Glycosidase inhibitors from the roots of Glyphaea brevis.

Ten phenylalkyl-substituted iminosugars ( 1 – 10 ) and a cinnamic acid derived glucoside ( 11 ) were isolated from the roots of Glyphaea brevis (Malvaceae). Their structures were elucidated by 1D and 2D NMR analysis, as well as by HR-ESIMS. Compounds 1 – 10 retain an unprecedented structure composed of an iminosugar-like core identified as 1-deoxyfuconojirimycin in glyphaeaside A 1 –A 4 ( 1 , 2 , 5 , 6 ), 1-deoxygalactonojirimycin in glyphaeaside B 1 –B 5 ( 3 , 4 , 7 – 9 ) or 1-deoxynojirimycin in glyphaeaside C ( 10 ), substituted by a β - d -glucopyranose in compounds 2 , 4 , 6 and 9 . These compounds feature a di-, tri- or tetra-hydroxylated nine-carbon chain at the pseudo-anomeric position, substituted by a terminal phenyl group. All alkyl C -iminosugars displayed potent and selective inhibition towards β -glucosidase with IC 50 values ranging from 0.15 to 68 μM. Compound 10 with an 1-deoxynojirimycin backbone was the most active and was found to act as a competitive inhibitor with K i = 31 nM, therefore emerging as one of the most potent inhibitor of β -glucosidase reported to date. Inhibition of β -mannosidase was observed with compounds 1 , 3 , 7 and 10 , but only weak inhibition could be detected with the alkyl- C -iminosugars on the other tested glycosidases ( α -glucosidase, α -fucosidase, α - and β -galactosidase). [ABSTRACT FROM AUTHOR]