Enantiospecific synthesis of 1-azafagomine.
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.
Ernholt
B V
BV
Department of Chemistry, Aarhus University, Aarhus C, Denmark.
Thomsen Ib
B
B
Lohse
A
A
Plesner
I W
IW
Jensen
K B
KB
Hazell
R G
RG
Liang
X
X
Jakobsen
A
A
Bols
M
M
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
C414749:1-azafagomine; D004791:Enzyme Inhibitors; D007212:Indolizines; D005959:Glucosidases; D006026:Glycoside Hydrolases