Synthesis of Uronic Acid 1-Azasugars as Putative Inhibitors of a-Iduronidase, b-Glucuronidase and Heparanase

Abstract

1-Azasugar analogues of L-iduronic acid (L-IdoA) and D-glucuronic acid (D-GlcA) and their corresponding enantiomers were synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding a-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 b-glucuronidase (b-GLU). The D-GlcA-configured 9 was a potent inhibitor of b-GLU and a moderate inhibitor of the endo-b-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.