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

• Published in: Organic & biomolecular chemistry Vol. 2; no. 3; pp. 619 - 629
• Main Authors: Bouquet, J, Auberger, N, Ashmus, R, King, D, Bordes, A, Fontelle, N, Nakagawa, S, Madden, Z, Proceviat, C, Kato, A, Désiré, J, Vocadlo, D. J, Blériot, Y
• Format: Journal Article
• Published: 19.01.2022
• DOI: 10.1039/d1ob02280f
• ISSN: 1477-0520

We report the synthesis of seven-membered iminosugars derived from a 3 S -acetamido-4 R ,5 R ,6 S -trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related exo-N -acetylhexosaminidases including human O -GlcNAcase (OGA), human lysosomal β-hexosaminidase (HexAB), and Escherichia coli 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 C -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. Epimerization/ C -alkylation of a seven-membered iminosugar with a broad hexosaminidase inhibition spectrum leads to low micromolar HexAB and NagZ inhibitors.