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 › peer-review

19 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2014.02.025

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title = "Design and synthesis of silicon-containing steroid sulfatase inhibitors possessing pro-estrogen antagonistic character",

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).",

keywords = "Breast cancer, Diphenylmethane, Estrogen antagonist, Silicon, Steroid sulfatase inhibitor",

author = "Daisuke Kajita and Masaharu Nakamura and Yotaro Matsumoto and Makoto Makishima and Yuichi Hashimoto",

note = "Funding Information: The work described in this paper was partially supported by a Grant-in-aid for Scientific Research from The Ministry of Education, Culture, Sports, Sciences and Technology, Japan , and a grant from the Japan Society for the Promotion of Science . ",

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doi = "10.1016/j.bmc.2014.02.025",

language = "English",

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AU - Kajita, Daisuke

AU - Nakamura, Masaharu

AU - Matsumoto, Yotaro

AU - Makishima, Makoto

AU - Hashimoto, Yuichi

N1 - Funding Information: The work described in this paper was partially supported by a Grant-in-aid for Scientific Research from The Ministry of Education, Culture, Sports, Sciences and Technology, Japan , and a grant from the Japan Society for the Promotion of Science .

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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).

AB - 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).

KW - Breast cancer

KW - Diphenylmethane

KW - Estrogen antagonist

KW - Silicon

KW - Steroid sulfatase inhibitor

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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