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

Daisuke Kajita; Masaharu Nakamura; Yotaro Matsumoto; Makoto Makishima; Yuichi Hashimoto

doi:10.1016/j.bmc.2014.02.025

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

Daisuke Kajita, Masaharu Nakamura, Yotaro Matsumoto, Makoto Makishima, Yuichi Hashimoto

Research output: Contribution to journal › Article

16 Citations (Scopus)

Abstract

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 compound 16a showed strong STS-inhibitory activity (IC ₅₀ = 0.17 μM). Further, its putative metabolite (12a) exhibited potent ERα-antagonistic activity (IC₅₀ = 29.7 nM).

Original language	English
Pages (from-to)	2244-2252
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	22
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2014.02.025
Publication status	Published - 2014 Apr 1
Externally published	Yes

Keywords

Breast cancer
Diphenylmethane
Estrogen antagonist
Silicon
Steroid sulfatase inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Kajita, D., Nakamura, M., Matsumoto, Y., Makishima, M., & Hashimoto, Y. (2014). Design and synthesis of silicon-containing steroid sulfatase inhibitors possessing pro-estrogen antagonistic character. Bioorganic and Medicinal Chemistry, 22(7), 2244-2252. https://doi.org/10.1016/j.bmc.2014.02.025

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abstract = "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 compound 16a showed strong STS-inhibitory activity (IC 50 = 0.17 μM). Further, its putative metabolite (12a) exhibited potent ERα-antagonistic activity (IC50 = 29.7 nM).",

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AU - Makishima, Makoto

AU - Hashimoto, Yuichi

PY - 2014/4/1

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