Synthèse et étude des propriétés complexantes de ligands dérivés des acides lactique et tartrique (Application à la réaction d'oxydation du catéchol)

Des ligands dérivés de l acide lactique et des ligands bis-amide dérivés de l acide tartrique ont été synthétisés par la réaction d aminolyse des esters. Ces ligands fonctionnalisés présentent sont des molécules originales qui présentent la particularité d être hydrosolubles. La stabilité thermodynamique des complexes formés entre ces ligands et des cations de la première série de transition et les modes de coordination ont été étudiés à l aide de différentes techniques telles que la potentiométrie, la spectrophotométrie UV-visible et la spectrométrie de masse. Les propriétés complexantes des ligands dépendent des hétéroatomes situés sur leur chaîne latérale. A l état solide, des composés de cuivre, de nickel et de cobalt ont été synthétisés. Ils ont été caractérisés par diffraction de rayons X et/ou par spectroscopie d absorption de rayons X (EXAFS). L étude des propriétés magnétiques et électrochimiques de certains de ces composés a également été menée. L activité catalytique des complexes dinucléaires de cuivre a été étudiée vis-à-vis de la réaction d oxydation du catéchol en quinone.Ligands derived from lactic acid and ligands bis-amide derived from tartaric were synthesized by ester aminolysis. These functionalized ligands are original molecules which present the particularity to be water-soluble. The thermodynamic stability of complexes formed with those ligands with transition metal and coordination mode were studied by using various techniques: potentiometry, UV-visible spectrophotometry and mass spectrometry. Complexation proprieties depend on the atoms located in lateral chain. In solid state, complexes of copper(II), nickel(II) and cobalt(II) were synthesized. They were characterized by X-Ray diffraction and/or X-Ray absorption spectroscopy (EXAFS). Study of magnetic and electrochemical properties of certain complexes was also led. Catalytic activity of dinuclear copper complexes was studied by using oxidation of catechol into quinone.REIMS-BU Sciences (514542101) / SudocSudocFranceF

Thermodynamic and spectroscopic studies of copper (II) complexes with three bis(amide) ligands derived from l-tartaric acid

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pH-Responsive Nanometric Polydiacetylenic Micelles Allow for Efficient Intracellular siRNA Delivery

A novel generation of pH-responsive photopolymerized diacetylenic amphiphile (PDA) micelles with a diameter of 10 nm was designed and optimized for the intracellular delivery of siRNAs. Dialysis and photopolymerization of the micelles allowed a strong reduction of the cytotoxicity of the nanovector, while the hydrophilic histidine headgroup permitted enhancing the siRNA delivery potential by improving the endosomal escape via imidazole protonation. These PDA-micellar systems were fully characterized by DLS, TEM, and DOSY-NMR experiments. The resulting bioactive complexes of PDA-micelles with siRNA were shown to have an optimal size below 100 nm

Structure–Activity Relationship Studies toward the Discovery of Selective Apelin Receptor Agonists

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Bisacodyl and its cytotoxic activity on human glioblastoma stem-like cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling

International audienceGlioblastoma is the most common malignant brain tumor. The heterogeneity at the cellular level, metabolic specificities and plasticity of the cancer cells are a challenge for glioblastoma treatment. Identification of cancer cells endowed with stem properties and able to propagate the tumor in animal xenografts has opened a new paradigm in cancer therapy. Thus, to increase efficacy and avoid tumor recurrence, therapies need to target not only the differentiated cells of the tumor mass, but also the cancer stem-like cells. These therapies need to be effective on cells present in the hypoxic, slightly acidic microenvironment found within tumors. Such a microenvironment is known to favor more aggressive undifferentiated phenotypes and a slow-growing "quiescent state" that preserves the cells from chemotherapeutic agents, which mostly target proliferating cells. Based on these considerations, we performed a differential screening of the Prestwick Chemical Library of approved drugs on both proliferating and quiescent glioblastoma stem-like cells and identified bisacodyl as a cytotoxic agent with selectivity for quiescent glioblastoma stem-like cells. In the present study we further characterize bisacodyl activity and show its efficacy in vitro on clonal macro-tumorospheres, as well as in vivo in glioblastoma mouse models. Our work further suggests that bisacodyl acts through inhibition of Ca(2+) release from the InsP3 receptors

Structure–Activity Relationship Studies toward the Discovery of Selective Apelin Receptor Agonists

Apelin is the endogenous ligand for the previously orphaned G protein-coupled receptor APJ. Apelin and its receptor are widely distributed in the brain, heart, and vasculature, and are emerging as an important regulator of body fluid homeostasis and cardiovascular functions. To further progress in the pharmacology and the physiological role of the apelin receptor, the development of small, bioavailable agonists and antagonists of the apelin receptor, is crucial. In this context, E339–3D6 (<b>1</b>) was described as the first nonpeptidic apelin receptor agonist. We show here that <b>1</b> is actually a mixture of polymethylated species, and we describe an alternative and versatile solid-phase approach that allows access to highly pure <b>27</b>, the major component of <b>1</b>. This approach was also applied to prepare a series of derivatives in order to identify the crucial structural determinants required for the ligand to maintain its affinity for the apelin receptor as well as its capacity to promote apelin receptor signaling and internalization. The study of the structure–activity relationships led to the identification of ligands <b>19</b>, <b>21</b>, and <b>38</b>, which display an increased affinity compared to that of <b>27</b>. The latter and <b>19</b> behave as full agonists with regard to cAMP production and apelin receptor internalization, whereas <b>21</b> is a biased agonist toward cAMP production. Interestingly, the three ligands display a much higher stability in mouse plasma (<i>T</i>_1/2 > 10 h) than the endogenous apelin-17 peptide <b>2</b> (<i>T</i>_1/2 < 4 min)