Ahmed Vanessa, Liu Yong, Silvestro Cassandra, Taylor Scott D
Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ont., Canada N2L 3G1.
Bioorg Med Chem. 2006 Dec 15;14(24):8564-73. doi: 10.1016/j.bmc.2006.08.033. Epub 2006 Sep 14.
Steroid sulfatase (STS) catalyzes the hydrolysis of steroidal sulfates such as estrone sulfate (ES1) to the corresponding steroids and inorganic sulfate. STS is considered to be a potential target for the development of therapeutics for the treatment of steroid-dependent cancers. Two steroidal and two coumarin- and chromenone-based boronic acids were synthesized and examined as inhibitors of purified STS. The boronic acid analog of estrone sulfate bearing a boronic acid moiety at the 3-position in place of the sulfate group was a good competitive STS inhibitor with a K(i) of 2.8microM at pH 7.0 and 6.8microM at pH 8.8. The inhibition was reversible and kinetic properties corresponding to the mechanism for slow-binding inhibitors were not observed. An estradiol derivative bearing a boronic acid group at the 3-position and a benzyl group at the 17-position was a potent reversible, non-competitive STS inhibitor with a K(i) of 250nM. However, its 3-OH analog, a known STS inhibitor, exhibited an almost identical affinity for STS and also bound in a non-competitive manner. It is suggested that these compounds prefer to bind in a hydrophobic tunnel close to the entrance to the active site. The coumarin and chromenone boronic acids were modest inhibitors of STS with IC(50)s of 86 and 171microM, respectively. Surprisingly, replacing the boronic acid group of the chromenone derivative with an OH group yielded a good reversible, mixed type inhibitor with a K(i) of 4.6microM. Overall, these results suggest that the boronic acid moiety must be attached to a platform very closely resembling a natural substrate in order for it to impart a beneficial effect on binding affinity compared to its phenolic analog.
类固醇硫酸酯酶（STS）催化甾体硫酸盐（如硫酸雌酮，ES1）水解为相应的类固醇和无机硫酸盐。STS被认为是开发治疗类固醇依赖性癌症疗法的潜在靶点。合成了两种甾体类以及两种基于香豆素和色原酮的硼酸，并将其作为纯化STS的抑制剂进行研究。在3位带有硼酸基团以取代硫酸根的硫酸雌酮硼酸类似物是一种良好的竞争性STS抑制剂，在pH 7.0时K(i)为2.8微摩尔，在pH 8.8时为6.8微摩尔。抑制作用是可逆的，未观察到对应于慢结合抑制剂机制的动力学性质。在3位带有硼酸基团且在17位带有苄基的雌二醇衍生物是一种有效的可逆非竞争性STS抑制剂，K(i)为250纳摩尔。然而，其3 - OH类似物（一种已知的STS抑制剂）对STS表现出几乎相同的亲和力，并且也是以非竞争性方式结合。提示这些化合物倾向于结合在靠近活性位点入口的疏水通道中。香豆素和色原酮硼酸是STS的适度抑制剂，IC(50)分别为86和171微摩尔。令人惊讶的是，将色原酮衍生物的硼酸基团替换为OH基团后得到一种良好的可逆混合型抑制剂，K(i)为4.6微摩尔。总体而言，这些结果表明，与酚类类似物相比，硼酸部分必须连接到与天然底物非常相似的平台上，才能对结合亲和力产生有益影响。
