bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of near‐infrared (NIR) spectroscopy for screening of raw materials used in the cell culture medium for the production of a recombinant therapeutic protein
Authors: Kirdar Alime Ozlem , Chen Guoxiang , Weidner James , Rathore Anurag S. 
Published: November 2009

AbstractControl of raw materials based on an understanding of their impact on product attributes has been identified as a key aspect of developing a control strategy in the Quality by Design (QbD) paradigm. This article presents a case study involving use of a combined approach of Near‐infrared (NIR) spectroscopy and Multivariate Data Analysis (MVDA) for screening of lots of basal medium powders based on their impact on process performance and product attributes. These lots had identical composition as per the supplier and were manufactured at different scales using an identical process. The NIR/MVDA analysis, combined with further investigation at the supplier site, concluded that grouping of medium components during the milling and blending process varied with the scale of production and media type. As a result, uniformity of blending, impurity levels, chemical compatibility, and/or heat sensitivity during the milling process for batches of large‐scale media powder were deemed to be the source of variation as detected by NIR spectra. This variability in the raw materials was enough to cause unacceptably large variability in the performance of the cell culture step and impact the attributes of the resulting product. A combined NIR/MVDA approach made it possible to finger print the raw materials and distinguish between good and poor performing media lots. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010
Out of control? An ethnographic analysis of the disposal of collectable objects through auction
Authors: Cheetham Fiona 
Published: November 2009

Abstract

This research contributes to our understanding of disposal by attempting to foreground the journey of the disposed object rather than examining disposal from the perspective of the seller as previous consumer researchers have done. Drawing on ideas taken from anthropological analyses of objects and markets the paper provides a glimpse of the cultural biographies of a number of collectable objects as they are disposed of through the public arena of auction. Analysing the disposal of meaningful possessions through auction provides a different context and associated dynamics to that studied in previous research on disposal. Ethnographic analysis indicates that in spite of the fact that the practices and rituals of auction facilitate a process of commoditisation which erases the cultural biography of objects, still traces of their previous cultural history transfer with these objects to their new owners. The objects themselves are implicated in this transfer of meaning indicating that objects do have some kind of social agency.

Copyright © 2009 John Wiley & Sons, Ltd.
Drug Metabolism for the Perplexed Medicinal Chemist
Authors: Testa Bernard 
Published: November 2009

AbstractTwo related and significant issues may elicit perplexity in medicinal chemists and are discussed here. First, a broad presentation of the pharmacological and toxicological consequences of drug metabolism should justify the significance of drug metabolism and serve as an incentive to further study. When comparing the pharmacological activities of a drug and its metabolite(s), a continuum is found which ranges from soft drugs (no active metabolites) to prodrugs (inactiveper se, as illustrated here with clopidogrel and prasugrel). Innumerable intermediate cases document drugs whose activity is shared by one or more metabolites, as exemplified with tamoxifen. The toxicological consequences of metabolism at the molecular, macromolecular, and macroscopic levels are manyfold. A brief overview is offered together with a summary of the reactions of toxification and detoxification of the antiepileptic valproic acid.The second issue discussed in the review is a comparison of the relative significance of cytochromes P450 and other oxidoreductases (EC 1), hydrolases (EC 3), and transferases (EC 2) in drug metabolism, based on a ‘guesstimate’ of the number of drug metabolites that are known to be produced by them. The conclusion is that oxidoreductases are the main enzymes responsible for the formation of toxic or active metabolites, whereas transferases play the major role in producing inactive and nontoxic metabolites.
Impact of Acute Streptozotocin‐Induced Diabetes on ABC Transporter Expression in Rats
Authors: Anger Gregory J. , Magomedova Lilia , Piquette‐Miller Micheline 
Published: November 2009

AbstractHepatic ABC efflux transporters control the cellular uptake (in basolateral membranes) and excretion (in apical membranes) of many substrates. Since type‐1 diabetes mellitus (T1DM) is associated with altered hepatobiliary excretion of many endogenous and exogenous substances, we examined key hepatic ABC transporters and levels of the endogenous substrate glutathione in rats with acute streptozotocin‐induced T1DM. Renal transporters and inflammatory markers were also examined.Abcb1, Abcc1–4, andAbcg2were measured using qRT‐PCR. Glutathione was measured in liver tissue, plasma, and urine. Inflammatory markers, including C‐reactive protein (CRP), were measured in plasmaviaELISA. In diabetic rats,Abcb1a, Abcc2, andAbcg2(apical) were decreased, whileAbcc4(basolateral) was increased.Abcb1aandAbcc2inversely correlated with plasma CRP. Diabetic and control rats exhibited similar hepatic glutathione, but levels in diabetic plasma were lower. When standardized to urinary output, diabetic rats excreted 6.7‐fold more glutathione in urine than controls. Renal transporter levels were normal in diabetic rats. Results show apical transporters involved in hepatobiliary excretion are downregulated in T1DM, possibly through an inflammation‐mediated process. Findings suggest that there may be a vectorial shift from hepatic to renal excretion for some substrates in T1DM.
Probabilistic Prediction of the Human CYP3A4 and CYP2D6 Metabolism Sites
Authors: Dapkunas Justas , Sazonovas Andrius , Japertas Pranas 
Published: November 2009

AbstractThis article briefly introduces the results ofin silicoprediction of the most probable metabolism sites for the human cytochrome P450 3A4 and 2D6 isoforms. Ligand‐based QSAR models have been developed using a novel GALAS modeling approach, and provide probabilities of being a target of CYP3A4 or CYP2D6 for any atom in a molecule. The GALAS‐model development methodology allows evaluation of the reliability of predictions in the form of estimated prediction Reliability Indices (RIs). For all the models considered in this study, the number of misclassifications and inconclusive results was reduced significantly when only predictions of high quality (RI>0.5) were taken into account, demonstrating thatRIreflects accuracy of prediction. The applicability domain of regioselectivity models is shown to be easily expandable to cover compound classes of interest to the user. The results obtained so far show promising perspectives for the utilization of the GALAS modeling in the analysis of regioselectivity for other important biotransformation enzymes – a work currently in progress.
Lipophilicity Determination of Highly Lipophilic Compounds by Liquid Chromatography
Authors: Guillot Amandine , Henchoz Yveline , Moccand Cyril , Guillarme Davy , Veuthey Jean‐Luc , Carrupt Pierre‐Alain , Martel Sophie 
Published: November 2009

AbstractDifferent experimental strategies using short columns in both conventional liquid chromatography (HPLC) and ultra‐high pressure liquid chromatography (UHPLC) were evaluated to allow, for the first time with these techniques, the lipophilicity determination of compounds with log P>5. Various organic modifiers, stationary phases, and elution modes were tested on 14 rigid compounds with a CLogP between 5 and 8, and 38 compounds with log Poct from 0 to 5. The best results in HPLC were obtained with the 20‐mm Discovery ® RP Amide C16 stationary phase in isocratic mode using MeOH as organic modifier. To improve analysis time, the UHPLC approach was then evaluated. Consequently, a generic method was developed with a 30‐mm Acquity BEH Shield RP18 column in gradient mode using MeOH as organic modifier, allowing a fourfold gain of time compared to the HPLC method, for the highly lipophilic compounds tested. Finally, the most rapid and accurate results were obtained with a 10‐mm HypersilTM GOLD Javelin HTS stationary phase in UHPLC, enabling an eightfold gain of time compared to the HPLC method.
Prediction of Pharmacokinetic Profile of Valsartan in Humans Based onin vitroUptake‐Transport Data
Authors: Poirier Agnès , Cascais Anne‐Christine , Funk Christoph , Lavé Thierry 
Published: November 2009

AbstractThe aim of this study was to evaluate a physiologically based pharmacokinetic (PBPK) model for predicting PK profiles in humans based on a model refined in rats and humansin vitrouptake‐transport data using valsartan as a probe substrate. Valsartan is eliminated unchanged, mostly through biliary excretion, both in humans and rats. It was, therefore, chosen as model compound to predictin vivoelimination based onin vitrohepatic uptake‐transport data using a fully mechanistic PBPK model. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used forin vitrouptake experiments. A mechanistic two‐compartment model was used to derive the active and passive transport parameters, namely uptakeMichaelis–Mentenparameters (VmaxandKm,u) together with passive diffusion (Pdif). These transport parameters were then used as input in a whole body physiologically based pharmacokinetic (PBPK) model. The uptake rate of valsartan was higher for rat hepatocytes (Km,u=28.4±3.7 μM,Vmax=1320±180 pmol/mg/min, andPdif =1.21±0.42 μl/mg/min) compared to human hepatocytes (Km,u=44.4±14.6 μM,Vmax=304±85 pmol/mg/min, andPdif=0.724±0.271 μl/mg/min). OATP1B1 and ‐1B3 parameters were correlated to human hepatocyte data, using experimentally established relative activity factors (RAF). Resulting PBPK simulations were compared for plasma‐ (humans and rats) and bile‐ (rats) concentration–time profiles following iv bolus administration of valsartan. Plasma clearances (CLP) for rats and humans were predicted within twofold relative to predictions based on respectivein vitrodata. The simulations were extended to simulate the impact of either OATP1B1 or ‐1B3 inhibition on plasma profile. The limited data set indicates that the mechanistic model allowed for accurate evaluation ofin vitrotransport data; and the resulting hepatic uptake transport kinetic parameters enabled the prediction ofin vivoPK profiles and plasma clearances, using PBPK modelling. Moreover, the interspecies difference in elimination rate observedin vivowas correctly reflected in the transport parameters determinedin vitro.
Recent Advances in Physicochemical and ADMET Profiling in Drug Discovery
Authors: Wang Jianling , Skolnik Suzanne 
Published: November 2009

AbstractThe drastic increase in the cost for discovering and developing a new drug along with the high attrition rate of development candidates led to shifting drug‐discovery strategy to parallel assessment of comprehensive drug physicochemical, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties alongside efficacy. With the proposal of a profiling paradigm and utilization of integrated risk assessment, one can exponentially enhance the predictive power of in vitro tools by taking into consideration the interplay among profiling parameters. In particular, this article will review recent advances in accurate assessment of solubility and other physicochemical parameters. The proper interpretation of these experimental data is crucial for rapid and meaningful risk assessment and rational optimization of drug candidates in drug discovery. The impact of these tools on assisting drug‐discovery teams in establishing in vitro–in vivo correlation (IVIVC) as well as structure–property relationship (SPR) will be presented.
A Fast Method for pKa Determination by Capillary Electrophoresis
Authors: Fuguet Elisabet , Ràfols Clara , Bosch Elisabeth , Rosés Martí 
Published: November 2009

AbstractIn this article, we describe a recently developed capillary‐electrophoresis method for the determination of acidity constants and compare it with other existing methods. The new method is based on the use of an internal standard (compound similar in nature and pKa value to the analyte), and offers several benefits, since it has all the advantages of capillary electrophoresis. In addition, it is very fast, because the exact measure of the pH of the separation electrolytes is not needed, and only a few electrophoretic runs are required to perform a pKa determination. The acidity constants of some monoprotic weak acids and bases were determined by this fast method, yielding a very good agreement with literature values.
Kinetic and Thermodynamic Solubility Values of Some Bioactive Compounds
Authors: Shoghi Elham , Fuguet Elisabet , Ràfols Clara , Bosch Elisabeth 
Published: November 2009

AbstractThermodynamic solubility is a decisive physicochemical property in drug development. The Chasing Equilibrium method offers an alternative to the classical procedures to measure the solubility of compounds with acid–base properties. The method is fast and yields accurate results. In this work, the solubility of several compounds including acids and bases was determined through the Chasing Equilibrium approach. A study of experimental conditions in terms of sample weight was performed to measure solubilities. The study shows that only a limited range of weights, depending on the nature and solubility of the compounds, is adequate to obtain reliable results.
Transporters – The View from Industry
Authors: Kohl Christopher 
Published: November 2009

AbstractThe involvement of transport proteins in the disposition of drugs is receiving much attention of the scientific community. Recently, researchers from academia have surmised that drug transport rather than passive diffusion is the regular mechanism for molecules to cross cell membranes. On bare face value, however, sound evidence of the impact of transport proteins on clinical pharmacokinetics has been a trickle rather than a stream of convincing studies during the last decade, in stark contrast to the number of in vitro studies published. Progress in this area may have been impeded by a number of factors. Only a limited number of small‐molecule drugs fall within the physicochemical property space (i.e., high hydrophilicity and low passive permeability) that makes them predestined as transport protein substrates without other pharmacokinetic processes (e.g., passive diffusion, metabolism, nonspecific binding to tissue proteins) blurring the picture. The vast majority of drug molecules are lipophilic enough to be amenable to passive diffusion across cell membranes and to undergo metabolism to some extent. In these cases, clinical evidence relies heavily on the observation of pharmacokinetic drug–drug interactions not readily explained by the interference with drug metabolizing enzymes. Given the circumstances outlined above, it is not surprising that, based upon clinical observations, the final assessment as to the overall relevance of drug transport for clinical pharmacokinetics is still pending.
Influence of Ionization State on the Activation of Temocapril by hCES1: A Molecular‐Dynamics Study
Authors: Vistoli Giulio , Pedretti Alessandro , Mazzolari Angelica , Bolchi Cristiano , Testa Bernard 
Published: November 2009

AbstractTemocapril is a prodrug whose hydrolysis by carboxylesterase 1 (CES1) yields the active ACE inhibitor temocaprilat. This molecular‐dynamics (MD) study uses a resolved structure of the human CES1 (hCES1) to investigate some mechanistic details of temocapril hydrolysis. The ionization constants of temocapril (pK1 and pK3) and temocaprilat (pK1, pK2, and pK3) were determined experimentally and computationally using commercial algorithms. The constants so obtained were in good agreement and revealed that temocapril exists mainly in three ionic forms (a cation, a zwitterion, and an anion), whereas temocaprilat exists in four major ionic forms (a cation, a zwitterion, an anion, and a dianion). All these ionic forms were used as ligands in 5‐ns MS simulations. While the cationic and zwitterionic forms of temocapril were involved in an ion‐pair bond with Glu255 suggestive of an inhibitor behavior, the anionic form remained in a productive interaction with the catalytic center. As for temocaprilat, its cation appeared trapped by Glu255, while its zwitterion and anion made a slow departure from the catalytic site and a partial egress from the protein. Only its dianion was effectively removed from the catalytic site and attracted to the protein surface by Lys residues. A detailed mechanism of product egress emerges from the simulations.
Engineering Allosteric Regulation into Biological Catalysts
Authors: Fastrez Jacques 
Published: November 2009

AbstractEnzymes and ribozymes constitute two classes of biological catalysts. The activity of many natural enzymes is regulated by the binding of ligands that have different structures than their substrates; these ligands are consequently called allosteric effectors. In most allosteric enzymes, the allosteric binding site lies far away from the active site. This implies that communication pathways must exist between these sites. While mechanisms of allosteric regulation were developed more than forty years ago, they continue to be revisited regularly. The improved understanding of these mechanisms has led in the past two decades to projects to transform several unregulated enzymes into allosterically regulated ones either by rational design or directed evolution techniques. More recently, ribozymes have also been the object of similar successful engineering efforts. In this review, after briefly summarising recent progress in the theories of allosteric regulation, several strategies to engineer allosteric regulations in enzymes and ribozymes are described and compared. These redesigned biological catalysts find applications in a variety of areas.
Induced‐Fit Binding of π‐Electron‐Donor Substrates to Macrocyclic Aromatic Ether Imide Sulfones: A Versatile Approach to Molecular Assembly
Authors: Colquhoun Howard M. , Zhu Zhixue , Williams David J. , Drew Michael G. B. , Cardin Christine J. , Gan Yu , Crawford Andrew G. , Marder Todd B. 
Published: November 2009

AbstractNovel macrocyclic receptors that bind electron‐donor aromatic substrates through π‐stacking donor–acceptor interactions are obtained by cycloimidisation of an amine‐functionalised aryl ether sulfone with pyromellitic and 1,4,5,8‐naphthalenetetracarboxylic dianhydrides. These macrocycles can form complexes with a wide variety of π‐donor substrates, including tetrathiafulvalene, naphthalene, anthracene, pyrene, perylene and functional derivatives of these polycyclic hydrocarbons. The resulting supramolecular assemblies range from simple 1:1 complexes to [2]‐ and [3]pseudorotaxanes and even (as a result of crystallographic disorder) an apparent polyrotaxane. Direct five‐component self‐assembly of a metal‐centred [3]pseudorotaxane is also observed on complexation of a macrocyclic ether imide with 8‐hydroxyquinoline in the presence of palladium(II) ions. Binding studies in solution were carried out by using 1H NMR and UV/Vis spectroscopy, and the stoichiometries of binding were confirmed by Job plots based on the charge‐transfer absorption bands. The highest association constants were found for strong π‐donor guests with large surface areas, notably perylene and 1‐hydroxypyrene, for which Ka values of 1.4×103 and 2.3×103 M−1, respectively, were found. Single‐crystal X‐ray analyses of the receptors and their derived complexes reveal large induced‐fit distortions of the macrocyclic frameworks as a result of complexation. These structures provide compelling evidence for the existence of strong attractive forces between the electronically complementary aromatic π systems of host and guest.
Expanding the Scope of Enantioselective FerroPHANE‐Promoted [3+2] Annulations with α,β‐Unsaturated Ketones
Authors: Pinto Nathalie , Neel Mathilde , Panossian Armen , Retailleau Pascal , Frison Gilles , Voituriez Arnaud , Marinetti Angela 
Published: November 2009

AbstractThe planar chiral 2‐phospha[3]ferrocenophane I has been shown to be the first efficient nucleophilic organocatalyst for the enantioselective synthesis of cyclopentenylphosphonates, through [3+2] cyclizations between diethyl allenylphosphonate and α,β‐unsaturated ketones. The same catalyst has also been applied to the highly enantioselective [3+2] cyclizations of allenic esters with dibenzylideneacetone and analogous bis‐enones, leading to functionalised cyclopentenes with either monocyclic or spirocyclic structures (ee 84–95 %). It has been shown that the residual enone functions in the resulting cyclopentenes can be involved in subsequent cyclization steps to afford unprecedented C2‐symmetric bis‐cyclopentenylketones. In order to provide insight into the behaviour of FerroPHANE I as a chiral catalyst in [3+2] cyclisations, the energetically most favoured isomers of the key phosphine‐allene adduct have been calculated by DFT methods. Factors likely to control the chiral induction process are highlighted.
Macrocyclic DNA‐Mismatch‐Binding Ligands: Structural Determinants of Selectivity
Authors: Granzhan Anton , Largy Eric , Saettel Nicolas , Teulade‐Fichou Marie‐Paule 
Published: November 2009

AbstractA collection of 15 homodimeric and 5 heterodimeric macrocyclic bisintercalators was prepared by one‐ or two‐step condensation of aromatic dialdehydes with aliphatic diamines; notably, the heterodimeric scaffolds were synthesized for the first time. The binding of these macrocycles to DNA duplexes containing a mispaired thymine residue (TX), as well as to the fully paired control (TA), was investigated by thermal denaturation and fluorescent‐intercalator‐displacement experiments. The bisnaphthalene derivatives, in particular, the 2,7‐disubstituted ones, have the highest selectivity for the TX mismatches, as these macrocycles show no apparent binding to the fully paired DNA. By contrast, other macrocyclic ligands, as well as seven conventional DNA binders, show lesser or no selectivity for the mismatch sites. The study demonstrates that the topology of the ligands plays a crucial role in determining the mismatch‐binding affinity and selectivity of the macrocyclic bisintercalators.
Quinoidal Oligothiophenes: Towards Biradical Ground‐State Species
Authors: Ponce Ortiz Rocío , Casado Juan , Rodríguez González Sandra , Hernández Víctor , López Navarrete Juan T. , Viruela Pedro M. , Ortí Enrique , Takimiya Kazuo , Otsubo Tetsuo 
Published: November 2009

AbstractA family of quinoidal oligothiophenes, from the dimer to the hexamer, with fused bis(butoxymethyl)cyclopentane groups has been extensively investigated by means of electronic and vibrational spectroscopy, electrochemical measurements, and density functional calculations. The latter predict that the electronic ground state always corresponds to a singlet state and that, for the longest oligomers, this state has biradical character that increases with increasing oligomer length. The shortest oligomers display closed‐shell quinoidal structures. Calculations also predict the existence of very low energy excited triplet states that can be populated at room temperature. Aromatization of the conjugated carbon backbone is the driving force that determines the increasing biradical character of the ground state and the appearance of low‐lying triplet states. UV/Vis, Raman, IR, and electrochemical experiments support the aromatic biradical structures predicted for the ground state of the longest oligomers and reveal that population of the low‐lying triplet state accounts for the magnetic activity displayed by these compounds.