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Stereochemical and conformational study on fenoterol by ECD spectroscopy and TD-DFT calculations
No full textFenoterol and its derivatives are selective β2-adrenergic receptor (β2-AR) agonists whose stereoselective biological activities have been extensively investigated in the past decade; a complete stereochemical characterization of fenoterol derivatives is therefore crucial for a better understanding of the effects of stereochemistry on β2-AR binding. In the present project, the relationship between chiroptical properties and absolute stereochemistry of the stereoisomers of fenoterol (1) was investigated by experimental ECD spectroscopy and time-dependent density functional theory (TD-DFT). DFT geometry optimizations were carried out at the RI-B97D/TZVP/IEFPCM(MeOH) level and subsequent TD-DFT calculations were performed using the PBE0 hybrid functional. Despite the large pool of equilibrium conformers found for the investigated compounds and the known limitations of the level of theory employed, the computational protocol was able to reproduce the experimental ECD spectra of the stereoisomers of 1. The main contribution to the overall chiroptical properties was found to arise from the absolute configuration of the chiral center in α-position to the resorcinol moiety. Based on this evidence, a thorough conformational analysis was performed on the optimized DFT conformers, which revealed the occurrence of a different equilibrium between conformational patterns for the diastereomers of fenoterol: the (R,R')/(S,S') enantiomeric pair showed a higher population of folded conformations than the (R,S')/(S,R') pair
Preface
No full textAccepted Manuscript version. The Published Journal Article is available on the Journal of Pharmaceutical and Biomedical Analysis, Volume 144, page vi (DOI: https://doi.org/10.1016/S0731-7085(17)31895-2).
© 2017. This Manuscript version is made available under the CC-BY-NC-ND 4.0 license. https://creativecommons.org/licenses/by-nc-nd/4.0/
Special Issue in honor of the retirement of Prof. Carlo Bertucci
Edited by Irving W. Wainer, Vincenza Andrisano, Manuela Bartolini, Daniele Tedesco
Journal of Pharmaceutical and Biomedical Analysis, Volume 144, Pages 1-278
(10 September 2017
Chiroptical properties and conformational flexibility of fenoterol and analogues: a combined experimental and theoretical study
Full text linkFenoterol 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
Book Review
No full textAbstract
Book reviewed in this article:
Drug Stereochemistry. Analytical Methods and Pharmacology: Second edition, revised and expanded (Clinical Pharmacology Series/18) Edited by Irving W. Wainer
Drug Resistance in Oncology: Edited by Beverly A. Teicher
Man & Mouse. Animals in Medical Research: Second Edition</jats:p
Abstract 5055: Multiplatform metabolomics analysis of growth arrest in pancreatic tumor xenografts
No full textAbstract
R,S-4-Methoxy-1-naphthylfenoterol, MNF, inhibits the G protein-coupled receptor GPR55. In this study, we determine the effect of MNF on human PANC-1 pancreatic tumor growth in mice and apply multiplatform metabolomics analysis to identify pathways associated with growth arrest.
Methods: Female Balb/c nude mice, 6-8 weeks old, 18-20g, were inoculated subcutaneously with 5 x 106 PANC-1 cells. On Day 8, mice were placed in groups of 10 using random block design based upon tumor volume. Mice received daily ip injections of vehicle or 40mgxkg-1 MNF 5 days/week for 3 treatment cycles. Mice were monitored daily and tumor volumes measured at beginning and end of each dosing cycle. On Day 33, mice were euthanized, and plasma samples and tumors collected. Tumor tissue was homogenized, extracted and analyzed using liquid chromatography-QTOF-MS, capillary electrophoresis-TOF-MS and gas chromatography-EI-Q-MS. Differences between groups were evaluated by unpaired t-test or Mann−Whitney test with post hoc Benjamini-Hochberg correction. Statistical significance was set at P≤0.05. Compound identification was accomplished using online databases and in-house standards
Results Tumor volume increased in vehicle-treated mice by ~700%, 142 ± 8 mm3 to 957 ± 79 mm3 and only ~250% in MNF-treated mice, 143 ± 8 mm3 to 259 ± 27 mm3. On Day 33, MNF was not detected in plasma but accumulated in tumor tissues, 43.9 ± 32.7 ng/g. Plasma L-lactate levels were reduced from 3.29 ± 0.66 mmol/L το 2.81 ± 0.60 mmol/L, P≤0.001. Differences in tumor tissue metabolome were observed with MNF compared to vehicle, which was reflected by significant, P≤0.05, changes in relative metabolite signals. MNF treatment was accompanied by the disruption of pyrimidine nucleotide biosynthesis at uridine 5'-monophosphate, UMP, and increased UMP degradation. Moreover, the +237% increase in ophthalmic acid and +95% increase in its precursor 2-aminobutyrate indicate higher oxidative stress and the +51% increase in 2-hydroxyproline suggest greater HFI-1α proteolysis upon MNF treatment.
Conclusions These results are consistent with our previous observations in PANC-1 cells showing that GPR55 inhibition attenuates activation of the EGFR-MEK-ERK, Wnt-β-catenin and PI3K/AKT pathways resulting in lower cyclin D1 expression and halting the cell cycle in G1. The reduction in HIF-1α expression and glycolytic flux in MNF-treated PANC-1 cells is in line with the decline in L-lactate plasma levels in MNF-treated mice. The data from this study indicate that MNF may be useful in the treatment of pancreatic cancer.
Citation Format: Irving W. Wainer, Danuta Dudzik, Michel Bernier, Coral Barbas. Multiplatform metabolomics analysis of growth arrest in pancreatic tumor xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5055. doi:10.1158/1538-7445.AM2017-5055</jats:p
Journal of Pharmaceutical and Biomedical Analysis, volume 144 - Special Issue in Honor of the Retirement of Prof. Carlo Bertucci
No full textThis journal is an international medium directed towards the needs of academic, clinical, government and industrial analysis by publishing original research reports and critical reviews on pharmaceutical and biomedical analysis. It covers the interdisciplinary aspects of analysis in the pharmaceutical, biomedical and clinical sciences, including developments in analytical methodology, instrumentation, computation and interpretation. Submissions on novel applications focusing on drug purity and stability studies, pharmacokinetics, therapeutic monitoring, metabolic profiling; drug-related aspects of analytical biochemistry and forensic toxicology; quality assurance in the pharmaceutical industry are also welcome
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
A novel class of allosteric modulators of AMPA/Kainate receptors
No full textThe rapid hydrolysis in vivo of IDRA21 to 2-amino-5-chlorobenzensulfonamide has been demonstrated by microdialysis experiments. The IDRA21 metabolite possess in vitro a biological activity similar to that of IDRA21 itself. Taking 2-amino-5-chlorobenzensulfonamide as lead compound, a novel class of AMPAR positive allosteric modulators has been prepared
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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