Synthesis and glycosidase inhibitory activity of isourea-type bicyclic sp2-iminosugars related to galactonojirimycin and allonojirimycin

A series of sp2-iminosugars featuring a fused piperidine–isourea bicyclic core and hydroxylation profiles of stereochemical complementarity with the ‘classical’ iminosugars galactonojirimycin and allonojirimycin have been prepared and their inhibitory activity evaluated against a panel of commercial glycosidases. The synthetic methodology involves 2-aminooxazoline pseudo-C-nucleosides, accessible from vic-hydroxycarbodiimide precursors, as key intermediates and is compatible with molecular diversity-oriented strategies. Alkyl, aryl and glycosyl substituents have been incorporated in order to assess the potential of non-glyconic interactions to modulate the enzyme selectivity. All the galactonojirimycin derivatives behaved as potent competitive inhibitors of β-glucosidases. The inhibition potency was higher for aliphatic substituents (in the nM range), but the highest selectivity within β-glucosidase isoenzymes was achieved for a N′-glucopyranosyl pseudodisaccharide analogue. Going from d-galacto to d-allo configuration further increased enzyme selectivity, but strongly penalized the inhibition potency.