Spacer-modified oligosaccharides with basic anchoring groups are inhibitors for endo-glycanases: porcine pancreatic alpha-amylase as model enzyme.
By coupling methyl 2,3,6-tri-O-acetyl-4-O-(5-azido-6-p-tolylsulfonyloxyhexyl)-alpha-D - glucopyranoside with 2-benzoylthioethyl 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranoside, a spacer-modified disaccharide derivative, methyl 4-O-(5-azido-9-alpha-D-glucopyranosyloxy-7-thianonyl)-alpha- D-glucopyranoside, was obtained and then enzymatically glucosylated to yield the spacer-modified tri- and tetra-saccharide methyl 4-O-(5-azido-9-alpha-maltosyloxy-7-thianonyl)-alpha-D-glucop yranoside and methyl 4-O-(5-azido-9-alpha-maltotriosyloxy-7-thianonyl)-alpha-D-gl ucopyranoside, respectively, the extended spacer spanning the length of two (1-->4)-linked pyranosyl units. The corresponding amines methyl 4-O-(5-amino-9-alpha-D-glucopyranosyloxy-7-thianonyl)-alpha- D-glucopyranoside, methyl 4-O-(5-amino-9-alpha-maltosyloxy-7-thianonyl)-alpha-D-glucop yranoside and methyl 4-O-(5-amino-9-alpha-maltotriosyloxy-7-thianonyl)-alpha-D-gl ucopyranoside, obtained by catalytic reduction, carry the basic functionality in a spacer position to allow ionic interaction with a catalytically active acidic group in porcine pancreatic alpha-amylase (PPA). Optimal inhibition of enzymic activity is by methyl 4-O-(5-amino-9-alpha-maltosyloxy-7-thianonyl)-alpha-D-glucop yranoside where three of the five subsites are occupied by glucosyl units and the spacer spanning the remaining subsites positions the amino group near the catalytic site.
Lehmann
J
J
Institut für Organische Chemie und Biochemie der Universität Freiburg, Germany.
Schmidt-Schuchardt
M
M
D000818:Animals; D001667:Binding, Competitive; D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry; D005960:Glucosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D009844:Oligosaccharides / Q000494:pharmacology*; D010179:Pancreas / Q000201:enzymology*; D013237:Stereoisomerism; D013552:Swine; D000516:alpha-Amylases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D004187:Disaccharides; D005960:Glucosides; D009844:Oligosaccharides; D006026:Glycoside Hydrolases; C020668:glycanase; D000516:alpha-Amylases