Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario, Canada N2L 3G1.
Bioorg Med Chem. 2012 Feb 15;20(4):1535-44. doi: 10.1016/j.bmc.2011.12.036. Epub 2012 Jan 5.
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.
甾体硫酸酯酶（STS）催化生物失活的磺化甾体的脱硫作用，生成生物活性的去磺化甾体，目前正在作为治疗乳腺癌和其他甾体依赖性癌症的治疗干预的靶标进行研究。在这里，我们报告了一系列 17β-芳基磺酰胺的 17β-氨基雌甾-1,3,5(10)-三烯-3-醇的合成及其作为 STS 抑制剂的评价。这些化合物中有一些是迄今为止报道的最有效的可逆 STS 抑制剂之一。在 17β-苯磺酰胺衍生物的 4′-位引入正烷基会导致活性增加，其中正丁基衍生物表现出最佳的活性，IC50 为 26 nM。进一步增加碳原子数（至正戊基）会导致活性降低。4′-n-丙基支链会导致活性降低，而 4′-n-丁基支链（叔丁基）会导致活性略有增加（IC50=18 nM）。对 3′和 4′取代的 17β-苯磺酰胺进行的取代研究，发现带有小供电子和吸电子基团的 3′-溴和 3′-三氟甲基衍生物是极好的抑制剂，IC50 分别为 30 和 23 nM。17β-2′-萘磺酰胺也是一种极好的抑制剂（IC50=20 nM），而 17β-4′-苯磺酰胺衍生物是所有研究化合物中活性最强的抑制剂，IC50 为 9 nM。
