1-N-Iminosugars:  Potent and Selective Inhibitors of β-Glycosidases

Abstract

A series of 1-N-iminosugars were synthesized to supply the need for glycosidase inhibitors that are both highly potent and selective for β-glycosidases. Designed on the basis of the transition-state model of the β-glucosidase reaction, these iminosugar inhibitors differ from the currently available inhibitors in possessing a nitrogen atom at the anomeric position of the pyranose ring, thereby generating a positive charge on the anomeric position rather than on the ring oxygen of the sugar. Their syntheses, starting with a readily available carbohydrate derivative, involve (i) introduction of an amino functionality as an azido group, (ii) formation of a 1-N-iminopyranose ring with reductive amination, and (iii) stereoselective introduction of a hydroxymethyl or methyl group and were accomplished in a highly stereoselective and efficient manner. The inhibitory potencies of the 1-N-iminosugars were evaluated against several α- and β-glycosidases, and they were found to be extremely potent and highly specific against the corresponding β-glycosidases, with K i values in the nanomolar range.

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

“…Strong and selective inhibitors of b-D-glucuronidase and a-L-iduronidase are thus of therapeutic interest. Siastatin B (1) [12] and its analogues 2 -4 [13], the pipecolic acids 5 [14] and 6 [15], and glucarolactam 8 [16] inhibit b-D-glucuronidases. The idarolactone 7 [17] is the only known inhibitor of human a-L-iduronidase.…”

New Synthetic Seven‐Membered 1‐Azasugars Displaying Potent Inhibition Towards Glycosidases and Glucosylceramide Transferase

“…Meanwhile, several other sugar analogues with nitrogen at the anomeric position have been prepared. [9] Wong has demonstrated the importance of the presence of a correctly orientated 2-hydroxy group for the generation of effective inhibition in glucose-derived iminosugars, [10] and, as expected, the potency of isofagomine was further improved by introducing a hydroxy group at the C-2 position to afford noeuromycin, a nanomolar b-glucosidase inhibitor. [11a] This compound proved to be unstable at neutral pH and to rearrange to the corresponding hydrated ketone, due to the labile hemiaminal moiety.…”

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.…”