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.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Glucosidases/antagonists & inhibitors , Indolizines/chemical synthesis , Enzyme Inhibitors/chemistry , Glycoside Hydrolases/antagonists & inhibitors , Indolizines/chemistry , Molecular Mimicry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
(6R)-6-(Hydroxymethyl)piperazin-2-one (1), (6S)-6-(hydroxymethyl)piperazin-2-one (2) and (6S)-6-[(1R, 2S, 3R)-1,2,3,4-tetrahydroxybutyl]piperazin-2-one (3) have been prepared in optically pure forms starting from D-glucosamine hydrochloride (4). The compounds (1-3) were tested for glycosidase inhibition.
