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 |
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Pages (from-to) | 2244-2252 |
Number of pages | 9 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 22 |
Issue number | 7 |
DOIs | |
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