Design, synthesis and biological evaluation of quinoxaline compounds as anti-HIV agents targeting reverse transcriptase enzyme

Infection by human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents, more active, less toxic and with increased tolerability to mutations. Quinoxaline derivatives are an emergent class of heterocyclic compounds with a wide spectrum of biological activities and therapeutic applications. These types of compounds have also shown high potency in the inhibition of HIV reverse transcriptase and HIV replication in cell culture. For these reasons we propose, in this work, the design, synthesis and biological evaluation of quinoxaline derivatives targeting HIV reverse transcriptase enzyme. For this, we first carried out a structure-based development of target-specific compound virtual chemical library of quinoxaline derivatives. The rational construction of the virtual chemical library was based on previously assigned pharmacophore features. This library was processed by a virtual screening protocol employing molecular docking and 3D-QSAR. Twenty-five quinoxaline compounds were selected for synthesis in the basis of their docking and 3D-QSAR scores and chemical synthetic simplicity. They were evaluated as inhibitors of the recombinant wild-type reverse transcriptase enzyme. Finally, the anti-HIV activity and cytotoxicity of the synthesized quinoxaline compounds with highest reverse transcriptase inhibitory capabilities was evaluated. This simple screening strategy led to the discovery of two selective and potent quinoxaline reverse transcriptase inhibitors with high selectivity index.Fil: Fabian, Lucas Emanuel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Taverna Porro, Marisa Lia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gomez, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; ArgentinaFil: Salvatori, Melina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Turk, Gabriela Julia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Moglioni, Albertina Gladys. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentin

The RNA-binding protein ESRP1 promotes human colorectal cancer progression

Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific RNA binding protein that controls several key cellular processes, like alternative splicing and translation. Previous studies have demonstrated a tumor suppressor role for this protein. Recently, however, a pro-metastatic function of ESRP1 has been reported. We thus aimed at clarifying the role of ESRP1 in Colorectal Cancer (CRC) by performing loss- and gain-of-function studies, and evaluating tumorigenesis and malignancy with in vitro and in vivo approaches. We found that ESRP1 plays a role in anchorage-independent growth of CRC cells. ESRP1-overexpressing cells grown in suspension showed enhanced fibroblast growth factor receptor (FGFR1/2) signalling, Akt activation, and Snail upregulation. Moreover, ESRP1 promoted the ability of CRC cells to generate macrometastases in mice livers. High ESRP1 expression may thus stimulate growth of cancer epithelial cells and promote colorectal cancer progression. Our findings provide mechanistic insights into a previously unreported, pro-oncogenic role for ESRP1 in CRC, and suggest that fine-tuning the level of this RNA-binding protein could be relevant in modulating tumor growth in a subset of CRC patients

Electronic excitations of individual nano-objects, analysed by electron energy loss spectroscopy with high spatial resolution

Ce travail portant sur les excitations électroniques des systèmes nanométriques dans le domaine d'énergie du visible-UV présente une approche fondée sur la technique de Spectroscopie de pertes d'énergie (EELS) résolue spatialement, utilisée dans un microscope électronique à balayage en transmission. Cette technique bénéficie les avantages simultanés de la caractérisation morphologique à l'échelle sub-nanométrique offerte par le microscope et de la grande variété d'informations sur les propriétés électroniques accessible par EELS.L'interprétation des résultats expérimentaux a été rendue possible grâce au développement parallèle d' outils théoriques adaptés, rendant compte des caractéristiques spécifiques de chaque système analysé. Parmi les principaux résultats, nous avons analysé la transition atomique 1s->2p dans l' Helium à haute densité inclus dans des métaux, et avons mis en évidence par des mesures locales un nouvel effet induit par la surface affectant l'évaluation de la densité interne de nanobulles individuelles. En partant de nos travaux antérieurs sur la réponse diélectrique de différents nanotubes, l'étude des nanotubes de nitrure de bore (BN) a été principalement motivée par la mesure du gap de tels nanostructures. Le gap optique a été déterminé comme étant constant, indépendamment du nombre de couches ou du rayon des tubes, en accord avec des calculs de structure de bande. Sa valeur a été trouvée proche de celle du h-BN volumique, comme théoriquement prévu. De plus, les spectres ne sont pas affectés par le coulage des feuillets entre eux, ni par la courbure, et on n'observe aucun effet de confinement.In this work on the electronic excitations in the visible-UV energy domain in nano-scale systems, I presented an approach based on the spatially resolved EELS technique called spectrum-imaging performed inside a STEM. Such a technique benefits from the simultaneous advantages of the morphological characterization offered by the microscope environment , of the large variety of information on the electronic properties of the sample accessible by EELS, and of the sub-nanometric resolution of the analyzed volume.The interpretation of experimental results has been possible only thanks to a parallel development of adapted theoretical tools, accounting for the specific characteristic of each analyzed system. Among the main results, we analyzed the 1s->2p atomic transition in high density helium enclosed in metals, we put in evidence by local measurements a new surface induced effect, affecting the estimation of He density in individual nanobubbles.Stemming from our previous works on the dielectric response of individual nanotubes, the study of BN nanotubes was mainly motivated by the measurement of the band-gap of such nanostructures. The optical gap has been shown to remain constant, independent on the number of layers or the radii of the tubes, in agreement with band structure calculations, and close to that of the h-BN bulk, as expected theoretically. Moreover spectra are not affected by the interlayer coupling, nor by the curvature.Furthermore, no confinement effect is observed.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Thermal Polymerization on the Surface of Iron Oxide Nanoparticles Mediated by Magnetic Hyperthermia: Implications for Multi-Shell Grafting and Environmental Applications

International audienceA fast and straightforward strategy for thermo-polymerization of polymer shells, at room temperature, at magnetic nanoparticles (MNP) surface under alternating magnetic field (AMF) is presented. The polymerization is triggered by the local heat generated by the MNP when exposed to AMF to polymerize an organic shell around the MNP by thermo-activation. This synthetic approach provides a versatile strategy for magnetic nanoparticles surface polymerization without macroscopic temperature increase, allowing efficient pathways to magnetically induce single layer by layer polymer shells. Using molecularly imprinted polymer layer polymerized at room temperature, this method provides an unprecedented multifunctionnal nanoplatform adapted to pollutant targeting