Synthesis of Uronic Acid 1‐Azasugars as Putative Inhibitors of α‐Iduronidase, β‐Glucuronidase and Heparanase

1‐Azasugar analogues of l‐iduronic acid (l‐IdoA) and d‐glucuronic acid (d‐GlcA) and their corresponding enantiomers have been synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding α‐iduronidase (IDUA). The compounds were efficiently synthesized in nine or ten steps from d‐ or l‐arabinose, and the structures were confirmed by X‐ray crystallographic analysis of key intermediates. All compounds were inactive against IDUA, although l‐IdoA‐configured 8 moderately inhibited β‐glucuronidase (β‐GLU). The d‐GlcA‐configured 9 was a potent inhibitor of β‐GLU and a moderate inhibitor of the endo‐β‐glucuronidase heparanase. Co‐crystallization of 9 with heparanase revealed that the endocyclic nitrogen of 9 forms close interactions with both the catalytic acid and catalytic nucleophile. Potential chaperones: Uronic acid 1‐azasugars (1‐N‐iminosugars) with l‐IdoA and d‐GlcA configurations and their corresponding enantiomers were efficiently synthesized from d‐ or l‐arabinose. Compounds were evaluated for the inhibtion of α‐iduronidase, β‐glucuronidase and heparanase, and for activity as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I).