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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-02112015-160331


Thesis type
Tesi di laurea magistrale LM5
Author
NOCCIOLINI, ALESSIA
URN
etd-02112015-160331
Thesis title
Stereoselective synthesis of carba analogues of a natural disaccharide as possible DC-SIGN ligands.
Department
FARMACIA
Course of study
CHIMICA E TECNOLOGIA FARMACEUTICHE
Supervisors
relatore Dott.ssa Di Bussolo, Valeria
Keywords
  • Disaccharides
  • DC-SIGN
Graduation session start date
04/03/2015
Availability
Full
Summary
DC-SIGN is a novel DC-specific adhesion receptor on human Dentritic cells, which is essential in binding antigens and in transfecting the infection to T cells. DC-SIGN binds ligand motifs through a terminal carbohydrate recognition domain (CRD)1. The main carbohydrate ligand recognized by DC-SIGN is the high mannose glycan (Man)9(GlcNAC)2, a branched oligosaccharide presented in multiple copies by several pathogen glycoproteins. In the branched oligosaccharide, the terminal disaccharide portion Manα1-2Man binds DC-SIGN almost as efficiently as the entire high mannose glycan (Man)9(GlcNAC). This suggest an important role of nonreducing end Manα1-2Man fragment of Man9 in DC-SIGN recognition2.
Recently2, it has been settled on a new class of DC-SIGN antagonists: pseudodisaccharides in which the reducing mannose unit is replaced by a conformationally restricted dimethyl cycloexandicarboxylate. The main purpose of this thesis project is to operate a stereoselective synthesis of new DC-SIGN antagonists, corresponding to the pseudodisaccharides previously performed, but with the important difference of the presence of a real D-carbamannose unit.
The crucial steps in the pathway towards the synthesis of the new pseudodisaccharides are: the transformation of the commercially available tri-O-acetyl-D-glucal into the 3,4-O-p-methoxybenzyl-D-glucal and the switch of them into the corresponding carba analogue. Then, after appropriate elaborations, the residual C(1)-C(2) double bond, is subjected to a stereoselective epoxidation to afford the pivotal 6-O-benzyl-β-epoxy-diol. After further elaborations, the new oxirane moiety undergoes to nucleophilic ring opening with azido ethanol, to afford the new carbaglycosylating agents: the tri-O-benzyl and the tri-O-acetyl-β-epoxides
Then, to build the pseudomannobiosides, the carbamannose units were connected to an appropriate glycosyl donor, the trichloroacetimidate (TCA) and the resulting pseudodisaccharides were subjected to different steps of deprotection in order to obtain the desired pseudodisaccharides fully-O-deprotected, with an ethoxy-amino and an ethoxy-azido functionality at the end.
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