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

Abstract

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.

Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease

“…While this focus has largely been replaced by the rational design of orally bioavailable lower molecular monomeric mannosides, several multivalent mannoside inhibitors have been reported, including glycodendrimers and neoglycoproteins [107-108], CD-based HMs [69, 109-114], glycoclusters [115-116], and others [117-120]. While these have been extensively reviewed previously [121-122], we present select examples of smaller, di-and tri-valent mannosides in the following discussion.…”

Dendritic glycopolymers based on dendritic polyamine scaffolds: view on their synthetic approaches, characteristics and potential for biomedical applications

“…2). 37 Moreover, recent progress has been achieved in establishing efficient glycodendrimers as antibacterial agents for humans 34,38 as alternatives to multi-resistant drug molecules such as, for example, ciprofloxacin and ampicillin. 34 In this regard, mannosylated lysine dendrons, additionally equipped with a 6-aminohexanoic acid linker between mannose units and surface groups of lysine dendrons, had been identified to be the better antagonists against Escherichia coli FimH than the unmodified mannosylated lysine dendron (Fig.…”

“…3). 38 There is still a high need to identify key factors determining the interactions of multivalent dendritic glycoconjugates for their successful inhibition of protein [24][25][26][27][28][29][30][31][32][33][34][35][36] and carbohydrate [39][40][41] cell receptors, but also for being able to develop (simplified) models. 14,42 Summarizing the most important key factors recently presented in some reviews, 1,4,5,18,43,44 one can state that a complex structure-activity relationship between the multivalent dendritic glycoconjugate and the complementary binding voids of the (protein) receptors exists.…”

Second Generation Amphiphilic Poly-Lysine Dendrons Inhibit Glioblastoma Cell Proliferation without Toxicity for Neurons or Astrocytes

“…The majority of the lower generation dendrons and dendrimers containing amino acids were obtained efficiently by solid-phase synthesis [33,34]. Despite the obvious advantages of this methodology, the reported milligram-scale quantity is often not sufficient for extensive biological testing.…”