Castanospermine-glucosides as selective disaccharidase inhibitors.
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. 8 alpha-glucosyl-CS and 7 alpha-glucosyl-CS were nearly as potent against sucrase activity as CS (IC50 values = 30, 40, and 20 nM respectively) but were 1/50 or less as potent as CS against lactase and trehalase activities. 8 beta-glucosyl-CS was 1/20 to 1/140 as potent as CS and 1 alpha-glucosyl-CS was 1/57 to 1/1500 as potent as CS against disaccharidase activities. 1 alpha-glc-CS was less selective than CS, whereas the other CS-glucosides were more selective. 7 alpha-glc-CS and 8 alpha-glc-CS were the most sucrase selective and were particularly ineffective against trehalase and lactase activities. 8 beta-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.
Rhinehart
B L
BL
Merrell Dow Research Institute, Cincinnati, OH 45215.
Robinson
K M
KM
King
C H
CH
Liu
P S
PS
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives*; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D004186:Disaccharidases / Q000037:antagonists & inhibitors*; D004187:Disaccharides / Q000494:pharmacology; D004793:Enzyme Reactivators / Q000494:pharmacology; D005960:Glucosides / Q000138:chemical synthesis / Q000494:pharmacology*; D006027:Glycosides / Q000494:pharmacology*; D007212:Indolizines; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D054836:Indolizidines
D017485:1-Deoxynojirimycin; D000470:Alkaloids; D004186:Disaccharidases; D004187:Disaccharides; D004793:Enzyme Reactivators; D005960:Glucosides; D006027:Glycosides; D007212:Indolizines; C059893:4-O-glucopyranosylmoranoline; C037806:castanospermine; D054836:Indolizidines