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

Bioorg Med Chem. 2014 Apr 1;22(7):2244-52. doi: 10.1016/j.bmc.2014.02.025. Epub 2014 Feb 28.

Authors

Daisuke Kajita¹, Masaharu Nakamura², Yotaro Matsumoto³, Makoto Makishima⁴, Yuichi Hashimoto¹

Affiliations

¹ Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
² Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: nakamura-nk@iam.u-tokyo.ac.jp.
³ Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
⁴ Department of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

PMID: 24630694
DOI: 10.1016/j.bmc.2014.02.025

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 (IC50=0.17μM). Further, its putative metabolite (12a) exhibited potent ERα-antagonistic activity (IC50=29.7nM).

Keywords: Breast cancer; Diphenylmethane; Estrogen antagonist; Silicon; Steroid sulfatase inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Estrogen Receptor alpha / antagonists & inhibitors*
Estrogen Receptor beta / antagonists & inhibitors*
HEK293 Cells
Humans
Models, Molecular
Molecular Structure
Organosilicon Compounds / chemical synthesis
Organosilicon Compounds / chemistry
Organosilicon Compounds / pharmacology*
Steryl-Sulfatase / antagonists & inhibitors*
Steryl-Sulfatase / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Estrogen Receptor alpha
Estrogen Receptor beta
Organosilicon Compounds
Steryl-Sulfatase