Scientia

Pharmaceutica

Review
Estrogen Receptor Ligands: A Review (2013–2015)
Shabnam Farzaneh and Afshin Zarghi *
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences,
P.O. Box 14155-6153, Tehran 19919-5338, Iran; Shabnamfa92@gmail.com
* Correspondence: zarghi@sbmu.ac.ir; Tel.: +98-21-8820096; Fax: +98-21-8866-5341

Academic Editor: Thomas Erker

Received: 24 November 2015; Accepted: 17 January 2016; Published: 13 April 2016

Abstract: Estrogen receptors (ERs) are a group of compounds named for their importance in both
menstrual and estrous reproductive cycles. They are involved in the regulation of various processes
ranging from tissue growth maintenance to reproduction. Their action is mediated through ER nuclear
receptors. Two subtypes of the estrogen receptor, ERα and ERβ, exist and exhibit distinct cellular
and tissue distribution patterns. In humans, both receptor subtypes are expressed in many cells and
tissues, and they control key physiological functions in various organ systems. Estrogens attract
great attention due to their wide applications in female reproductive functions and treatment of
some estrogen-dependent cancers and osteoporosis. This paper provides a general review of ER
ligands published in international journals patented between 2013 and 2015. The broad physiological
profile of estrogens has attracted the attention of many researchers to develop new estrogen ligands
as therapeutic molecules for various clinical purposes. After the discovery of the ERβ receptor,
subtype-selective ligands could be used to elicit beneficial estrogen-like activities and reduce adverse
side effects, based on the different distributions and relative levels of the two ER subtypes in different
estrogen target tissues. Therefore, recent literature has focused on selective estrogen ligands as highly
promising agents for the treatment of some types of cancer, as well as for cardiovascular, inflammatory,
and neurodegenerative diseases. Estrogen receptors are nuclear transcription factors that are involved
in the regulation of many complex physiological functions in humans. Selective estrogen ligands
are highly promising targets for treatment of some types of cancer, as well as for cardiovascular,
inflammatory and neurodegenerative diseases. Extensive structure-activity relationship studies of
ER ligands based on small molecules indicate that many different structural scaffolds may provide
high-affinity compounds, provided that some basic structural requirements are present.

Keywords: estrogens; estrogen receptor α; estrogen receptor β; ligand; patent; cancer

1. Introduction

1.1. Estrogen
Estrogens are a group of compounds named for their importance in both menstrual and estrous
reproductive cycles. They are primary female sex hormones. Estrogens readily diffuse across the cell
membrane. Inside the cell, they bind and activate estrogen receptors.

Estrogen Receptor Subtypes

Two subtypes of the estrogen receptor, ERα and ERβ, exist and exhibit distinct cellular and
tissue distribution patterns. In humans, both receptor subtypes are expressed in many cells and
tissues, and they control key physiological functions in various organ systems such as reproductive,
skeletal, cardiovascular, and central nervous systems. ERα is mainly expressed in the mammary gland,
uterus, ovary (thecal cells), bone, male reproductive organs (testes and epididymis), prostate (stroma),

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liver, and adipose tissue. In contrast, ERβ is predominant in the prostate (epithelium), bladder,
ovary (granulosa cells), colon, adipose tissue, and immune system. However, both subtypes are
markedly expressed in the cardiovascular and central nervous systems. Estradiol and hormone
replacement therapies target both the ERs, but this often leads to an increased risk of breast and
endometrial cancers, and thromboembolism. Also, selective estrogen receptor modulators (SERMs),
structurally, are various compounds that interact with intracellular estrogen receptors in different
target organs as ER agonists or antagonists [1]. Ideal SERMs would possess antagonist activity
in the mammary gland and uterus, and agonist activity in other target tissues that benefit from
estrogen-like actions such as the cardiovascular, skeletal, and central nervous systems [2]. Alternatively,
subtype-selective ligands could be used to elicit beneficial estrogen-like activities and reduce adverse
side effects, based on the different distributions and relative levels of the two ER subtypes in the
different estrogen target tissues mentioned above [3].

1.2. Potential Clinical Applications of Estrogens

1.2.1. Cancer
The role of ERs in many cancers such as breast cancer, prostate cancer, and colorectal cancer has
been extensively studied. Suppression of estrogen production in the body is a treatment for breast
cancer. Especially in breast cancer, activation of ERα by estrogens is considered to be responsible
for enhanced proliferation, whereas this is counteracted by the presence of ERβ, which exerts
an anti-proliferative effect [4].

1.2.2. Neuropathies
Estrogen directly influences brain function through estrogen receptors located on neurons in
multiple areas of the brain. There is considerable evidence that indicates the important role of
estradiol in the central nervous system (CNS) for different kinds of diseases, including pathologies
associated with depression, anxiety, and Alzheimer’s disease. At neuronal synapses, estrogen increases
the concentration of neurotransmitters such as serotonin, dopamine, and norepinephrine. It affects
their release, reuptake, and enzymatic inactivation [5]. A recent study reported that aged female mice
responded favorably to estrogen administration and exhibited greater anti-anxiety and antidepressant
behavior [6].

1.2.3. Cardiovascular Disease

Estrogen has a number of effects on cardiovascular function and disease. The regular production
of estrogens in pre-menopausal women places them at a lower risk for cardiovascular disease relative
to men. However, this cardioprotective effect vanishes after menopause [7]. Several mechanisms
are involved in this cardioprotective role such as the effects of estrogen on lipoprotein levels,
vasomotor function, LDL oxidation, coagulation, and collagen and elastin synthesis [8].

1.2.4. Osteoporosis
Osteoporosis is a major health problem associated with estrogen deficiency in postmenopausal
women. Many studies have indicated that estrogens play an important role in bone homeostasis,
not only in women but also in men [9]. Estrogen replacement therapy (ERT) is clinically used to
prevent osteoporosis.

2. Estrogen Receptor Ligands

ERs are nuclear transcription factors that are involved in the regulation of many complex
physiological functions in humans. The term SERM describes synthetic ER ligands that display
tissue-selective pharmacology. This concept was first described in 1990 [10]. As anti-estrogens,
they oppose the action of estrogens in certain tissues while mimicking the action of endogenous
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estrogens in others. Over the past few years, many reviews have covered the progress in the
in others.of
development Over the past
estrogen few years,
receptors many reviews
[11–15]. have
We herein coveredanthe
provide progressand
overview in the development
update of
of compounds
estrogen receptors [11–15]. We herein provide an overview and update of compounds that have been
that have been recently reported as estrogen receptor ligands, with a particular focus on their potential
recently
clinical reported as estrogen receptor ligands, with a particular focus on their potential clinical
applications.
applications.
3. Steroidal Ligands
3. Steroidal Ligands
Zhang et al. reported a new series of 11β-ether-17α-ethinyl-3,17ß-estradiol that demonstrates
Zhang et al. reported a new series of 11β-ether-17α-ethinyl-3,17ß-estradiol that demonstrates
strong ER antagonist activity. The ethers were particularly interesting as they were highly active
strong ER antagonist activity. The ethers were particularly interesting as they were highly active anti-
anti-estrogens that were
estrogens that weremore
morestable
stablethan
thanother
other substituents.
substituents. Among
Among these
these ethers,
ethers, compounds
compounds 1 and12and 2
(Figure 1) bind
(Figure veryvery
1) bind strongly to to
strongly both
bothERα
ERαand
andERβ [16].
ERβ [16].

OH OH
H H
O O

HO HO
1 2

OAc
N
F
N N
H3CO
O N
N
H3CO AcO N
OCH3 Cl
O N
H
3 4
O
O
N OH
N N
O N O2N
N O
N
N
Cl O
O N
H
5 6
Figure1.
Figure 1. Steroidal
Steroidal Ligands.
Ligands.

Combretastatin A4 analogues on a steroidal framework were reported to have anti-breast cancer

Combretastatin
properties. Recently,A4 analogues on a steroidal
natural compounds have framework
increasinglywere
beenreported
used in to have anti-breast
traditional medicines. cancer
properties. Recently, isnatural
CombretastatinA4 compounds
one of these have
compounds increasingly
that been and
induce apoptosis used actinastraditional medicines.
an antiangiogenic
agent [17]. Twenty-two
Combretastatin A4 is one analogues were synthesized
of these compounds that by the Combretastatin
induce apoptosis and A4actsteroidal
as an framework
antiangiogenic
agentand among
[17]. them, compound
Twenty-two analogues 3 (Figure
were 1) was the most
synthesized byactive in both MCF-7 and
the Combretastatin A4MDA-MB-231 cells
steroidal framework
with IC 50 7.5 μM and 5.5 μM [18].
and among them, compound 3 (Figure 1) was the most active in both MCF-7 and MDA-MB-231 cells
with IC50 Recently,
7.5 µM and Huang et al. reported two new series of novel C6-piperazine-substituted purine
5.5 µM [18].
steroid–nucleosides and C6-cyclo secondary amine-substituted purine steroid-nucleoside analogues.
Recently, Huang et al. reported two new series of novel C6-piperazine-substituted purine
Nucleoside analogues showed an important role in the development of antitumor drugs [19–21].
steroid–nucleosides and C6-cyclo secondary amine-substituted purine steroid-nucleoside analogues.
Among them, C6-aminopurine derivatives had a wide range of biological properties and displayed
Nucleoside analogues showed
antitumor activity [22–24]. an important
In addition, rolederivatives
piperazine in the development of antitumor
showed a broad spectrum of drugs [19–21].
biological
Among them, C6-aminopurine
activities, such as anticancerderivatives had aTherefore,
activity [25,26]. wide range of analogues
these biological were
properties and displayed
synthesized and
antitumor activity
evaluated [22–24].
for their In addition,
anticancer activity.piperazine derivatives showed apurine
Among C6-piperazine-substituted broadsteroid–nucleosides
spectrum of biological
analogues,
activities, suchcompound
as anticancer4 (Figure 1) showed
activity the Therefore,
[25,26]. best results these
on the analogues
MCF-7 cell were
line [27]. However, and
synthesized
compound 5 (Figure 1) displayed only moderate anticancer activity against the MCF-7
evaluated for their anticancer activity. Among C6-piperazine-substituted purine steroid–nucleosides cell line [28].
analogues, compound 4 (Figure 1) showed the best results on the MCF-7 cell line [27]. However,
compound 5 (Figure 1) displayed only moderate anticancer activity against the MCF-7 cell line [28].
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Bandyopadhyay
Sci. Pharm. et al. [29] also reported a new series of 2- and 4-nitroestradiol derivatives.412
2016, 84, 409-427 They
Bandyopadhyay
showed that compound et al. [29] also
6 (Figure reported
1), as well as aa known
new series of 2- and
ER-targeting 4-nitroestradiol
drug, derivatives.
4-hydroxytamoxifen (4-
They
HT), Bandyopadhyay
showed
reduced thatthecompoundet al. [29]
viability also reported
(Figure awell
1), asand
of6 ER-positive new series
as of 2- cells
a known
ER-negative and 4-nitroestradiol
ER-targeting drug,
with similar derivatives.
TheThey
4-hydroxytamoxifen
efficacy. toxicity
showed that by 6compound 6 (Figure 1), as well as awith
exhibited
(4-HT), reduced wasviability
the slightly better
of than
ER-positive4-HT,andknown an ER-targeting
IC50 value
ER-negative drug,
cellsofwith 4-hydroxytamoxifen
approximately
similar 2 μMThe
efficacy. in (4-
breast
toxicity
HT), reduced the viability of ER-positive and ER-negative cells with similar efficacy. The toxicity
cancer cells.
exhibited These
by 6 was data better
slightly indicate that
than selective
4-HT, novel
with an IC50nitroestradiol compounds2 µM
value of approximately effectively
in breastcause
cancer
exhibited by 6 was slightly better than 4-HT, with an IC50 value of approximately 2 μM in breast
cytotoxicity
cells. These data in breast
indicatecancer
thatcells and their
selective novel cytotoxicity might
nitroestradiol occur in an effectively
compounds ER-independentcause manner.
cytotoxicity
cancer cells. These data indicate that selective novel nitroestradiol compounds effectively cause
in breast cancerincells
cytotoxicity and
breast theircells
cancer cytotoxicity might occur
and their cytotoxicity in anoccur
might ER-independent manner.manner.
in an ER-independent
4. Non-Steroidal Ligands
4. Non-Steroidal
4. Non-SteroidalLigands
Ligands
4.1. 2,3-Diaryl Isoquinolinone
4.1. 4.1.
2,3-Diaryl
A
Isoquinolinone
2,3-Diaryl Isoquinolinone
new series of 2,3-diaryl isoquinolinone derivatives were reported as anti-breast cancer agents
targeting
A new
A newERα
seriesand
series vascular
ofof
2,3-diaryl endothelial
2,3-diaryl isoquinolinone
isoquinolinone growth factor receptor
derivatives
derivatives were
were 2reported
(VEGFR-2).
reported ERα iscancer
as anti-breast
as anti-breast responsible
cancer for
agentsagents
estrogen-induced
targeting
targetingERαERαandandproliferation
vascular in breast
vascularendothelial
endothelial growth cancer in
growthfactor which angiogenesis
factorreceptor
receptor plays
2 (VEGFR-2).
2 (VEGFR-2). an important
ERα ERα role in
is responsible
is responsible both
for for
local tumor growth
estrogen-induced
estrogen-induced and distant
proliferation
proliferation ininmetastasis
breast cancer
breast cancerin many
ininwhich cancers
which [30]. Therefore,
angiogenesis
angiogenesis plays Tang
an important
plays et al.role
an important [31]inrole
reported
bothin both
a local
new
local tumorseries
tumor of compounds
growth
growth anddistant
and with
distant characteristics
metastasis
metastasis in
inmany
many of cancers
both selective
cancers [30]. estrogen
Therefore,
[30]. Therefore, receptor
Tang modulators
et al. et
Tang [31]al.reported and
[31] reported
VEGFR-2
a new seriesinhibitors.
a new series
of of It was anticipated
compounds
compounds with for these of
with characteristics
characteristics compounds
ofboth
both withestrogen
selective
selective dual targets
estrogen to gain
receptor more
modulators
receptor efficiency
modulators and
and
asVEGFR-2 inhibitors.
anti-breast cancer Itagents
was anticipated
with fewer forside
theseeffects.
compounds VEGFR-2with dual targetspossessing
inhibitors to gain more anefficiency
indol-2-one
VEGFR-2 inhibitors. It was anticipated for these compounds with dual targets to gain more efficiency
as anti-breast
scaffold, such ascancer agents
sunitinib with
and fewer sidebear
YM231146, effects.
some VEGFR-2
structuralinhibitors possessing
similarities an indol-2-one
with SERMs (Figure 2).
as anti-breast
scaffold,
cancer
such as
agentsand
sunitinib
with fewer side
YM231146, bear
effects.
some
VEGFR-2similarities
structural
inhibitors possessing an indol-2-one
All compounds possess an aromatic scaffold and flexible side chain with a with SERMs
tertiary amine (Figure 2).
substituent
scaffold,
All such as sunitinib
compounds possess anand YM231146,
aromatic scaffold bear
and some structural
flexible side chain similarities
with a tertiary with
amine SERMs (Figure 2).
substituent
on the end. Based upon that, 2,3-diaryl isoquinolinone derivatives were synthesized and evaluated.
All compounds
on the end. possess anthat,
aromatic scaffold and flexible side chain with a tertiary amine substituent
Among theseBased upon
series, compounds 2,3-diaryl
7 andisoquinolinone
8 (Figure 3) had derivatives
the best were synthesized
affinity for ERα and and evaluated.
the inhibition
onrates
the end.
Among Based
werethese
upon
series,
as potent
that, 2,3-diaryl
ascompounds
tamoxifen.7The 8isoquinolinone
andresults (Figure
of a3) had the
VEGFR-2
derivatives
best
kinaseaffinitywere
for synthesized
inhibition ERα andshowed
assay
and
the inhibitionevaluated.
that these
rates these
Among were as potentcompounds
series, as tamoxifen.7The and results
8 of a VEGFR-2
(Figure 3) had kinase
the bestinhibition
affinity assay
for showed
ERα and that
the these
inhibition
derivatives had moderate-to-strong inhibitory activities compared with sunitinib. Compound 8
derivatives
rates were as had moderate-to-strong
potent as tamoxifen. inhibitory
The results activities
of a compared
VEGFR-2 kinasewithinhibition
sunitinib. assay
Compound showed 8 that
showed the best results for both ERα and VEGFR-2 kinase inhibition.
showed
these the besthad
derivatives results for both ERα and VEGFR-2
moderate-to-strong inhibitorykinase inhibition.
activities compared with sunitinib. Compound 8
showed the best results for both ERα and VEGFR-2 kinase inhibition.

N
N
O
O
OO N N
N N
H H

F F N N
H H
O O
N N
O O ( )(n )n R1R1 H H
OO NN
R2R2 Sunitinib
Sunitinib N
O O
Tamoxifen
Tamoxifen NN N
33 O
R
R O
R4R4

OH
OH NH NH

diaryl
diarylisoquinolinones
isoquinolinones O
HO O N
O
HO O H N
N H
O N
O
Acolbifene YM231146
Acolbifene YM231146
Figure
Figure 2. Chemicalstructures
2. Chemical structures of
of SERMS,
SERMS,VEGFR-2
VEGFR-2inhibitors, andand
inhibitors, designed compounds
designed [31]. [31].
compounds
Figure 2. Chemical structures of SERMS, VEGFR-2 inhibitors, and designed compounds [31].

O N O N
O O N O
O O N
HO HO O
HO N N
HO
N N

OH OH
7 OH 8 OH
7 8

Figure 3. 2,3-Diaryl isoquinolinone derivatives.

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Figure 3. 2,3-Diaryl isoquinolinone derivatives.

4.2. Diphenylmethane Skeleton and Related Analogues
4.2. Diphenylmethane Skeleton and Related Analogues
Maruyama et al. [32,33] have shown that the diphenylmethane skeleton can have a steroid
role. Bisphenol
MaruyamaAethas estrogenic
al. [32,33] have activity
shown thatandthebisphenol AF and skeleton
diphenylmethane HPTE have agonist
can have activity
a steroid role.for
Bisphenol A has estrogenic activity and bisphenol AF and HPTE have
ERα with antagonist activity for ERβ (Figure 4). Therefore, these compounds would bind to ERα agonist activity for ERα with
in aantagonist activity to
similar manner for17β-estradiol,
ERβ (Figure 4). butTherefore,
selectivelythese
forcompounds
ERβ. Manywould bind to
analogues of ERα in a similar
bisphenol A were
alsomanner to 17β-estradiol,
synthesized but selectively
and their agonist for ERβ.activities
and antagonist Many analogues of bisphenol
were evaluated. Results A showed
were also that
synthesized and their agonist and antagonist activities were evaluated. Results
longer linear alkyl chains at the central carbon decreased the agonistic activities for both ERα and showed that longer
ERβ,linear
butalkyl chainsthe
increased at the central carbon
antagonist decreased
activities for boththe ERαagonistic
and ERβ.activities
Among for these
both ERα and
series, ERβ, but 9
compound
increased the antagonist activities for both ERα and ERβ. Among these series,
(Figure 4) displayed potent ERα-antagonist activity with a 28-fold selectivity over ERβ. As described, compound 9 (Figure
4) displayed
central potent
alkyl chains ERα-antagonist
were critical for potentactivity
ERwith a 28-foldactivities,
antagonistic selectivityindicating
over ERβ.that
As described, central
the hydrophobicity
alkyl chains were critical for potent ER antagonistic activities, indicating that the hydrophobicity at
at the central moiety is important for strong antagonistic activity. On the other hand, sila-substitution
the central moiety is important for strong antagonistic activity. On the other hand, sila-substitution
(C/Si exchange) of existing drugs is an attractive approach to find new drug candidates. Because
(C/Si exchange) of existing drugs is an attractive approach to find new drug candidates. Because
silicon-containing analogues are more lipophilic and larger in molecular size than their carbon
silicon-containing analogues are more lipophilic and larger in molecular size than their carbon
analogues [34–37], a new series of sila-analogues were synthesized with the aim of increasing
analogues [34–37], a new series of sila-analogues were synthesized with the aim of increasing
hydrophobicity
hydrophobicity or molecular
or molecular size.size.
However, both both
However, sila-analogues 10 and1011and
sila-analogues (Figure 4) showed
11 (Figure decreased
4) showed
activities compared with carbon derivatives [38].
decreased activities compared with carbon derivatives [38].
Also, in in
Also, 20152015Ohta
Ohtaetetal.al.[39]
[39]reported
reportedthethediphenylamine skeletonasasER
diphenylamine skeleton ERantagonist
antagonistcandidates
candidates
containing
containing a basic
a basicalkylamino
alkylaminoside side chain
chain on
on one
one of
of the two phenol
the two phenolgroups
groupsofofthethediphenylamine
diphenylamine
agonist core structure. The results indicated that compounds with cyclic
agonist core structure. The results indicated that compounds with cyclic alkylamine showed alkylamine showed higher
higher
ER-antagonistic
ER-antagonistic activity
activitythan
thanthe thecorresponding
corresponding acyclic derivatives
derivativesininaacell
cellproliferation
proliferation assay
assay using
using
thetheMCF-7 cell line. Compound
Compound1212showed showedthe thehighest
highestantiestrogenic
antiestrogenic activity
activity (IC50 1.3××1010−7 − 7 M),
MCF-7 cell line. 50 ==1.3 M),
being
being 1010 times
times more
more potentthan
potent thantamoxifen.
tamoxifen.

F3C CF3 CCl3

HO OH HO OH HO OH
Bisphenol A Bisphenol AF Bisphenol HPTE
n-Pr n-Pr Et Et n-Bu n-Bu
Si Si

HO OH HO OH HO OH
Me Me Me Me Me Me
9 10 11

N
O

N
n-C6H13

HO

12
Figure4.4.Diphenylmethane
Figure Diphenylmethane skeleton
skeletonanalogues.
analogues.

4.3.4.3. Deoxybenzoin
Deoxybenzoin Analogues
Analogues
Estrogenic
Estrogenic effects
effects of of three
three substituted
substituted deoxybenzoins
deoxybenzoins were
were reported
reported byby Chandrasekharan
Chandrasekharan et et
al.al.
[40].
[40]. These compounds were designed as CMPD3 (13, Figure 5), CMPD6 (14, Figure 5), and CMPD9
These compounds were designed as CMPD3 (13, Figure 5), CMPD6 (14, Figure 5), and CMPD9
(15, Figure 5) which possess –COOH, –(CH2)4–CH3, and –CH3 substitutions, respectively, on the 20
6 shows the structure of this series. Most of the compounds of this group were selective estrogen-
related receptor modulators or co-activator selective ligands [41].

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414
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(15, Figure 5) which possess –COOH, –(CH2)4–CH3, and –CH3 substitutions, respectively, on the 2′
(15, Figure 5) which possess –COOH, –(CH2)4–CH3, and –CH3 substitutions, respectively, on the 2′
position of the 2,4-dihydroxyphenyl ring of deoxybenzoin. Results showed that all three compounds
R showed
position of the 2,4-dihydroxyphenyl ring of deoxybenzoin. Results that all three compounds
increased the
the proliferation
proliferationofofthe
theMCF-7
MCF-7cell
cell O and
line
line showed
and similar
showed affinity
similar for both
affinity ERα ERα
for both and ERβ
and
increased the proliferation of the MCF-7 cell line and showed similar affinity for both ERα and ERβ
receptors.
ERβ receptors. N
receptors. N
H
HO OH HO
HO OH HO OH
HO OH HO OH HO OH
O R = H, P-CH3, P-CF3, P-OCH3O
, P-OH, m-CH3, m-CF3, m-OCHO
3
O O O
Figure 6. Hydrazide derivatives. CH3
COOH (CH2)4CH3
COOH OH (CH2)4CH3 OH CH3 OH
OH
4.5. Fluoren-3-one Derivatives OH
13 (CMPD3) 14 (CMPD6) OH 15 (CMPD9)
13 (CMPD3) 14 (CMPD6) 15 (CMPD9)
Recently a new group of 7-hydroxyfluoren-3-one
Figure 5. Deoxybenzoin derivatives
derivatives.
Figure 5. Deoxybenzoin derivatives. were reported as selective ERβ,
such as compounds 16–18 (FigureFigure 5. Deoxybenzoin derivatives.
7) [42,43].
4.4. Hydrazide
4.4. Derivatives
Hydrazide Derivatives
Derivatives
4.4. Hydrazide
Recently hydrazide
Recently hydrazidederivatives
derivativeswere
werepatented
patentedas asestrogen-related
estrogen-relatedreceptor
receptor(ERR)
(ERR)ligands.
ligands.Figure
Figure6
6 Recently
shows the hydrazide
structure ofderivatives
this series. were
Most patented
of the as estrogen-related
compounds of this receptor
group (ERR)
were ligands.
selective Figure
estrogen-
6shows
showsthethe
structure of this
structure series.
of this Most
series. of the
Most of compounds
the compounds of this
ofgroup were selective
this group estrogen-related
were selective estrogen-
related receptor
receptor modulatorsmodulators
or or co-activator
co-activator selective selective
ligands ligands
[41]. [41].
related receptor modulators or co-activator selective ligands [41].
R
O R
R
O
O
N
NNN
N
H
N
H
H
HO
HO
HO 3, P-OCH3, P-OH, m-CH3, m-CF3, m-OCH3
R = H, P-CH3, P-CF
R == H,
R H, P-CH
P-CH33,, P-CF
P-CF33,, P-OCH
P-OCH33,, P-OH,
P-OH, m-CH
m-CH33,, m-CF
m-CF33,, m-OCH
m-OCH33
Figure 6. Hydrazide derivatives.
Figure 6. Hydrazide derivatives.
4.5. Fluoren-3-one Derivatives
4.5. Fluoren-3-one Derivatives
Recently a new group of 7-hydroxyfluoren-3-one derivatives
O were reportedOas selective ERβ,
Recently
Recently a new group of Br derivatives
7-hydroxyfluoren-3-one
7-hydroxyfluoren-3-one derivatives were Br
were reported
reported as
as selective
selective ERβ,
ERβ,
such as compounds 16–18 (Figure
Cl O
7) [42,43].
such as compounds 16–18 (Figure 7) [42,43].
F
Br O Br O
Cl O Br O Br O
Cl O HO HO
HO F
F Cl
Cl
HO HO
HO 16 HO 17 HO
Cl18
HO
Cl Cl
Cl Figure 7. Fluoren-3-one analogues as selective ERβ.
16 17 18
4.6. Triphenylethylene Coumarin
16 17 18
Figure 7. Fluoren-3-one analogues as selective ERβ.
Novel triphenylethylene–coumarin
Figure
Figure 7. hybrid derivatives
7. Fluoren-3-one
Fluoren-3-one analogues
analogues as ascontaining
selective different types and increasing
selective ERβ.
ERβ.
numbers of amino ethoxy
4.6. Triphenylethylene Coumarinside chains were reported and evaluated in 2013 [44]. These derivatives
4.6.
4.6. Triphenylethylene
were Coumarin
subjected to anti-proliferative
Triphenylethylene Coumarin tests against five tumor cells and tamoxifen were used as a
Novel triphenylethylene–coumarin hybrid derivatives containing different types and increasing
Novel
Novel triphenylethylene–coumarin hybrid derivatives containing
containingindifferent types and increasing
numbers oftriphenylethylene–coumarin
amino ethoxy side chains were hybrid derivatives
reported and evaluated different
2013 [44].types andderivatives
These increasing
Sci. Pharm.
numbers 2016,
of 84,
amino 409-427; doi:10.3797/scipharm.1511-02
ethoxy side chains were reported and evaluated in www.mdpi.com/journal/scipharm
2013 [44]. These derivatives
numbers of amino ethoxy side chains were reported and evaluated in 2013
were subjected to anti-proliferative tests against five tumor cells and tamoxifen were used as a [44]. These derivatives
were
were subjected
control.to
subjected
positive to anti-proliferative
Theanti-proliferative tests
derivatives displayedtests against
against five
fivetumor
a broad-spectrumtumorcellscellsand
and andtamoxifen
good tamoxifenwere wereused
anti-proliferative used as as
activity.a
positive
aBetween control.
positivethese
control. The derivatives
The derivatives
compounds displayed
displayed
(19–22, Figure a broad-spectrum
a broad-spectrum
8), compound and
19 showed good
andthe
good anti-proliferative
bestanti-proliferative activity.
results. Therefore,activity.
these
Between
Between these
these compounds
compounds (19–22,
(19–22, Figure
Figure8),8),
compound
compound 19 showed
19 showedthe best
the results.
best Therefore,
results. these
Therefore,
observations suggested that: (1) the number of the amino alkyl chain on 3,4-diphenylcoumarin had
observations
these suggested
observations that: (1)
suggested the(1)
that: number of theofamino
the activity,
number the alkyl alkyl
amino chainchain
on 3,4-diphenylcoumarin had
considerable impact on anti-proliferative and two side chains wereonmore
3,4-diphenylcoumarin
preferable for this
considerable
had considerable
activity; impact on
impact
(2) the weaker anti-proliferative
on anti-proliferative
basic activity,
amino group on the and
activity, two side
and two
side chain chains were
side chains
indicated more preferable
were more
a detrimental for
preferable
influence this
for
on anti-
activity;
this (2) the
activity; (2)weaker
the basicbasic
weaker amino group
amino on the
group onside
the chain
side indicated
chain a detrimental
indicated a influence
detrimental on anti-
influence on
proliferative activity.
proliferative activity.
anti-proliferative activity.
Sci. Pharm. 2016, 84, 409-427 415
Sci. Pharm. 2016, 84, 409–427 415
Sci. Pharm. 2016, 84, 409-427 415
Also, in 2015, Smith et al. [45] patented some compounds that have a coumarin scaffold as
estrogen
Also, receptor
Also,in in
2015, modulators.
2015,Smith al.The
Smithetetal. [45]general
[45] patented
patentedstructure
some of 23 showed
some compounds
compounds estrogen
thathave
that receptor
haveaacoumarin
coumarin antagonist
scaffold
scaffold as as
activity
estrogen and can
receptor also be an estrogen
modulators. The receptor
general degrader.
structure of 23 showed estrogen receptor antagonist
estrogen receptor modulators. The general structure of 23 showed estrogen receptor antagonist activity
andactivity
can also
andbecan
analso
estrogen
be an receptor
estrogen degrader.
receptor degrader.
OH
N
O OH
N
O

N
N N
O O O
O O O O O O
N
O 19 O O 20
19 20
N N
O N O N
O N
O N

O
O

N
H3CO O O N O O O
H3CO O O O O O
2121 22
22
R55
R

RR44
6
R6
R
11
RO
11
RO

OO 22
RR
R10
R10 RR77
NN
O
O R3R3
R88
R

RR1 1

R &&
1R1 R2R=2 =CC 1–C
1–C alkyl,CC1–C
6 6alkyl, 1–C66fluoro
fluoro alkyl,
alkyl, R
R33 == C
C11–C
–C66fluoro
fluoroalkyl,
alkyl,
R 4–11= -H, Halogen, -CN
R = -H, Halogen, -CN
4–11

23
23
Figure8.8.Triphenylethylene-coumarin
Triphenylethylene-coumarin hybrids.
Figure
Figure 8. Triphenylethylene-coumarin hybrids.
hybrids.

4.7. Combination of Anti-Estrogen and Receptor Tyrosine Kinase (RTK) Inhibitors

4.7. Combination of Anti-Estrogen and Receptor Tyrosine
Tyrosine Kinase
Kinase (RTK)
(RTK)Inhibitors
Inhibitors
A combination of anti-estrogen and receptor tyrosine kinase (RTK) inhibitors was patented as a
A combination
combination of ofanti-estrogen
anti-estrogenandandreceptor
receptor tyrosine
tyrosine kinase
kinase (RTK)
(RTK) inhibitors
inhibitors waswas patented
patented as a
useful agent for the treatment of cancer by Novartis. Receptor tyrosine kinases (RTKs) are
as a useful
useful agentagent
for for
the the treatment
treatment of of cancerbybyNovartis.
cancer Novartis.Receptor
Receptortyrosine
tyrosinekinases
kinases (RTKs)
(RTKs) are
transmembrane polypeptides that regulate developmental cell growth. A combination of fulvestrant
transmembrane polypeptides that regulate developmental cell growth.
growth. A combination
with RTK inhibitors such as compound 24 (Figure 9) displayed significant improvement in the
of fulvestrant
with RTK inhibitors
treatmentinhibitors such as compound
of proliferative diseases [46]. 24 (Figure 9) displayed significant
(Figure 9) displayed significant improvement in the
treatment of proliferative
proliferative diseases
diseases [46].
[46].

F NH2 N R
F NH2 N R
N
H
N
N O H
H
N O
H 24
24 kinase (RTK) inhibitors.
Figure 9. Receptor tyrosine
Figure 9. Receptor
Figure 9. Receptor tyrosine kinase (RTK)
tyrosine kinase (RTK) inhibitors.
inhibitors.
Sci. Pharm. 2016, 84, 409–427 416
Sci. Pharm. 2016, 84, 409-427 416

4.8. 1,1,2-Triarylolefine
1,1,2-Triarylolefine Derivatives
Derivatives
A group of 1,1,2-triarylolefines were patented as estrogen receptor antagonists
antagonists (25,
(25, Figure
Figure 10).
10).
Most of
of the
the synthesized
synthesizedcompounds
compoundsofofthis thisgroup
grouphad
hadhigh anti-estrogenic
high effects
anti-estrogenic with
effects minimal
with or no
minimal or
estrogen
no estrogenreceptor agonist
receptor activity
agonist [47].[47].
activity

(R4 )n
B
R2

(R5 )P

A C
3
(R )m R1
Ring A, B, C: indanyl, indenyl, naphtyl, 5- or 6-membered monocyclic heteroaryl
R1: tetrazole, optionally substituted piperidinyl
R2: halogen, -NO2, -CN
R3: halogen, -NO2, -CN, -OH, -OR, -CO2R
25
R4

B
R3

R2
N
C
N
H
R1

R5
Ring B and C: phenyl, naphtyl, 5-membered monocyclic heteroaryl
R1: -C(=O)-Z, carboxylic acid bioisostere (Z = OH, OR, -NR)
R2: C1–C6 alkyl, C1–C6 fluoroalkyl
R3: H, alkyl or halogen
R4: H, halogen, -CN, -OH, -OR
R5 and R6: H, C1–C4 alkyl or halogen
26

Figure 10.
Figure 10. 1,1,2-Triarylolefine.
1,1,2-Triarylolefine.

Relating to the patent mentioned above, some new compounds were patented by Smith et al. as
Relating to the patent mentioned above, some new compounds were patented by Smith et al.
estrogen receptor modulators in 2015 [48,49]. This patent with formula 26 (Figure 10) showed that
as estrogen receptor modulators in 2015 [48,49]. This patent with formula 26 (Figure 10) showed
these compounds diminished the effects of estrogen at estrogen receptors and are useful for the
that these compounds diminished the effects of estrogen at estrogen receptors and are useful for the
treatment ER-related diseases. These compounds were tested in different cells related to estrogen and
treatment ER-related diseases. These compounds were tested in different cells related to estrogen and
were tested in a clinical trial, demonstrating good results and high affinity to the estrogen receptor.
were tested in a clinical trial, demonstrating good results and high affinity to the estrogen receptor.
4.9. Aptamer
4.9. Aptamer Modulators
Modulators of
of Estrogen
Estrogen Receptors
Receptors
Shi Hua
Shi Hua etet al.
al.[50]
[50]patented
patentedaanucleic
nucleicacid
acidaptamer
aptamermolecule
molecule that
that includes
includes a domain
a domain that
that binds
binds to
to an
an estrogen
estrogen receptor.
receptor. Examples
Examples of aptamer
of aptamer molecules
molecules include
include those
those thatthat
bindbind to ERα
to ERα and those
and those that
that bind
bind to ERβ.
to ERβ. TheseThese compounds
compounds have ahave
highaaffinity
high affinity to the estrogen
to the estrogen receptor;receptor;
therefore,therefore, this
this strategy
strategy
can canfor
be used be used for that
patients patients
havethat have estrogen-dependent
estrogen-dependent cancer. cancer.
Sci. Pharm. 2016, 84, 409–427 417

5. Tamoxifen Analogues
Sci. Pharm. 2016, 84, 409-427 417

A new seriesAnalogues
5. Tamoxifen of novel tamoxifene analogues were evaluated for their anti-proliferative activity
on breast cancer (MCF-7) and their activity was comparable or even higher than tamoxifen.
A new series of novel tamoxifene analogues were evaluated for their anti-proliferative activity
These derivatives maintained the triarylethylene skeleton of tamoxifen having OH groups at the para
on breast cancer (MCF-7) and their activity was comparable or even higher than tamoxifen. These
position of the phenyl
derivatives rings of
maintained thetamoxifen and substituted
triarylethylene skeleton of the side chain
tamoxifen of tamoxifen
having OH groups withat an
theamide
para side
chain.position
One ofofthe most active compounds in this series, such as 27 (Figure 11), had
the phenyl rings of tamoxifen and substituted the side chain of tamoxifen with an amide anti-proliferative
activity
sideabout
chain.four
Onetimes
of thehigher
most than
activetamoxifen
compounds [51].
in this series, such as 27 (Figure 11), had anti-
Recently,
proliferativeprodigiosene
activity about(Figure
four times 12)higher
conjugates of the tamoxifen
than tamoxifen [51]. analogue (29, Figure 11) and
Recently,
estrone (28, Figureprodigiosene (Figure 12)Prodigiosenes
11) were reported. conjugates of the tamoxifena analogue
constitute (29, Figure compounds
class of tripyrrolic 11) and
based on the natural product prodigiosin that share a common 4-methoxypyrrolyldipyrrinbased
estrone (28, Figure 11) were reported. Prodigiosenes constitute a class of tripyrrolic compounds core unit.
Theyon the demonstrated
have natural product anticancer
prodigiosin activities
that share a[52,53].
common 4-methoxypyrrolyldipyrrin
Conjugating prodigiosenescore to aunit. They that
molecule
have demonstrated anticancer activities [52,53]. Conjugating prodigiosenes to a molecule that already
already possesses selectivity toward the tumor should help to deliver the drug at a specific site [54–63].
possesses selectivity toward the tumor should help to deliver the drug at a specific site [54–63].
Between these two compounds, the prodigiosin conjugates with the tamoxifen analogue (29, Figure 11)
Between these two compounds, the prodigiosin conjugates with the tamoxifen analogue (29, Figure
displayed excellent
11) displayed growthgrowth
excellent inhibition against
inhibition the ER-positive
against cellcell
the ER-positive lineline
MCF-7, with
MCF-7, withbetter
betteractivity
activity than
tamoxifen itself against
than tamoxifen itself this cellthis
against linecell
[64].
line [64].

O O
O O O
O ( )n
O O ( )n
HN O
N
N
HN HN
OH
HN HN
H
n=2
n=2
HO
O
27 28 29
NO2
N
O
N HO
HO O H
N N
(CH2)11CH3
O F

N
O

30 31 32
HN

N
O F

Me

33

Figure11.
Figure 11. Tamoxifen
Tamoxifen analogues.
analogues.

Another class of antagonists is the selective estrogen receptor down-regulators (SERDs). This
Another class of antagonists
class of compounds binds to ERisand
the induces
selective estrogen
the receptor down-regulators
rapid down-regulation of ER [65–68](SERDs). This class
and they have
of compounds
no agonisticbinds to ER
activity andtissues.
in any induces the rapid
SERDs down-regulation
are divided of ER
into two groups [65–68]
based and they
on their have no
chemical
structures.
agonistic activityOne is steroidal
in any tissues. compounds, such asinto
SERDs are divided fulvestrant (Figure
two groups 12),onwhich
based their has a steroidal
chemical structures.
One is steroidal compounds, such as fulvestrant (Figure 12), which has a steroidal structure with
Sci. Pharm. 2016, 84, 409–427 418

Sci. Pharm. 2016, 84, 409-427 418

a long alkyl side chain at the 7α position of the 17ß-estradiol core [68–70]. The other group contains
structure with a long alkyl side chain at the 7α position of the 17ß-estradiol core [68–70]. The other
non-steroidal compounds, such as GW5638 (Figure 12). The structure of GW5638 is similar to tamoxifen
group contains
Sci. Pharm. 2016, 84,non-steroidal
409-427 compounds, such as GW5638 (Figure 12). The structure of GW5638 is
and contains an acrylic acid side chain extending from the triphenylethylene core [71]. Shoda et418 al. [72]
similar to tamoxifen and contains an acrylic acid side chain extending from the triphenylethylene
reported
core
the design
[71]. with
Shoda
and synthesis
et al. alkyl
of
[72] reported
tamoxifen
theatdesign
derivatives that induced down-regulation of the ER.
structure a long side chain the 7α and synthesis
position of theof17ß-estradiol
tamoxifen derivatives thatThe
core [68–70]. induced
other
Accordingly, a new
down-regulation series of tamoxifen
of the ER. Accordingly,
group contains non-steroidal derivatives
compounds, a new with
suchseries long alkyl
of tamoxifen
as GW5638 chains was
(Figurederivatives designed. Among
with longofalkyl
12). The structure chains
GW5638 isthem,
compound
was 30 (Figure
designed. Among11) had
them,a strong
compound antagonist
30 effect.
(Figure 11) had a strong antagonist effect.
similar to tamoxifen and contains an acrylic acid side chain extending from the triphenylethylene
core [71]. Shoda et al. [72] reported the design and synthesis of tamoxifen derivatives that induced
down-regulation of the ER. Accordingly, a new series of tamoxifen
OH derivatives with long alkyl chains
O
was designed. Among them, compound 30 (Figure 11) had a strong antagonist effect.
N H
HN F
H OH O O
O H F
S F
HO
N HN H F
HN F
O O F
H H F
S F
prodigiosene HO fulvestrant
HN F
O F
HO
OH
prodigiosene fulvestrant
O
HO
OH

GW5638
Figure 12. Estrogen ligands.
Figure 12. Estrogen ligands.

In this regard, a series of novel fluorescent GW5638

tamoxifen derivatives (FLTX1) were also reported as
In this regard,
unique a seriesCompound
and SERM-like. of novel fluorescent
31Figure
(Figure tamoxifen
11), as a novel
12. Estrogen derivatives
ligands. fluorescent(FLTX1)
(FLTX1),were also reported
specifically labels as
unique and SERM-like.
intracellular Compound sites,
tamoxifen-binding 31 (Figure 11), asERα,
including a noveland fluorescent
displays unique(FLTX1), specifically labels
pharmacological
properties
In this
intracellular both in vitro
regard, and of
a series
tamoxifen-binding insites,
vivo. including
novel FLTX1 exhibits
fluorescent the
tamoxifen
ERα, andpotent anti-estrogenic
derivatives
displays (FLTX1)
unique properties
were alsoofreported
pharmacological tamoxifen as
properties
in breast
unique cancer
and cells
SERM-like. without the
Compound estrogenic
31 (Figureagonistic
11), as effect
a novel on the uterus
fluorescent
both in vitro and in vivo. FLTX1 exhibits the potent anti-estrogenic properties of tamoxifen in breast [73].
(FLTX1), specifically labels
cancer Malo-Forest
intracellular
cells without et al.
the [74] reported
tamoxifen-binding
estrogenic sites,fluorinated
agonistic including
effect on derivatives
ERα, andofdisplays
the uterus tamoxifen.
[73]. The activities
unique of these
pharmacological
fluorinated
properties bothanalogues
in vitroareandsimilar
in vivo.orFLTX1
betterexhibits
than tamoxifen
the potent and among them,properties
anti-estrogenic compound of 32 (Figure
tamoxifen
Malo-Forest et al. [74] reported fluorinated derivatives of tamoxifen. The activities of these
11) was the
in breast mostcells
cancer active on the the
without MCF7 cell line.agonistic
estrogenic In particular,
effectason opposed to tamoxifen,
the uterus [73]. both geometrical
fluorinated analogues are similar or better than tamoxifen and among them, compound 32 (Figure 11)
isomers behave similarly.
Malo-Forest et al. [74]This behavior
reported may be due
fluorinated to in vitro of
derivatives isomerization
tamoxifen. of Thetheactivities
compounds.of these
was the most active
Abdellatif et on
al. the
[75] MCF7
also cell
showed line.
that In particular,
replacement of as
the
fluorinated analogues are similar or better than tamoxifen and among them, compoundopposed
dimethylaminoto tamoxifen,
group both32 geometrical
in tamoxifen
(Figurefor
isomers behave
piperazino similarly.
or This
N-methylpiperazino behavior and may
by be due
changing to
thein vitro
ethyl isomerization
group by methyl
11) was the most active on the MCF7 cell line. In particular, as opposed to tamoxifen, both geometrical of the compounds.
substitution of the
Abdellatif
phenyl
isomers ring etwith
behave al. [75] also
a fluorine
similarly. showed
This atom hadthat
behavior replacement
excellent
may of the
anti-proliferative
be due to in vitro dimethylamino
activity on
isomerization of the group
MCF-7 in
the compounds. celltamoxifen
line.
for piperazino
Among these
Abdellatif N-methylpiperazino
orderivatives, compound
et al. [75] also showed 33 and
that by changing
(Figure 11) showed
replacement the
of the the ethyl group by
best results.
dimethylamino methyl
group substitution
in tamoxifen for of
the phenyl Cho
piperazino et or
ring al. [76]apatented
with fluorinecompositions
N-methylpiperazino atom and hadby and methods
changing
excellent theforethyl
covalently
group bonding
anti-proliferative by methyl
activity a polycarboxylic
substitution
on the MCF-7 offatty
the line.
cell
Amongacid
phenylandring
these SERD as shown
with
derivatives, in Scheme
a fluorine
compoundatom had1.
33The conjugated
excellent
(Figure compounds
11)anti-proliferative
showed the bestare useful
activity
results. for the
on increasing
MCF-7solubility
cell line.
of the SERD
Among these as well as targeting
derivatives, compound the 33SERD to a11)
(Figure solid tumor.
showed the Compounds
best results. have been shown to be
Cho et al. [76] patented compositions and methods for covalently bonding a polycarboxylic fatty
interestingly
Cho et al.efficacious
[76] patented against tamoxifen-resistant
compositions and methods tumors. Currently,
for covalently there is
bonding only one approved
a polycarboxylic fatty
acid and SERD as shown in Scheme 1. The conjugated compounds are useful for increasing solubility
drug thatSERD
acid and bindsas toshown
estrogen receptors
in Scheme 1.for
Theuse in patients
conjugated suffering from
compounds tamoxifen-resistant
are useful cancer.
for increasing solubility
of the SERD as well as targeting the SERD to a solid tumor. Compounds have been shown to be
of the SERD as well as targeting the SERD to a solid tumor. Compounds have been shown to be
interestingly efficacious
interestingly efficacious against
against tamoxifen-resistant
O
tamoxifen-resistant tumors.Currently,
tumors. Currently, there
there is only
is only one one approved
approved
drug drug
that binds to estrogen receptors for use in patients suffering from tamoxifen-resistant
that binds to estrogen receptors for use in patients suffering from tamoxifen-resistant cancer. cancer.

O (L)

SERD residue Long chain fatty acid moiety

(L)
Scheme 1. Covalently bonding a polycarboxylic fatty acid and SERD.

SERD residue Long chain fatty acid moiety

Scheme 1. Covalently bonding a polycarboxylic fatty acid and SERD.

Scheme 1. Covalently bonding a polycarboxylic fatty acid and SERD.
 COOH

Sci.Sci.
Pharm. 2016,
Pharm. 84, 409-427
2016, 84, 409–427 419 419
COOH

Preferably, the SERD is selected from the group consisting of O compound 34 (Figure 13). In this
group, Preferably, the SERD
HO
results showed that is selected from
compound the group
35 had consisting
the best activity,ofbeing
compound
O even 34 (Figure
more 13).than
potent In this
group, results
fulvestrant. showed that 34
compound 35 had the best activity, being even 35
more potent than fulvestrant.
Figure 13. SERD (34) and fatty acid-SERD conjugate (35).
COOH
COOH
6. Carborane Analogues
Carboranes are man-made compounds that have no counterparts in nature. Their unique
bonding, structure, and properties predetermine them to be used and tested in many applications.
During the last decade it has been shown that 17α-substituted arylestradiol sharing a lipophilic
COOH
aromatic moiety displayed high affinity for binding to ERα and ERβ receptors [61,77–83]. As a result,
O
Sedlak et al. [84] reported a new series of 17α-(carboranylalkyl)estradiols as ligands for estrogen
HO
receptors α and β. Results showed that all of the tested O
compounds (Figure 14) had estrogenic
34 35
activity, although none of them were able to fully activate either ER like 17β-estradiol. Relative
transcription activityFigure (RTA)
13. 13.
Figure SERDisSERD
shown
(34)(34)
and in Table
fatty
and 1.acid-SERD
Results
acid-SERD
fatty also
conjugate showed (35).that compound 37a is 30 times
(35).
conjugate
more selective for ERα than ERβ and it is the most potent ligand for ERα among the tested
6. Carborane
6. Carborane Analogues
compounds. They also showed that the length and the position of the double bond in the alkenyl
Analogues
linker
Carboranes are important
are for the affinity of that the ligand to the receptor. Smaller carborane unique
groups require
Carboranes areman-made
man-made compounds
compounds that have havenono counterparts
counterparts in nature.
in nature. TheirTheir
unique bonding,
bonding, shorter linkers
structure, to efficiently
and properties activate
predetermine ERs.
structure, and properties predetermine them tothem be usedto be
and used
testedandintested
many in many applications.
applications. During the
During the last decade
last decade it has been shown it has been shown that 17α-substituted arylestradiol sharing a lipophilic
Tablethat 17α-substituted
1. Activation of steroidarylestradiol sharing a lipophilic
receptors by carboranyl compounds. aromatic moiety
aromatic
displayed moiety
highdisplayed high
affinity for affinity
binding to for
ERαbinding
and ERβ to ERα and ERβ
receptors receptors
[61,77–83]. As [61,77–83]. As a result,
a result, Sedlak et al. [84]
Sedlak et al. [84] reported a new series of
reported a new series of 17α-(carboranylalkyl)estradiols 17α-(carboranylalkyl)estradiols
RTA(%) RTA(%) as ligands for estrogen
as ligands for estrogen receptors α and β.
Compound
receptors
Results αshowedand β.thatResults
all ofshowed
the tested that all of the (Figure
compounds tested ERαcompounds
14) had ERβ (Figureactivity,
estrogenic 14) hadalthough
estrogenicnone
activity, although none of them were
of them were able to fully activate eitherAgonist able to fully activate
100
ER like 17β-estradiol. either ER like 17β-estradiol.
100 transcription activity
Relative Relative
(RTA)
transcription
is shown inactivity
Table 1.(RTA)
Resultsis shown in Table
also showed 1. compound
36a
that Results also showed
2437a that compound
26
is 30 times 37a is
more selective for30ERα
timesthan
more selective for ERα than ERβ and it is the
36b most potent
52 ligand
ERβ and it is the most potent ligand for ERα among the tested compounds. They also showed that 35 for ERα among the tested
compounds.
the length They and thealso showedofthat
position the length
the double 36cand
bond in the
the position
20
alkenyl of the
linker double
16are bond for
important in the
the alkenyl
affinity of
linker are important for the affinity of the ligand
36d to the receptor.
53 Smaller
43 carborane
the ligand to the receptor. Smaller carborane groups require shorter linkers to efficiently activate ERs. groups require
shorter A linkers
new to efficiently
series activate ERs.
of fluorinated carboranyl 37aphenols were 58 also reported
40 as ERβ selective ligands.
37b 71 63
Compound 38 (Figure 15) in this series displayed 8.5-fold greater selectivity for ERβ. Therefore,
Table 1. Activation of steroid37c receptors by carboranyl
16 compounds.
14 cage reduced the ERα binding
introduction of a fluorine atom at the 9-position of the m-carborane
affinity [85]. 37dRTA(%) RTA(%) 31 27
Compound
ERα ERβ
Agonist 100 HO 100( )n CB
36a 24 26
36b 52 35
36c 20 16
36d
HO 53 43
37a
36a, n = 1 37a, n = 0, CB = O-CB 40
58
36b, n = 137b 37b, n = 0, CB 71= m-CB 63
37c
36c, n = 1 37c, n = 0, CB16= S-CoCB214
Sci. Pharm. 2016, 84, 409-427 420
36d, n = 137d 37d, n = 0, CB 31= SS-CoCB 272

H H
C HO
C ( )n S
C CB
S+ CO CO
C S+

O-CBHO m-CB S-CoCB2 SS-CoCB2

36a, n = 1 37a,Figure
n = 0, CB 17α-Carboranylalkylestradiols.
= O-CB
Figure 14.
14. 17α-Carboranylalkylestradiols.
36b, n = 1 37b, n = 0, CB = m-CB
A new series36c,
of n = 1 37c, n =carboranyl
fluorinated 0, CB = S-CoCB
phenols
2 were also reported as ERβ selective ligands.
36d, n 15)
Compound 38 (Figure = 1 37d, n =series
in this 0, CB =displayed
SS-CoCB28.5-fold greater selectivity for ERβ. Therefore,
introduction of a fluorine atom at the 9-position of the m-carborane cage reduced the ERα binding
affinity [85].
Sci. Pharm. 2016, 84, 409-427 420
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2016, 84, 409–427 420

H H
Table 1. H
Activation H
C
of steroid receptors by carboranyl compounds.
C C S
CC S++ CO S
C S CO
C
CompoundC S+
RTA(%) ERα CORTA(%) ERβ CO
S+
Agonist 100 100
36a m-CB
O-CB 24S-CoCB2 26 SS-CoCB2
O-CB
36b m-CB 52S-CoCB2 35 SS-CoCB2
Figure
36c 14. 17α-Carboranylalkylestradiols.
20 16
Figure 14. 17α-Carboranylalkylestradiols.
36d 53 43
A new series of fluorinated37a 58
carboranyl phenols were also 40reported as ERβ selective ligands.
A new series of fluorinated37bcarboranyl phenols
71 were also 63
reported as ERβ selective ligands.
Compound 38 (Figure 15) in this series displayed 8.5-fold greater selectivity for ERβ. Therefore,
Compound 38 (Figure 15) in this37cseries displayed 16 8.5-fold greater
14 selectivity for ERβ. Therefore,
introduction of a fluorine atom at37d
the 9-position 31
of the m-carborane cage reduced the ERα binding
27 cage
introduction of a fluorine atom at the 9-position of the m-carborane reduced the ERα binding
affinity [85].
affinity [85].

F
F
HO
HO
38
38
Figure 15.
Figure 15. Fluorinated carborane as ERβ selective.
Figure 15. Fluorinated carborane as ERβ selective.

Ogawa et al. [86] designed and synthesized novel estrogen receptor modulators containing
Ogawa et al. [86] designed and synthesized novel estrogen receptor modulators containing
Ogawa
various hydrophobic bent-core structures. Previously discovered m-carborane derivative (39, Figure
various hydrophobic
hydrophobicbent-core
bent-corestructures.
structures.Previously
Previouslydiscovered m-carborane
discovered m-carborane derivative (39,(39,
derivative Figure 16)
Figure
16) displayed ER partial agonistic activity in ERα trans activation assays. In this series, compounds
displayed ER partial agonistic activity in ERα trans activation assays. In this series, compounds
16) displayed ER partial agonistic activity in ERα trans activation assays. In this series, compounds with
with pseudo cyclic, tetrahydropyrimidinone, m-benzene, adamantine, and 9,10-dimethyl-m-
pseudo
with cyclic, cyclic,
pseudo tetrahydropyrimidinone, m-benzene,
tetrahydropyrimidinone, adamantine,
m-benzene, and 9,10-dimethyl-m-carborane
adamantine, and 9,10-dimethyl-m-
carborane were synthesized. Among them, compound 44 with a 9,10-dimethyl-m-carborane cage
were synthesized.
carborane Among them,
were synthesized. Among compound 44 with a449,10-dimethyl-m-carborane
them, compound cage showed
with a 9,10-dimethyl-m-carborane cage
showed a greater ER-binding affinity than compound 39 with two methyl groups into the m-
a greater ER-binding affinity than compound 39 with two methyl groups into the
showed a greater ER-binding affinity than compound 39 with two methyl groups into the m- m-carborane cage.
carborane cage. Compound 39 had an increase of Hansch hydrophobic value (π value) [87,88].
Compound
carborane 39 had
cage. an increase
Compound 39 of
hadHansch hydrophobic
an increase value
of Hansch (π value) [87,88].
hydrophobic value (π value) [87,88].

N N N
N O N O N O
O O O

O N
OH O N
OH N
O N
O
HO HO HO
HO HO HO
39 40 41
39 40 41
N N N
N O N O N O
O O O

CH3
CH3
CH3
CH3
HO HO HO
HO HO HO
42 43 44
42 43 44

Figure 16. Hydrophobic bent-core structures.

Figure 16. Hydrophobic bent-core structures.
Figure 16. Hydrophobic bent-core structures.
Sci. Pharm. 2016, 84, 409–427 421
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7. 7.Metal
MetalComplexes
Complexes
7. Metal Complexes
Estrogenic
Estrogenic steroid conjugates
steroid conjugatespossessing
possessingmetal chelates
metal at theat17α-position
chelates represent
the 17α-position an attractive
represent an
Estrogenic steroid conjugates possessing metal chelates at the 17α-position represent an
delivery vector
attractive as avector
delivery targeting
as a strategy
targeting [89–92]. In this In
strategy [89–92]. regard, ZhangZhang
this regard, et al.etsynthesized
al. synthesizeda new
a
attractive delivery vector as a targeting strategy [89–92]. In this regard, Zhang et al. synthesized a
newof
series series of estrogen-derived
estrogen-derived metal metal complexes
complexes andand appliedthe
applied thesquaramide
squaramide structure
structureasasthethecore of of
core
new series of estrogen-derived metal complexes and applied the squaramide structure as the core of
thethe metal
metal bindingunit.
binding unit.Results
Resultsshowed
showed thatthat all of the
the compounds
compounds ininthis series
this were
series wereagonists
the metal binding unit. Results showed that all of the compounds in this series were agonists on ERα.
on on
agonists ERα.
ERα.
Compared
Compared toto
thetheneutral
neutralfree
freeligand
ligand(45,
(45, Figure 17), the binding affinity of compound 46a–c forfor
ERα
Compared to the neutral free ligand (45,Figure thebinding
Figure 17), the bindingaffinity
affinityof of compound
compound 46a–c46a–c
for ERα ERα
increased,
increased,
increased,while
while the
the the
while binding
binding affinity
affinity
binding of 46a–c
ofof46a–c
affinity for
46a–cfor ERβ
forERβ all decreased
all decreased
ERβ all [93].
decreased[93].
[93].

NN NH
NH OO
HH
NN
NN OO
HO
HO
HH
45

NN NN OO
Cl
Cl Pd
NN Pd
NN OO
HO
HO
46a
46a

N N O
Cl N N O
Cl Cl Ni
Cl N Ni
N N O
HO O
HO N
46b
46b

N N O
Cl N
Cl Zn N O
ClN
Cl Zn N O
HO N
N O
HO 46c
46c
Figure
Figure 17.17.Novel
Noveltype
type of
of targeting
targetingagents
agentsforfor
ER.
ER.
Figure 17. Novel type of targeting agents for ER.
Recently, new ferrocenyl compounds with different alkyl chain lengths were synthesized and
Recently,
evaluated new ferrocenyl
against compounds
hormone-dependent with
breast different
cancer alkyl new
cells. alkyl
Seven chain lengths compounds
were synthesized and
Recently, new ferrocenyl compounds with different chainferrocenyl
lengths were synthesized having and
evaluated
evaluated
against
differentagainsthormone-dependent
chain lengths breast
(suberic, adipic,breast
hormone-dependent
cancer
succinic) cells.
werecells.
cancer
Seven
synthesized
Seven new
new ferrocenyl
andferrocenyl compounds
all of themcompounds
displayed strong having
having
different chain lengths
anti-proliferative (suberic,
activity adipic,
against succinic) were
hormone-dependent synthesized
and and
independent all of them
breast displayed
cancer
different chain lengths (suberic, adipic, succinic) were synthesized and all of them displayed strong cell strong
lines.
Interestingly, among
anti-proliferative thisagainst
activity series, compound 47, having a succinimide
hormone-dependent and group (Figure
independent 18), cancer
breast was the cell
mostlines.
anti-proliferative activity against hormone-dependent and independent breast cancer cell lines.
active compound against
Interestingly, hormone-dependent MCF-7 breast cancer cells, group
presumably owing to an the
Interestingly,among
amongthis
this series, compound47,47,
series, compound having
having a succinimide
a succinimide group (Figure (Figure 18),
18), was thewas
most
antagonist effect on ERα [94].
most active compound against hormone-dependent MCF-7 breast cancer cells, presumably owing to
active compound against hormone-dependent MCF-7 breast cancer cells, presumably owing to an
anantagonist
antagonisteffect
effecton
onERα
ERα [94].
[94].
Fe

Fe

O
N
O
O
N
47
O
Figure 18. Ferrocenyl compound.
47
Figure18.
Figure 18. Ferrocenyl
Ferrocenyl compound.
compound.
Sci. Pharm. 2016, 84, 409–427 422
Sci. Pharm. 2016, 84, 409-427 422

In 2014, some thiosemicarbazone

thiosemicarbazone ligandsligands and their rhenium(I) carbonyl complexes were
synthesized,
synthesized, characterized,
characterized, andand
theirtheir
estrogen receptor
estrogen bindingbinding
receptor affinitiesaffinities
were determined (48, Figure
were determined
(48, Figure
19). In 19).allIncompounds
general, general, alldisplayed
compounds displayed
values values
of less than 50%offorless than affinity
binding 50% forfor binding affinity
both estrogen
for both estrogen
receptor subtypes.receptor subtypes.
The results
results indicated
indicated that
thatthe
thetype
typeofofhalogen
halogenononthethe rhenium
rhenium atom
atom does
does notnot seem
seem to have
to have an
an effect
effect on on
thethe affinity
affinity of of
thethe complex
complex forfor
thethe receptor,but
receptor, butthe
thehydroxyl
hydroxylgroup
groupat atthe
the para
para position
position of
phenyl ring plays a positive role. In any case, the nature of the the R
R33 and R55 groups seems
seems to be more
significant [95].

H R5
N
R1
HN SH
N
R2 Re x
R3 R4Co CoCo
R1 = OMe, R2 = Me, R3 = OMe, R4 = H, R5 = H, Me, Ph, X = Cl, Br
48
Figure
Figure 19.
19. Rhenium(Ι)
Rhenium(I) thiosemicarbazone
thiosemicarbazone complexes.
complexes.

8.
8. Conclusions
Conclusions
Since
Since activation
activationofofERα ERαis associated
is associated withwithproliferative
proliferative responses
responses in theinmammary
the mammary gland and in
gland
the
anduterus,
in the the development
uterus, of selective
the development ofERα antagonists
selective or selective ERα
ERα antagonists ligands with
or selective ERα mixed
ligandstissue-
with
selective agonist/antagonist activity is a promising strategy for the
mixed tissue-selective agonist/antagonist activity is a promising strategy for the production production of new therapeutic of
agents. In contrast,
new therapeutic the therapeutic
agents. In contrast, potentials of ERβ agonists
the therapeutic potentials for oftheERβtreatment
agonists of other
for thepathologies
treatment
such as pathologies
of other prostate cancer such or cardiovascular
as prostate cancer or diseases attract researchers
cardiovascular diseases attract to develop
researchers selective ERβ
to develop
agonists as safe and efficacious drugs. This review provides an overview
selective ERβ agonists as safe and efficacious drugs. This review provides an overview and update of and update of compounds
that have been
compounds that recently
have been reported
recentlyas estrogen
reported receptor receptor
as estrogen ligands, ligands,
with a with particular focus focus
a particular on their
on
structure-activity relationships and their potential clinical applications.
their structure-activity relationships and their potential clinical applications. The compounds were The compounds were
classified based on
classified based on chemical
chemical structure
structure in in steroidal
steroidal and and non-steroidal
non-steroidal ligands.ligands. Atypical
Atypical ER ER ligands
ligands
including
including carborane analogues and
carborane analogues and estrogenic
estrogenic metal metal complexes
complexes were were also also described.
described.
SERMs are compounds that exhibit tissue-specific
SERMs are compounds that exhibit tissue-specific estrogen receptor agonist estrogen receptor agonist or or antagonist
antagonist
activity
activity [2]. They represent a diverse group of molecules with varying levels of estrogen agonist and
[2]. They represent a diverse group of molecules with varying levels of estrogen agonist and
antagonist activity in different tissues. With unique and different patterns
antagonist activity in different tissues. With unique and different patterns of ER subtype expression of ER subtype expression
seen
seen in
in the
the breast,
breast, bone,
bone, CNS,
CNS,and andcardiovascular
cardiovascularsystem, system,ER ERligands
ligandsincluding
includingSERMs SERMscan can exert
exerta
wide
a widerange
rangeofofphysiological
physiologicaleffects
effectsrelated
relatedtotobothbothpathological
pathologicaland and therapeutic
therapeutic processes.
processes. The The most
most
important clinical successes achieved in the ER ligand field over the
important clinical successes achieved in the ER ligand field over the past decades mainly involve past decades mainly involve
SERMs
SERMs or or ERα
ERα antagonists
antagonists which
which areare used
used in in the
the treatment
treatment of of estrogen-related
estrogen-related cancerscancers such
such as as breast
breast
cancer, osteoporosis, and cardiovascular diseases [47]. The classical treatment
cancer, osteoporosis, and cardiovascular diseases [47]. The classical treatment in ER-positive breast in ER-positive breast
cancer
cancer isis oral
oraltamoxifen
tamoxifenasasa afirst-generation
first-generation SERM.
SERM. However,
However, overovertime or by
time or chance
by chancemutation, ER-
mutation,
positive breast cancer not only becomes resistant to tamoxifen, as
ER-positive breast cancer not only becomes resistant to tamoxifen, as tamoxifen becomes an agonisttamoxifen becomes an agonist
which inducesproliferation.
which induces proliferation.Unlike
UnlikeSERMs
SERMslike like tamoxifen,
tamoxifen, SERDs
SERDs areare
notnot ER agonists
ER agonists whichwhich
limitlimit
side
side effects throughout the body such as endometrial hyperplasia
effects throughout the body such as endometrial hyperplasia or uterotrophy and bone demineralization or uterotrophy and bone
demineralization
which make them which much moremaketolerable
them much more tolerable
therapies. Unfortunately,therapies.
thereUnfortunately,
is only one approvedthere ishormonal
only one
approved hormonal estrogen receptor-targeted medication for tamoxifen-resistant
estrogen receptor-targeted medication for tamoxifen-resistant cancer, the SERD fulvestrant. Due cancer, the SERD to
fulvestrant.
solubility issues of fulvestrant, it has to be prepared in oil and used as an IM injection whichIM
Due to solubility issues of fulvestrant, it has to be prepared in oil and used as an is
injection which is extremely painful and unpleasant for patients. Therefore,
extremely painful and unpleasant for patients. Therefore, there is a need to develop new SERDs there is a need to develop
new SERDs
with with oral
oral activity activity as alternative
as alternative treatment treatment
for patients forsuffering
patients suffering from tamoxifen-resistant
from tamoxifen-resistant cancers.
cancers. Conjugation of a SERD and a polycarboxylic fatty
Conjugation of a SERD and a polycarboxylic fatty acid is a good strategy to form acid is a good strategy to form
fatty fatty acid-
acid-drug
drug conjugate
conjugate compounds.
compounds. The conjugate
The conjugate compoundscompounds are usefulare useful for increasing
for increasing solubilitysolubility of the
of the SERDs
SERDs as well as targeting the SERD to solid tumors. In particular, the compounds have been shown
to be interestingly efficacious against tamoxifen-resistant tumors. The authors believe that in the near
Sci. Pharm. 2016, 84, 409–427 423

as well as targeting the SERD to solid tumors. In particular, the compounds have been shown to
be interestingly efficacious against tamoxifen-resistant tumors. The authors believe that in the near
future, several new SERDs will be introduced in this field for the treatment of tamoxifen-resistant
cancers. In fact, new orally bioavailable SERDs hold promise as a next generation therapy for the
treatment of ER-positive breast cancer as monotherapy as well as in combination with agents that
target other pathways involved in endocrine-resistant states. In addition to SERDs, a great deal of
attention is presently being paid to ERβ agonists. Recently, a remarkable rise of interest in developing
ER modulators displaying the same beneficial effects of estrogens without the adverse side effects
was observed after the discovery of a second ER subtype, ERβ. Therefore, the recent literature has
focused on selective ERβ ligands as highly promising targets for the treatment of some types of
cancer, as well as for cardiovascular and inflammatory bowel diseases. Because of the high therapeutic
potential of ERβ ligands, we should expect that in the coming years more ERβ-selective agonists will be
launched in the market for the treatment of different pathologies such as breast cancer, prostate cancer,
colorectal cancer, cardiovascular diseases, and neurodegenerative diseases.

Author Contributions: This paper has two authors with the same contribution.
Conflicts of Interest: The authors declare no conflict of interest.

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