Cyanodeoxy‐Glycosyl Derivatives as Substrates for Enzymatic Reactions

Synthetic routes for the preparation of new sugar nitriles 8 – 10 derived from 2‐acetamido‐2‐deoxy‐β‐ D ‐glucopyranosides bearing a cyano group at the C‐5 or C‐6 position are presented. In an attempt to prepare the glycosyl azide 10 by treatment of tosylate 23 with KCN/DMF at 60 °C, an intramolecular 1,3‐dipolar cycloaddition reaction occurred to give the highly constrained nonisolable tetrazole 24 , which was readily converted into the imino‐azido compound 25 through an azido‐tetrazole tautomerism. Compounds 8 and 10 werefound to be poorer substrates of fungal β‐ N ‐acetylhexosaminidases than compound 9 and none of these compounds was accepted as substrates of the nitrilase or nitrile hydratase. Docking of the nitriles 8 – 10 in the active site of the β‐ N ‐acetylhexosaminidase from Aspergillus oryzae gave interaction energies comparable with the natural substrate. Based on these data, which indicate strong binding of these compounds ( 8 > 9 > 10 ) to the active site, it has been proposed that some cyano derivatives may act as competitive inhibitors of β‐ N ‐acetylhexosaminidases. This hypothesis is consistent with enzyme inhibition experiments which showed strong inhibitory properties of compound 9 ( K I = 0.37 m M ) and in particular of compound 8 ( K I = 7.6 μ M ). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)