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 journalArticle

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 languageEnglish
Pages (from-to)2244-2252
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number7
DOIs
Publication statusPublished - 2014 Apr 1
Externally publishedYes

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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