A cyclic phosphonamidate analogue of glucose as a selective inhibitor of inverting glycosidases.
Recent work in the synthesis of cyclic phosphonate analogues of glucose [Darrow, J.W.; Drueckhammer, D.G. (1994) J. Org. Chem. 1994, 59, 2976] has been extended to the synthesis of a corresponding phosphonamidate analogue. A phosphonate salt, phosphonate methyl ester, and phosphonamidate analogue were tested as inhibitors of two inverting alpha-glycosidases, (trehalase and glucoamylase), and two retaining glycosidases, (alpha-glucosidase and beta-glucosidase). No inhibition of any of these enzymes was observed with the phosphonate salt or methyl ester. However, the phosphonamidate gave moderate competitive inhibition of the two inverting glycosidases and the retaining alpha-glucosidase but no inhibition of beta-glucosidase. The phosphonamidate showed enhanced binding relative to a simple monosaccharide only with the inverting glycosidases. This enhanced binding is believed to be due to hydrogen bonding interactions between the phosphonamidate group and two active site carboxylate residues implicated in catalysis. The selectivity toward inverting glycosidases is consistent with differences in distance of an active site carboxylate from the anomeric carbon of the glycoside substrate for the inverting versus the retaining glycosidases.
Darrow
J W
JW
Department of Chemistry, Stanford University, CA 94305, USA.
Drueckhammer
D G
DG
D000818:Animals; D005087:Glucan 1,4-alpha-Glucosidase / Q000037:antagonists & inhibitors; D005947:Glucose / Q000031:analogs & derivatives*; D065089:Glycoside Hydrolase Inhibitors; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D013552:Swine; D014198:Trehalase / Q000037:antagonists & inhibitors; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors
D065089:Glycoside Hydrolase Inhibitors; D006026:Glycoside Hydrolases; D001617:beta-Glucosidase; D014198:Trehalase; D005087:Glucan 1,4-alpha-Glucosidase; D005947:Glucose