title: Synthesis and evaluation of general mechanism-based inhibitors of sulfatases based on (difluoro)methyl phenyl sulfate and cyclic phenyl sulfamate motifs.
abstract: 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.
authors.affiliation: Department of Chemistry and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Hanson
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Whalen
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D001192:Arylsulfatases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D001665:Binding Sites; D001667:Binding, Competitive; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000201:enzymology; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; D013463:Sulfuric Acid Esters; C005741:sulfamic acid; D001192:Arylsulfatases; C007482:dimethyl sulfate