Polycyclisation anionique : Progrès vers la synthèse de 14[bêta]-hydroxystéroïdes

La thèse porte sur la réaction de polycyclisation anionique, soit le tandem double Michael-aldol intramoléculaire intervenant entre une cyclohex-2-énone-2-carboxylée et un [bêta]-cétoester [gamma],[delta minuscule]-insaturé (réactif de Nazarov), pouvant mener directement à des produits au squelette tétracyclique de type stéroïdien. Les synthèses de nouveaux réactifs de Nazarov et cyclohexénones seront exposées, de même que les cycloadditions double Michael permettant de coupler ces synthons avec une diastéréosélectivité excellente, dans certains cas. Les condensations aldoliques intramoléculaires ont été testées avec plusieurs cycloadduits tricycliques et ont permis d'obtenir, en conditions basiques, des 13[alpha]-méthyl, 14[alpha]-hydroxystéroïdes.La synthèse d'[alpha]-bromocétones a permis d'effectuer, en milieu réducteur, la condensation d'aldol menant au squelette des 13[bêta]-méthyl, 14[bêta]-hydroxystéroïdes, ou cardénolides, qui sont des produits naturels intéressants en ce qui a trait, entre autres, à leur activité cardiotonique. Enfin, certaines modifications de groupements fonctionnels, nécessaires pour atteindre certaines cibles synthétiques, ont été élaborées avec une décaline modèle

The Role of Actin in Spindle Orientation Changes during the Saccharomyces cerevisiae Cell Cycle

In the budding yeast Saccharomyces cerevisiae, the mitotic spindle must align along the mother-bud axis to accurately partition the sister chromatids into daughter cells. Previous studies showed that spindle orientation required both astral microtubules and the actin cytoskeleton. We now report that maintenance of correct spindle orientation does not depend on F-actin during G2/M phase of the cell cycle. Depolymerization of F-actin using Latrunculin-A did not perturb spindle orientation after this stage. Even an early step in spindle orientation, the migration of the spindle pole body (SPB), became actin-independent if it was delayed until late in the cell cycle

Etude structurale de protéines par résonance magnétique nucléaire (application à la beta-lactoglobuline et la lipocaline lacrymale)

La BLG et la LCN1 sont deux protéines présentes respectivement dans le lait et dans les larmes. Elles appartiennent à la superfamille des lipocalines, protéines de transport de ligands hydrophobes. La béta-lactoglobulne (BLG) est la lipocaline la plus connue et étudiée d'un point de vue structural. Une étude RMN a été mis en place pour apporter des renseignements sur le comportement dynamique de la protéine en solution et lors de la liaison avec le ligand. Malgré la mise au point d'un protocole de solubilisation des corps d'inclusion lors de son expression dans E. Coli, la faible solubilité de la BLG caprine ne nous a pas permis de poursuivre son étude RMN. La lipocaline lacrymale (LCN1) possède une analogie de séquence et de fonction avec la beta-lactoglobuline (BLG). Sa structure n'est pas encore connue. Ainsi, il nous a semblé intéressant d'étudier la structure et le comportement en solution de la LCN1 à l'aide de logiciels bioinformatiques et de diverses techniques spectroscopiques (dichroïsme circulaire, fluorescence, spectrométrie de masse et RMN) en s'apuyant sur l'ensemble de l'étude structurale de la BLG. Nous avons aussi pu montrer une analogie de structure entre les deux protéines. Une trop grande flexibilité de la protéine en solution a fortement diminué la sensibilité des expériences de RMN 3D qui n'ont pu aboutir. Ce travail a mis en évidence l'importance de la préparation biochimique de l'échantillon et la place prépondérante de toutes les techniques spectrales dans l'étude structurale des protéines.ROUEN-BU Sciences (764512102) / SudocSudocFranceF

Treatment adequacy for social anxiety disorder in primary care patients.

OBJECTIVES:There is a gap between clinical practice guidelines for social anxiety disorder and clinical practice that needs to be addressed to ensure the delivery of evidence-based treatments. The objectives of this study were: 1) to describe mental health service utilization in a cohort of primary care patients with social anxiety disorder; 2) to examine treatment adequacy for pharmacotherapy and psychotherapy according to indicators based on clinical practice guidelines; and 3) to explore correlates of treatment adequacy. METHOD:The "Dialogue" project (Quebec, Canada) is a large study conducted in 67 primary care clinics. After a mental health screening in primary care (n = 14 833), participants with anxiety or depressive symptoms took part in a telephone/web structured interview on mental health symptoms and service utilization (n = 1956). This study included 289 participants meeting DSM-IV criteria for social anxiety disorder. RESULTS:Overall, 86.2% of participants reported consulting for mental health reasons over the past 12 months. Only 23.6% of our sample reported the detection of social anxiety disorder by a healthcare professional in the past 12 months. Approximately 2 in 5 respondents with social anxiety disorder reported receiving pharmacotherapy or psychotherapy meeting our treatment adequacy indicators. Antidepressant medication was the most common treatment. Logistic regression models showed that the detection of major depression (OR = 4.651; 95% CI: 2.559-8.453) or other anxiety disorder(s) (OR = 2.957; 95% CI: 1.555-5.625) were associated with receiving any adequate treatment, but the detection of social anxiety disorder itself was not (OR = 1.420; 95% CI: 0.696-2.899). CONCLUSION:Low rates of detection and treatment adequacy based on our indicators demonstrate that efforts must be made to ensure the quality of care for individuals with social anxiety disorder in primary care

Ampholytic and Polyelectrolytic Starch as Matrices for Controlled Drug Delivery

The potential of the polyampholytic and polyelectrolytic starch compounds as excipients for drug controlled release was investigated using various tracers differing in terms of solubility and permeability. Ampholytic trimethylaminecarboxymethylstarch (TMACMS) simultaneously carrying trimethylaminehydroxypropyl (TMA) cationic groups and carboxymethyl (CM) anionic groups was obtained in one-step synthesis in aqueous media. Trimethylaminestarch (TMAS) and carboxymethylstarch (CMS) powders were also synthesized separately and then homogenized at equal proportions in liquid phase for co-processing by spray drying (SD) to obtain polyelectrolytic complexes TMAS-CMS (SD). Similarly, equal amounts of TMAS and CMS powders were dry mixed (DM) to obtain TMAS:CMS (DM). Monolithic tablets were obtained by direct compression of excipient/API mixes with 60% or 80% drug loads. The in vitro dissolution tests showed that ampholytic (TMACMS) and co-processed TMAS-CMS (SD) with selected tracers (one from each class of Biopharmaceutical Classification System (BCS)), were able to control the release even at very high loading (80%). The presence of opposite charges located at adequate distances may impact the polymeric chain organisation, their self-assembling, and implicitly the control of drug release. In conclusion, irrespective of preparation procedure, ampholytic and polyelectrolytic starch materials exhibited similar behaviours. Electrostatic interactions generated polymeric matrices conferring good mechanical features of tablets even at high drug loading

Synthesis of N-glycosides. An alternative approach based on diastereoselective base coupling and SN2 cyclization

Chemical equation presented Acyclic diastereoselection is achieved for the formation of thioaminyl acetals. The highly intramolecular stereocontrolled SN2 displacement of the thioaminyls allows for the formation of cyclic nucleoside derivatives. This versatile approach may provide easy access to a large variety of N-glycosides