Digital archive of theses discussed at the University of Pisa


Thesis etd-06212015-095710

Thesis type
Tesi di laurea magistrale LM5
Thesis title
Stereoselective synthesis of a new carba sulfonamide pseudomannobioside as possible DC-SIGN ligand.
Course of study
relatore Prof.ssa Di Bussolo, Valeria
  • mimic
  • tosyl amino group
  • DC-SIGN ligand
  • 1.2-mannobioside
Graduation session start date
Enveloped (Env) viral particles usually contain different types of surface proteins the majority of which is modified by the addition of N-linked, O-linked carbohydrate chains or both. The key role of these carbohydrates in protein function and immune recognition is that to mask the antigenicity of the polypeptide backbone of the Env. At the same time carbohydrates guide the presentation of the whole glycoprotein to antigen-presenting cells. Glycans on gp120 interacts particularly with two host proteins: the endocytosis receptor of human macrophage membranes and serum lectin known as mannose-binding protein. Viral Env interacts first of all with a C-type lectin, dendritic cells-specific intercellular adhesion molecule 3 (ICAM-3-grabbing nonintegrin (DC-SIGN) also known as CD209. Interaction of DC-SIGN with viral envelope is mediated by a CRD (Carbohydrate Recognition Domain) of the protein, which uses a Ca2+ ion to link the oxygen atoms of carbohydrates hydroxyl groups. Indeed, this domain can play a significant role in the stereospecific recognition of carbohydrates via the relative stereochemistry (cis or trans) of two adjacent hydroxyl groups: for instance, hydroxyl groups on C(3)- and C(4) position of mannose serve as coordination ligands for the Ca2+.
Many studies on the binding affinity and antiviral activity demonstrated that analogous compounds (compounds 1a/1b) of natural oligosaccharide ligand, Man9(GlcNAc)2, bind efficiently DC-SIGN protein. The design of DC-SIGN high affinity ligands which mimics the terminal two mannose residues of the natural ligand, Manα1,2-Man, is one of the issues pursue in laboratory where I carried out my thesis.

The main purpose of my thesis project was to perform a stereoselective synthesis of the new pseudodisaccharide 2, characterized by the presence of a protected amino group on C(4) position of the carbamannose unit.
This synthetic approach starts with the transformation of the commercially available tri-O-acetyl-D-glucal (+)-3 into the primary alcohol (+)-4 and the switch of them into the corresponding carba analogue (-)-5, in which a metilene group replaces the endocyclic oxygen present in (+)-4. Then, after appropriate elaborations, the carba skeleton of (-)-5 was transformed into vinyl epoxide (-)-6, precursor of the key vinyl aziridine (+)-7. Ring opening of aziridine (+)-7 and appropriate elaborations allow the formation of protected trans amino-alcohol 8. Then, stereoselective epoxidation of residual C(1)-C(2) double bond of 8 give pivotal epoxy derivative 9β. The new oxirane moiety represents a new carbaglycosylating agent and was suitable to nucleophilic ring opening with azido ethanol to produce the glycosyl acceptor 10.

Glycosylation reaction of glycosyl acceptor 10 by typical glycosyl donor, the trichloroacetimidate TCA (-)-11, was successfully carried out to afford the glycoconjugate 12 in a completely stereoselective fashion. The resulting pseudodisaccharide 12 was finally subjected to different steps of deprotection in order to obtain the desired fully-O-deprotected pseudomannobiosides 2.

Interesting the aromatic ring of the tosyl group on nitrogen in C(4) position could represent a useful moiety of interaction with DC-SIGN binding site through additional lipophilic van der Walls connections. Pseudodisaccharide 2 will be send to Professor Fieschi at Institute de Biologie Structurale in Grenoble in order to evaluate its affinity with DC-SIGN lectin and its activity.

• N. Varga, I. Sutkeviciute, C. Guzzi, J. McGeagh, I. Petit-Haertlein, S. Gugliotta, J. Weiser, J. Angulo, F. Fieschi, A. Bernardi. Chem. Eur. J., 19 (2013), pp. 4786–4797.
• Y. Guo, H. Feinberg, E. Conroy, D. A. Mitchell, R. Alvarez, O. Blixt, M. E. Taylor, W. I. Weis, K. Drickamer, Nat. Struct. Mol. Biol. 2004, 11, 591–598/A. E. Cho, V. Guallar, B. J. Berne, R. Friesner, J. Comput. Chem. 2005, 26, 915–931.
• Reina J.J., Sattin S., Invernizzi D., Mari S., Martínez-Prats L., Tabarani G., Fieschi F., Delgado R., Nieto PM., Rojo J., Bernardi A.. ChemMedChem. 2007 Jul; 2(7):1030-6.