Structural variation of the 3-acetamido-4,5,6-trihydroxyazepane iminosugar through epimerization and C -alkylation leads to low micromolar HexAB and NagZ inhibitors

We report the synthesis of seven-membered iminosugars derived from a 3 -acetamido-4 ,5 ,6 -trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related -acetylhexosaminidases including human -GlcNAcase (OGA), human lysosomal β-hexosaminidase (HexAB), and NagZ. Capitalizing on the flexibility of azepanes and the active site tolerances of hexosaminidases, we explore the effects of epimerization of stereocenters at C-3, C-5 and C-6 and -alkylation at the C-2 or C-7 positions. Accordingly, epimerization at C-6 (L-ido) and at C-5 (D-galacto) led to selective HexAB inhibitors whereas introduction of a propyl group at C-7 on the C-3 epimer furnished a potent NagZ inhibitor.