Boronic acids as inhibitors of steroid sulfatase
Boronic acids as inhibitors of steroid sulfatase
复制标题
DOI：
10.1016/j.bmc.2006.08.033
复制
发表时间：
2006-12-15
影响因子：
3.5
通讯作者：
Taylor, Scott D.
中科院分区：
文献类型：
--
作者：
Ahmed, Vanessa;Liu, Yong;Taylor, Scott D.
甾体硫酸酯酶（STS）催化甾体硫酸酯如硫酸雌酮（ESI）水解为相应的甾体和无机硫酸酯。STS被认为是开发用于治疗类固醇依赖性癌症的治疗剂的潜在靶标。两个甾体和两个香豆素和色烯酮为基础的硼酸的合成和研究作为抑制剂纯化STS。在3-位带有硼酸部分代替硫酸基团的硫酸雌酮的硼酸类似物是一种良好的竞争性STS抑制剂，其Ki在pH 7.0时为2.8 μ M，在pH 8.8时为6.8 μ M。该抑制是可逆的，未观察到与缓慢结合抑制剂的机制相对应的动力学性质。在3位带有硼酸基团和在17位带有苄基基团的雌二醇衍生物是一种有效的可逆的、非竞争性STS抑制剂，Ki为250 nM。然而，它的3-OH类似物，一种已知的STS抑制剂，表现出几乎相同的STS亲和力，也结合在一个非竞争性的方式。有人建议，这些化合物更喜欢结合在一个疏水隧道靠近入口的活性位点。香豆素和苯并吡喃酮硼酸是适度的STS抑制剂，IC（50）分别为86和171 μ M。令人惊奇的是，用OH基团取代色烯酮衍生物的硼酸基团得到了良好的可逆的混合型抑制剂，其Ki为4.6 μ M。总体而言，这些结果表明，硼酸部分必须连接到非常类似于天然底物的平台上，以便与其酚类类似物相比，它对结合亲和力产生有益的影响。(c)2006爱思唯尔有限公司保留所有权利。
Steroid sulfatase (STS) catalyzes the hydrolysis of steroidal sulfates such as estrone sulfate (ESI) 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 2.8 mu M at pH 7.0 and 6.8 mu M 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 250 nM. 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 171 mu M, 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 4.6 mu M. 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. (c) 2006 Elsevier Ltd. All rights reserved.