Steroid sulfatase (STS) catalyzes the hydrolysis of the sulfate ester group in biologically inactive sulfated steroids to give biologically active steroids. Inhibitors of STS are considered to be potential therapeutics for treating hormone-dependent cancers such as ER+ breast cancer. A series of 4-substituted 17b-arylsulfonamides of 17b-aminoestra-1,3,5(10)-trien-3-ol were prepared and examined as STS inhibitors. The presence of a NO2 or Br at the 2-position of the A-ring resulted in a decrease in potency compared to their A-ring-unsubstituted counterparts. However the presence of a nitro group or fluorine atom at the 4-position of the A-ring resulted in an increase in potency and one of these compounds exhibited a Ki app value of 1 nM. Modeling studies provided insight into how these compounds interact with active site residues. The anti-proliferative activity of the 30-Br, 30-CF3, 4-NO2-30-Br and 4-NO2-30-CF3 derivatives were examined using the NCI 60-cell-line panel and found to have mean graph midpoint values of 1.9–3.4 lM.