Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5221334 | Tetrahedron | 2012 | 9 Pages |
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 Nâ²-glucopyranosyl pseudodisaccharide analogue. Going from d-galacto to d-allo configuration further increased enzyme selectivity, but strongly penalized the inhibition potency.
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