title: 17β-Arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol as highly potent inhibitors of steroid sulfatase.
abstract: Steroid sulfatase (STS) catalyzes the desulfation of biologically inactive sulfated steroids to yield biologically active desulfated steroids and is currently being examined as a target for therapeutic intervention for the treatment of breast and other steroid-dependent cancers. Here we report the synthesis of a series of 17β-arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol and their evaluation as inhibitors of STS. Some of these compounds are among the most potent reversible STS inhibitors reported to date. Introducing n-alkyl groups into the 4'-position of the 17β-benzenesulfonamide derivative resulted in an increase in potency with the n-butyl derivative exhibiting the best potency with an IC(50) of 26 nM. A further increase in carbon units (to n-pentyl) resulted in a decrease in potency. Branching of the 4'-n-propyl group resulted in a decrease in potency while branching of the 4'-n-butyl group (to a tert-butyl group) resulted in a slight increase in potency (IC(50)=18 nM). Studies with 3'- and 4'-substituted substituted 17β-benzenesulfonamides with small electron donating and electron withdrawing groups revealed the 3'-bromo and 3'-trifluoromethyl derivatives to be excellent inhibitors with IC(50)'s of 30 and 23 nM, respectively. The 17β-2'-naphthalenesulfonamide was also an excellent inhibitor (IC(50)=20 nM) while the 17β-4'-phenylbenzenesulfonamide derivative was the most potent inhibitor of all the compounds studied with an IC(50) of 9 nM.
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario, Canada N2L 3G1.
authors.forename: Yaser A
authors.initials: YA
authors.lastname: Mostafa
authors.forename: Scott D
authors.initials: SD
authors.lastname: Taylor
mesh_terms: D001192:Arylsulfatases / Q000737:chemistry* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D001192:Arylsulfatases; D043266:Steryl-Sulfatase