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

Authors


  • Presented at the 25th International Carbohydrate Symposium, Tokyo, Japan, August 1–6, 2010.

Abstract

The pKa values of six amine-linked pseudodisaccharides have been determined by using an NMR-based titration method. The pKa varies significantly depending on the linkage position and is inversely correlated with the number of electronegative groups in the β-position to the amino group. Four of the pseudodisaccharides contain α-altroside moieties, the conformations of which were determined in the protonated and neutral states, again by using NMR techniques. In the neutral state, 2-amino-2-deoxyaltrosides and 3-amino-3-deoxyaltrosides were both found to occupy 4C1 and OS2 conformations. On protonation, little change in the population 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., 1C4, approximately 10 % populated) was observed. 3-Amino-3-deoxyaltrosides have been shown to act as glycosidase inhibitors and insights into conformational equilibria as a function of protonation state should facilitate the design of better glycosidase inhibitors based on flexible monosaccharide amines.

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