trans, trans-2-C-Aryl-3,4-dihydroxypyrrolidines as potent and selective β-glucosidase inhibitors: Pharmacological chaperones for Gaucher disease

Chemical Chaperones to Inhibit Endoplasmic Reticulum Stress: Implications in Diseases

“…Compound 31 -assisted folding of mutant enzyme prevents its degradation by the ER proteostasis function. 96 Compound 32 also strongly inhibited β-glucosidase. 97 Similarly, a defect in lysosomal α-galactosidase A (α-Gal A) causes Fabry disease due to accumulation of neutral glycosphingolipids bearing a terminal α-galactosyl residue.…”

Design, synthesis and glycosidase inhibition of DAB derivatives with C-4 peptide and dipeptide branches

“…1,4-Dideoxy-1,4-imino- d -arabinitol ( 1 , DAB) is among the most studied iminosugars due to its widespread isolation from various sources 1–3 and significant glycosidase inhibition. The trihydroxylated pyrrolidine shows potent inhibition against yeast α-glucosidase, 2,4–9 rat intestinal sucrase, 9 α,α-trehalase 9,10 and glycogen phosphorylase, 11 and is also found to be a moderate or weak inhibitor of a series of α-glucosidases from various sources, 9,10,12 β-glucosidase, 10,12 α-mannosidase 10,12 and amyloglucosidase. 12 In contrast, many naturally occurring and synthetic derivatives of DAB have been found with the tendency of narrowing down their inhibition spectra.…”

“…When the modification strategy was applied at the C-4 position, compounds 10–13 showed potent and specific α-glucosidase inhibition, 21 whereas the C-4 hydroxymethyl depleted C -arylated DABs 14 were powerful and selective human β-glucocerebrosidase inhibitors. 9 The two series of C-4 modified derivatives of DAB ( 10 , 11 , 13 and 14 ) not only help understand the interaction modes of DAB derivatives with the corresponding enzymes, but also unveiled the potential of realizing more possibilities with further C-4 structural modifications (Fig. 1).…”

Design and synthesis of iso-allo-DNJ and l-isoDALDP derivatives: pursuit of potent and selective inhibitors of α-glucosidase

“…15 Similarly, DAB ( 8a ), the analogue of DMDP ( 3 ) was also a strong and competitive inhibitor of yeast α-glucosidase 16 and glycogen phosphorylase, 17 and also a potent inhibitor of porcine kidney trehalase. 18 Therefore, the C-5 hydroxymethyl groups of these compounds might have different influences on their binding conformations and glycosidase inhibitions. As another derivation strategy of DNJ ( 1 ), DMJ ( 2 ) and DMDP ( 3 ), C -branched iminosugars 11–13 were developed with the original hydroxymethyls used as substituents.…”