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31.
Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors 下载免费PDF全文
Dr. Cinzia Maria Francini Dr. Anna Lucia Fallacara Dr. Roberto Artusi Dr. Laura Mennuni Dr. Alessia Calgani Dr. Adriano Angelucci Prof. Silvia Schenone Prof. Maurizio Botta 《ChemMedChem》2015,10(12):2027-2041
Src family kinases (SFKs) are a family of non‐receptor tyrosine kinases (TKs) implicated in the regulation of many cellular processes. The aberrant activity of these TKs has been associated with the growth and progression of cancer. In particular, c‐Src is overexpressed or hyperactivated in a variety of solid tumors and is most likely a strong promoting factor for the development of metastasis. Herein, the synthesis of new 4‐aminoimidazole and 2‐aminothiazole derivatives and their in vitro biological evaluation are described for their potential use as SFK inhibitors. Initially, 2‐aminothiazole analogues of dasatinib and 4‐aminoimidazole derivatives were synthesized and tested against the SFKs Src, Fyn, Lyn, and Yes. Five hits were identified as the most promising compounds, with Ki values in the range of 90–480 nm . A combination of molecular docking, homology modeling, and molecular dynamics were then used to investigate the possible binding mode of such compounds within the ATP binding site of the SFKs. Finally, the antiproliferative activities of the best candidates were evaluated against SH‐SY5Y and K562 cell lines. Compound 3 b [2‐(4‐{2‐methyl‐6‐[(5‐phenylthiazol‐2‐yl)amino]pyrimidin‐4‐yl}piperazin‐1‐yl)ethanol] was found to be the most active inhibitor. 相似文献
32.
We have constructed new yeast vectors for targeted integration and conditional expression of any sequence at the Saccharomyces cerevisiae TYR1 locus which becomes disrupted. We show that vector integration is not neutral, causing prototrophy for tyrosine and auxotrophy for the vector's selectable marker (uracil or leucine, depending on the vector used). This feature allows a double screening of transformed yeast cells, improving the identification of colonies with the desired chromosomal structure. The GAL10 gene promoter has been added to drive conditional expression of cloned sequences. Using these vectors, chromosomal structure verification of recombinant clones is no longer necessary, since the noise of non-homologous recombination, as well as spontaneous reversion of the selected phenotype, can easily be identified. The ability of the vector to conditionally control gene expression has been confirmed using the gene for the green fluorescent protein (GFP) as a reporter. 相似文献
33.
Alessia Marigo 《Mathematics of Control, Signals, and Systems (MCSS)》2010,22(2):129-153
Limited capacity of communication channels has strongly pushed the analysis of control systems subject to a quantized input
set. Quantized control system of type x
+ = x + u, where the u takes values in a set of 2m + 1 integer numbers, symmetric with respect to 0 arise in some fundamental situations, e.g., flat, nilpotent, and linear
systems with quantized feedback. In this paper we consider this special type of systems and analyze the reachable set after
K steps. We find explicit expressions, for each K and for each m, of m input values such that the reachable set after K steps is as large as possible. 相似文献
34.
Sabine Bertho Ilse Haeldermans Ann Swinnen Wouter Moons Tom Martens Laurence Lutsen Dirk Vanderzande Jean Manca Alessia Senes Annalisa Bonfiglio 《Solar Energy Materials & Solar Cells》2007,91(5):385-389
A new approach is presented in order to improve the thermal stability of polymer: [6-6]-phenyl C61 butyric acid methyl ester (PCBM) bulk heterojunction solar cells. The central idea in this approach is the use of a polymer with high glass transition temperature (Tg), well above the normal operating temperatures of the devices. In this paper, a PPV-derivative with a Tg of 150 °C was used as an electron donor and the thermal stability of the obtained solar cells was compared with solar cells based on the reference material poly[2-methoxy-5-(3′,7′-dimethyloctyloxy)-1,4-phenylene vinylene] (MDMO-PPV) with a Tg of 45 °C. The use of the material with higher glass transition temperature resulted in a significant improvement of the thermal stability of the photovoltaic parameters. Furthermore, a systematic transmission electron microscope (TEM) study demonstrates that the better thermal stability of performance coincides with a more stable active layer morphology. Both improvements are attributed to the reduced free movement of the electron donor material (PCBM) within the active layer of the solar cell. 相似文献
35.
Kevin A. Pears Momtchil Stavrev Alessia Scire Ralf Koepe Matthias Markert Ulrich Egger Lee Donohue 《Microelectronic Engineering》2005,81(1):156-161
Carbon hard mask structures have been used to etch a variety of materials typically used in sub 90 nm DRAM manufacture. The results indicate that carbon hard masks can be used very effectively to structure oxide, nitride and metal films giving the CD performance required for the technologies being investigated. 相似文献
36.
Francesco S. Interesse Pacifico Ruggiero Francesco Lamparelli Gerolmina D'Avella 《Zeitschrift für Lebensmitteluntersuchung und -Forschung A》1981,172(2):100-103
Summary Common wheat o-diphenolase at different purification steps has been submitted to column isoelectric focusing electrophoresis. The fraction purified with calcium phosphate gel shows multiple forms focused at pI 3.60, 4.95, 6.80, and 9.60. The enzyme activity and the purification degree of the four enzymatic components obtained have been calculated. The major fraction recovered after purification by chromatography on DEAE-cellulose does not display other multiple forms; however, it has some enzymatically inactive proteins well separated in the pH-gradient. The enzymatic protein, focused at pI 9.60, thus achieves a 1753-fold purification over the crude extract. The application of the technique allows a characterization of the wheat o-diphenolase and its recovery in highly purified form.
Isoenzyme von o-Diphenoloxydase aus Weichweizen, identifiziert durch isoelektrisches Fokussieren über Säule
Zusammenfassung Weichweizen-o-Diphenoloxydasen verschiedener Reinigungsstufen wurden über eine Säule isoelektrisch focussiert. Das durch Calciumphosphatgel gereinigte Enzym (Fraktion C) zeigt 4 multiple Formen, focussiert bei pI 3,60; 4,65; 6,80 und 9,60. Die Aktivität und der Reinheitszustand von diesen vier Formen wurden berechnet. Die Fraktion C wurde durch Chromatographie über Cellulose weiter gereinigt. Die in größeren Mengen gewonnene Fraktion zeigte beim isoelektrischen Focussieren keine multiple Formen mehr, nur eine Trennung von enzymatisch inaktiven Proteinen beim pH-Gradienten. Das enzymatisch aktive Protein, focussiert bei pI 9,60, zeigte einen 1753 mal besseren Reinheitszustand als das Rohenzym. Die Anwendung dieser Technik erlaubt die Charakterisierung der Weichweizen-o-Diphenoloxydasen und ihre Gewinnung in einem hochgereinigten Zustand.相似文献
37.
Francesco S. Interesse Pacifico Ruggiero Gerolmina D'Avella Francesco Lamparelli 《Journal of the science of food and agriculture》1980,31(5):459-466
o-Diphenolase extracted from Triticum aestivum (cv. Nettuno) and purified in various steps gave a 250-fold purification over the crude extract. This purified enzyme showed maximum relative activity towards 4-methylcatechol, generally high or moderate activity towards di- and polyphenols, and very low activity towards monophenols. Total activity, determined at each step of purification, showed that treatment with ammonium sulphate and calcium phosphate gel gave rise to an activation of o-diphenolase, thus revealing a latency of enzymatic activity. In the pH profile activity towards 4-methylcatechol two optima at pH 5.3 and 6.9 were observed. 相似文献
38.
Arianna Giacomini Sara Taranto Sara Rezzola Sara Matarazzo Elisabetta Grillo Mattia Bugatti Alessia Scotuzzi Jessica Guerra Martina Di Trani Marco Presta Roberto Ronca 《International journal of molecular sciences》2020,21(24)
Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers. 相似文献
39.