Synthesis of Thiazolo[5,4-f]quinazolin-9(8H)-ones as Multi-Target Directed Ligands of Ser/Thr Kinases

International audienceA library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano- benzo[d]thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer’s disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinase

Synthesis of bioactive 2-(arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff reaction or Cu- catalyzed intramolecular C-S bond formation

International audienceA library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases

Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I

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Simultaneous observations of lower tropospheric continental aerosols with a ground-based, an airborne, and the spaceborne CALIOP lidar system

International audienceWe present an original experiment with multiple lidar systems operated simultaneously to study the capability of the Cloud-Aerosol LIdar with Orthogonal Polarization (CALIOP), on board the Cloud-Aerosol Lidar Pathfinder Satellite Observation (CALIPSO), to infer aerosol optical properties in the lower troposphere over a midlatitude continental site where the aerosol load is low to moderate. The experiment took place from 20 June to 10 July 2007 in southern France. The results are based on three case studies with measurements coincident to CALIOP observations: the first case study illustrates a large-scale pollution event with an aerosol optical thickness at 532 nm (τa532) of ∼0.25, and the two other case studies are devoted to background conditions due to aerosol scavenging by storms with τa532 <0.1. Our experimental approach involved ground-based and airborne lidar systems as well as Sun photometer measurements when the conditions of observation were favorable. Passive spaceborne instruments, namely the Spinning Enhanced Visible and Infrared Imager (SEVERI) and the Moderate-resolution Imaging Spectroradiometer (MODIS), are used to characterize the large-scale aerosol conditions. We show that complex topographical structures increase the complexity of the aerosol analysis in the planetary boundary layer by CALIOP when τa532 is lower than 0.1 because the number of available representative profiles is low to build a mean CALIOP profile with a good signal-to-noise ratio. In a comparison, the aerosol optical properties inferred from CALIOP and those deduced from the other active and passive remote sensing observations in the pollution plume are found to be in reasonable agreement. Level-2 aerosol products of CALIOP are consistent with our retrievals

[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors

Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer's disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Defects in the innate immune system in the lung with attendant bacterial infections contribute to lung tissue damage, respiratory insufficiency, and ultimately death in the pathogenesis of cystic fibrosis (CF). Professional phagocytes, including alveolar macrophages (AMs), have specialized pathways that ensure efficient killing of pathogens in phagosomes. Phagosomal acidification facilitates the optimal functioning of degradative enzymes, ultimately contributing to bacterial killing. Generation of low organellar pH is primarily driven by the V-ATPases, proton pumps that use cytoplasmic ATP to load H(+) into the organelle. Critical to phagosomal acidification are various channels derived from the plasma membrane, including the anion channel cystic fibrosis transmembrane conductance regulator, which shunt the transmembrane potential generated by movement of protons. Here we show that the transient receptor potential canonical-6 (TRPC6) calcium-permeable channel in the AM also functions to shunt the transmembrane potential generated by proton pumping and is capable of restoring microbicidal function to compromised AMs in CF and enhancement of function in non-CF cells. TRPC6 channel activity is enhanced via translocation to the cell surface (and then ultimately to the phagosome during phagocytosis) in response to G-protein signaling activated by the small molecule (R)-roscovitine and its derivatives. These data show that enhancing vesicular insertion of the TRPC6 channel to the plasma membrane may represent a general mechanism for restoring phagosome activity in conditions, where it is lost or impaired.Fil: Riazanski, Vladimir. University of Chicago; Estados UnidosFil: Gabdoulkhakova, Aida G.. University of Chicago; Estados UnidosFil: Boynton, Lin S.. University of Chicago; Estados UnidosFil: Eguchi, Raphael R.. University of Chicago; Estados UnidosFil: Deriy, Ludmila V.. University of Chicago; Estados UnidosFil: Hogarth, D. Kyle. University of Chicago; Estados UnidosFil: Loaëc, Nadège. ManRos Therapeutics; FranciaFil: Oumata, Nassima. ManRos Therapeutics; FranciaFil: Galons, Hervé. Universite de Paris; FranciaFil: Brown, Mary E.. University of Chicago; Estados UnidosFil: Shevchenko, Pavel. University of Chicago; Estados UnidosFil: Gallan, Alexander J.. University of Chicago; Estados UnidosFil: Yoo, Sang Gune. University of Chicago; Estados UnidosFil: Naren, Anjaparavanda P.. Cincinnati Children’s Hospital Medical Center; Estados UnidosFil: Villereal, Mitchel L.. University of Chicago; Estados UnidosFil: Beacham, Daniel W.. Thermo Scientific; Estados UnidosFil: Bindokas, Vytautas P.. University of Chicago; Estados UnidosFil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Meijer, Laurent. ManRos Therapeutics; FranciaFil: Nelson, Deborah J.. University of Chicago; Estados Unido

Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK &amp; CLK Kinases

A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer’s disease and Down syndrome. We assembled a small library of marine sponge- and ascidian-derived 2-aminoimidazolone alkaloids, along with several synthetic analogues, and tested them on a panel of mammalian and protozoan kinases. Polyandrocarpamines A and B were found to be potent and selective inhibitors of DYRKs and CLKs. They inhibited cyclin D1 phosphorylation on a DYRK1A phosphosite in cultured cells. 2-Aminoimidazolones thus represent a promising chemical scaffold for the design of potential therapeutic drug candidates acting as specific inhibitors of disease-relevant kinases, and possibly other disease-relevant targets

Emperor in the Byzantine Epigraphy (641-1204)

L’épigraphie byzantine est en science en construction dans le domaine de l’épigraphie médiévale. Ce travail repose sur la présentation d’un corpus de 229 inscriptions historiques comportant le nom de l’empereur byzantin, annotées et commentées, présenté par une étude globale du dossier. L’étude de la nature ainsi que de la répartition géographique et chronologique des inscriptions permet de souligner une nette domination de la capitale. En effet, la moitié du corpus est constitué des inscriptions de Constantinople, en particulier lors des périodes difficiles (VIIe-IXe siècles). La répartition chronologique est assez régulière mais avec une part assez importante des inscriptions d’époque macédonienne (867-1055). Les titulatures impériales sont à la fois stéréotypées et variées. Autour de la formule incontournable de pistos en Christos basileus autokrator, les épithètes correspondent souvent à l’idéologie impériale du moment ou du contexte, ce qui produit une assez grande variété des titres. Enfin, l’inscription est souvent incompréhensible pour des populations en majorité analphabètes. Du coup, en tant qu’objet elle est aussi un instrument idéologique qui permet de marquer le territoire de l’empreinte impériale, en particulier lors de la mise en défense d’une région, ou de la construction d’églises. En tant qu’objet présenté à la vue de tous, le texte inspire la crainte aux ennemis de l’Empire et le respect des populations locales envers leur empereur.The Byzantine epigraphy is a science under construction in the sphere of medieval epigraphy. This work is based on the presentation of a corpus of 229 historical inscriptions with the name of the Byzantine Emperor, annotated with commentary, presented by a comprehensive study of the file. The study of nature together with the geographical and chronological distribution of inscriptions allows to underline a clear domination of the capital. In fact, half of the corpus consists of Constantinople inscriptions, especially during difficult times (7th-9th centuries). The chronological distribution is fairly regular but with a sizeable part of the Macedonian inscriptions (867-1055). Imperial titulatures are both stereotypical and varied. Around the essential title pistos en Christos basileus autokrator, epithets often correspond to the imperial ideology of the moment or context, which produces a considerable variety of titles. Finally, inscription is often incomprehensible to the majority of the population, for the greater part illiterate. So, as an object, it is also an ideological instrument to mark out the territory of the imperial inprint, especially in the defense of a region, or when he building up of churches. As an object presented in plain sight, the text inflicts fear on the enemies of the Empire and generates respect of local people to their emperor

Pratique salutogénique par les sages-femmes en période périnatale : revue systématique de la littérature

L’objectif est de comprendre si l’exercice salutogénique des sages-femmes pourrait favoriser la bonne santé des patientes en période périnatale.Matériels et méthodes : il a été procédé à une revue de la littérature à partir d’articles publiés entre 2011 et 2021.Résultats : en période périnatale, le sentiment de cohérence est un facteur prédictif des issues obstétricales, de la santé psychologique, de la peur de l’accouchement, de la perception du soutien social et du sentiment d’auto-efficacité. Certains éléments freinent la pratique salutogénique : contrainte de temps, modèle de soins basé sur les risques et manque de continuité des soins. Les sages-femmes sont actrices de salutogenèse, puisqu’elles ont pour objectif la transmission de connaissances et la promotion de la santé.Conclusion : une pratique salutogénique des sages-femmes permettrait de renforcer le sentiment de cohérence des femmes en période périnatale, mais des modifications concernant le système de santé actuel sont nécessaires afin de permettre une prise en charge favorisant réellement la santé des femmes en période périnatale

Le lambeau libre antébrachiale en reconstruction carcinologique cervico-faciale

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF