Design and synthesis of conformationally constrained trisaccharides for probing protein-carbohydrate interactions
Amiot, Nicolas C R
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This dissertation first describes a computer modeling study aimed at understanding reported enthalpy/entropy compensation phenomena occurring upon binding of trisaccharide 51 with lectin Concanavalin A. The design of new cyclic trisaccharides 70, 71 and 72, assisted by computer modeling, is also presented in this dissertation. The study of these new compounds was intended to further understand the role of carbohydrate ligand conformational properties in protein-carbohydrate interactions. A synthesis toward cyclic trisaccharides 70 and 71 is described. Their rigidity was increased by the introduction of a methyl group at C-6 of the Glc-NAc moiety. One of the challenging aspects of these syntheses was the introduction of the methyl moiety by converting a 6-hydroxyl to an aldehyde, followed by a Grignard reaction. The latter lowyielding step, performed on a suitably protected glucoseamine, was challenging but successful. The macrocyclization step, however, could not be completed through any of the attempted approaches. My efforts were then focused on the synthesis and characterization of conformationally constrained trisaccharide 72. Compound 72 was designed to be a much more rigid molecule than 51. The synthesis of 72 presented two major challenges. First, one of the building blocks required the synthesis of a non-natural, non-commercially available 4- amino sugar. The second challenge came from the formation of a carbamate bond at the cyclization stage, which has never been used with oligosaccharides. Two different approaches yielding trisaccharide 72 are described. In the last part of this dissertation, the synthesis of trisaccharide 74 and 75 is described. These compounds were specifically designed to conduct Biacore experiments aiming to study the kinetics of protein-carbohydrate interactions. They are similar to compound 51, to which an amino-propyl linker was added. The synthesis had therefore to be modified accordingly, using the appropriate building blocks. A high-yielding synthesis route was also developed for the building block bearing the linker, granting yields of 80% or above. Compounds 74 and 75 were then assembled following a route similar to 51.