Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design

β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer’s disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors

Aproximación estereoselectiva a alcaloides de Stemona basada en nitronas : en ruta hacia (-)-stenina /

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Total Synthesis of the Phenolic Glycolipid Mycoside B and the Glycosylated p-Hydroxybenzoic Acid Methyl Ester HBAD-I, Virulence Markers of Mycobacterium tuberculosis

The phenolic glycolipid mycoside B, present in Mycobacterium bovis and hypervirulent strains of Mycobacterium tuberculosis, has been synthesized for the first time. Multiple methyl groups were introduced by the extensive use of catalytic asymmetric 1,4-addition reactions, asymmetric hydrogenation of a β-keto ester afforded the basis for the central 1,3-diol moiety, and introduction of the 2-O-methyl-α-L-rhamnoside unit was achieved by stereoselective glycosylation with p-iodophenol and subsequent Sonogashira coupling, providing a basis for the generation of analogues. In addition, the related monosaccharide HBAD-I, present in the same species, has been efficiently synthesized for the first time by selective methylation of the hydroxy group at C-2 of a rhamnoside.

Synthetic studies on Stemona alkaloids. Construction of the sessilifoliamides B and C and 1,12-secostenine skeleton

An original synthetic approach to the Stemona alkaloids stenine and sessilifoliamides B and C has been explored. The strategy relies on the early construction of the pyrroloazepine core (rings A and B) and latter addition of the furanone (ring D) and ethyl chain at C-10, which are the common structural features of the three alkaloids. The formation of the azabicyclic nucleus through an intramolecular Morita-Baylis-Hillman reaction of a properly substituted pyrrolidone has been extensively investigated by modifications on the substrate and all the parameters involved in the process and an efficient protocol in terms of yield and stereoselectivity has been developed. Despite many alternative tactics were explored, insurmountable difficulties found in the last synthetic steps have frustrated the completion of the syntheses. However, along the way, a plethora of new compounds was prepared, some of them containing the full skeleton of the targeted alkaloids, which can be useful for future synthetic applications

«Salut al cor/salud en el corazón»: resultados del programa de educación sanitaria en salud cardiovascular de Mútua Terrassa

Objetivo: Mejorar los conocimientos de la población sobre hábitos cardiosaludables mediante un programa de formación complementado por una Web y actividades comunitarias. Diseño: Ensayo clínico controlado donde la intervención es la participación en el Aula de Formación en Salud Cardiovascular (AFSC). Emplazamiento: Población de 80.000 habitantes. Participantes: Pacientes, ambos sexos, 55-70 años, con al menos un factor de riesgo cardiovascular (RCV). Intervención: El grupo intervención estaba formado por los pacientes que participaron en el AFSC. La intervención constaba de un curso presencial de 20 h en el que se ofrecía una Web de apoyo y se organizaban actividades complementarias. Las clases fueron impartidas por 3 enfermeras de atención primaria. Mediciones principales: La variable principal fue el conocimiento sobre el RCV. Variables secundarias: edad, sexo, factores de RCV, estilos de vida, visitas a los centros, consumo farmacéutico, adherencia terapéutica y satisfacción con el programa. Resultados: Se evaluaron los datos de los pacientes de los 10 primeros cursos (n = 150). Se observa una mejora estadísticamente significativa en el conocimiento general sobre el RCV en el GI (de 87,3 al 100%) respecto al GC (84,5 al 92,7%), p < 0,001 y una mejora en la actividad física (GI: del 71,2 al 83,1% frente GC: del 72,6 al 78,2%), p = 0,05. El número de visitas totales en atención primaria (medicina y enfermería) disminuyó más en el GI que en el GC. La valoración del curso ha sido elevada. Conclusiones: Se demuestra la efectividad de esta experiencia para mejorar conocimientos sobre salud cardiovascular y algunos hábitos de vida saludable

CD1c Presentation of Synthetic Glycolipid Antigens with Foreign Alkyl Branching Motifs

Human CD1c is a protein that activates αβT cells by presenting self antigens, synthetic mannosyl phosphodolichols, and mycobacterial mannosyl phosphopolyketides. To determine which molecular features of antigen structure confer a T cell response, we measured activation by structurally divergent Mycobacterium tuberculosis mannosyl-β1-phosphomycoketides and synthetic analogs with either stereorandom or stereospecific methyl branching patterns. T cell responses required both a phosphate and a β-linked mannose unit, and they showed preference for C30–34 lipid units with methyl branches in the S-configuration. Thus, T cell responses were strongest for synthetic compounds that mimicked the natural branched lipids produced by mycobacterial polyketide synthase 12. Incorporation of methylmalonate to form branched lipids is a common bacterial lipid-synthesis pathway that is absent in vertebrates. Therefore, the preferential recognition of branched lipids may represent a new lipid-based pathogen-associated molecular pattern.