Study Of Carbohydrate-carbohydrate Interaction: Total Synthesis Of Two Deoxy Lewis~x Pentaosyl Glycosphingolipids And Molecular Dynamics Simulations Of Lewis~x Cluster

Since their discovery by Hakomori in 1989-1993,carbohydrate-carbohydrate interactions, as a new type of molecular interaction involved in cell adhesion and signal transduction, have been the subject of extensive experimental researches.One of these structures involved in this new interaction is the Lewis~x(Le~x)determinant(Galβ1→4[Fucα1→3] GlcNAcβ1→R).Le~x glycosphingolipids(Le~x GSLs)form microdomains on cell surface, and the interaction between Le~x GSLs microdomains was proposed to be responsible for the initial step of cell adhesion and induces embryogenesis and metastasis.However,the detailed molecular mechanism of this weak homotypic interaction and also the role of calcium ions remain unclear,necessitating the establishment of new models to elucidate the nature of this phenomenon.In this dissertation chemical synthesis of deoxy Le~x pentaosyl glycosphingolipids and computational molecular dynamics simulations were performed,in order to provide insights into functions of calcium ions and the hydroxyl groups of the Le~x trisaccharide in this type of interaction.This thesis contains five chapters.ChapterⅠintroduces the discovery of this homotypic interaction and describes a variety of experimental techniques which have been used to investigate this interaction.ChapterⅡdetails the first total synthesis of two deoxy Le~x pentaosyl glycosphingolipids,in order to gain an insight into the functions played by the hydroxyl groups of the Le~x trisaccharide.3d-deoxy and 4d-deoxy Le~x pentaosyl glycosphingolipids have been prepared by 46 steps through a highly stereo- and regioselective convergent synthetic route.The two products are important molecular materials for carbohydrate-carbohydrate interaction study.Furthermore,during the course of the syntheses,the regioselective glycosylations of glucosamine were studied,and the usefulness of ethyl 2,3,4-tri-O- benzyl-1-thio-α-L-fucopyranoside as a fucosylation donor was discovered in preparation of Le~x trisaccharides.These topics were discussed individually in ChapterⅢandⅣ.ChapterⅤdescribes the development of a new molecular model to simulate this homotypic interaction between Le~x clusters in explicit water solvent with and without calcium ions.Accurate analysis of both trajectories yielded precious information about the energetic of Le~x-Le~x dimerization.The investigations of the hydrogen bond network and the calcium ions affinity with specific hydroxyl groups along the trajectory,give precious and new insights on this interaction.