Evaluation of Isofagomine and Its Derivatives As Potent Glycosidase Inhibitors

Abstract

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.

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

“…1). Sierks and colleagues showed that IFG inhibits yeast isomaltase, with a K i of 7.2 μM, a value somewhat lower than the 100 μM IC50 value we determined for the human enzyme [26]. The failure of IFG and NB-DNJ to inhibit lactase is consistent with previous work showing that galactose analogs such as NB-DGJ but not glucose analogs are good inhibitors of this enzyme [9].…”

A New Intramolecular Reaction for the Regioselective Debenzylation or Protection of Alcohols

“…Benzyl-b-d-arabinopyranoside 12 [9] and benzyl-3,4-isopropylidene-b-d-arabinopyranoside 14 [10] gave the expected acetals 13 and 15 in 44 % and 41 % yield, respectively. Again instability of the benzylidene compounds accounts for the diminished yields.…”

Inhibition of Catalytic and Glucan-Binding Activities of a Streptococcal GTF Forming Insoluble Glucans

“…bon and the anomeric carbon with a nitrogen [Dong et al, 1996], is a stronger inhibitor of ß-glucosidase, glucoamylase and isomaltase than deoxynojirimycin but its effect on GTF-I is slight and isofagomine does not seem to have potential for application as a GTF inhibitor.…”

“…Glucamine was obtained from Tokyo Kasei Kogyo (Chuo-ku, Tokyo, Japan). Isofagomine was a kind gift of M. Bols [Dong et al, 1996]. Acarbose, N-dodecyldeoxynojirimycin, the amine hydrofluorides Dectaflur (9-octadecenylamine-hydrofluoride), Olaflur (N)-octadecyltrimethylamine-N,N,N)-tris (2-ethanol)-dihydrofluoride) and Xidecaflur (bishydroxylated oleyl amine hydrofluoride) were provided by GABA International, Munchenstein, Switzerland.…”