Synthesis and evaluation of calystegine B2 analogues as glycosidase inhibitors.
A practical synthesis of polyhydroxylated 6-oxa-nor-tropanes incorporating the essential structural features of calystegine B(2) from 5-deoxy-5-thioureido and 5-ureido-L-idofuranose precursors is presented. The methodology relies on the ability of pseudoamide-type nitrogen atoms (thiourea, urea, and carbamate) to undergo nucleophilic addition to the masked aldehyde group of the monosaccharide. The generated hemiaminal functionality may further undergo in situ intramolecular glycosidation to give the bicyclic aminoacetal compounds, the whole process being favored by the anomeric effect. A series of derivatives bearing different substituents at nitrogen has been prepared and screened against several glycosidases in comparison with xylonojirimycin-type piperidine analogues. Interestingly, strong and highly specific inhibition of bovine liver beta-glucosidase was observed for 6-oxacalystegine B(2) analogues incorporating aromatic pseudoaglyconic groups. On the basis of these data, a 1-azasugar inhibition mode is proposed for this family of glycomimetics.
García-Moreno
M I
MI
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, E-41071 Seville, Spain.
Benito
J M
JM
Ortiz Mellet
C
C
García Fernández
J M
JM
D000818:Animals; D001667:Binding, Competitive; D002240:Carbohydrate Sequence; D002417:Cattle; D003069:Coffee / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D065089:Glycoside Hydrolase Inhibitors; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D009662:Nortropanes / Q000138:chemical synthesis* / Q000494:pharmacology; D027861:Prunus / Q000201:enzymology; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D012991:Solanaceous Alkaloids; D013237:Stereoisomerism; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors
D003069:Coffee; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D009662:Nortropanes; D012991:Solanaceous Alkaloids; C095613:calystegine B(2); D006026:Glycoside Hydrolases; D001617:beta-Glucosidase