title: Enantiospecific synthesis of 1-azafagomine.
abstract: For the first time the two enantiomeric forms of the glycosidase inhibitor 1-azafagomine have been synthesised starting from D- and L-xylose. D-Xylose was converted to the 2,3,5-tribenzylfuranose, which upon reductive amination with tert-butyl carbazate gave the protected 1-hydrazino-1-deoxypentitol in high yield. N-acetylation, mesylation of the 4-OH, removal of the Boc group, cyclisation and deprotection gave (+)-1-azafagomine ((+)-1). By a similar sequence of reactions, L-xylose was converted to (-)-1-azafagomine ((-)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond beta-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement. The rate constants for binding and release were found to be 3.3 x 10(4)M(-1)s(-1) and 0.011 s(-1), respectively, yielding Ki = 0.33 microM.
authors.affiliation: Department of Chemistry, Aarhus University, Aarhus C, Denmark.
authors.forename: B V
authors.initials: BV
authors.lastname: Ernholt
authors.forename: B
authors.initials: B
authors.lastname: Thomsen Ib
authors.forename: A
authors.initials: A
authors.lastname: Lohse
authors.forename: I W
authors.initials: IW
authors.lastname: Plesner
authors.forename: K B
authors.initials: KB
authors.lastname: Jensen
authors.forename: R G
authors.initials: RG
authors.lastname: Hazell
authors.forename: X
authors.initials: X
authors.lastname: Liang
authors.forename: A
authors.initials: A
authors.lastname: Jakobsen
authors.forename: M
authors.initials: M
authors.lastname: Bols
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005959:Glucosidases / Q000037:antagonists & inhibitors*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry; D018716:Molecular Mimicry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C414749:1-azafagomine; D004791:Enzyme Inhibitors; D007212:Indolizines; D005959:Glucosidases; D006026:Glycoside Hydrolases