Vers la synthèse totale de la griséoviridine, antibiotique de type streptogramine

Les streptogramines sont des macrolides antibiotiques de type apparentés pour lesquels pratiquement aucun germe ne présente actuellement de résistance acquise. Ils sont en fait constitués d'un mélange de deux groupes de composés A et B d'action synergique. L'objectif de ce travail de thèse a consisté en la synthèse totale de la griséoviridine, streptogramine du groupe A. La stratégie reposait sur la préparation initiale des fragments Nord-Est (C11-N23) et Sud-Ouest (C12-C22) en vue de leur couplage. La synthèse du fragment Nord-Est (C11-N23) a été réalisée selon deux approches différentes, soit par réaction de macrolactonisation, soit par couplage acétylénique-soufre dans des conditions réductrices. La synthèse du fragment Sud-Ouest est axée sur une réaction d'aldolisation énantiosélective. A ce jour, le couplage des deux unités est en cours.CERGY PONTOISE-BU Neuville (951272102) / SudocSudocFranceF

Trifluoromethylthiolation of tryptophan and tyrosine derivatives

The incorporation of fluorinated groups into peptides significantly affects their biophysical properties. We report herein the synthesis of Fmoc-protected trifluoromethylthiolated tyrosine (CF$_3$S-Tyr) and tryptophan (CF$_3$S-Trp) analogues on a gram scale (77–93% yield) and demonstrate their use as highly hydrophobic fluorinated building blocks for peptide chemistry. The developed methodology was successfully applied to the late-stage regioselective trifluoromethylthiolation of Trp residues in short peptides (66–80% yield) and the synthesis of various CF$_3$S-analogues of biologically active monoamines. To prove the concept, Fmoc-(CF$_3$S)Tyr and -Trp were incorporated into the endomorphin-1 chain (EM-1) and into model tripeptides by solid-phase peptide synthesis. A remarkable enhancement of the local hydrophobicity of the trifluoromethylthiolated peptides was quantified by the chromatographic hydrophobicity index determination method, demonstrating the high potential of CF$_3$S-containing amino acids for the rational design of bioactive peptides

Incorporation of CF3-Pseudoprolines into Peptides: a Methodological Study.

International audience: The peptide coupling reactions allowing the incorporation of trifluoromethyl substituted oxazolidine-type pseudoprolines (CF3-psiPro) into peptide chains have been studied. While standard protocols can be used for the peptide coupling reaction at the C-terminal position of the CF3-psiPro, acid chloride activation has to be used for the peptide coupling reaction at the N-terminal position to overcome the decrease of nucleophilicity of the CF3-psiPro. We demonstrate that the N-amidification of a diastereomeric mixture of CF3-psiPro using Fmoc protected amino acid chloride without base gave the corresponding dipeptides as a single diastereomer (6 examples). The ratio of the cis and trans amide bond conformers was determined by NMR study, highlighting the role of the Xaa side chains in the control of the peptide backbone conformation. Finally a tripeptide bearing a central CF3-psiPro has been successfully synthesized

Introducing the Chiral Constrained α‐Trifluoromethylalanine in Aib Foldamers to Control, Quantify and Assign the Helical Screw‐Sense**

International audienceOligomers of α-aminoisobutyric acid (Aib) are achiral peptides that adopt 310 helical structures with equal population of left- and right-handed conformers. The screw-sense preference of the helical chain may be controlled by a single chiral residue located at one terminus. 1H and 19F NMR, X-ray crystallography and circular dichroism studies on new Aib oligomers show that the incorporation of a chiral quaternary α-trifluoromethylalanine at their N-terminus induces a reversal of the screw-sense preference of the 310-helix compared to that of a non-fluorinated analogue having an l-α-methyl valine residue. This work demonstrates that, among the many particular properties of introducing a trifluoromethyl group into foldamers, its stereo-electronic properties are of major interest to control the helical screw sense. Its use as an easy-to-handle 19F NMR probe to reliably determine both the magnitude of the screw-sense preference and its sign assignment is also of remarkable interest

Inviting Trifluoromethylated Pseudoprolines into Collagen Model Peptides

Numerous Collagen Model Peptides (CMPs) have been engineered using proline derivatives substituted at their C(3) and/or C(4) position in order to stabilize or to functionalize collagen triple helix mimics. However, no example has been reported so far with C(5) substitutions. Here, we introduce a fluorinated CMP incorporating trifluoromethyl groups at the C(5) position of pseudoproline residues. In tripeptide models, our NMR and Molecular Dynamics (MD) studies have shown that, when properly arranged, these residues meet the structural requirements for triple helix assembly. A host-guest CMP could be synthesized and its NMR analysis in solution confirmed the presence of structured homotrimers that we interpret as triple helices. MD calculations showed that the triple helix model remained stable throughout the simulation, with all six trifluoromethyl groups pointing outwards from the triple helix. Pseudoprolines substituted at the C(5) positions appeared as valuable tools for the design of new fluorinated collagen mimicking peptides

De l’âge du Bronze à l’âge du Fer en France et en Europe occidentale (Xe-VIIe siècle av. J.-C.)

Les actes du XXXe colloque de l’Association Française pour l’Étude de l’Âge du Fer (A.F.E.A.F.) - Saint-Romain-en-Gal, 2006 - rassemblent en un seul volume les 16 communications du thème régional et les 28 du thème spécialisé, co-organisé avec l’Association pour la Promotion des Recherches sur l’âge du Bronze (A.P.R.A.B.). La question du territoire est la trame de fond de la partie régionale, suscitée par le dynamisme et les résultats de l’archéologie à Lyon et dans la région (du Mâconnais à la Loire et aux Alpes). Cette question est abordée par l’examen des sources écrites, d’utiles synthèses et la présentation de sites remarquables, en contexte d’habitat ou funéraire. L’enjeu du thème spécialisé était s’éclaircir la difficile question du passage de l’âge du Bronze à l’âge du Fer. Comment cerner les signes du changement, l’expliquer, en saisir le moment ? La plupart des auteurs ont choisi une fourchette chronologique large et se sont placés dans l’optique d’une évolution d’ordre endogène. Le critère du métal n’apparaît pas comme le plus pertinent. La fragmentation des faciès céramiques, la rupture de l’unité culturelle prévalant entre le XIIe et le VIIe siècles, des comportements nouveaux constatés dans les habitats et les pratiques funéraires : la situation est contrastée dans une Europe étudiée ici avec des exemples allant de l’Espagne à l’Italie, de la Grande-Bretagne à la Bohême.So dynamic was archaeology in Lyon and its surrounding region (Macon, the Loire Country and the Alps), that focus was kept on regional topics and that the question of «territory» was kept as the main line of research. The question has been tackled from many angles: written sources, enlightening summaries and synthetized works, presentation of quite remarkable sites, whether settlement sites or burial sites. The whole point was to shed light on the transitional phase between the Bronze Age and the Iron Age. What are the signs of a change, how to explain them, how to pinpoint them? Most scientists have led their research on a fairly large time span, always in the perspective of an endogenous evolution. The metal criterion do not come up as the most relevant factor anymore. Differenciation in pottery groups and disruption in the cultural cohesion prevail between the XIIthand the VIIth centuries. New practices arise in settlement patterns as well as funeral rites: the situation in Europe here under study, is richly contrasted and documented with case studies coming from a zone spreading from Spain to Italy, from Great Britain to Bohemia. The records of the 30th «A.F.E.A.F., Association Française pour l’Étude de l’Âge du Fer» ’symposium - Saint-Romain en Gal, 2006 - gather in one single volume the 16 papers on regional issues, as well as 28 papers on more specific issues, organized in collaboration with the Association pour la Promotion des Recherches sur l’âge du Bronze (A.P.R.A.B.)