Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor

Research Paper

Synthesis and biological evaluation of novel cyclopropyl

derivatives as subtype-selective ligands for estrogen

receptor

Zunyuan Wang^a,*, Yewei Yang^a,*, Xiaoliang Zheng^b, Tao Zhang^a, Wenhai Huang^a, Dongmei Yan^b,

Wenjun Zhang^b, Xiaoju Wang^band Zhengrong Shen^a

^aInstitute of Materia Medica and ^bCenter for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, China

Keywords

Abstract

biological evaluation; cyclopropyl derivatives;

estrogen receptor; subtype-selective;

synthesis

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.

Correspondence

Zhengrong Shen, Institute of Materia

Medica, Zhejiang Academy of Medical

Sciences, Hangzhou 310013, China.

E-mail: shenzr@zjams.com.cn

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.

Received September 18, 2017

Accepted February 10, 2018

doi: 10.1111/jphp.12908

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.

*These authors contributed equally to this

article.

regulate the tissue-speciﬁc gene expression in response to

estrogens. As ERa appears to be the dominant regulator of

Introduction

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.^[1]Currently,

antiestrogen is one of the ﬁrst-line therapeutic strategies for

the treatment of estrogen-dependent breast cancer,^[2]for

example suppression of ovarian function by luteinizing

hormone-releasing hormone analogues such as goserelin,^[3]

inhibition of estrogen biosynthesis by aromatase inhibitors

such as anastrozole^[4]and the ER antagonism by selective

estrogen receptor modulators (SERMs) such as tamoxifen

(TAM).^[5]

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.^[7]

Although ERa and ERb are the main subtypes of ER,

their ligand binding domains (LBDs) share only modest

homology (58% identity),^[8]which might explain the

distinct physiological outcomes in vivo.^[6]Crystal struc-

ture of ERa/ERb binding cavities shows that each is

ꢀ

composed of 23 residues within 4A 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

subtype-selective ligands.^[9]

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.^[6]ERa

and ERb also react differently to the ligands and therefore

Selective estrogen receptor modulators are structurally

different compounds that speciﬁcally interact with intracel-

lular ERs as ER agonists or antagonists.^[10,11]Currently,

TAM is the most commonly used SERM; however, patients

often develop the acquired drug resistance on TAM

1

Novel cyclopropyl derivatives

Zunyuan Wang et al.

therapy.^[12]Other side effects include endometrial carci-

noma and hot ﬂushes, which further limit its application in

clinic use.^[13]

(RBA) and transcriptional activity of these novel cyclo-

propyl derivatives.

Recently, we compared the structures of pre- or post-

clinic SERMs in the literatures and found that most com-

pounds have a similar scaffold of diphenylethene and a

common basic ether side chain.^[14]Previously, we showed

the compounds with a conjugated diphenylethene skeleton,

such as 2-phenylbenzofuran derivatives, had a high ER

binding afﬁnity and subtype-selective activity.^[15]Cyclo-

propyl group is a common pharmacophore in many bio-

logically active molecules,^[16]and more importantly, this

group is considered as an ethylene bioisostere.^[17,18]Many

cyclopropyl derivatives were designed and synthesized as

ligands for ERs. For example, by converting the alkene

bond of TAM to cyclopropane, a cyclopropyl derivative

(Figure 1a) of TAM was synthesized.^[19]Further, a series of

1,1-dichloro-2,2,3-triaryl cyclopropanes were designed, and

the compound (Figure 1b) functioned as a pure antiestro-

gen with antiproliferative activity on MCF-7 cells.^[20]

C-cyclopropylalkylamide (Figure 1c) was found to inhibit

estradiol-induced proliferation of the ER-positive MCF-7

cells without any effects on ER-negative MDA-MB-231

human breast cancer cells.^[21]Recently, Yeo et al.^[22]

designed three cyclopropyl derivatives with raloxifene side

chain as subtype-selective ligands for ER, and one of them

(Figure 1d) showed a high subtype selectivity for ERa with

ratios of 64 (ERa/ ERb).

While much effort has been devoted to the development

of the antiestrogen derivatives, more focuses are being on

the improvement of subtype selectivity for ERa. Com-

pound d in Figure 1 exhibited a high subtype selectivity for

ERa and therefore could be a leading compound for further

improvement of ERa-speciﬁc compounds. By systemati-

cally modifying the ketone chain and the cyclopropane ring

in compound d, we designed a series of trisubstituted

cyclopropyl derivatives with different substituted amine at

the end of the basic ether side chains of SERMs. Herein, we

reported the chemical synthesis, relative binding afﬁnities

Materials and Methods

Chemistry

The synthetic route of the target compounds was outlined

in Figure 2. Details of the synthesis and characterization

(IR, NMR, MS, HRMS) are available in the Appendix S1.

Docking

The molecular docking study was performed as

reported.^[15]Brieﬂy, the Discovery Studio 2.5/ﬂexible dock-

ing protocol with published crystal structure of E2/ERa

complex (PDB ID:1A52) or E2/ERb complex (PDB ID:

3OLS) was used, respectively. Based on methods within

CHARMm to sample side chain and ligand conformations,

the side chains of amino acids in the LBD were allowed to

move during docking in an induced ﬁt model. During the

docking and subsequent scoring, all the parameters were

remained the default setting except the best conformation

method for the generate ligand conformations.

Bioactivity

Fluorescence polarization-based binding afﬁnity

assay

The Polar Screen Estrogen Receptor-a or b Competitor

Assay kit (Invitrogen, Carlsbad, USA) was employed

according to the manufacturer’s protocol with 20 n^MERa

or ERb and 9 nM ﬂuorescent estrogen. The binding afﬁnity

was assessed by the Synergy 2 SLFPA MODEL Multi-Detec-

tion Microplate Reader (BioTek Instruments, Inc.,

Winooski, VT, USA) with excitation at 485 nm (20 nm

bandpass) and emission at 528 nm (20 nm bandpass).

Curve ﬁtting was performed using GraphPad Prism^âsoft-

ware from GraphPad^TMSoftware Inc (La Jolla, CA, USA).

The IC₅₀of 17b-estradiol (Sigma, Burlington, MA, USA),

4-hydroxy-tamoxifen (4-OH-TAM; International Labora-

tory, South San Fransico, CA, USA) and test compounds

were determined by inhibiting the binding of the ﬂuores-

cent estrogen ligand to the isolated recombinant full-length

human ERa or ERb by 50%. These values were used to nor-

malize as RBA. The RBAa and RBAb of 17b-estradiol were

set to 100.

Dual-luciferase reporter assay

293T cells were seeded at 10 000 cells/well in a 96-well opa-

que tissue culture plate using phenol red-free DMEM

Figure 1 The structures of some reported cyclopropanes.

2

Zunyuan Wang et al.

Novel cyclopropyl derivatives

Figure 2 The synthetic route of novel cyclopropyl derivatives.

containing 5% charcoal-tripped FBS. pGL4.35[luc2P/9X

GAL4UAS/Hygro] Vector and pBIND-ERa Vector (Promega

Corporation, Madison, USA) were co-transfected into the

cells using Lipofectamine and Plus^TMReagent (Invitrogen).

After 24-h transfection, the medium was changed to fresh

medium containing 10 nmol/l 17b-estradiol and test com-

pounds or 4-OH-TAM at the concentration from 0.01 to

10 lmol/l. After 24-h incubation, cells were lysed and used

in activity measurements with the Dual-Glo^âLuciferase

Assay System (Promega Corporation) as per manufacturer’s

instruction. The relative luciferase unit (RLU) was measured

using the Synergy 2 SLFPA MODEL Multi-Detection Micro-

plate Reader (BioTek Instruments, Inc.). Final results were

obtained from the RLU of ﬁreﬂy luciferase normalized

against Renilla luciferase.

Viability assay

Viability assay was performed using WST-1 reagent

(Roche, Mannheim, Germany) as per manufacturer’s

Table 1 The binding afﬁnities on ERs by ﬂuorescence polarization technology

Compound

IC₅₀for ERa (mol/l)

RBA^afor ERa (%)

IC₅₀for ERb (mol/l)

RBA^afor ERb (%)

RBA^aratio (ERa/ERb)

17b-Estradiol

2.09E-08

5.53E-07

2.57E-06

6.27E-06

1.38E-06

1.79E-06

2.42E-06

2.32E-06

1.08E-06

6.38E-06

100

2.67E-08

2.24E-07

100

1.00

4-OH-TAM

3.73

0.82

0.33

1.51

1.17

0.87

0.90

1.93

0.33

1.90

1.96

b

9a

9b

9c

/

a selectivity

13.73

b

/

2.45E-05

0.11

b

9d

9e

9f

/

a selectivity

19.3

b

/

b

/

9g

2.70E-05

1.70E-05

0.10

0.16

9h

2.06

^aRBA = (IC_{50 Estradiol}/IC_{50 compound}) 9 100. ^bNot detectable in our experimental conditions.

3

Novel cyclopropyl derivatives

Zunyuan Wang et al.

Figure 3 The agonistic/antagonistic functions of compounds on ERa in dual-luciferase reporter assay system in which 293T cells were transfected

with the luciferase reporter plasmid with estrogen responsive element and human ERa expression plasmid.

4

Zunyuan Wang et al.

Novel cyclopropyl derivatives

instruction.^[23,24]Brieﬂy, 293T cells were seeded into 96-

well culture plate at a concentration of 5000 cells/well.

The test compounds were added at the concentration

from 0.1 to 10 lmol/l. After 3-day exposure, the cell via-

bility was assayed using WST-1 reagent.

5000 cells in each well. The test compounds were added at

the concentration from 0.08 to 50 lmol/l. After 3-day expo-

sure, the cell viability was assayed using WST-1 reagent.

Statistical analysis

Data are expressed as mean Æ SD. Statistical signiﬁcance

of the differences between groups was analysed by one-way

ANOVA followed by Newman–Keuls multiple comparisons

tests using SPSS 10.0 for windows (SPSS Inc., Chicago, IL,

USA). P < 0.05 was considered statistically signiﬁcant.

Anti-cell-proliferation assay

The effects of eight novel compounds 9a-h on breast cancer

MCF-7 cell proliferation were carried out by WST-1 assay.

The assay was performed by 96-well plates, with seeding of

Figure 4 The cytotoxicity of compounds in 293T cells by WST-1 assay (*P <0.05).

5

Novel cyclopropyl derivatives

Zunyuan Wang et al.

ketone 7 was synthesized according to the procedure of

Aggarwal,^[25]in which the starting material 6 was obtained

as reported.^[26]With this critical intermediate 7 ready, a

one-pot process including direct condensation of chloro-

group in the side chain with various substituted amines

and then reduction in cyclopropyl ketone by sodium boro-

hydride was developed for practical preparation of 8a-h.

The aimed compounds 9a-h were easily obtained by a fol-

lowing hydrogenolysis debenzylation. The structures of

these eight novel cyclopropyl derivatives 9a-h were con-

Results and Discussion

Chemistry

The synthetic route of the target compounds is shown in

Figure 2. Routine condensation of 4-hydroxyacetophenone

1 with 3-chloro-1-bromopropane 2 in the presence of

potassium carbonate afforded 1-[4-(3-chloro-propoxy)-

phenyl]-ethanone 3. By a cross-aldol condensation of 3

with 4-benzyloxybenzaldehyde 4, (E)-3-(4-benzyloxy-phe-

1

ﬁrmed by IR, MS, HRMS, H and ¹³C-NMR, as shown in

nyl)-1-[4-(3-chloro-propoxy)-phenyl]-propenone

5 was

the experimental section.

generated. By a cyclopropanation reaction of 5 with

phenyldiazomethane 6 in the presence of catalytic amounts

of transition metal catalyst and catalytic amounts of pen-

tamethylene sulﬁde, the critical intermediate cyclopropyl

The cyclopropanation reaction of enones with dia-

zomethane commonly had no high stereoselectivity,

because the sulﬁde used in our experiment was not a chiral

Figure 5 The effects of compound on breast cancer MCF-7 cell proliferation by WST-1 assay (*P <0.05).

6

Zunyuan Wang et al.

Novel cyclopropyl derivatives

promoter.^[25]Therefore, the critical intermediate 7 was

obtained as stereoisomers. The following reduction in

ketone by sodium borohydride also afforded racemic alco-

hol. In this case, a stereoisomers mixture was used for the

preliminary bioactivity evaluations with respect to com-

pounds 9a-h.

orientation of the 2-aminoethoxyphenyl side chain relative

to the central core of the molecule has been postulated to

inﬂuence the properties of SERMs.^[27]

While much effort has been focused on the ERb-selective

agonists,^[28,29]there were less studies for ERa-selective

ligands.^[30]The importance of the ERa subtype in tumour

progression and resistance to TAM, however, makes ERa a

desirable drug target,^[31]especially in the ﬁeld of selective

estrogen receptor downregulators (SERDs).^[32]Based on a

compound (Figure 1d) reported^[22]as a lead strcuture,

eight novel cyclopropyl derivatives with different substi-

tuted amine at the end of the basic ether side chains were

synthesized and evaluated in this work. To our delight, all

the compounds exhibited ERa binding afﬁnity, and ﬁve of

these cyclopropyl derivatives (9a, 9b, 9d, 9e and 9f) exhib-

ited an undetectable binding afﬁnity to ERb in our experi-

mental conditions, indicating these ﬁve compounds are

mainly speciﬁc to ERa. Other three compounds also

showed selectivity on ERa than ERb subtype, especially 9g,

not only showed highest RBA for ERa (1.93%), but also

resulted in a RBA (ERa/ERb) ratio of 19.3.

The agonistic/antagonistic functions of these eight new

compounds were tested by dual-luciferase reporter assay on

293T cell. As shown in Figure 3, all these cyclopropane

derivatives showed antagonistic activity on ERa, particu-

larly, compounds 9a, 9c-f showed a full functional antago-

nist for ERa. In order to eliminate false-positive results,

viability assay was carried out also using 293T cell. All these

compounds exhibited no cytotoxicities, except 9g at high

concertration (Figure 4). Although compound 9g showed

weak cytotoxicity, it was not yet sufﬁcient to have a signiﬁ-

cant effect on its activity of ERa or ERb. Our results

revealed that 9g had a signiﬁcant antagonistic effect on ERa

at the concentration of 10 lmol/l, whereas it shows syner-

gistic agonism with estrogen at 1 lmol/l, which commonly

exists in SERMs compounds and is one of the major causes

of SERM side effects.

Biological activity

The binding afﬁnities of the eight novel compounds 9a-

h to ERs were determined by ﬂuorescence polarization

technology using 17b-estrogen and 4-hydroxy-tamoxifen

(4-OH-TAM, which is the metabolites and active form

of TAM) as the positive controls. The polarization values

were determined by competition between the ﬂuores-

cent-labelled 17b-estradiol and the testing ligands with

increasing concentration. The shift in polarization value

indicated the binding between the testing ligand and the

receptor. Relative binding afﬁnities for each ligand were

calculated as the ratio of IC₅₀value for 17b-estradiol to

the compound. The RBA value for 17b-estradiol was

arbitrarily set to 100. As shown in Table 1, all the com-

pounds exhibited potent ER binding ability, although the

overall binding afﬁnity was lower than 17b-estradiol or

4-OH-TAM.

With regard to the ER subtype selectivity, classical

endogenous17b-estradiol did not show any subtype speci-

ﬁcty, while 4-OH-TAM showed nearly twofold selectivity

on ERa over ERb. Compared to 17b-estradiol or 4-OH-

TAM, all the cyclopropyl derivatives exhibited a remarkable

selectivity for ERa. The selectivity was highly affected by

the substituted amine at the end of the side chain. For

example, in the compounds 9a, 9b and 9c with different-

numbered ring at the end of the side chain, the six-num-

bered ring compound 9c exhibited a weak binding to ERb,

while the other two did not bind at all. This effect was also

observed in the traditional SERMs, where the spatial

(a)

(b)

Figure 6 The docking study of novel cyclopropyl derivatives with ERa (a): overlay of 9a-h in binding pockets of ERa; (b): the phenolic hydroxy of

9g formed a hydrogen bonds with ERa Arg394).

7

Novel cyclopropyl derivatives

Zunyuan Wang et al.

Further, the antiproliferative action was tested in ER-

positive MCF-7 breast cancer cells, as shown in Figure 5.

All eight compounds showed anti-cell-proliferation effect

at the concentration of 50 lmol/l, which was ﬁve times

higher than the effective concentration in dual-luciferase

reporter assay. This may be related to the anti-cell prolifera-

tive effects which were partially offset by other pro-cell pro-

liferation factors that are present in the assay system, such

as the presence of pro-growth factors in serum and estro-

gen-like effects of phenol red in medium. It is interesting

that compound 9e showed a potent anti-cell-proliferation

effect at the concentration of 10 lmol/l. In combination

with its demonstrated biological activity in dual-luciferase

reporter assay, this result suggested the potent value of fur-

ther study of the compound 9e.

explanation of ER subtype preference for these ﬁve com-

pounds. The poor binding behaviour may be resulted from

the smaller cavity size of ERb than ERa.^[8]Other three

compounds (9c, 9h, 9g) showed no bonding poses in this

docking model and displayed poor binding afﬁnities to

ERb in the experiment (Table 1). This result probably indi-

cated different binding mode or site,^[33]which need a

further and deep understanding in our future work.

Conclusion

Eight novel cyclopropyl derivatives were designed and syn-

thesized for the development of new selective ER modula-

tors. Although these cyclopropyl derivatives showed lower

binding afﬁnities for ERs compared to 17b-estradiol, ﬁve of

these compounds (9a, 9b, 9d, 9e and 9f) only bound to

ERa. The study of antiestrogen activity also demonstrated

that compounds 9a, 9c-f acted as full functional antagonists

for ERa. These compounds had no or very low cytotoxicity

and showed anti-cell-proliferation effect in ER-positive

MCF-7 breast cancer cells. These primary results presented

a promising lead compound for further development of

novel subtype-selective SERMs.

Docking

In an attempt to provide explanation of the ERa subtype

preference for targeted compounds, molecular docking

study was performed, as seen in Figure 6.

All the cyclopropyl derivatives could dock into the ERa

easily, with similar conﬁgurations when superimposed. All

the basic ether side chains of 9a-h extend out of the binding

pockets, with different spatial orientations at the end (Fig-

ure 6a). This kind of binding mode was stabilized by a

hydrogen bond. For example, the phenolic hydroxy of 9g

formed a hydrogen bond with ERa/Arg394, with the bind-

ing energy of À140 Kcal/mol (Figure 6b). Considering the

inactivity of 8a-h, this observation could explain the signiﬁ-

cant ERa binding afﬁnity of our compounds and hence elu-

cidate the importance of the phenol functionality in terms

of hydrogen bonding.

Declarations

Conﬂict of interest

The Author(s) declare(s) that they have no conﬂicts of

interest to disclose.

Acknowledgements

This work was supported by National Natural Science

Foundation of China [81102380], Science Technology

Department of Zhejiang Province [2015C33197], and

Health and Family Planning Commission of Zhejiang Pro-

vince [XKQ-01001].

Interestingly, there was a huge difference in the molecu-

lar docking study for ERb. Compounds 9a, 9b, 9d, 9e and

9f showed no bonding poses at all, which were in accor-

dance with the undetectable ERb binding afﬁnities in

Table 1. These docking results provided rational

ﬂuorouracil as adjuvant therapy in

premenopausal patients with node-

Bowel Project P-1 Study. J Natl Can-

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Supporting Information

Additional Supporting Information

may be found in the online version of

this article:

Appendix S1. Experimental.

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Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor

DOI: 10.1111/jphp.12908

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Article abstract of DOI:10.1111/jphp.12908

Full text of DOI:10.1111/jphp.12908

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