title: Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitor.
abstract: Steroid sulfatase (STS) catalyzes the hydrolyis of steroidal sulfates such as estrone sulfate (ES1) and is considered to be an attractive target in the treatment of steroid dependent cancers. A non-hydrolyzable estrone sulfate (ES1) analogue bearing an alpha,alpha-difluorosulfonamide moiety at the 3-position on the A-ring, compound , was synthesized. Key to the success of this synthesis was the first use of the allyl group as a sulfonamide protecting group. The pK(a) of this ES1 mimic in 0.1 M bis-tris propane, 10% DMSO was determined to be 8.05 using 19F NMR. Compound is a reversible inhibitor with a K(i) similar to that of its sulfonate analogue at pH 7.0. It is more potent than its non-fluorinated sulfonamide analogue and, its inhibitory potency increases with increasing pH, a trend opposite to that of other STS inhibitors. Possible reasons for this are presented.
authors.affiliation: Dept. of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario, CanadaN2L 3G1.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ahmed
authors.forename: Bryan
authors.initials: B
authors.lastname: Hill
authors.forename: Scott D
authors.initials: SD
authors.lastname: Taylor