Synthesis and evaluation of general mechanism-based inhibitors of sulfatases based on (difluoro)methyl phenyl sulfate and cyclic phenyl sulfamate motifs

Several model mechanism-based inhibitors (MbIs) were designed and evaluated for their ability to inhibit sulfatases. The MbI motifs were based on simple aromatic sulfates, which are known to be commonly accepted substrates across this highly conserved enzyme class, so that they might be generally useful for sulfatase labeling studies. (Difluoro)methyl phenol sulfate analogs, constructed to release a reactive quinone methide trap, were not capable of irreversibly inactivating the sulfatase active site. On the other hand, the cyclic sulfamates (CySAs) demonstrated inhibition profiles consistent with an active site-directed mode of action. These molecules represent a novel scaffold for labeling sulfatases and for probing their catalytic mechanism.

Sulfatases are emerging as an important class of enzymes that modulate the activity of a variety of small molecules and complex glycans by cleaving sulfate esters. Herein, general mechanism-based inhibitors modeled from commonly accepted phenyl sulfate substrates of this enzyme class were designed and evaluated. Phenyl cyclic sulfamate motifs were found to be novel specific-irreversible inhibitors that will be useful for probing the catalytic mechanism of sulfatases.Figure optionsDownload as PowerPoint slide