title: 2-difluoromethyloestrone 3-O-sulphamate, a highly potent steroid sulphatase inhibitor.
abstract: Steroid sulphatase is a target enzyme of growing therapeutic importance. The synthesis and in vitro biological evaluation of three novel 2-substituted analogues of oestrone 3-O-sulphamate (EMATE), an established steroid sulphatase inhibitor, are described. One inhibitor, 2-difluoromethyloestrone 3-O-sulphamate (6), was found to have an IC50 of 100 pM and be some 90-fold more potent than EMATE in inhibiting steroid sulphatase activity in a placental microsomal preparation, rendering this agent the most potent steroidal STS inhibitor in vitro reported to date. Lowering of the pKa value of the leaving parent steroid phenol by the 2-difluoromethyl group during irreversible enzyme sulphamoylation most likely facilitates the potent inactivation of steroid sulphatase by (6). However, our preliminary molecular docking studies using the X-ray crystal structure of steroid sulphatase suggest that F.......H interactions between the 2-difluoromethyl group of (6) and hydrogen bond donor residues lining the catalytic site of STS might also contribute to the high potency observed for (6).
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Bath BA2 7AY, UK.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Reed
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.forename: James J
authors.initials: JJ
authors.lastname: Robinson
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leblond
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D010920:Placenta / Q000201:enzymology; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*
chemical_list: C484900:2-difluoromethyloestrone 3-O-sulfamate; D004791:Enzyme Inhibitors; D004970:Estrone; D043266:Steryl-Sulfatase