Phosphodiesters serve as potentially tunable aglycones for fluoro sugar inactivators of retaining ß-glycosidases.

2-Deoxy-2-fluoroglycosides bearing dibenzyl phosphate and phosphonate aglycones were synthesised and tested as covalent inactivators of several retaining α- and ß-glycosidases. ß-d-Gluco-, -manno- and -galacto-configured benzyl-benzylphosphonate derivatives efficiently inactivated ß-gluco-, ß-manno- and ß-galactosidases, while α-gluco- and α-manno-configured phosphate and phosphonate derivatives served instead as slow substrates.

N-Alkylated aziridines are easily-prepared, potent, specific and cell-permeable covalent inhibitors of human ß-glucocerebrosidase.

ß-Glucocerebrosidase deficiency leads to Gaucher disease and is a potential marker of Parkinson's disease. We have identified N-octyl conduritol aziridine as a potent and specific covalent inactivator of GBA1 in living cells. This compound is a promising lead towards a positron emission tomography probe intended to image GBA1 activity.