Synthesis and biological evaluation of novel cyclopropyl
derivatives as subtype-selective ligands for estrogen
*, Yewei Yang
*, Xiaoliang Zheng
, Tao Zhang
, Wenhai Huang
, Dongmei Yan
, Xiaoju Wang
and Zhengrong Shen
Institute of Materia Medica and
Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, China
biological evaluation; cyclopropyl derivatives;
estrogen receptor; subtype-selective;
Zhengrong Shen, Institute of Materia
Medica, Zhejiang Academy of Medical
Sciences, Hangzhou 310013, China.
Received September 18, 2017
Accepted February 10, 2018
*These authors contributed equally to this
Objectives Tamoxifen is the most commonly used selective estrogen receptor
modulators (SERMs); however, patients often develop the acquired drug resis-
tance on tamoxifen therapy. The aim of this study was to develop new SERMs.
Methods Several novel cyclopropyl derivatives were designed and synthesized.
The binding afﬁnities of these compounds as well as the selectivity on subtype of
estrogen receptor (ER) were assessed by ﬂuorescence polarization. The antagonis-
tic activity was also evaluated by dual-luciferase reporter assay.
Key ﬁndings Our data identiﬁed ﬁve compounds (9a, 9b, 9d, 9e and 9f) with a
higher selectivity on ERa than ERb subtype, warranting further development as a
subtype-selective ER modulator. The study of antiestrogen activity also demon-
strated that compounds 9a, 9c-f acted as full functional antagonists for ERa.
These compounds had no or very low cytotoxicity.
Conclusions Although these cyclopropyl derivatives showed lower binding
afﬁnities on ERs compared to 17b-estradiol, ﬁve of these compounds exhibited
binding to ERa only and therefore might serve as a promising lead compound
for further development of novel subtype-selective SERMs.
Breast cancer is one of the leading causes of death and the
most frequent cancer in women. More than 70% of breast
cancer express estrogen receptors (ERs), and the presence
of estrogen stimulates the tumour growth.
antiestrogen is one of the ﬁrst-line therapeutic strategies for
the treatment of estrogen-dependent breast cancer,
example suppression of ovarian function by luteinizing
hormone-releasing hormone analogues such as goserelin,
inhibition of estrogen biosynthesis by aromatase inhibitors
such as anastrozole
and the ER antagonism by selective
estrogen receptor modulators (SERMs) such as tamoxifen
Estrogen receptors mainly have two subtypes, ERa and
ERb, with distinct tissue distribution and bioactivity. ERa
predominates in the uterus and the mammary gland and is
mostly responsible for the female reproductive functions,
whereas ERb plays roles in many other organs, such as the
central nervous, urogenital and immune systems.
and ERb also react differently to the ligands and therefore
regulate the tissue-speciﬁc gene expression in response to
estrogens. As ERa appears to be the dominant regulator of
estrogen-regulated gene expression in breast cancer, partic-
ular attention has been paid to develop the antagonists for
ERa for the treatment of breast cancer.
Although ERa and ERb are the main subtypes of ER,
their ligand binding domains (LBDs) share only modest
homology (58% identity),
which might explain the
distinct physiological outcomes in vivo.
ture of ERa/ERb binding cavities shows that each is
composed of 23 residues within 4
A of the estrogen
ligand. Of these 23 residues, only two positions have dif-
ferent amino acids, that is Leu384 and Met421 in ERa,
and Met336 and Ile373 in ERb. Those slight differences
in the binding cavities challenge the development of ER
Selective estrogen receptor modulators are structurally
different compounds that speciﬁcally interact with intracel-
lular ERs as ER agonists or antagonists.
TAM is the most commonly used SERM; however, patients
often develop the acquired drug resistance on TAM
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 910–918