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

Abstract

AbstractThe 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.