Design and synthesis of silicon-containing steroid sulfatase inhibitors possessing pro-estrogen antagonistic character.
Design and synthesis of silicon-containing steroid sulfatase inhibitors possessing pro-estrogen antagonistic character.
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具有前雌激素拮抗特性的含硅类固醇硫酸酯酶抑制剂的设计和合成。
DOI：
10.1016/j.bmc.2014.02.025
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发表时间：
2014
影响因子：
3.5
通讯作者：
Daisuke Kajita 他４名
中科院分区：
文献类型：
--
作者：
Noshi;M.;Daisuke Kajita 他４名
类固醇硫酸酯酶（STS）是治疗绝经后乳腺癌的潜在靶点。已经报道了几种甾体STS抑制剂，但甾体化合物难以优化，并且可能与其他靶标相互作用。另一方面，我们已经表明，二苯基甲烷（CH 4）衍生物作为雌激素受体（ER）的激动剂和拮抗剂。在这里，我们的目的是设计和合成非甾体DPM型STS抑制剂，也将作为前雌激素拮抗剂，释放代谢产物与ERα-拮抗活性后，水解STS。我们合成了一系列化合物，并通过STS抑制活性测定和ER报告基因测定来评价它们的生物活性。其中含硅化合物16具有较强的STS抑制活性（IC_（50）= 0.17 μM）。此外，其推定代谢产物（12 a）表现出强效ERα拮抗活性（IC 50 = 29.7 nM）。
Steroid sulfatase (STS) is a potential target for treatment of postmenopausal hormone-dependent breast cancer. Several steroidal STS inhibitors have been reported, but steroidal compounds are difficult to optimize and may interact with other targets. On the other hand, we have shown that diphenylmethane (DPM) derivatives act as estrogen receptor (ER) agonists and antagonists. Here, we aimed to design and synthesize non-steroidal DPM-type STS inhibitors that would also serve as pro-estrogen antagonists, releasing a metabolite with ERα-antagonistic activity upon hydrolysis by STS. We synthesized a series of compounds and evaluated their biological activities by means of STS-inhibitory activity assay and ER reporter gene assay. Among them, silicon-containing compound16ashowed strong STS-inhibitory activity (IC50= 0.17 μM). Further, its putative metabolite (12a) exhibited potent ERα-antagonistic activity (IC50= 29.7 nM).