Synthesis, Conformational Studies and Mannosidase Stability of a Mimic of 1,2‐Mannobioside

Abstract

Dimethyl (1S,2S,4S,5S)‐4‐allyloxy‐5‐(α‐mannosyloxy)cyclohexane‐1,2‐dicarboxylate (3) was designed as a structural mimic of α(1,2)mannobioside (1). Its synthesis and structural analysis by NMR spectroscopy and molecular modelling are described. The results show that 3, like 1, populates two low‐energy conformations — stacked (S) and extended (E) — that are in fast dynamic equilibrium around the glycosidic linkage. Thus, the data confirm the expectation that the pseudo‐disaccharide can be used as a structural mimic of mannobioside. The mannosidase stability of 3 was found to be significantly higher (sixfold) than that of natural mannobioside. This is a very useful feature of this mimic and is encouraging for its future development. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Efficient synthesis of phenylene-ethynylene rods and their use as rigid spacers in divalent inhibitors

“…We have been developing pseudo-disaccharide molecules such as 23 [32] (Scheme 7) as mimics of mannose disaccharides for the interaction with DC-SIGN and other C-lectins [33–35]. This molecule and its derivatives [36] contain lipophilic moieties that generally increase their affinity for the target proteins, but can create solubility problems.…”

DC-SIGN as a Target for Drug Development Based on Carbohydrates

“…The latter acts as a mimic of a reducing end mannose residue and features a spacer-arm terminated with azido or amino functionality, useful to generate multivalent DC-SIGN ligands. The design of the mimic (14) was supported by modelling, showing that the molecule replicates the conformational behavior of the natural disaccharide, but mostly populates its extended conformation (E) [31]. Furthermore, this molecule is more stable than the natural counterpart to jack-bean mannosidase-catalyzed hydrolysis [31].…”

“…The design of the mimic (14) was supported by modelling, showing that the molecule replicates the conformational behavior of the natural disaccharide, but mostly populates its extended conformation (E) [31]. Furthermore, this molecule is more stable than the natural counterpart to jack-bean mannosidase-catalyzed hydrolysis [31]. Saturation transfer difference (STD)-NMR experiments proved that (14) interacts with DC-SIGN and infection studies of DC-SIGN expressing Jurkat cells by a pseudo-typed Ebola virus showed that (14) acts as an inhibitor of viral entry with an IC 50 value of 0.6 mM.…”

Interfering with the Sugar Code: Design and Synthesis of Oligosaccharide Mimics

“…[36a] the pseudo-1,2-mannobioside 14 [38] (Figure 7), which contains a mannose unit connected to a conformationally locked diol 4 ( Figure 2). The latter acts as a mimic of a reducing end mannose residue and features a spacer-arm terminated with azido or amino functionality, useful to generate multivalent DC-SIGN ligands.…”