Synthesis and glycosidase inhibition of 5-C-alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives

5-C-Branched Deoxynojirimycin: Strategy for Designing a 1-Deoxynojirimycin-Based Pharmacological Chaperone with a Nanomolar Affinity for Pompe Disease

“…The epimeric 5-C-heptyl-DNJs and the other C-5 branched DNJ derivatives were obtained in our recently reported work. 40 The treatment of nitrone 1 readily prepared on a large scale from L-sorbose 41 with the heptyl Grignard reagent gave a mixture of the easily separated protected epimeric hydroxylamines 2 (12% yield) and 3 (46% yield). The hydrogenation of 2 and 3 gave 5C-heptyl-DNJ and 5-C-heptyl-L-ido-DNJ in the yields of 71 and 99%, respectively (Scheme 1).…”

Introduction of C-alkyl branches to l-iminosugars changes their active site binding orientation

“…We first compared the influence of 5- C -alkylation on GAA affinity for DNJ and l - ido -DNJ. The 5- C -alkylated DNJ and l - ido -DNJ derivatives were obtained in our previous work, 33 and the synthetic route of 5- C -methyl-DNJ and 5- C -methyl- l - ido -DNJ was described in Scheme 1 as an example. Our design strategy was based on experience gained in our previous studies on 5- C -heptyl-DNJ.…”

“…5- C -Methyl-1,5-dideoxy-1,5-imino- l -iditol (5- C -methyl- l - ido -DNJ) and the other C-5 branched l - ido -DNJ derivatives were obtained in our recently reported work. 33 The affinity of human lysosomal acid α-glucosidase (GAA) was performed according to our previous method. 32 Briefly, GAA activity was used in combination with Myozyme (Genzyme; Boston, MA) and 4-methylumbelliferyl-α- d -glucopyranoside (Sigma-Aldrich Co; St Louis, Mo, USA).…”

Stereoselective Access to Iminosugar C,C-Glycosides from 6-Azidoketopyranoses

“…The scarce examples reported in the literature emphasize the difficulty to predict the impact of the quaternarization of the carbon adjacent to the nitrogen in polyhydroxylated piperidines on their glycosidase inhibition profile. Indeed, this structural modification either abolished inhibition of the parent iminosugar or led to improved inhibitory potency. , To the best of our knowledge, there are only two reports, respectively using a chemoenzymatic route (Wong) and an allylic azide rearrangement (Murphy), of six-membered iminosugars displaying a complete hydroxyl pattern (Figure A). In sharp contrast with the broad palette of methods allowing access to iminosugar C -glycosides and sugar C , C -glycosides, − syntheses of iminosugar C , C -glycosides are scarce, illustrating the challenging introduction of a quaternary carbon atom α to a nitrogen atom. − Indeed, a vast array of so-called C -branched iminosugars have been reported, in which a quaternary carbon at the C-2, C-3, or C-4 positions has been built.…”

“…Indeed, this structural modification either abolished inhibition of the parent iminosugar 8 or led to improved inhibitory potency. 9,10 To the best of our knowledge, there are only two reports, respectively using a chemoenzymatic route (Wong) 11 and an allylic azide rearrangement (Murphy), 12 of six-membered iminosugars displaying a complete hydroxyl pattern (Figure 1A). In sharp contrast with the broad palette of methods allowing access to iminosugar C-glycosides 13 and sugar C,C-glycosides, 14−16 syntheses of iminosugar C,Cglycosides are scarce, illustrating the challenging introduction of a quaternary carbon atom α to a nitrogen atom.…”