Marine Pyrrolocarbazoles and Analogues: Synthesis and Kinase Inhibition

Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Contribution à la chimie des flavonoïdes (Voies d'accès aux dihydroflavonols: vers une synthèse biomimétique de flavonols et une synthèse de tanins condensés. Vers une synthèse de pigments anthocyaniques sophistiqués)

Le squelette flavonoïde a jusqu à présent été caractérisé dans plus de 8000 structures naturelles et l ensemble de ces structures constitue de ce fait une famille de métabolites secondaires largement répandue dans le règne végétal. En plus de cette exceptionnelle diversité, il est clairement établi que les flavonoïdes jouent un rôle essentiel dans l équilibre de la plante au sein de son milieu naturel. Par ailleurs, de nombreuses études épidémiologiques ont montré qu une alimentation riche en flavonoïdes est bénéfique pour la santé humaine. Dans ce contexte, il n est pas étonnant que ces métabolites secondaires apparaissent actuellement comme de sérieux candidats dans la prévention et le traitement de nombreuses maladies humaines.Dans une optique d obtention de flavonoïdes purs à grande échelle, la synthèse totale apparaît comme la méthode de choix et notre étude s est justement inscrite dans le cadre de la recherche de nouvelles stratégies de synthèse de flavonoïdes.Until now, the flavonoid skeleton has been characterized in more than 8000 natural structures and, that s why all these structures constitue a family of secondary metabolites largely widespread in the plant kingdom. In addition to this exceptional diversity, it is clearly established that flavonoids play an essential role in the plant s equilibrium. Otherwise, many epidemiological studies have shown that a well-balanced diet rich in flavonoids is beneficial to human health. In such a context, it is not surprising that these secondary metabolites nowadays appear as serious candidates in the prevention and the treatment of a large number of human diseases.In order to have pure flavonoids in a large scale, total synthesis seems to be the method of choice. Our study lies precisely in the scope of the research of new strategies for synthesizing flavonoids.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Carbenes and Nitrenes: Chapter 4

International audienceA general review has appeared on catalyst design assisted by computations featuring some examples of carbenes acting either as organocatalysts or in situ generated reagents in metal-catalysed reactions. The decomposition of propylamine and propylammonium in the gas phase has been investigated by density functional theory and composite quantum chemistry methods. The formation of carbene–borane complexes has found numerous applications in recent years and allowed the identification of unprecedented reaction mechanisms. Computational studies have been conducted on the reaction mechanism of lithium and magnesium carbenoid cyclopropanations. The reactivity of photogenerated diphenylcarbene has been found to be controlled by the presence of additional protic molecules. Under metal-free conditions, nitrene-transfer reactions to olefins are still challenging. The development and optimization of aziridination reactions under transition metal catalysis are still attracting much attention

Cu I –USY as a Ligand-Free and Recyclable Catalytic System for the Ullmann-Type Diaryl Ether Synthesis

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Aged red wine pigments as a source of inspiration for organic synthesis—the cases of the color-stable pyranoflavylium and flavylium-(4→8)-flavan chromophores

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Copper and Heme-Mediated Abeta Toxicity: Redox Chemistry, Abeta Oxidations and Anti-ROS Compounds

International audienceOxidative stress mediated by reactive oxygen or nitrogen species (ROS/RNS) seems to be implicated in several diseases including neurodegenerative ones. In one of them, namely Alzheimer's disease, there is a large body of evidence that the aggregation of the peptide amyloid-beta (Abeta) is implicated in the generation of the oxidative stress. Redox active metal ions play a key role in oxidative stress, either in the production of ROS/RNS by enzymes or loosely bound metals or in the protection against ROS, mostly as catalytic centers in enzymes. In Alzheimer's disease, it is thought that metals (mostly Cu, Fe and heme) can bind to amyloid-beta and that such systems are involved in the generation of oxidative stress. In the present article, we review the role of ROS/RNS produced by redox active Cu ions and heme compounds in the context of the amyloid cascade. We focus on (i) the coordination chemistry of Cu and heme to Abeta; (ii) the role of the corresponding Abeta adducts in the (catalytic) production of ROS/RNS; (iii) the subsequent degradation of Abeta by these reactive species and (iv) the use of antioxidants, in particular metal sequestering compounds and direct antioxidants like polyphenols as a therapeutic strategies