New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway

Modélisation mathématique de l'hématopoïèse et des hémopathies : développement, dynamique et traitement

National audienceL'étude de l'hématopoïèse normale et pathologique, de par la complexité du sujet, requiert une approche multi-disciplinaire. L'utilisation de modèles mathématiques, lorsqu'il s'agit de comprendre la dynamique de populations de cellules, le développement de cancers ou l'effet d'un traitement, est particulièrement appropriée. Les modèles mathématiques, calibrés à partir d'observations expérimentales, peuvent être des outils d'aide à la décision en clinique, permettant par exemple de prédire l'effet d'un traitement ou d'en optimiser le dosage. Dans cette revue, nous commencerons par présenter différents modèles et formalismes mathématiques qui se sont développés au cours des décennies pour modéliser l'hématopoïèse, et qui sont encore pour certains à la base des travaux les plus récents. Nous aborderons ensuite les enjeux méthodologiques liés à l'inférence mathématique, permettant de s'assurer de la validité et robustesse des résultats. Enfin, nous terminerons par illustrer l'utilisation de modèles mathématiques dans trois champs d'application : l'initiation et le développement des hémopathies malignes, la dérégulation de leur hématopoïèse et leurs traitements

Cardiac variables of eventing horses at rest and after cross-country in international competitions

International audienc

Cardiac variables of eventing horses at rest and after cross-country in international competitions

International audienc

Last-Step Pd-Mediated C-11 CO Labeling of a Moxestrol-Conjugated o-lodobenzyl Alcohol: From Model Experiments to in Vivo Positron Emission Tomography Studies

The fast, efficient, and functional group tolerant last-step radiolabeling of bioconjugates is crucial for positron emission tomography (PET) applications. In this context, o-iodobenzyl alcohol based structures were identified as ideal tags for an easy Pd-catalyzed carbonylation after bioconjugation, and a moxestrol-conjugated precursor was chosen as the model compound for the further studies. Despite scale and time constraints, conditions developed with [C-12]CO and [C-13]CO were easily transferred to the C-11 isotope, and the desired radioactive product was obtained in amounts up to 740 MBq with radiochemical purities higher than 99%. Radio-high-performance liquid chromatography analyses of rat blood samples demonstrated excellent in vivo stability within the time of the acquisition. MicroPET-magnetic resonance imaging showed excretion pathways similar to moxestrol, and molecular modeling was also performed to evaluate the potential ability of this conjugate to bind estrogen receptors alpha. Thus, being both synthetically and biologically suitable, this strategy clears the path to potential novel biotracers for preclinical PET imaging

Diastereoselective Three-Component Vinylogous Mannich Reaction of Nitrogen Heterocycles, Acyl/Sulfonyl Chlorides, and Silyloxyfurans/pyrroles

A one-step, 3-component vinylogous Mannich reaction of trimethylsilyloxyfuran or <i>N</i>-protected <i>tert</i>-butyldimethylsilyloxypyrrole with a variety of nitrogen-containing heterocycles in the presence of diverse electrophiles is described. The reaction products were generally obtained in high yields and as a single diastereoisomer having the (<i>R</i>*,<i>R</i>*) relative configuration based on crystallographic studies of several derivatives. Several azaheterocycles were successfully used for this reaction, such as isoquinolines, quinoline, phenanthridine, quinazoline, phthalazine, and β-carboline, and electrophiles included acetyl chloride, methyl chloroformate, methyl chloromalonate, 2-bromobutanoyl chloride, and arylsulfonyl chlorides. The products of the vinylogous Mannich reactions were subjected to further transformations, leading to highly functionalized and stereochemically defined tetracyclic derivatives that are valuable building blocks for the preparation of natural products or medicinal agents

Diastereoselective Three-Component Vinylogous Mannich Reaction of Nitrogen Heterocycles, Acyl/Sulfonyl Chlorides, and Silyloxyfurans/pyrroles

A one-step, 3-component vinylogous Mannich reaction of trimethylsilyloxyfuran or <i>N</i>-protected <i>tert</i>-butyldimethylsilyloxypyrrole with a variety of nitrogen-containing heterocycles in the presence of diverse electrophiles is described. The reaction products were generally obtained in high yields and as a single diastereoisomer having the (<i>R</i>*,<i>R</i>*) relative configuration based on crystallographic studies of several derivatives. Several azaheterocycles were successfully used for this reaction, such as isoquinolines, quinoline, phenanthridine, quinazoline, phthalazine, and β-carboline, and electrophiles included acetyl chloride, methyl chloroformate, methyl chloromalonate, 2-bromobutanoyl chloride, and arylsulfonyl chlorides. The products of the vinylogous Mannich reactions were subjected to further transformations, leading to highly functionalized and stereochemically defined tetracyclic derivatives that are valuable building blocks for the preparation of natural products or medicinal agents

X-ray absorption spectroscopy investigations on radioactive matter using MARS beamline at SOLEIL synchrotron

International audienceThe MARS beamline at the SOLEIL synchrotron is dedicated to the characterization of radioactive material samples. One great advantage of the beamline is the possibility to characterize about 380 radionuclides by different X-ray techniques in the same place. This facility is unique in Europe. A wide energy range from around 3.5 keV to 36 keV K-edges from K to Cs, and L3 edges from Cd to Am and beyond can be used. The MARS beamline is optimized for X-ray absorption spectroscopy techniques (XANES/EXAFS), powder diffraction (XRD) but x-ray fluorescence (XRF) analysis, High Energy Resolution Fluorescence Detected -XAS (HERFD-XAS), X-ray Emission (XES) and μ-XAS/XRD are also possible. A description of the beamline as well as its performances are given in a first part. Then some scientific examples of XAS studies from users are presented which cover a wide variety of topics in radiochemistry and nuclear materials