Structural variation of the 3-acetamido-4, 5, 6-trihydroxyazepane iminosugar through epimerization and C-alkylation leads to low micromolar HexAB and NagZ inhibitors. Issue 3 (23rd December 2021)

• Record Type: Journal Article
• 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.
• Is Part Of: Organic & biomolecular chemistry. Volume 20:Issue 3(2021)
• Page Start: 619
• Page End: 629
• Publication Date: 2021-12-23
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/d1ob02280f
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Epimerization/ C -alkylation of a seven-membered iminosugar with a broad hexosaminidase inhibition spectrum leads to low micromolar HexAB and NagZ inhibitors. Abstract : 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.