Synthesis of 2-acetamido-1,2-dideoxy-d-galacto-nojirimycin [DGJNAc] from d-glucuronolactone: the first sub-micromolar inhibitor of α-N-acetylgalactosaminidases

Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of N‐Alkylation on Hexosaminidase Inhibition

“…DGJNAc ( 1 D ) was a potent inhibitor of α‐GalNAcase with an IC 50 value of 0.32 μ M against chicken liver and a K i value of 0.17 μ M against Charonia lampas 12. None of the other three NH iminosugars (compounds 1 L , 2 D , or 2 L ) significantly inhibited α‐GalNAcase from chicken liver (Table 1).…”

“…The interest in selective inhibitors of hexosaminidases is due to their potential use in the chemotherapy of a wide range of diseases,9 including O ‐GlcNAcase inhibition10 and cancer metastasis 11. DGJNAc is rare example of a potent inhibitor of α‐GalNAcases 12. Specific α‐GalNAcase inhibition is of interest in the studies of Schindler–Kanzaki disease,13 the treatment of cancer by the protection of macrophage‐activating factor,14 and the modification of a number of pathogens by the inhibition of endo ‐GalNAcases 15.…”

Synthesis of the enantiomers of XYLNAc and LYXNAc: comparison of β-N-acetylhexosaminidase inhibition by the 8 stereoisomers of 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols

“…The acetonide 26D which has only C-5 OH unprotected allows introduction of azide with inversion, reduction of the lactone at C6 and inversion of configuration at C3 to afford the azido diol 27L in 70% yield on a multigram scale. 24,45 L-Glucuronolactone acetonide 26L 46,47 was converted to the enantiomer L-XYLNAc 20L by an identical procedure.…”

Pharmacological chaperones for human α- N -acetylgalactosaminidase

“…DGJNAc was originally hypothesized to be an inhibitor of α-NAGAL by extension of observations on the Fabry disease equivalents (DGJ and α-GAL A) (17). However, a report of the specific synthesis and testing of the compound appeared only recently (29) [and not in a sometimes-cited earlier paper (42)]. Here, we describe biochemical, structural, and cellular studies on the interaction and chaperoning of human α-NAGAL by DGJNAc.…”

“…Crystal structures of N201Q α-NAGAL, an engineered variant that produces high-quality crystals (36), were solved with DGJ bound, DGJNAc bound, or with an empty active site. DGJNAc was synthesized as described (29). For limited proteolysis studies, purified wild-type or E367K α-NAGAL was incubated overnight in 4 M urea, pH 7.2, in the presence and absence of DGJ or DGJNAc.…”