sensitivity. A significant influence of the substituents on the single‐molecule SERRS sensitivity is found, showing that various chemical effects are responsible for surface enhancement in addition to the electromagnetic enhancement effect.
A Microscopic Model for the Fluctuations of Local Field and Spontaneous Emission of Single Molecules in Disordered Media
Authors: Vallée Renaud A. L. , Van Der Auweraer Mark , De Schryver Frans C. , Beljonne David , Orrit Michel
Published: January 2005

We develop a microscopic model to describe the observed temporal fluctuations of the fluorescence lifetime of single molecules embedded in a polymer at room temperature. The model represents the fluorescent probe and the macromolecular matrix on the sites of a cubic lattice and introduces voids in the matrix to account for its mobility. We generalize Lorentz's approach to dielectrics by considering three domains of electrostatic interaction of the probe molecule with its nanoenvironment: 1) the probe molecule with its elongated shape and its specific polarizability, 2) the first few solvent shells with their discrete structure and their inhomogeneity, 3) the remainder of the solvent at larger distances, treated as a continuous dielectric. The model is validated by comparing its outcome for homogeneous systems with those of existing theories. When realistic inhomogeneities are introduced, the model correctly explains the observed fluctuations of the lifetimes of single molecules. Such a comparison is only possible with single‐molecule observations, which provide a new access to local field effects.
Arias‐Stella reaction in a cervicovaginal smear of a woman undergoing infertility treatment: A case report
Authors: Lui Millie , Boerner Scott
Published: January 2005

Arias‐Stella reaction commonly is seen in gestational endometrium, but rarely is described outside the endometrium, particularly in nonpregnant women. Although the cytological diagnoses of Arias‐Stella reaction by cervical Papanicolaou (Pap) smears in pregnant, postpartum, and postabortal women are documented, to our knowledge, this is the first report of Arias‐Stella reaction in a cervicovaginal smear of a nonpregnant woman undergoing infertility treatment with clomiphene and beta‐human chorionic gonadotropin (β‐HCG). The cytological features observed in this case were characteristic of Arias‐Stella reaction but mimic malignancy leading to initial misinterpretation. It is of paramount importance to recognize this phenomenon in cervical Pap smears, especially in women receiving ovulation‐inducing agents and exogenous hormonal treatment to avoid this potential cytological pitfall. Diagn. Cytopathol. 2005;32:94–96. © 2005 Wiley‐Liss, Inc.