The structural basis of the inhibition of human glycosidases by castanospermine analogues

Abstract

A series of epimers and deoxy derivatives of castanospermine has been synthesized to investigate the contribution of the different chiral centres to the specificity and potency of inhibition of human liver glycosidases. Castanospermine inhibits all forms of α- and β-D-glucosidases, but alteration to any of the five chiral centres in castanospermine markedly decreases the inhibition. 6-Epicastanospermine, which is related to D-pyranomannose in the same way as castanospermine is to D-pyranoglucose, does not inhibit lysosomal (acidic) α-mannosidase, but is a good inhibitor of the cytosolic or neutral α-mannosidase. Conversely, 1-deoxy-6-epicastanospermine inhibits acidic α-mannosidase strongly, but not the neutral α-mannosidase. An explanation of this different inhibition based on preferential recognition of different configurations of mannose by different forms of α-mannosidase is postulated. All derivatives of 6-epicastanospermine also have the minimum structural feature for the inhibition of α-L-fucosidase, but those with a β-anomeric substituent do not inhibit the enzyme, or do so very weakly. 1-Deoxy-6,8a-diepicastanospermine, which has four chiral centres identical with α-L-fucose, is, however, a potent inhibitor of α-L-fucosidase (K(i) 1.3 μM).