Synthesis Of Several Glycoclusters And Study Of Their Bioactivities

In this dissertation, a series of cluster galactosides and cluster mannosides were synthesized, which target asialoglycoprotein receptor (ASGPR) and plant lectin Concanavalin A (Con A) respectively.1. Structurally well defined di-, tri- and tetra- valent cluster galactosides were synthesized in a convenient way. Glutamic acids were assembled as di-, tri-, and tetra- branched scaffolds. Galactose was used as saccharide unit since it can be recognized by ASGPR. 2-(2'-Chloroethoxy) ethanol acted as the arm connecting the saffolds and the saccharide. Di-, tri- and tetra- valent cluster galactosides G-13, G-16 and G-19 were obtained as target compounds.2. The binding affinities of cluster galactoses G-13, G-16 and G-19 to liver cells asialoglycoprotein receptor (ASGPR) were determined by in vitro binding studies. The IC50 values of G-13, G-16 and G-19 are 1.24, 0.130 and 0.0138 mM respectively, while ICso of galactose alone is 38.0 mM. Tetravalent cluster galactose G-19 shows the highest affinity to ASGPR. Based on binding studies and molecule dynamic simulations, the number of galactose, the distance between two galactoses in the cluster moleculees and the flexibility of the cluster molecules are showed to be important factors affecting their binding activities.3. Nine cluster mannosides were synthesized via three different methods.a) The coupling of 1,6-hexanediamine or tris (2-aminoethyl)amine with 2,3,4,6-tetra-(9-acetyl-a-Z)-mannopyranoside (M-5) was accomplished using NHS/DCC as coupling reagent, to give the protected di- and tri- valent cluster mannosides. After deprotection, the target molecules M-7 and M-9 were obtained.b) Similarly, cluster mannosides were synthesied as the preparation of clustergalactosides except that the glycosylation procedure in which a-Trichloroacetimidate mannosyl donor was reacted with 2-(2'-chloroethoxy) ethanol. The divalent and trivalent cluster mannosides were obtained after deprotection.c) The Ugi four-component reactions were explored to prepare the cluster mannosides. Three divalent cluster mannosides (M-18, M-19, and M-20) were obtained by Ugi four-component reaction, using 2'-oxoethyl 2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside (M-4), 1,6-hexanediamine, methyl isocyanoacetate, and three different acids (benzoic acid, acetic acid or cyclohexanecarboxylic acid ). The acetate groups were removed smoothly to give the target divalent cluster mannosides M-21, M-22 and M-23.The Ugi four-component reactions using M-5, benzaldehyde, methyl isocyanoacetate and two different amines (1,6-hexanediamine or tris(2-aminoethyl) amine) were also accomplished to afford the divalent cluster and trivalent cluster. After deprotection, cluster mannosides M-25 and M-27 were obtained.4. Based on the results from ELLA and molecule dynamic simulations, a cross-link mode of interactions between the cluster mannosides and Con A is proposed The DOCK study also support the result from ELLA, that divalent cluster M-25 may interact better with Con A than trivalent cluster M-27. These results indicate that the optimum binding properties of the clusters may depend not only on the valence and substitution, but also on the tree-dimensional arrangements of the functional groups.These work provide some technical methods on the synthesis of multivalent glycocluster. Moreover, they will facilitate further understanding the interaction between multivalent ligand and receptor.