Identification of 10-dehydrooxyglycyuralin E as a selective human estrogen receptor alpha partial agonist

Nao Saito; Keiko Kawase; Naoya Yamashita; Yingzhan Tang; Ying Wang; Jian Wang; Yongxiang Liu; Ning Li; Wei Li; Mao-Sheng Cheng; Kazuo Koike; Yuichiro Kanno; Kiyomitsu Nemoto

doi:10.1016/j.bioorg.2019.102977

Identification of 10-dehydrooxyglycyuralin E as a selective human estrogen receptor alpha partial agonist

Bioorg Chem. 2019 Jul:88:102977. doi: 10.1016/j.bioorg.2019.102977. Epub 2019 May 8.

Authors

Affiliations

¹ Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
² Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, PR China.
³ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, PR China; Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan. Electronic address: liwei@phar.toho-u.ac.jp.
⁴ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, PR China. Electronic address: mscheng@syphu.edu.cn.
⁵ Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
⁶ Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan. Electronic address: ykanno@phar.toho-u.ac.jp.

PMID: 31100617
DOI: 10.1016/j.bioorg.2019.102977

Abstract

Selective estrogen receptor modulators (SERMs) act as either agonist or antagonist of estrogen receptor (ER) in a tissue selective manner and have been used in several diseases such as breast cancer, postmenopausal syndrome, osteoporosis, and cardiovascular diseases. However, current SERMs may also increase the risk of serious side effects and trigger drug resistance. Herein, a screening program, that was designed to search for novel SERMs, resulted in the identification of a series of 2-arylbenzofuran-containing compounds that are ligands for ERα, when applying the Gaussia-luciferase reporter assay. One of these compounds, 10-dehydrooxyglycyuralin E (T9) was chemically synthesized. T9 showed anti-estrogenic/proliferative activity in ERα-positive breast cancer cells. Pretreatment of T9 prevented the mRNA expression of GREB1, which is an estrogen response gene. Furthermore, by an in silico docking simulation study we demonstrated that T9 showed interactions directly to ERα. Taken together, these results demonstrated that T9 is a candidate of SERMs and a useful seed compound for the foundation of the selective activity of SERMs.

Keywords: Anti-estrogenic activity; Anti-proliferative activity; Breast cancer; Estrogen receptor (ER); Partial agonist; Selective estrogen receptor modulators (SERMs).

Publication types

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

MeSH terms

Benzofurans / chemical synthesis
Benzofurans / chemistry
Benzofurans / pharmacology*
Cell Line, Tumor
Dose-Response Relationship, Drug
Estrogen Receptor alpha / agonists*
Humans
Molecular Docking Simulation
Molecular Structure
Selective Estrogen Receptor Modulators / chemical synthesis
Selective Estrogen Receptor Modulators / chemistry
Selective Estrogen Receptor Modulators / pharmacology*
Structure-Activity Relationship

Substances

Benzofurans
Estrogen Receptor alpha
Selective Estrogen Receptor Modulators