Synthesis and evaluation of hydroxymethylaminocyclitols as glycosidase inhibitors

The Journal of Organic Chemistry
Ana TraperoAmadeu Llebaria

Abstract

Four series of C7N aminocyclitol analogues of glucose were synthesized by stereocontrolled epoxide opening of hydroxyl protected forms of the cyclohexane epoxides cyclophellitol and 1,6-epi-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 Ki'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 Ki 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...Continue Reading

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Citations

May 13, 2017·ChemMedChem·Zhiyang Liu, Shutao Ma
Jul 31, 2019·Medicinal Research Reviews·Alice TamburriniAnna Bernardi
Jul 22, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ping-An WangMu-Qiong Li

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