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  • 17β-Arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol as highly potent inhibitors of steroid sulfatase.

17β-Arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol as highly potent inhibitors of steroid sulfatase.

Bioorganic & medicinal chemistry (2012-01-24)
Yaser A Mostafa, Scott D Taylor
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sulfatase from Aerobacter aerogenes, Type VI, buffered aqueous glycerol solution, 2-5 units/mg protein (biuret), 10-20 units/mL
Sigma-Aldrich
Sulfatase from Helix pomatia, Type H-1, sulfatase ≥10,000 units/g solid
Sigma-Aldrich
Sulfatase from abalone entrails, Type VIII, lyophilized powder, 20-40 units/mg solid
Sigma-Aldrich
Sulfatase from Helix pomatia, Type H-2, aqueous solution, ≥2,000 units/mL
Sigma-Aldrich
Sulfatase from Patella vulgata (keyhole limpet), Type IV, essentially salt-free, lyophilized powder, ≥10 units/mg solid