776 research outputs found
Chiroptical properties and conformational flexibility of fenoterol and analogues: a combined experimental and theoretical study
No full textFenoterol is a selective β 2 -adrenergic receptor (AR) agonist used in the treatment of asthma, which is
under scrutiny as possible drug against congestive heart failure. Fenoterol is currently used as a racemic
mixture of the (R,R′)- and (S,S′)-enantiomers, whose stereochemistry was previously determined by
electronic circular dichroism (ECD) analysis through the application of a semi-empirical sector rule. [1]
Recently, a series of fenoterol derivatives has been synthesized and tested: [2-3] their absolute
configuration was determined by chemical correlation with synthetic precursors, but no further
stereochemical characterization has been carried out. In addition, stereoselectivity in the binding to β 2 -
AR has been demonstrated, with (R,R′)- and (R,S′)-fenoterol displaying higher affinity compared to
(S,R′)- and (S,S′)-fenoterol, and a tridimensional quantitative structure-activity relationship model (3D-
QSAR) based on comparative molecular field analysis (CoMFA) has been developed to rationalize the
binding of fenoterol derivatives to β 2 -AR. [2-3]
The relationship between chiroptical properties and absolute stereochemistry of fenoterol and its
derivatives has been investigated [4] by experimental ECD analysis and quantum chemical (QC)
calculations using time-dependent density functional theory (TD-DFT). [5-6] The stereoisomers of three
compounds have been considered: fenoterol (1), (4′′-methoxy-1′′-naphthyl)fenoterol (2), and (4′′-methoxy-
1′-desmethyl)fenoterol (3). Due to the high conformational flexibility of the investigated structures and the
consequent large pool of equilibrium conformers, DFT geometry optimizations were carried out using the
resolution of identity (RI) approximation and the B97D functional with empirical dispersion corrections; [7]
TD-DFT calculations were then performed using the PBE0 functional. The accuracy of this protocol in
reproducing the experimental ECD spectra of fenoterol derivatives will be evaluated.
[1] F. Beigi, C. Bertucci, W. Zhu, K. Chakir, I.W. Wainer, R.P. Xiao, D.R. Abernethy, Chirality, 2006, 18, 822-827.
[2] K. Jóźwiak, K. Chakir, M.J. Tanga, I. Berzetei-Gurske, L. Jimenez, J.A. Kozocas, A. Woo, W. Zhu, R.P. Xiao,
D.R. Abernethy, I.W. Wainer, J. Med. Chem., 2007, 50, 2903-2915.
[3] K. Jóźwiak, A.Y.H. Woo, M.J. Tanga, L. Toll, L. Jimenez, J.A. Kozocas, A. Plazinska, R.P. Xiao, I.W. Wainer,
Bioorg. Med. Chem., 2010, 18, 728-736.
[4] ISCRA project IsC08_SCCFPM (ID: HP10CU0YHL) granted by CINECA, Bologna, Italy.
[5] J. Autschbach, Chirality, 2009, 21, E116-E152.
[6] L. Goerigk, H. Kruse, S. Grimme, in: N. Berova, P.L. Polavarapu, K. Nakanishi, R.W. Woody (Eds.),
Comprehensive chrioptical spectroscopy, vol. 1, 2011, Hoboken: Wiley & Sons, pp. 643-673.
[7] S. Grimme, WIREs Comput. Mol. Sci., 2011, 1, 211-228
Classification of LC chiral stationary phases: Wainer Types I–V revisited
No full textThe method of classifying LC chiral stationary phases (CSPs) introduced by Irving Wainer in 1987 became widely adopted largely because it was based on the mechanisms by which the different CSP Types (I–V) achieved chiral recognition and was an integral part of a ‘how to do chiral LC’ package. The classification became less used perhaps because it was thought that it was not clear to which Type some of the newer CSPs should be assigned. Its only modern day significance seemed to be in single enantiomer drug patent litigation cases in defining the ‘state-of-the-art’ of chiral LC in the late 1980s. However, on closer inspection, it is clear that even with the introduction of many new commercially available CSPs, the Wainer classification, perhaps with minor modifications, remains a useful suitable vehicle for distinguishing between different groups (Types) of CSPs as an aid to chiral LC method development
The rapid and direct determination of ATPase activity by ion exchange chromatography and the application to the activity of heat shock protein-90
No full textAdenosine nucleotides are involved as substrates or co-factors in several biochemical reactions, catalyzed by enzymes, which modulate energy production, signal transduction and cell proliferation. We here report the development and optimization of an ion exchange liquid chromatography (LC) method for the determination of ATP, ADP and AMP. This method is specifically aimed at the determination of the ATP-ase activity of human heat shock protein 90 (Hsp90), a molecular chaperone that has emerged as target enzyme in cancer therapy. Separation of the three nucleotides was achieved in a 15-min run by using a disk shaped monolithic ethylene diamine stationary phase of small dimensions (2mmx6mm i.d.), under a three-solvent gradient elution mode and UV detection at 256nm. The described direct LC method resulted highly specific as a consequence of the baseline separation of the three adenosine nucleotides and could be applied to the determination of the enzymatic activity of ADP/ATP generating or consuming enzymes (such as kinases). Furthermore, comparison of the LOD and LOQ values of the LC method with those obtained with the malachite green assay, which is one of the most used indirect screening methodologies for ATP-ase activity, showed that the LC method has a similar range of application without presenting the drawbacks related to contamination by inorganic phosphate ions and glycerol, which are present in Hsp90 commercial samples
Reflection of equatorial Kelvin waves at eastern ocean boundaries Part I: hypothetical boundaries
No full textA baroclinic shallow-water model is developed to investigate the effect of the orientation of the eastern ocean boundary on the behavior of equatorial Kelvin waves. The model is formulated in a spherical polar coordinate system and includes dissipation and non-linear terms, effects which have not been previously included in analytical approaches to the problem. Both equatorial and middle latitude response are considered given the large latitudinal extent used in the model. Baroclinic equatorial Kelvin waves of intraseasonal, seasonal and annual periods are introduced into the domain as pulses of finite width. Their subsequent reflection, transmission and dissipation are investigated. It is found that dissipation is very important for the transmission of wave energy along the boundary and for reflections from the boundary. The dissipation was found to be dependent not only on the presence of the coastal Kelvin waves in the domain, but also on the period of these coastal waves. In particular the dissipation increases with wave period. It is also shown that the equatorial ?-plane approximation can allow an anomalous generation of Rossby waves at higher latitudes. Nonlinearities generally have a small effect on the solutions, within the confines of this model
Tensões entre memória e história em testemunhos: Getúlio Vargas e seu legado político nos relatos de Samuel Wainer e Carlos Lacerda
No full textIn this article I analyse two testimonies from the recent Brazilian history, especially related to the Vargas era, produced by Samuel Wainer and Carlos Lacerda. Though sometimes these journalists have tried to present their reports with the status of history, I point out that mecanisms of memory, such as selection and deformation, both attached to the present, remain in their narratives. Besides, it seems that many scholars did not consider such details and integrated their points of view without self-criticism.Analiso, neste artigo, dois testemunhos da história recente do Brasil, especialmente relacionados à era Vargas, produzidos por Samuel Wainer e Carlos Lacerda. Apesar de haverem apresentado seus relatos com o estatuto de história, indico que mecanismos da memória, tais como seleção e deformação, ambos ligados ao presente, permanecem em suas narrativas. Ademais, parece que muitos estudiosos não consideraram tais detalhes e integraram os pontos de vista deles sem criticá-los
The synthesis and initial characterization of an immobilized purinergic receptor (P2Y1) liquid chromatography stationary phase for online screening
No full textTENSÕES ENTRE MEMÓRIA E HISTÓRIA EM TESTEMUNHOS: Getúlio Vargas e seu legado político nos relatos de Samuel Wainer e Carlos Lacerda<em>TENSIONS BETWEEN MEMORY AND HISTORY IN TESTIMONIES</em>
No full textAnaliso, neste artigo, dois testemunhos da história recente do Brasil, especialmente relacionados à era Vargas, produzidos por Samuel Wainer e Carlos Lacerda. Apesar de haverem apresentado seus relatos com o estatuto de história, indico que mecanismos da memória, tais como seleção e deformação, ambos ligados ao presente, permanecem em suas narrativas. Ademais, parece que muitos estudiosos não consideraram tais detalhes e integraram os pontos de vista deles sem criticá-los.
Palavras-Chave: Política. História. Memória.
Abstract
In this article I analyse two testimonies from the recent Brazilian history, especially related to the Vargas era, produced by Samuel Wainer and Carlos Lacerda. Though sometimes these journalists have tried to present their reports with the status of history, I point out that mecanisms of memory, such as selection and deformation, both attached to the present, remain in their narratives. Besides, it seems that many scholars did not consider such details and integrated their points of view without self-criticism.
Keywords: Politics. History. Memory
- …
