Designed glycopeptidomimetics disrupt protein−protein interactions mediating amyloid β‑peptide aggregation and restore neuroblastoma cell viability

How anti-Alzheimer’s drug candidates that reduce amyloid 1−42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aβ1−42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aβ1−42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aβ1−42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic β-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aβ1−42 aggregation

Applications des alcools fluorés (milieu réactionnel pour la synthèse d'hétérocycles et perspectives dans la conception de matériaux hybrides)

Fluoro-alcohols like hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE) display unique properties like high hydrogen bond donating ability, poor nucleophilicity, high ionizing power and low pKa s compared to their non fluorinated counterparts. Owing to these properties HFIP/TFE are known to promote different reactions. HFIP was explored as an effective solvent system for the synthesis of 2,3-unsaturated glycosides via Ferrier rearrangement of 3,4,6 tri-O-acetyl glucal. Aza-Michael addition of anilines onto Michael acceptors was found to proceed easily in polar protic solvents like HFIP,TFE and water, without the assistance of any promoting agent. The reaction was found to depend largely on solvent as well as on the nature of the electrophile. The selectivity of the reaction to afford mono or diaddition products or even quinolines can be achieved by finely tuning the solvent. HFIP and TFE were explored as efficient solvent systems for the Povarov reaction in the synthesis of nitrogen containing heterocycles. The applications of the Povarov/ oxidation reaction were studied further in the synthesis of the hetereocycles like aminoquinolines and phenanthrolines. we also assessed the synthesized phenanthrolines as potential ligands in two different reactions like AuCl-catalyzed C-C double bond cleavage and the oxidative Heck coupling. On the other hand, keeping into consideration the growing demand of green chemistry, we synthesized a recoverable novel hybrid organic-inorganic material containing HFIP moiety. The novel material was used as an organo-catalyst in the reactions: sulfoxidation, epoxide opening with aromatic amines, aza-Michael, Ferrier rearrangement. Unfortunately the preliminary studies were not encouraging. On the other hand, due to the presence of HFIP moiety, the material might bind selectively with specific functional groups and thus might find applications in drug delivery as a good drug carrier as well. In a preliminary study the novel material has shown considerable adsorption towards carboxylic acids.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

An Overview of 4‐ and 5‐Halo‐1,2,3‐triazoles from Cycloaddition Reactions

International audience1,2,3-triazoles are important scaffolds in several fields, and there is still a demand to construct these compounds, most notably the disubstituted 4, 5 compounds. The latter are obtained in different ways, but the 4-and 5-halo triazoles are generally the key intermediates in their synthesis. These halogenated compounds are an extraordinary platform leading to a great chemical diversity around the 4 and 5 positions. However, their own pathways are generally put aside at the expense of the substituted triazoles. This review is focused on the main synthesis of 5-and 4-halo 1,2,3-triazoles from cycloaddition followed or not by halogenation reaction. Unlike the halogens (iodine, bromine, and chlorine), the 5-and 4-fluoro 1,2,3triazoles will be presented separately due to their relatively more difficult and still recently challenging synthesis

Synthesis of NCF3, NCF2H and NCH2CF3 motifs

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The main and recent syntheses of the N-CF3 motif

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Synthèse et activité antitumorale d'analogues fluorés de produits naturels issus de Goniothalamus (Nouveaux aspects de synthèse dans les alcools fluorés)

Cette thèse repose essentiellement sur la synthèse, l évaluation biologique, et l étude de la stabilité métabolique d analogues fluorés de quatre produits naturels issus de Goniothalamus (goniothalamine, goniodiol, goniotriol, et howiinol A) possédant une activité cytotoxique intéressante.Tout d abord, afin de mieux comprendre les effets du fluor sur les propriétés physiques, physico-chimiques et biologiques de molécules à visée thérapeutique, une étude statistique a été réalisée à partir d une base de données de produits bioactifs répertoriés dans la littérature de 1990 à 2008. Nous avons ensuite effectué la synthèse d analogues fluorés de ces quatre styryllactones. Leur activité cytotoxique a été évaluée sur différentes lignées tumorales. Leur stabilité vis-à-vis du métabolisme oxydatif a été étudiée en présence de systèmes catalytiques biomimétiques. La dernière partie est consacrée à une étude méthodologique de synthèse, l insertion stéréosélective de dérivés diazocarbonylés dans des fonctions acides. Les réactions, réalisées dans les alcools fluorés, sont efficaces et ne nécessitent aucun catalyseurThis thesis is focused on the synthesis, the biological evaluation, and the study of the metabolic stability of four natural products isolated from Goniothalamus (goniothalamin, goniodiol, goniotriol, and howiinol A) which exhibit interesting cytotoxic activity. In order to better understand the effects of fluorine on physical, physico-chemical, and biological properties of bioactive compounds, we first realized a statistical study from a knowledge database of bioactive compounds reported on literature from 1990 to 2008. We next proposed the synthesis of fluorinated analogues of these four styryllactones. Cytotoxicity was next evaluated against differents cancer cell lines. Their stability toward oxidative metabolism was studied in presence of biomimetic catalytic systems. The last part is dedicated to a methodological study about the stereoselective insertion of diazocarbonyl derivatives into acidic functions. The reactions, achieved in fluorinated alcohols, were efficient and didn t need any catalystCHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Hexafluoroisopropanol as a Solvent for Halogenation of (Het)aromatics

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Friedel–Crafts alkylation reaction with fluorinated alcohols as hydrogen-bond donors and solvents

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Bisulfate Salt-Catalyzed Friedel–Crafts Benzylation of Arenes with Benzylic Alcohols

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