Synthesis and evaluation of sulfamide-type indolizidines as glycosidase inhibitors.
A practical synthesis of reducing sulfamide-derived iminosugar glycomimetics related to the indolizidine glycosidase inhibitor family is reported. The polyhydroxylated bicyclic system was built from readily accessible hexofuranose derivatives through a synthetic scheme that involves 5,6-cyclic sulfamides. Further intramolecular nucleophilic addition of the sulfamide nitrogen atom to the masked aldehyde group of the monosaccharide in the open chain form afforded the target sugar mimics. By starting from d-glucose and d-mannose precursors, 2-aza-3,3-dioxo-3-thiaindolizidine derivatives with hydroxylation profiles that matched those of (+)-castanospermine and 6-epi-(+)-castanospermine were obtained. In vitro screening against a panel of glycosidases evidenced a high selectivity towards alpha-mannosidase.
Benltifa
Mahmoud
M
Laboratoire des Glucides UMR CNRS 6219, Université de Picardie Jules Verne, 33 Rue Saint-Leu, F-80039 Amiens, France.
García Moreno
M Isabel
MI
Ortiz Mellet
Carmen
C
García Fernández
José M
JM
Wadouachi
Anne
A
D000447:Aldehydes / Q000737:chemistry; D002460:Cell Line / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D006900:Hydroxylation; D054836:Indolizidines / Q000138:chemical synthesis / Q000494:pharmacology*; D007212:Indolizines / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D018716:Molecular Mimicry; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D043323:alpha-Mannosidase / Q000037:antagonists & inhibitors
D000447:Aldehydes; D004791:Enzyme Inhibitors; D054836:Indolizidines; D007212:Indolizines; D013449:Sulfonamides; D006026:Glycoside Hydrolases; D043323:alpha-Mannosidase; C037806:castanospermine