Improved cellular inhibitors for glycoprotein processing α-glucosidases: biological characterisation of alkyl- and arylalkyl-N-substituted deoxynojirimycins

A series of N-alkyl- and N-arylalkyl-DNJ compounds have been evaluated for their efficacy for inhibition of endoplasmic reticulum resident alpha-glucosidases in cells. A recently developed free oligosaccharide (FOS) assay allowed the products Of glucosidase inhibition to be quantified and compounds compared for relative inhibitory activity. A N-alkyl chain of one to six carbon atoms provided a flexible linker between deoxynojirimycin (DNJ) and a phenyl, cyclohexyl or cyclopentyl group to explore the requirements for glucosidase inhibition. The most effective compounds were those in which the linker contained four to six carbon atoms and a phenyl group. These compounds all significantly inhibited alpha-glucosidase I at concentrations of 100 mu M following addition to cells for 24 h whereas DNJ was without effect. Inhibition of alpha-glucosidase 11 was evident by all inhibitors, consistent with a previously identified mechanism of action of imino sugar inhibitors in cells. (C) 2009 Elsevier Ltd. All rights reserved.