ABSTRACT
We report the synthesis of seven-membered iminosugars derived from a 3S-acetamido-4R,5R,6S-trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related exo-N-acetylhexosaminidases including human O-GlcNAcase (OGA), human lysosomal ß-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.
Subject(s)
Acetylglucosaminidase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Imino Sugars/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , Acetylglucosaminidase/metabolism , Alkylation , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Humans , Imino Sugars/chemical synthesis , Imino Sugars/chemistry , Molecular Conformation , beta-N-Acetylhexosaminidases/metabolismABSTRACT
The Lewis acid-catalyzed nucleophilic opening of a D-gluco-configured bicyclic hemiaminal has been examined. Several Lewis acids and silylated nucleophiles have been screened allowing the introduction of acetophenone, phosphonate or nitrile at the pseudoanomeric position in satisfactory yields and high 1,2 trans stereoselectivities. Their skeletal rearrangement triggered by the N-benzyl anchimeric assistance provided the corresponding L-ido-configured piperidines displaying various functional groups at C-6 position in good yield.
Subject(s)
Imino Sugars/chemistry , Lewis Acids/chemistry , Piperidines/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
A series of pentahydroxylated pyrrolidines, displaying five contiguous stereogenic centres and epimeric to α-glucosidase inhibitor homoDMDP, have been synthesized. The key step involves a γ-aminoalcohol rearrangement applied to polyhydroxylated azepanes. These five-membered iminosugars demonstrate micromolar inhibition of glycosidases.