Cysteine‐Based Mannoside Glycoclusters: Synthetic Routes and Antiadhesive Properties

Abstract

Clustermannosides of different valency were synthesised based on cysteine. By employing the orthogonally protected amino acid as scaffold molecule, a variety of structurally varied products can be obtained according to different synthetic routes. Testing of the prepared glycoclusters as inhibitors of type 1 fimbriae mediated bacterial adhesion is reported, giving hints about the influence of sugar valency, sugar scaffolding, and the nature of the glycosidic aglycon in this testing system.

Bi- and trivalent glycopeptide mannopyranosides as inhibitors of type 1 fimbriae-mediated bacterial adhesion: variation of valency, aglycon and scaffolding

“…The same is true for multivalency effects that have frequently been observed with miscellaneous cluster mannopyranosides as ligands for type 1 fimbriated bacteria, especially with bi-and trivalent glycoclusters. [21][22][23][24][25] A possible explanation, why multivalent mannopyranosides perform well as inhibitors of FimH, can be found in a statistical effect (basically an elevated local mannoside concentration), 26 on the other hand, it has been speculated that secondary binding sites on the fimbrial lectin might be occupied by multivalent mannnosides, hence resulting in an increased affinity of such ligands. 27 On this account, a number of open questions about carbohydrate recognition of type 1 fimbriated E. coli bacteria have formed the basis of a study, in which bi-and trivalent low-molecular weight glycopeptides have been synthesized and tested as inhibitors of type 1 fimbriae-mediated bacterial adhesion to a mannancoated surface.…”

S-Fluorenylmethyl protection of the cysteine side chain upon Nα-Fmoc deprotection

“…Synthesis of 3-dimer was started from the known N , S -protected glycoamino acid derivative 1 [2], which can be obtained by peptide coupling of 2-aminoethyl α-D-mannopyranoside [11] and the corresponding protected cysteine derivative, Fmoc-Cys(Trt)-OH (Scheme 1). Fmoc-deprotection by using morpholine as the base gave the free amine 2 , and then removal of the S -trityl protecting group under oxidative conditions (iodine in methanol) led to the cystine derivative 3-dimer after in situ oxidation of the intermediate free thiol in good yield.…”

“…As O -acetylated building blocks are often advantageous over the OH-free analogues for SPPS [2–4], our next step was to apply the synthesis outlined in Scheme 1 to the O -acetylated glycoamino acid derivative 4 (Scheme 2). The O -acetylated mannopyranside 4 can be prepared by Staudinger ligation of O -acetyl-protected 2-azidoethyl α-D-mannopyranoside [11] and the cysteine derivative Fmoc-Cys(Trt)-OH as described earlier [1].…”

“…Glycoamino acid derivatives 1 [1], 2 [2], 3 [3], 4 [2], 5 [2] and 6 [3] were prepared according to the literature. Anhydrous DMF was purchased; other solvents were dried for reactions or distilled for chromatography.…”

Glycopeptides and -Mimetics to Detect, Monitor and Inhibit Bacterial and Viral Infections: Recent Advances and Perspectives

“…Following a different approach, the Lindhorst group used the amino acid cysteine as a scaffold to generate cysteine-based glycoclusters that can act as FimH inhibitors [34]. Here, functionalized mannose moieties were coupled to cysteine to prepare divalent glycoconjugates (Figure 1b).…”