Chemo-enzymatic synthesis of pseudo-glyo-amino acids, analogues of sialyl Lewis x antigen

• Main Author: Bridiau, Nicolas
• Other Authors: LIttoral ENvironnement et Sociétés (LIENSs), La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), Université de La Rochelle, Thierry Maugard
• Format: Doctoral or Postdoctoral Thesis
• Language: French
• Published: HAL CCSD 2009
• Subjects: Metastase; Selectines; Hydrolases; CAZY; Maillard reaction; Métastases; Sélectines; Réaction Maillard; [SDV.BBM]Life Sciences [q-bio]/Biochemistry; Molecular Biology; [CHIM.ORGA]Chemical Sciences/Organic chemistry; antartic*
• Online Access: https://hal.science/tel-03520765

This thesis deals with the chemoenzymatic synthesis of pseudoglycosyl amino acid building-blocks carrying the sialyl Lewis x antigen (sLex), where the sialic acid is replaced by a succinic ester as a substitute for the carboxylate function involved in selectin/sLex interaction. These compounds could potentially act as antimetastatic inhibitors of endothelial vascular cell/malignant tumor cell interactions. The work is broken down into four parts. The first one consists in the study of N- and pseudo-C-glycosylation of aromatic amines by Maillard reaction, which allowed to obtain the worthwhile products β-N-acetyl-D-glucosaminyl- and β-N-lactosaminyl-p-aminophenylalanine as well as the Amadori compound N-[β-D-galactosyl-1,4-(1-deoxyfructos-1-yl)]-p-aminophenylalanine. The second part describes the synthesis of N-acetyl-lactosamine (LacNAc) by transgalactosylation of the N-acetyl-D-glucosamine (GlcNAc), catalysed in aqueous and hydro-organic media by the β-galactosidases of Kluyveromyces lactis and Bacillus circulans. The third part mainly reports the search for α-L-transfucosidases activities by screening of various commercial enzymatic preparations of glycosidases in parallel with the use of two α-L-fucosidases of Thermotoga maritima, the wild type and its P25 mutant obtained by directed evolution, for the enzymatic synthesis of αFuc-1,3-GlcNAc, in aqueous and hydro-organic media. Eventually in the last part, our focus is on the succinic anhydride condensation on LacNAc, catalysed by the Candida antartica lipase B in anhydrous organic medium, which led to the formation of the desired mono-, di- and tri-succinylated LacNAc derivatives. Cette thèse a pour objet la synthèse chimio-enzymatique de pseudo-glyco-aminoacides portant une structure analogue de l’antigène Lewis x sialylé (sLex) où l’acide sialique est remplacé par un ester succinique mimant la fonction carboxylate impliquée dans l’interaction sélectine/sLex. Ces composés pourraient jouer le rôle d’inhibiteurs d’interactions cellule endothéliale ...