1-(3-p-Tolyl­isoxazol-5-yl)cyclo­hexa­nol

The title compound, C16H19NO2, contains two mol­ecules in the asymmetric unit. Each mol­ecule is composed of three inter­connected rings, two essentially planar rings, viz. the isoxazole and the methyl­benzyl aromatic ring [maximum deviations of 0.0027 (13) and 0.0031 (19) Å from the isoxazole and methylbenzyl ring planes, respectively, in the first molecule, 0.0018 (12) and 0.019 (2) Å in the second molecule], and one cyclo­hexa­nol ring having a chair conformation. Although the two mol­ecules have similar bond distances and angles, they differ in the orientation of the cyclo­hexa­nol ring with respect to the tolyl­isoxazole unit. In the first mol­ecule, the dihedral angle between the isoxazole and methyl­benzyl rings is 22.03 (8)° and between the isoxazole and cyclo­hexa­nol rings is 30.15 (8)°. The corresponding values in the second mol­ecule are 6.13 (10) and 88.44 (8)°, respectively. In the crystal, the molecules are linked by O—H⋯O and O—H⋯N hydrogen bonds, building up a zigzag chain parallel to the a axis

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

N-alcoylation du 4(5)-nitroimidazole et des bases puriques et pyrimidiques par chimie radicalaire S_R_N1. Acces a de nouveaux analogues de nucleosides

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 83255 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Conception, synthèse et étude de nouveaux analogues de nucléosides (application dans le domaine des antiviraux et antitumoraux)

Malgré des progrès importants réalisés ces dernières années, la lutte contre les infections virales et les cancers demeure un problème de santé mondiale. Ce bref bilan met en évidence la nécessité de développer de nouvelles molécules pour contourner les limites des traitements disponibles actuellement. Il est donc nécessaire de développer de nouvelles méthodes de synthèse pour accéder à ces composés afin d évaluer leur activité biologique, et de nouveaux outils d analyse pour étudier les interactions mises en jeu. Cette thèse, articulée autour de trois grands thèmes, s inscrit dans ce contexte. Nous avons tout d abord mis au point une méthode de synthèse de 1,2,3-triazolyl-nucléosides substitués en positions 4 et 5, par une réaction tandem clic/addition électrophile. Des tests biologiques ont montré la forte activité anticancéreuse de ces composés contre la LMC. Nous avons ensuite développé une stratégie de modification post-synthétique d oligonucléotides par réaction clic. Elle permet de modifier de manière site-spécifique des oligonucléotides portant un groupement azide. Cette méthode présente plusieurs avantages et peut être utilisée pour de nombreuses applications, principalement pour le marquage spécifique des acides nucléiques. Enfin, nous avons conçu une nouvelle famille de ligands de l ARN TAR du VIH-1 capables de se lier sélectivement à certaines structures secondaires de type tige-boucle ou tige-renflement, via l action coopérative de plusieurs motifs de reconnaissance dont une nucléobase qui se lie spécifiquement à une paire de base UA. Parallèlement, une nouvelle méthode de criblage de triplet de bases par spectrométrie de masse est actuellement à l étude.Despite significant progress made in recent years, the fight against viral infections and cancer remains a global health problem. This brief summary underlines the need for new compounds in order to overcome the limits of the drugs currently available. Therefore, there is a significant need to develop new methodologies for the synthesis of new bioactive molecules, and new analytical tools for the study of the involved drug/biological target interactions. To this end, the main objective of this thesis is to address these issues following the investigation of three major themes. We first developed a strategy for the synthesis of 1,2,3-triazolyl-nucleosides substituted at positions 4 and 5, using a tandem click/electrophilic addition reaction. Biological tests showed strong anticancer activity against CML for these compounds. We then developed a strategy for post-synthetic modification of oligonucleotides by click chemistry. This reaction allows post-synthetic transformation of oligonucleotides bearing an azide group in a site-specific manner. Therefore, this strategy has a great potential in various applications such as specific labelling of nucleic acids. Finally, we designed a new family of HIV-1 TAR RNA ligands that selectively bind to secondary structures such as stem-loop or stem-bulge, through a cooperative action of several recognition patterns. Among them, we used a modified nucleobase that can specifically recognize an AU base pair. Meanwhile, a new method of screening for this type of base triplets by mass spectrometry is being investigated.NICE-BU Sciences (060882101) / SudocSudocFranceF

Synthèse et évaluation de l'activité antivirale de C-nucléosides et de nucléotides de type PNA G-clamps

Beaucoup de virus pathogènes pour l'homme, en particulier le virus de l'hépatite C - VHC, le virus de l'immunodéficience humaine VIH, ou encore les virus de la famille des Flaviviridae (virus de la dengue - DENV, de la fièvre jaune - YFV, du Nil Occidental WNV,...), causent de vastes épidémies et sont responsables de millions de morts par an dans le monde. Depuis plus de 40 ans, les analogues de nucléosides sont au centre de la recherche antivirale. Cependant, l'apparition de phénomènes de résistance et de toxicité engendrés par ces molécules reste un problème majeur dans les thérapies antivirales actuelles, d'où l'urgence de développer de nouvelles molécules antivirales et de rechercher constamment de nouvelles cibles biologiques. Dans ce contexte, deux approches ont été développées : la première approche est basée sur la conception et la synthèse d'une nouvelle famille de C-nucléosides. Dans ce cadre, nous avons mis au point une méthode de synthèse originale permettant d'accéder à une série de nouveaux analogues de nucléosides. L'activité antivirale des différentes molécules synthétisées a été évaluée sur différents virus. La seconde approche est basée sur le ciblage de fragments d'ARN génomique du VHC. Ces séquences d'ARN sont hautement conservées dans la plupart des souches virales et sont fortement impliquées dans les processus de réplication. Dans ce cadre, nous avons conçu de nouveaux monomères de type G-Clamps en vue de leur incorporation dans des oligomères PNA antisens ciblant la boucle IIId de l'IRES (site d'entrée interne du ribosome) de l'ARN du VHC.Naturally occuring and synthetic analogues of nucleosides have been the cornerstone of antiviral therapy over the last decades. They became a tool of choice for treatment of viral infections (HIV, HCV, HBV ...) responsible for million of deaths every year around the world. Moreover, the emergence of resistance and clinical toxicities due to the currently approved drugs has generated new interest for the search of new biological targets and so far new and effective antiviral agents. To achieve this goal, our research project was focused on the development of two approaches based on: the design, the synthesis and the antiviral evaluation (BVDV, DENV, YFV, WNV, HIV...) of a new class of C-nucleosides, the synthesis of new PNA analogues incorporating G-clamp modified nucleobases. These analogues were designed to target the IIId stem-loop of 5'-IRES (Internal Ribosomal Entry site), a highly conserved HCV RNA sequence that is involved in viral replication.NICE-BU Sciences (060882101) / SudocSudocFranceF

Synthèse stéréosélective de nucléosides ratiométriques fluorescents de type 2-aryl-3-hydroxychromone (incorporation dans des séquences d'oligonucléotides et étude des propriétés biophysiques)

La spectroscopie de fluorescence est un outil extrêmement sensible pour étudier les interactions acides nucléiques/ligands et leur dynamique. Cependant, les sondes fluorescentes dérivées d analogues de nucléosides actuellement disponibles présentent des inconvénients qui limitent leur utilisation. C est pourquoi, la recherche d analogues nucléosidiques présentant des propriétés de fluorescence optimisées fait l objet d efforts soutenus. D autres part, les 3-hydroxychromones (3-HC) sont des sondes de fluorescence sensibles qui possèdent des propriétés remarquables, exploitées entre autres, pour étudier les membranes et les protéines. Cependant, aucune étude avec des acides nucléiques marqués avec ces sondes n a encore été décrite. Dans ce contexte, notre objectif a été de synthétiser plusieurs analogues nucleosidiques de type 2-aryl-3-HC, d étudier les propriétés spectroscopiques des sondes libres, de les incorporer dans des séquences d oligonucleotides et d étudier les propriétés biophysiques et photophysiques des oligonucléotides marqués par ces sondes. Au cours de ce travail, nous avons développé deux stratégies de synthèse pour accéder à plusieurs analogues de nucléosides ayant comme partie aglycone un groupement aryle. Puis, nous avons réalisé la synthèse de 8 sondes de fluorescence de type 2-aryl-3-HC. L élaboration de ces sondes, nous a conduit à mettre au point plusieurs voies de synthèse originales. Les propriétés d absorption et de fluorescence des composés obtenus ont ensuite été déterminées. Ces études ont montré que chaque sonde avait sa propre signature spectrale et que certaines d entre elles étaient particulièrement sensibles à la nature du milieu. Enfin, les sondes les plus prometteuses ont été incorporées dans des séquences d oligonucléotides.From its high sensitivity, fluorescence spectroscopy is an important tool for studying nucleic acid/ligand interactions and their dynamic. Recently, several fluorescent nucleoside analogues were reported in the literature. However, these classically used dyes display severe limitations in a number of cases which largely limit their applications. Consequently, there is a strong demand for new sensitive nucleoside probes with improved spectroscopic properties. On the other hand, 3- hydroxychromones (3-HC) have been shown to be powerful fluorescence probes for a large variety of applications in model membranes, biomembranes and proteins. However, until now, no study with 3-HC labelled nucleic acids was described in literature. In this context, our objective was to synthesize new modified fluorescent nucleosides where the natural base is substituted or functionalized by a 3-HC chromophore, to study the spectroscopic properties of these dyes, to incorporate them into oligonucleotides and to study the biophysical and photophysical properties of the 3-HC labelled oligonucleotides. To attain this goal, we have first developed two strategies to obtain several nucleoside analogues bearing at the anomeric position different aryl groups. In a second step, using these procedures and other original routes eight 3-HC fluorescent probes were prepared and characterized for their absorption and fluorescence properties. These studies showed that each probe has its own spectral signature and some of them are particularly sensitive to the nature of the environment. Finally, the probes with the highest sensitivity to environment change and the most appropriate photophysical properties in aqueous media were selected and incorporated into oligonucleotides.NICE-BU Sciences (060882101) / SudocSudocFranceF

Synthèse d'une nouvelle famille de nucléosides par cycloaddition dipolaire-1,3 et des réactions tandem (application en cancérologie)

NICE-BU Sciences (060882101) / SudocSudocFranceMoroccoFRM

Expression level of GRP78/BiP as a predictor of favorable or unfavorable outcomes in cancer patients

International audienc

Microwave-Assisted and Efficient Solvent-free Knoevenagel Condensation. A Sustainable Protocol Using Porous Calcium Hydroxyapatite as Catalyst

A sustainable Knoevenagel condensation of a series of aldehydes with malononitrile and ethyl cyanoacetate is described. The process is based on the combination of microwave activation and hydroxyapatite catalysis under solvent-free conditions. Products are obtained in and high yields after short reaction times. The effects of the specific surface of porous calcium hydroxyapatite and microwave activation are discussed

Visualization of intracellular lipid droplets using lipophilic benzothiazole-based push-pull fluorophores at ultralow concentration

International audienceIn this study we describe the development of new lipophilic and biocompatible benzothiazole-based push-pull fluorophores as potent fluorogenic probes for the specific staining of intracellular lipid droplets (LDs) at ultralow concentration (≤ 100 nM). These new fluorophores, harboring a D-π-A framework featuring an extended π-conjugated spacer, a lipophilic tertiary amine (D) and hydrophobic aryl groups (A), were prepared by an efficient and practical synthetic route. The photophysical studies of these compounds underlined their high polarity sensitivity, characterized by a strong solvatochromic effect and the large Stokes shifts values (λ em 465-630 nm, Δλ up to 6751 cm-1). Finally, the in cellulo investigations of D1 revealed its ability to selectivity accumulate in LDs and to allow their remarkable visualization using confocal fluorescence microscopy