Diazo transfer and click chemistry in the solid phase syntheses of lysine-based glycodendrimers as antagonists against Escherichia coli FimH.
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.
PharmaQAM, Department of Chemistry, Université du Québec à Montréal, PO Box 8888, Succ Centre-ville, Montréal, Québec, Canada.
Alex
A
Papadopoulos
Tze Chieh
TC
Shiao
René
R
Roy
D018830:Adhesins, Escherichia coli; D000818:Animals; D050091:Dendrimers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006384:Hemagglutination / Q000187:drug effects; D008239:Lysine / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques / Q000379:methods*
D018830:Adhesins, Escherichia coli; D050091:Dendrimers; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; D008239:Lysine