Evaluation of isofagomine and its derivatives as potent glycosidase inhibitors.
A pseudo-aza-monosaccharide and several pseudo-aza-disaccharide compounds were constructed based on replacement of the anomeric carbon with a nitrogen and the ring oxygen with a carbon. The inhibition constants of these compounds toward five different glycosidases, alpha-glucosidase, beta-glucosidase, isomaltase, alpha-mannosidase, and glucoamylase, were obtained. Isofagomine, the pseudo-aza-monosaccharide, shows a broad spectrum of strong inhibition against glycosidases. It is the most potent inhibitor of beta-glucosidase from sweet almonds reported to date and also a strong inhibitor of glucoamylase, isomaltase, and alpha-glucosidase. Isofagomine inhibits beta-glucosidase, glucoamylase, and isomaltase more strongly than 1-deoxynojirimycin where the ring oxygen has been replaced with a nitrogen. The alpha-1,6- linked pseudo-disaccharide showed very strong inhibition toward glucoamylase, being nearly as potent an inhibitor as acarbose. Pseudo-disaccharides in which the anomeric nitrogen was methylated to favor formation of either the alpha or beta substrate linkage generally had weakened inhibition for the glycosidases studied most likely due to steric interference with the various active sites. These results indicate that the presence of a basic group at the anomeric center is important for carbohydrase inhibition. The presence of a charged carboxylate group near the anomeric carbon which interacts with the basic nitrogen is suggested for these enzymes, particularly for beta-glucosidase. The presence of a second alpha-linked glucosyl residue is also critical for strong inhibition of glucoamylase.
Dong
W
W
Chemical and Biochemical Engineering Department, University of Maryland Baltimore County, Baltimore, Maryland 21228, USA.
Jespersen
T
T
Bols
M
M
Skrydstrup
T
T
Sierks
M R
MR
D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005087:Glucan 1,4-alpha-Glucosidase / Q000037:antagonists & inhibitors; D065089:Glycoside Hydrolase Inhibitors; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D050112:Imino Pyranoses; D066298:In Vitro Techniques; D007700:Kinetics; D008361:Mannosidases / Q000037:antagonists & inhibitors; D008969:Molecular Sequence Data; D009005:Monosaccharides / Q000737:chemistry / Q000494:pharmacology; D009834:Oligo-1,6-Glucosidase / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D043323:alpha-Mannosidase; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors
D004187:Disaccharides; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D050112:Imino Pyranoses; D009005:Monosaccharides; D010880:Piperidines; C098432:isofagomine; D006026:Glycoside Hydrolases; D008361:Mannosidases; D009834:Oligo-1,6-Glucosidase; D001617:beta-Glucosidase; D043323:alpha-Mannosidase; D005087:Glucan 1,4-alpha-Glucosidase