N‐Alkyl‐, 1‐C‐Alkyl‐, and 5‐C‐Alkyl‐1,5‐dideoxy‐1,5‐imino‐(l)‐ribitols as Galactosidase Inhibitors

Abstract

A series of 1,5-dideoxy-1,5-imino-(l)-ribitol (DIR) derivatives carrying alkyl or functionalized alkyl groups were prepared and investigated as glycosidase inhibitors. These compounds were designed as simplified 4-epi-isofagomine (4-epi-IFG) mimics and were expected to behave as selective inhibitors of β-galactosidases. All compounds were indeed found to be highly selective for β-galactosidases versus α-glycosidases, as they generally did not inhibit coffee bean α-galactosidase or other α-glycosidases. Some compounds were also found to be inhibitors of almond β-glucosidase. The N-alkyl DIR derivatives were only modest inhibitors of bovine β-galactosidase, with IC50 values in the 30-700 μM range. Likewise, imino-L-ribitol substituted at the C1 position was found to be a weak inhibitor of this enzyme. In contrast, alkyl substitution at C5 resulted in enhanced β-galactosidase inhibitory activity by a factor of up to 1000, with at least six carbon atoms in the alkyl substituent. Remarkably, the 'pseudo-anomeric' configuration in this series does not appear to play a role. Human lysosomal β-galactosidase from leukocyte lysate was, however, poorly inhibited by all iminoribitol derivatives tested (IC50 values in the 100 μM range), while 4-epi-IFG was a good inhibitor of this enzyme. Two compounds were evaluated as pharmacological chaperones for a GM1-gangliosidosis cell line (R301Q mutation) and were found to enhance the mutant enzyme activity by factors up to 2.7-fold.

Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones

“…A series of 1,5-dideoxy-1,5-imino-( l )-ribitol (DIR) derivatives carrying alkyl or functionalized alkyl groups were synthesized and evaluated for their glycosidase inhibitory capacity. 63 These molecules, which were designed as 4- epi -isofagomine ( 9 ) mimics, were found to be highly selective β-Gal inhibitors when compared to α-glycosidases; however, when considering the origin of the enzyme, the activity diminished in the coffee > almond > bovine > human series. The activity was markedly increased upon alkylation of the C5, with data suggesting that the “pseudo-anomeric” configuration of the series does not play a significant role.…”

Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: lessons from Gaucher, GM1-gangliosidosis and Fabry diseases

“…Recent results by Martin and coworkers further support this notion. 108 These authors found that the galactoconfigured glycomimetic 4-epi-isofagomine (67), a strong inhibitor of b-Gal (IC 50 0.4 mM), was able to promote a 2.7-fold activity enhancement in GM1 fibroblasts harboring the R201C mutation when used at 10 mM concentration. Interestingly, the a-5-C-hexyl-DIR derivative 68 (Fig.…”

In vitro protein expression changes in RAW 264.7 cells and HUVECs treated with dialyzed coffee extract by immunoprecipitation high performance liquid chromatography

“…In particular, DCE usually induces different beneficial effects on both RAW 264.7 cells and HUVECs in the absence of cellular stress and apoptosis, By contrast to AC. Therefore, some DCE elements other than AC elements play are considered to play an important role as chemical chaperones to assist the functions of different signaling proteins in cells 42 and affect global protein expression in RAW 264.7 cells and HUVECs.…”