Synthesis and Evaluation of Hydroxymethylaminocyclitols as Glycosidase Inhibitors

Abstract

Four series of C 7 N aminocyclitol analogues of glucose were synthesized by stereocontrolled epoxide opening of hydroxyl protected forms of the cyclohexane epoxides cyclophellitol and 1,6epi-cyclophellitol. The resulting hydroxymethyl substituted aminocyclitols were tested as glycosidase inhibitors. Cyclitols having an amino group in an α configuration at a position equivalent to the anomeric in the sugar were found to be low micromolar inhibitors of the α-glucosidase from baker's yeast with K i 's near to 2 μM. On the other hand, N-octyl aminocyclitols having the nitrogen substituents in an α or β configuration were found to be good inhibitors of recombinant β-glucocerebrosidase with K i values between 8.3 and 17 μM, and also inhibited lysosomal β-glucosidase activity in live cells at low-micromolar concentrations. A computational docking study suggests a differential binding among the different series of β-glucocerebrosidase inhibitors. In agreement with the experimental results, the binding poses obtained indicate that the presence of an alkyl lipid substituent in the inhibitor mimicking one of the lipid chains in the substrate is critical for potency. In contrast, the matching of hydroxymethyl substituents in the aminocyclitols and the parent glucosylceramide does not seem to be strictly necessary for potent inhibition, indicating the risk of simplifying structural analogies in sugar mimetic design.

Recent Advances in Synthetic α‐Glucosidase Inhibitors

“…The introduction of ac arboxamide group at the N1 positioni nduces an increase in the inhibitory activity against a-glucosidase. [29] Another strategy to modify quercitol is replacement of the 1'-hydroxy group with an amino group. [26] Notably,t he racemate of 50 also possesses higher activity than the levo enantiomer.…”

“…SAR studies indicatet hat the position of the amino and hydroxy groups is crucial for their inhibitory activity,a nd the lipid chain is also ac ritical structure. [29] Another strategy to modify quercitol is replacement of the 1'-hydroxy group with an amino group. Following this guideline, epimers 56 and 57 have been synthesized and evaluated as potent rice AGIs.…”

Design and synthesis of glycomimetics: Recent advances

“…The amino‐carbasugar structural motif of aminocyclitols is particularly important since it is found in a variety of biologically active compounds like aminoglycoside antibiotics and alkaloids . In addition, aminocyclitol derivatives have been reported as inhibitors of glycosidases . Aminocyclitols 33 were obtained by McMurry coupling from the fully protected aldehyde 34 , obtained in turn by oxidation of diol 35 generated via reductive ring opening of 36 with LiAlH 4 .…”

A New Class of Glucosyl Thioureas: Synthesis and Larvicidal Activities

“…Firstly, due to the lack of structural information about chitin synthase, the details of the chitin synthesis process remain elusive, but researchers have found that β-(1-4)-glycosidic bond formation between aminosaccharides with inversion of the configuration at the anomeric center occurs in the transfer of GlcNAc residues to chitin [23]. Natural CSIs such as trehazolin [35,36,37,38], salbostatin [39,40,41], and validoxylamine [42,43,44], possess a similar structure to UDP-GlcNAc, so we can hypothesize that chitin synthase perhaps mistakes these natural CSIs for chitin synthetic precursors to complete chitin synthesis resulting in interruption of chitin formation. Secondly, in the GlcNAc part of the chitin precursor, the hemiacetal hydroxyl group and amino group are located on the 1- and 2- positions of the glucose ring, whereas these two groups are arranged at 2- and 1- positions in the sugar ring of the abovementioned natural CSIs.…”