A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C

Background: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. Methodology/Principal Findings: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome. Conclusions/Significance: Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome

A step-economical multicomponent synthesis of 3D-shaped aza-diketopiperazines and their drug-like chemical space analysis

A rapid and atom economical multicomponent synthesis of complex aza-diketopiperazines (aza-DKPs) driven by Rh(I)-catalyzed hydroformylation of alkenylsemicarbazides is described. Combined with catalytic amounts of acid and the presence of nucleophilic species, this unprecedented multicomponent reaction (MCR) enabled the formation of six bonds and a controlled stereocenter from simple substrates. The efficacy of the strategy was demonstrated with a series of various allyl-substituted semicarbazides and nucleophiles leading to the preparation of 3D-shaped bicyclic aza-DKPs. Moreover, an analysis of their 3D molecular descriptors and “drug-likeness” properties highlights not only their originality in the chemical space of aza-heterocycles but also their great potential for medicinal chemistry

Diastereoselective Synthesis of Novel Aza-diketopiperazines via a Domino Cyclohydrocarbonylation/Addition Process

Herein, we report an unprecedented, short and diastereo-selective synthesis of newly reported aza-diketopiperazine (aza-DKP) scaffolds starting from amino acids. The strategy is based on a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation of allyl-substituted aza-DKP, followed by a diastereoselective functionalization of the platform. This methodology allows the synthesis of novel bicyclic and tricyclic aza-DKP scaffolds incorporating six- or seven-membered rings, with potential applications in medicinal chemistry

Design and synthesis of new heterocyclic scaffolds and application to the discovery of chemokine CXCL12 and CCLl7 neutraligands

Les chimiokines forment une vaste famille de cytokines chimioattractantes surtout connues pour leur implication dans des phénomènes pro-inflammatoires. Ainsi, l’obtention de composés modulant l’action de ces protéines apparaît aujourd’hui comme un enjeu primordial. L’utilisation de petites molécules organiques capables d’interférer directement avec les chimiokines (concept de « neutraligands ») se révèle être une stratégie originale pour développer de nouveaux outils pharmacologiques ainsi que de potentiels agents thérapeutiques. Dans ce contexte, nous avons développé des neutraligands de la chimiokine CXCL12 pour des applications potentielles dans le traitement de l’asthme, du lupus ou de la maladie de Crohn. Des neutraligands radiomarqués ont également été développés afin d’étudier les paramètres pharmacocinétiques de ces dérivés. Dans une seconde partie, le concept de neutraligand a été également étendu avec succès à la chimiokine CCL17. Des études autour des aza-dicétopipérazines, châssis « drug-like », ont ainsi permis d’obtenir deux nouveaux neutraligands dont le potentiel thérapeutique va être évalué prochainement dans la dermatite atopique et l’asthme. Dans une dernière partie, nous avons cherché à élargir la diversité structurale autour des aza-dicétopipérazines en réalisant la synthèse de bi- et tricycles par cyclohydrocarbonylation, fonctionnalisés ensuite de manière diastéréosélective. L’accès à ces composés a également été optimisé en développant une réaction « one-pot » plus rapide et plus efficace permettant ainsi de faciliter la préparation de chimiothèques focalisées autour du motif aza-dicétopipérazine.Chemokines are a large family of chemoattractant cytokines best known for theirinvolvement in proinflammatory processes. Thus, compounds that could modulate theaction of these proteins are crucial. Neutraligands are small organic compounds thatare capable of directly interfering with chemokines. This novel strategy is of importanceto develop new pharmacological tools and potential therapeutic agents. In this context,we have developed novel compounds neutralizing the chemokine CXCL12 for potentialapplications in the treatment of asthma, lupus or Crohn's disease. Radiolabeled probeshave also been synthesized to investigate the pharmacokinetic characteristics of thesederivatives. Neutraligand strategy has also been successfully extended to thechemokine CCL17. Studies of aza-diketopiperazines, a drug-like scaffold, haveprovided two compounds with therapeutic potential in atopic dermatitis and asthma. We also expanded the diversity around aza-diketopiperazines by designing andsynthesizing novel bi- or tricyclic compounds using cyclohydrocarbonylation. Thesederivatives were further diastereoselectively functionalized. Access to thesecompounds has also been optimized by performing a "one-pot" reaction, giving a rapidand efficient access to original, 3D-shaped and “drug-likeness” aza-diketopiperazinebased libraries

Design and synthesis of new heterocyclic scaffolds and application to the discovery of chemokine CXCL12 and CCLl7 neutraligands

Les chimiokines forment une vaste famille de cytokines chimioattractantes surtout connues pour leur implication dans des phénomènes pro-inflammatoires. Ainsi, l’obtention de composés modulant l’action de ces protéines apparaît aujourd’hui comme un enjeu primordial. L’utilisation de petites molécules organiques capables d’interférer directement avec les chimiokines (concept de « neutraligands ») se révèle être une stratégie originale pour développer de nouveaux outils pharmacologiques ainsi que de potentiels agents thérapeutiques. Dans ce contexte, nous avons développé des neutraligands de la chimiokine CXCL12 pour des applications potentielles dans le traitement de l’asthme, du lupus ou de la maladie de Crohn. Des neutraligands radiomarqués ont également été développés afin d’étudier les paramètres pharmacocinétiques de ces dérivés. Dans une seconde partie, le concept de neutraligand a été également étendu avec succès à la chimiokine CCL17. Des études autour des aza-dicétopipérazines, châssis « drug-like », ont ainsi permis d’obtenir deux nouveaux neutraligands dont le potentiel thérapeutique va être évalué prochainement dans la dermatite atopique et l’asthme. Dans une dernière partie, nous avons cherché à élargir la diversité structurale autour des aza-dicétopipérazines en réalisant la synthèse de bi- et tricycles par cyclohydrocarbonylation, fonctionnalisés ensuite de manière diastéréosélective. L’accès à ces composés a également été optimisé en développant une réaction « one-pot » plus rapide et plus efficace permettant ainsi de faciliter la préparation de chimiothèques focalisées autour du motif aza-dicétopipérazine.Chemokines are a large family of chemoattractant cytokines best known for theirinvolvement in proinflammatory processes. Thus, compounds that could modulate theaction of these proteins are crucial. Neutraligands are small organic compounds thatare capable of directly interfering with chemokines. This novel strategy is of importanceto develop new pharmacological tools and potential therapeutic agents. In this context,we have developed novel compounds neutralizing the chemokine CXCL12 for potentialapplications in the treatment of asthma, lupus or Crohn's disease. Radiolabeled probeshave also been synthesized to investigate the pharmacokinetic characteristics of thesederivatives. Neutraligand strategy has also been successfully extended to thechemokine CCL17. Studies of aza-diketopiperazines, a drug-like scaffold, haveprovided two compounds with therapeutic potential in atopic dermatitis and asthma. We also expanded the diversity around aza-diketopiperazines by designing andsynthesizing novel bi- or tricyclic compounds using cyclohydrocarbonylation. Thesederivatives were further diastereoselectively functionalized. Access to thesecompounds has also been optimized by performing a "one-pot" reaction, giving a rapidand efficient access to original, 3D-shaped and “drug-likeness” aza-diketopiperazinebased libraries

Étude de la butée sur un écran de largeur limitée en sol frottant

International audienceThis paper deals with the problem of the three dimensional passive earth pressures. First, the model tests carried out allows one to deduce the mode of failure of wall of limited breadth. Then, a theoretical study based on the kinematical approach of the limit analysis theory is investigated. Three translational kinematically admissible failure mechanisms are considered. The smallest upper-bound solutions of the three dimensional passive earth pressures are presented and discussed.De nombreux ouvrages mobilisent la résistance passive du sol de manière tridimensionnelle. L'objectif de cet article est de quantifier la butée des terres sur un ecran de largeur limitée. Une campagne d'essais sur modèle réduit a permis de mettre en évidence différents modes de rupture suivant l'élancement de l'écran. Les schémas de rupture obtenus ont permis d'élaborer un modèle de calcul de la butée tridimensionnelle dans le cas des écrans peu élands. L'outil théorique retenu est l'approche cinématique de l'analyse limite. Trois mécanismes de rupture de type translationnel sont envisagés. Les résultats obtenus ont permis de dégager le meilleur majorant de l 'effort de butée

Comparative Study of the Synthesis and Structural and Physicochemical Properties of Diketopiperazines vs Aza-diketopiperazines

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Convenient Access to Fluorescent Probes by Chemoselective Acylation of Hydrazinopeptides: Application to the Synthesis of the First Far-Red Ligand for Apelin Receptor Imaging

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Discovery of a Locally and Orally Active CXCL12 Neutraligand (LIT-927) with Anti-inflammatory Effect in a Murine Model of Allergic Airway Hypereosinophilia

International audienceWe previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor. While both 1 and 57 reduce eosinophil recruitment in a murine model of allergic airway hypereosinophilia, 57 is the only one to display inhibitory activity following oral administration. Thereby, we here describe 57 as the first orally active CXCL12 neutraligand with anti-inflammatory properties. Combined with a high binding selectivity for CXCL12 over other chemokines, 57 represents a powerful pharmacological tool to investigate CXCL12 physiology in vivo and to explore the activity of chemokine neutralization in inflammatory and related diseases