bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractThe (+)‐, (−)‐, 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

AbstractChiral 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

Abstract(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

Abstract1,2‐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

Abstract(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

AbstractA 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

AbstractHere 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

AbstractWe 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

Abstract2(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

AbstractThe 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

AbstractA 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

AbstractThe 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

AbstractConscious 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

AbstractAn 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

AbstractAcyclic 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

AbstractBACKGROUNDThe 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.METHODSAll 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.RESULTSSeven 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.CONCLUSIONSThe 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

AbstractBACKGROUNDVascular 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.METHODSBetween 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.RESULTSSerum 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.CONCLUSIONSThe 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.