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 IC50 of 26nM. 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 (IC50=18nM). 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 IC50’s of 30 and 23nM, respectively. The 17β-2′-naphthalenesulfonamide was also an excellent inhibitor (IC50=20nM) while the 17β-4′-phenylbenzenesulfonamide derivative was the most potent inhibitor of all the compounds studied with an IC50 of 9nM.