Non‐Glycosidically Linked Pseudodisaccharides: Thioethers, Sulfoxides, Sulfones, Ethers, Selenoethers, and Their Binding to Lectins

Abstract

Hydrolytically stable non‐glycosidically linked tail‐to‐tail pseudodisaccharides are linked by a single bridging atom remote from the anomeric centre of the constituent monosaccharides. Some such pseudodisaccharides with sulfur or oxygen bridges were found to act as disaccharide mimetics in their binding to the Banana Lectin and to Concanavalin A. A versatile synthetic route to a small library of such compounds is described.

Protecting Group-Free Glycoligation by the Desulfurative Rearrangement of Allylic Disulfides as a Means of Assembly of Oligosaccharide Mimetics

“…The reaction sequence can be used to assemble mimics of either classical “head to tail”-linked oligosaccharides (Table 1, entries 1–7, 9) or can be used to provide mimics of non-glycosidically-linked disaccharides (Table 1, entry 8) which are of current interest. 33 For the mimics of the classical head to tail oligomers, the ligation can be conducted according to either of the two design principles set out in Scheme 1, but at least for the mimics of the β-(1→3)-glucans the employment of the anomeric thiol (Scheme 1b) results in a shorter reaction time than the use of an anomeric sulfenyl donor (Scheme 1a) as is seen from a comparison of entries 6 and 7 (Table 1). We believe that this difference in reactivity is due to the steric hindrance about the thiol derived from precursor 37 (Table 1, entry 6) which retards both sulfenyl transfer and especially the critical desulfurative 2,3-sigmatropic rearrangement step.…”

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

“…Aside from the more conventional isosteres listed above, the glycosidic linkage has also been replaced by other functionalities (sulfones, sulfoxides), or the linkage position has been varied to non-natural analogues which has enhanced stability [59,60,61,62]. As this has been a very well covered area of glycomimetics with many prominent examples, it has not been covered further in this review.…”

“…Several methods have been established to synthesize thiosugars to obtain glycomimetics such as 13 and 14 (Figure 4) [126]. As it was previously reported that S -linked pseudodisaccharides bound better to the plant lectin concanavalin A (ConA) than their respective O -derivatives [60], isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR experiments were used to evaluate the binding of these 2-thioglycosides to ConA. Surprisingly, the 2-deoxy-2-thio-mannoside derivative 14 was observed to bind ConA much better than Man itself [126,127], although STD NMR experiments suggested that this enhancement in affinity is actually the result of a slightly altered binding mode.…”

pKa‐Determination and Conformational Studies by NMR Spectroscopy of D‐Altrose‐Containing and other Pseudodisaccharides as Glycosidase Inhibitor Candidates

“…Molecular mechanics models of canonical ring conformations were generated for 1-4, and potential energy minimisation was carried out to find the geometry-optimised local energy minima. Based on the geometrical torsion angle relationships of protons in each conformation under consideration, the 3 J H,H coupling constants were calculated and subsequently used in least-squares-fitting procedures (Table S1 gives the values for the contributing conformations, i.e., 4 [18,20] and, therefore, the three-state equilibrium 4 C 1 h S h 1 C 4 for each of the six skew conformers was analysed using the four 3 J H,H coupling constants in the ring of the altroside.…”

“…[4] A hypothesis to explain this behaviour is that one monosaccharide can mimic another monosaccharide by binding to a protein in such a way that some key interactions, e.g., hydrogen bonding or hydrophobic interactions, are conserved. Addition of a second monosaccharide to the structure to give a non-glycosidically linked pseudodisaccharide may be advantageous; this second monosaccharide moiety would bind to the protein in the same way as a second monosaccharide component of a natural (glycosidic) disaccharide, so increasing the 74 distribution was seen for the 3-amino-3-deoxyaltrosides, but for the 2-amino-2-deoxyaltrosides, a shift in equilibrium position towards the skew conformer (more than 80 % populated) takes place, and also a small amount of the other chair conformer (i.e., 1 C 4 , approximately 10 % populated) was observed.…”