Mostafa Yaser A, Kralt Braden, Rao Praveen P N, Taylor Scott D
Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario N2L 3G1, Canada.
School of Pharmacy, Health Sciences Campus, 200 University Ave. West, Waterloo, Ontario N2L 3G1, Canada.
Bioorg Med Chem. 2015 Sep 1;23(17):5681-92. doi: 10.1016/j.bmc.2015.07.019. Epub 2015 Jul 16.
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 17β-arylsulfonamides of 17β-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 3'-Br, 3'-CF3, 4-NO2-3'-Br and 4-NO2-3'-CF3 derivatives were examined using the NCI 60-cell-line panel and found to have mean graph midpoint values of 1.9-3.4 μM.
类固醇硫酸酯酶（STS）催化生物活性硫酸化类固醇中的硫酸酯基团水解，生成生物活性类固醇。STS抑制剂被认为是治疗激素依赖性癌症（如雌激素受体阳性（ER(+)）乳腺癌）的潜在疗法。制备了一系列17β-氨基雌-1,3,5(10)-三烯-3-醇的4-取代17β-芳基磺酰胺，并作为STS抑制剂进行了研究。与A环未取代的对应物相比，A环2位存在NO2或Br会导致效力降低。然而，A环4位存在硝基或氟原子会导致效力增加，其中一种化合物的Ki(app)值为1 nM。模型研究深入了解了这些化合物与活性位点残基的相互作用方式。使用NCI 60细胞系面板检测了3'-Br、3'-CF3、4-NO2-3'-Br和4-NO2-3'-CF3衍生物的抗增殖活性，发现其平均图形中点值为1.9 - 3.4 μM。
