Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4-d]pyrimidines

In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 microM. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.     

Na2BaMg（PO4）2： synthesis, crystal structure and europium photoluminescence properties

Na2BaMg(PO4)2 was synthesized and characterized by X-ray diffraction, differential thermal analysis (DTA), 31P NMR spectroscopy and photoluminescence measurements. This compound crystallized in the P3m...     

Encoding and selective activation of "metabolic memories" in the rat.

Experiment 1 used Pavlovian conditioning procedures to show that rats formed distinct memorial representations of 2 (peanut oil and sucrose pellets) unconditioned stimuli (USs) that could be activated by 2 different conditioned stimuli (CSs). After training in Experiment 2, rats injected with the lipid antimetabolite Na-2-mercaptoacetate (MA) responded more to the CS for oil than to the CS for sucrose. This pattern was not shown by rats that received isotonic saline or systemic 2-deoxy-d-glucose (a glucose antimetabolite). By contrast, intracerebroventricular infusion of the glucose antimetabolite 5-thioglucose selectively promoted responding to the CS for sucrose (Experiment 4). Thus, lipoprivic and glucoprivic treatments selectively promoted the activation of the memories of fat and carbohydrate USs, respectively. In Experiment 3, the capacity of MA to augment responding to a CS for oil was abolished for rats that received subdiaphragmatic vagal deafferentation. This indicates that the capacity of lipoprivic signals to selectively activate the representations of fat USs may depend on vagal afferent fibers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

4C1--Nonlinear effects in an NMR experiment

We have studied multiple-photon transition in a low-field nuclear magnetic resonance (NMR) experiment. It is well known that a saturation of the NMR occurs when using a sufficiently high alternating magnetic field which induces multiple-photons transitions. We show theoretically that these multiphoton transitions are accompanied by an harmonic generation. For an-photon transition, this generation occurs mostly on thenth and (n pm 1)th harmonic. For an irradiating field2H_{1} cos omegat of pulsation ω such thatnomega= gamma H_{0}=omega_{0}where H0is the steady field and θ is the angle between H0and H1the amplitudesSmin{n}max{n}andSmin{n}max{n+1}of these components are given bySmin{n}max{n} = f_{n}(theta) (H_{1})^{n},Smin{n}max{n+1} = cos theta f_{n}(theta) (H_{1})^{n+1}. We have verified these equations in a low-field NMR experiment (H_{0} = 0.7Gs/s), polarizing first a flowing liquid in a high magnetic field. The liquid then flows in a modified Bloch spectrometer. The receiving coil is still perpendicular to the steady field but it is possible to adjust the angle θ between the axis of the emission coils (H1field) and the steady-field H0. Using a synchronous detection at the output of the receiving coil on the pulsation(n - 1) omega, nomega, or(n + 1) omega, we have directly detected multiphoton transistions. The above equations have been verified forn = 2ton = 5. There are slight discrepancies at high excitation which may be explained taking into account a large saturation.     

Reinforcement of single-walled carbon nanotube bundles by intertube bridging

During their production, single-walled carbon nanotubes form bundles. Owing to the weak van der Waals interaction that holds them together in the bundle, the tubes can easily slide on each other, resulting in a shear modulus comparable to that of graphite. This low shear modulus is also a major obstacle in the fabrication of macroscopic fibres composed of carbon nanotubes. Here, we have introduced stable links between neighbouring carbon nanotubes within bundles, using moderate electron-beam irradiation inside a transmission electron microscope. Concurrent measurements of the mechanical properties using an atomic force microscope show a 30-fold increase of the bending modulus, due to the formation of stable crosslinks that effectively eliminate sliding between the nanotubes. Crosslinks were modelled using first-principles calculations, showing that interstitial carbon atoms formed during irradiation in addition to carboxyl groups, can independently lead to bridge formation between neighbouring nanotubes.     

Les qualités psychométriques de l'échelle de comportements d'adaptation Loranger-Pépin.

Presents results of 3 studies on the psychometric properties of the LP-ABC (M. Loranger and M. Pépin, 1993), a French-language instrument for assessing general functioning in adults with mental retardation. The studies involved a total of 299 male and female Canadian adults with mental retardation. Results confirm the internal consistency, construct validity, criterion validity, discriminant validity, interrater reliability, and test–retest reliability of the LP-ABC. (English abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)