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J Org Chem. 2007 Nov 23;72(24):9032-45. Epub 2007 Nov 3.

Multi-mannosides based on a carbohydrate scaffold: synthesis, force field development, molecular dynamics studies, and binding affinities for lectin Con A.

Author information

1
Laboratoire des Glucides UMR CNRS 6219, Faculté des Sciences, Université de Picardie Jules Verne, 33 Rue Saint-Leu, 80039, Amiens Cedex 1, France.

Abstract

A short and efficient strategy for the synthesis of multi-valent mannosides based on a selectively functionalized carbohydrate scaffold was reported involving (i) direct regioselective azidation of unprotected commercial saccharides, (ii) acetylation, (iii) grafting of the mannosyl ligands by click chemistry, and (iv) deacetylation. New glycoclusters with a valency ranging from 1 to 4 and different spatial arrangements of the epitopes were obtained. Binding affinities of the new glycoclusters toward concanavalin A (Con A) lectin were investigated by an enzyme-linked lectin essay (ELLA). The synthetic multi-valent compounds exhibited a remarkable cluster effect with a relative potency per mannoside residue ranging from 8.1 to 9.1 depending on the structures. ELLA experiments were in agreement with the establishment of favorable interactions between triazole ring and Con A, increasing the binding affinity. A new force field topology database was developed in agreement with the GLYCAM 2004 force field. Molecular dynamics performed on representative glyco-conjugates revealed interesting structural features such as rigidity of the scaffold for a well-defined presentation of the ligands and highly flexible mannose counterparts. The new glycoconjugates reported may be promising tools as probes or effectors of biological processes involving lectins.

PMID:
17979282
DOI:
10.1021/jo071248a
[Indexed for MEDLINE]

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