Design and synthesis of silicon-containing steroid sulfatase inhibitors possessing pro-estrogen antagonistic character

被引：20

作者：

Kajita, Daisuke ^{[1
]}

Nakamura, Masaharu ^{[1
]}

Matsumoto, Yotaro ^{[2
]}

Makishima, Makoto ^{[3
]}

Hashimoto, Yuichi ^{[1
]}

机构：

[1] Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan

[2] Teikyo Univ, Fac Pharmaceut Sci, Itabashi Ku, Tokyo 1738605, Japan

[3] Nihon Univ, Sch Med, Dept Biochem, Itabashi Ku, Tokyo 1738610, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 07期

基金：

日本学术振兴会;

关键词：

Steroid sulfatase inhibitor; Estrogen antagonist; Silicon; Diphenylmethane; Breast cancer; ENDOCRINE THERAPY; BREAST; APPROXIMATION; CHEMISTRY;

D O I：

10.1016/j.bmc.2014.02.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 ER alpha-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 compound 16a showed strong STS-inhibitory activity (IC50 = 0.17 mu M). Further, its putative metabolite (12a) exhibited potent ER alpha-antagonistic activity (IC50 = 29.7 nM). (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：2244 / 2252

页数：9

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