Diazo Transfer and Click Chemistry in the Solid Phase Syntheses of Lysine-Based Glycodendrimers as Antagonists against Escherichia coli FimH

• Published in: Molecular pharmaceutics 2012-03, Vol.9 (3), p.394-403
• Main Authors: Papadopoulos, Alex, Shiao, Tze Chieh, Roy, René
• Format: Article
• Language: English
• Subjects: Adhesins, Escherichia coli; Animals; Dendrimers - chemical synthesis; Dendrimers - chemistry; Dendrimers - pharmacology; Escherichia coli; Fimbriae Proteins - antagonists & inhibitors; Guinea Pigs; Hemagglutination - drug effects; Lysine - chemistry; Solid-Phase Synthesis Techniques - methods
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp200490b

Uropathogenic Escherichia coli infections, ultimately leading to cystitis and pyelonephritis, are initially mediated by the adhesion of the bacterial FimH to the transmembrane glycoprotein uroplakin-1a present at the surface of urothelial cells. The adhesion is based on the recognition and high avidity binding between the high-mannose glycans of the uroplakin and the FimH, a mannose-specific lectin located at the tip of type 1 fimbriae. We found that synthetic multiantennary mannopyranosides glycodendrons, harboring triazole functionality at the anomeric position, were potent hemagglutination inhibitors of guinea pig erythrocytes and E. coli. A mannosylated dendrimer exposing up to sixteen sugar residues showed an HAI titer of 1 μM and was thus 500-fold more potent than the corresponding monovalent methyl α-d-mannopyranoside. The synthesis of the glycodendrons involved highly efficient solid-phase synthesis of branched l-lysine scaffolds, diazo transfer reaction on the terminal amine residues, and 1,3-dipolar copper-catalyzed azide–alkyne cycloaddition using propargyl α-d-mannopyranoside.