Castanospermine-glucosides as selective disaccharidase inhibitors

Abstract

Castanospermine (CS) is a potent but non-selective inhibitor of many glycohydrolases including the intestinal disaccharidases. Several CS-glucosides were synthesized to investigate the effect of an attached glucopyranosyl residue on the potency and selectivity of CS toward inhibition of intestinal disaccharidases. 8α-glucosyl-CS and 7α-glucosyl-CS were nearly as potent against sucrase activity as CS ( ic 50 values = 30, 40, and 20 nM respectively) but were 1/50 or less as potent as CS against lactase and trehalase activities. 8β-glucosyl-CS was 1/20 to 1/140 as potent as CS and 1α-glucosyl-CS was 1/57 to 1/1500 as potent as CS against disaccharidase activities. 1α-glc-CS was less selective than CS, whereas the other CS-glucosides were more selective. 7α-glc-CS and 8αḡlc-CS were the most sucrase selective and were particularly ineffective against trehalase and lactase activities. 8β-glc-CS was similar to CS except for relatively weaker trehalase inhibition. In summary, selectivity toward certain disaccharidases was achieved by glucosylation of CS hydroxyls. However, a simple structural comparison of the CS-glucoside to a disaccharide substrate did not reliably predict which disaccharidase would be more inhibited by the CS-glucoside.