Inositolphosphoglycan Mediators Structurally Related to Glycosyl Phosphatidylinositol Anchors: Synthesis, Structure and Biological Activity

• Published in: Chemistry : a European journal 2000-10, Vol.6 (19), p.3608-3621
• Main Authors: Martín-Lomas, Manuel, Khiar, Noureddine, García, Salud, Koessler, Jean-Luc, Nieto, Pedro M., Rademacher, Thomas W.
• Format: Article
• Language: English
• Subjects: Animals; Carbohydrate Conformation; Carbohydrate Sequence; carbohydrates; conformation analysis; Crystallography, X-Ray; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glycosylphosphatidylinositols - chemistry; Inositol Phosphates; inositols; Male; Models, Molecular; Molecular Sequence Data; Oligosaccharides - chemistry; Oligosaccharides - metabolism; Oligosaccharides - pharmacology; Polysaccharides; Rats; synthesis design; transduction; Trypanosoma brucei brucei - metabolism
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/1521-3765(20001002)6:19<3608::AID-CHEM3608>3.0.CO;2-Q

The preparation of the pseudopentasaccharide 1 a, an inositolphosphoglycan (IPG) that contains the conserved linear structure of glycosyl phosphatidylinositol anchors (GPI anchors), was carried out by using a highly convergent 2+3‐block synthesis approach which involves imidate and sulfoxide glycosylation reactions. The preferred solution conformation of this structure was determined by using NMR spectroscopy and molecular dynamics simulations prior to carrying out quantitative structure–activity relationship studies in connection with the insulin signalling process. The ability of 1 a to stimulate lipogenesis in rat adipocites as well as to inhibit cAMP dependent protein kinase and to activate pyruvate dehydrogenase phosphatase was investigated. Compound 1 a did not show any significant activity, which may be taken as a strong indication that the GPI anchors are not the precursors of the IPG mediators. Se ha llevado a cabo la síntesis del pseudopentasacárido 1 a—un inositolfosfoglicano (IPG) que contiene la estructura lineal de los glicosil fosfatidilinositoles de anclaje (GPI anchors)—siguiendo un esquema sintético [2+3] altamente convergente que implica reacciones de glicosilación por el método del imidato y por el método del sulfóxido. Se ha determinado también la conformación preferida de esta molécula en solución utilizando métodos de dinámica molecular y espectroscopía de RMN como un paso necesario para futuros estudios de relación estructura‐actividad en conexión con el proceso de señalización de la insulina. Por último, se ha estudiado la capacidad del compuesto 1 a para estimular la lipogénesis en adipocitos de rata, inhibir la quinasa dependiente de AMP cíclico y activar la fosfatasa de la piruvato deshidrogenasa. El compuesto 1 a no muestra ninguna actividad significativa en estos sistemas lo que indica que los GPI de anclaje no son los precursores de los segundos menajeros de tipo IPG.