N-Arylbenzamides: Extremely simple scaffolds for the development of novel estrogen receptor agonists

Article abstract of DOI:10.3109/14756366.2011.642374

The research of estrogen receptor (ER) ligands has benefited in the last decade from the implementation of combinatorial chemistry. The general pharmacophore has been identified and subsequently a multitude of compounds have been synthesized. Surprisingly, up to now simple amides have not been taken into consideration. Here we show that amides resulting from the condensation of hydroxybenzoic acids with aminophenols result in compounds retaining the pharmacophore structure of an ER ligand with a clear estrogenic activity.

Full text of DOI:10.3109/14756366.2011.642374

Journal of Enzyme Inhibition and Medicinal Chemistry, 2011, 1–5, Early Online
© 2011 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.642374
RESEARCH ARTICLE
N-Arylbenzamides: extremely simple scaffolds for the
development of novel estrogen receptor agonists
Antonio Caldarelli, Paolo Minazzi, Pier Luigi Canonico, Armando A. Genazzani, and
Giovanni B. Giovenzana
DISCAFF & DFB Center, Università degli Studi del Piemonte Orientale “A. Avogadro”, Novara, Italy
Abstract
The research of estrogen receptor (ER) ligands has benefited in the last decade from the implementation of
combinatorial chemistry. The general pharmacophore has been identified and subsequently a multitude of
compounds have been synthesized. Surprisingly, up to now simple amides have not been taken into consideration.
Here we show that amides resulting from the condensation of hydroxybenzoic acids with aminophenols result in
compounds retaining the pharmacophore structure of an ER ligand with a clear estrogenic activity.
Keywords: Estrogen, receptor, amides, scaffold, agonist
Introduction
precise steric hydrophobic centers mimicking steric 7α
and 11β-substituents, (5) hydrophobicity and (6) a ring
structure6. Indeed, such understanding has led the phar-
maceutical industry to develop a number of estrogen ago-
nists and antagonists to modulate the hormonal activity
in the different body districts and health conditions7.
In the last decades, the search for compounds
endowed with higher affinity and selectivity (eventually
with respect to the ER subtype) has led to the preparation
or isolation of different estradiol analogs, the best known
families being diarylethanes (e.g. hexestrol8,9), di/tri-
arylethenes (e.g. diethylstilbestrol10,11, tamoxifen12,13) and
phytoestrogens14,15 (flavones, flavanones, isoflavones,
etc.). In addition to these, a large number of synthetic
estradiol analogs have been built over the pharmacoph-
ore model16. e main variations are observed in the
central region, where different substructures have been
employed to bear two phenolic ring with the OH-OH
distance predicted by the established model. To this
purpose, several analogs with central spacing structures
such as five-membered heterocyclic rings17,18 have been
synthesized and tested. Additional derivatives involve
fusion of one of the phenolic ring with carbo-19,20 and
e regulation of the reproductive systems and of many
functions in liver, bones, central nervous system and
cardiovascular systems are some examples of the effects
of estrogens, endocrine molecules exemplified by 17β-
estradiol (Figure 1)1 e latter binds to the estrogen recep-
tor (ER), known to be present in two isoforms (ER-α and
ER-β), leading to a conformational change that allows
the ER to act as transcription factor, giving rise to gene
expression changes and modulatory functions2.
ERs are known to be able to recognize non-steroido-
genic substances. Indeed, the promiscuity of the ER has
led to the development of molecules with estrogenic and
therapeutical potential3. In the past decades, the tremen-
dous effort made to characterize the interaction of the ER
with its ligands and the activation cascade4 has led to a
detailed knowledge of the receptor-ligand interactions
and the pharmacophore is actually known5,6
.
e pharmacophore ligand model (Figure 1) sum-
marizes the key structural features deducted from 17β-
estradiol: (1) H-bonding ability of the phenolic ring
mimicking the 3-OH, (2) H-bond donor mimicking the
17β-OH, (3) O-O distance between 3 and 17β-OH, (4)
Antonio Caldarelli and Paolo Minazzi contributed equally to this work.
Address for Correspondence: Dr. Giovanni B. Giovenzana, DISCAFF & DFB Center, Università degli Studi del Piemonte
Orientale “A. Avogadro”, Via Bovio 6, 28100, Novara, Italy. Tel: +39-(0)321-375846. Fax: +39-(0)321-375821.
E-mail: giovanni.giovenzana@pharm.unipmn.it
(Received 03 October 2011; revised 11 November 2011; accepted 12 November 2011)
1

2
A. Caldarelli et al.
Figure 1. 17-β estradiol and a simplified model of the ER
pharmacophore.
hetero-cycles21, five-membered rings being a common
choice22–24 and leading to well known leads such as ralox-
ifen25. Quite surprisingly, simpler spacing substructures
have been scarcely employed26,27 and we were therefore
prompted to explore if simpler functional groups could be
engaged in the preparation of efficient estrogen analogs.
In particular, we were interested in the use of a simple car-
boxylic amide as the central section of novel potential ER
ligands. e amide group can be readily assembled from
carboxylic acids and amines precursors, each of them
bearing the required structural features; its size is such
that the phenolic rings may be positioned with a correct
OH-OH distance. e restricted rotation around the C-N
bond imparts an overall molecular rigidity while main-
taining a residual conformational mobility. e nitrogen
atom may be eventually decorated with substituents in
order to fine-tuning the lipophilicity of the molecule.
Finally, the easy formation of the amide functional group
is compatible with solid-phase and combinatorial syn-
thetic methods, allowing eventual wide-range screening
to be performed with limited synthetic efforts.
Inthiswork, wereportthepreparationofasmalllibrary
of eight polyhydroxy-N-arylbenzamides (Figure 2), and
preliminary tests on their activity towards ERs.
Figure 2. N-arylbenzamides library.
CD3OD) δ 167.7, 157.5, 139.6, 136.5, 129.4, 129.2, 118.5,
118.1, 114.2, 112.1, 113.3, 108.1 ppm; MS(EI): 230.2
(M·H+); m.p. 187.5–188.7°C.
Material and methods
General procedure for the synthesis of
compounds (1–8)
e aminophenol (1.0 mmol), the hydroxybenzoic acid
(1.0 mmol) and EDC (N-(3-Dimethylaminopropyl)-
N′-ethylcarbodiimide hydrochloride, 1.2 mmol) were
dissolved in acetone (5 mL). e mixture was stirred
and refluxed 12 h under N2 atmosphere. e solvent
was evaporated and the residual solid was dissolved in
ethyl acetate and washed three times with 1 M aq HCl,
and 10% aq Na2CO3. e organic phase was dried over
Na2SO4 and evaporated in vacuum to give the desired
polyhydroxyamide.
3-Hydroxy-N-(4-hydroxyphenyl)benzamide (2)
1H NMR (300 MHz, CD3OD) δ 7.42 (d, J = 8.8 Hz, 2H),
7.37-7.28 (m, 3H), 6.87 (ddd J = 7.8, 2.4, 1.4 Hz, 1H), 6.78
(d, J = 8.8, Hz, 2H) ppm; 13C NMR (75.4 MHz, CD3OD)
δ 167.5, 157.6, 154.4, 136.4, 130.2, 129.3, 123.1, 118.4,
118.0, 114.9, 114.1 ppm; MS(EI): 230.1 (M·H+); m.p.
208.0–209.2°C.
4-Hydroxy-N-(3-hydroxyphenyl)benzamide (3)
1H NMR (300 MHz, CD3OD) δ 7.80 (d, J = 8.9 Hz, 2H),
7.26 (t, J = 2.3 Hz 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.05 (ddd,
J = 8.1, 2.3, 1.1 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.56 (ddd,
J = 8.1, 2.3, 1.1 Hz, 1H) ppm; 13C NMR (75.4 MHz, CD3OD)
δ 167.4, 161.0, 157.5, 139.8, 131.4, 129.4, 129.1, 125.7,
114.8, 112.2, 111.1, 108.2 ppm; MS(EI): 230.1 (M·H+); m.p.
200.8–201.6°C.
3-Hydroxy-N-(3-hydroxyphenyl)benzamide (1)
1H NMR (300 MHz, CD3OD) δ 7.34 (dt, J = 7.5, 1.5 Hz, 1H),
7.31−7.27 (m, 3H), 7.14 (t, J = 8.0 Hz, 1H), 7.06 (ddd, J = 8.2,
1.2, 1.2 Hz, 1H), 6.97 (ddd, J= 7.8, 2.5, 1.4 Hz, 1H), 6.58
(ddd, J = 8.0, 2.5, 1.2 Hz, 1H) ppm; 13C NMR (75.4 MHz,
Journal of Enzyme Inhibition and Medicinal Chemistry

Development of novel estrogen receptor agonists
3
(Sigma Aldrich, Germany) and 1% DCC stripped medium
(Invitrogen, USA). After 6 h, cells were transfected by 0.2
µL of Lipofectamine (Invitrogen, USA) mixed with 33 ng
of reporter plasmid, ERE-Luc, 33 ng of CMV-ERa and
33 ng pGL4.73 Renilla luciferase (Promega, as a normal-
izer of transfection). Sixteen hours after transfection,
cells were treated by the compounds for 24 h. All com-
pounds were dissolved in dimethyl sulfoxide (DMSO)
(Sigma Aldrich, Germany). DMSO treatment served as
negative control.
ereafter, luciferase assay was performed by Dual-
Glo luciferase assay (Promega, USA), following the pro-
ducer indication. e sample-value of firefly luciferase
was devided by the relative renilla luciferase value to
normalize the transfection level.
4-Hydroxy-N-(4-hydroxyphenyl)benzamide (4)
1H NMR (300 MHz, CD3OD) δ 7.79 (d, J = 8.6, Hz, 2H), 7.40
(d, J = 8.9 Hz 2H), 6.85 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 9.2
Hz, 2H) ppm; 13C NMR (75.4 MHz, CD3OD) δ 168.6, 162.4,
155.6, 131.7, 130.5, 126.7, 124.5, 116.2 ppm; MS(EI): 230.2
(M·H+); m.p. 198–199.5°C.
2,4-Dihydroxy-N-(3-hydroxyphenyl)benzamide (5)
1H NMR (300 MHz, CD3OD) δ 7.80 (d, J = 8.9 Hz, 1H), 7.23
(t, J = 2.1 Hz, 1H), 7.14 (t, J= 8.0 Hz, 1H),7.06 (dd, J = 8.7, 2.3
Hz, 1H) 7.00 (bd, J= 8.0 Hz, 1H), 6.57 (ddd, J = 8.0, 2.4, 0.9
Hz, 1H) 6.33 (d, J= 2.4 Hz, 1H) ppm; 13C NMR (75.4 MHz,
CD3OD) δ 167.9, 162.8, 161.7, 157.6, 139.1, 129.9, 129.2,
112.3, 111.2, 108.3, 108.2, 107.4, 102.6 ppm; MS(EI): 246.1
(M·H+); m.p. 214.9–215.8°C.
Statistic was performed according to the t-student test.
2,4-Dihydroxy-N-(4-hydroxyphenyl)benzamide (6)
1H NMR (300 MHz, CD3OD) δ 7.76 (d, J = 8.9 Hz, 1H), 7.36
(d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.39-6.29 (m, 2H)
ppm; 13C NMR (75.4 MHz, CD3OD) δ 168.2, 162.3, 162.0,
154.5, 129.6, 129.5, 123.6, 115.0, 107.9, 107.3, 102.7 ppm;
MS(EI): 246.2 (M·H+); m.p. 201.4–201.8°C.
Results and discussion
Dihydroxy-N-phenylbenzamides 1–4 are the simplest
members of the library and are derived from all the
possible combinations of 3- and 4-hydroxybenzoic
acids with 3- and 4-aminophenols. e aminophenols
were retained even in compounds 5–8, while includ-
ing an additional hydroxyl group in the benzoic acid
counterpart. Trihydroxyamides 5–6 originate from
2,4-dihydroxybenzoic acid, seeking the formation of an
intramolecular hydrogen bond between the additional
2-OH group and the amide group with a potential gain
in the conformational rigidity. Entries 7–8 embody two
OH groups exchangeable through rotation of their aryl
ring around the Ar-C=O single bond, thereby doubling
the hydrogen bond ability of this aryl ring.
Transcriptional activity of estrogen is a straightforward
method to study estrogenic potential of a compound28.
To evaluate the possibility that these compounds exhibit
an estrogenic activity we transfected HEK293 cells with
three plasmids: Estrogen responsive element-luciferase
(to monitor estrogenic activity), CMV-hERα (to provide
an high expression of ERα in the cell line29)and Renilla
luciferase pGL4.73 (Promega, as a normalizer of transfec-
tion). Cells were treated with Phenol Red-free medium
and stripped bovine serum for 24 h at the reported con-
centration, and then luciferase signal was measured by
Dual-Glo luciferase assay (Promega) and reported in
Figure 3. Cells that are not transfected with CMV-hERα,
did not produce any firely luciferase signal (data not
shown).
3,5-Dihydroxy-N-(3-hydroxyphenyl)benzamide (7)
1H NMR (300 MHz, CD3OD) δ 7.26 (t, J = 2.2 Hz, 1H), 7.21
(t, J = 8.0 Hz, 1H), 7.05 (m, 1H), 6.78 (d, J = 2.2 Hz, 2H) 6.58
(ddd, J = 7.8, 2.4, 1.0 Hz, 1H), 6.44 (t, J = 2.3, Hz, 1H) ppm;
13C NMR (75.4 MHz, CD3OD) δ 169.2, 159.9, 158.8, 140.9,
138.6, 130.4, 113.4, 112.5, 110.0, 107.0, 106.7ppm; MS(EI):
246.1 (M·H+); m.p. 220.5–221.1°C.
3,5-Dihydroxy-N-(3-hydroxyphenyl)benzamide (8)
1H NMR (300 MHz, CD3OD) δ 7.41 (d, J = 8.8 Hz, 2H),
6.78-6.74 (m, 3H), 6.44 (t, J = 2.1 Hz, 1H) ppm; 13C NMR
(75.4 MHz, CD3OD) δ 169.0, 158.8, 154.6, 137.4, 130.5,
124.4, 115.2, 105.2, 105.7 ppm; MS(EI): 246.2 (M·H+); m.p.
229.7–230.8°C.
Biological methods
Plasmids
Estrogen responsive element-luciferase (ERE-Luc),
kindly provided by Dr. J-M. Renoir, is a reporter for
estrogen driven transcriptional activity, where the
Firefly luciferase gene expression is under the control
of the ERE. Cyto Megalo Virus (CMV)-hERα present the
constitutive expression of the human ER α drove by the
strong promoter of CMV, it allows an high expression of
the human ER α. e pGL4.73 Renilla Luciferase plasmid
from Promega (Milan, Italy) presents an elevated expres-
sion of the Renilla luciferase gene and served as transfec-
tion normalizer.
A preliminary test of estrogen activity was conducted
for all compound exposing the cells after transfection by
the reporter plasmid to 100nM of drug, only compounds
3, 4, 6 and 7 showed a statistical significance (p<0.05).
Consequently, a dose/effect curve was performed for 3, 4,
6 and 7 (Figure 3). Compounds 3 and 4 resulted the most
active with an estrogenic activity at 100nM of 219% and
335%, respectively compared to the control. Compound 3
showed the most interesting agonistic activity, maintain-
ing a statistically significant agonistic activity up to 10nM.
Cell culture, transfection and luciferase assay
HEK293 cell line was cultured in RPMI-1640, 10% fetal
calf serum (Invitrogen, USA), Penicilin/streptomicyn 1%
(Sigma Aldrich, Germany). At the day of transfection,
10000 cells were seed in a 96 well plate in 50 µL of OPTI-
MEM (Invitrogen, USA) Penicilin/streptomicyn 1%
© 2011 Informa UK, Ltd.

4
A. Caldarelli et al.
Figure 3. Normalized firefly luciferase level reporting the estrogenic activity of the compounds after 24h exposure, compared to EtOH-
treated control. E2 (17-β estradiol) served as positive control for the assay.
ese data allow extrapolating some indications on
the structure-activity relationships. Amides 3 and 4 are
characterized by the presence of the 4-OH group, closely
superimposable to the 3-OH group of 17β-estradiol,
known to be essential for the activity. e presence of
an additional 2-OH groups on the benzoic acid counter-
part results in the reduction or loss of activity, probably
as a result of a different conformation deriving from the
intramolecular hydrogen bond or steric hindrance. It is
worthwhile to note that amide 2 could be considered the
“inverted” amide of the active entry 3 and this inversion
of the carboxylic acid and the amine moiety results in
the nearly complete loss of the activity; the 4-OH group
should be located in the benzoic acid moiety, the latter
playing the role of the A ring of 17β-estradiol.
molecules with defined characteristics. Here, we show
that an almost unlimited combination of different sub-
structures, maintaining few pharmacophores hallmarks
in molecules presenting elevated versatility, could be
used to generate large libraries that can be produced and
tested in an automated manner, with a potential impact
in the field of drug discovery.
Acknowledgments
A.C. gratefully acknowledges financial support from
Regione Piemonte (Azione Linea B). Dr. J-M. Renoir,
(UMR CNRS 8612, Universitè Paris-Sud, Châtenay-
Malabry, FR) is kindly acknowledged for the supply of
ERE-Luc and CMV-hERα plasmids.
Conclusions
Declaration of interest
In conclusion, we prepared a series of N-phenylbenza-
mides with the aim to produce a minimal structure that
retains the estrogen pharmacophores hallmark. Here
we demonstrated that the one-step condensation of
an aminophenol with hydroxybenzoic acids results in
simple amides that can satisfy some of the key structural
features required in the interaction with ERs. In particu-
lar, compound 3, presenting a structure that can be easily
superimposed to the natural ER ligand, shows the higher
agonistic activity, confirming the quality of the structural
design. e simplicity of the reported scaffold paves the
way for a wide array of potential structural variations,
through a fine-tuning of the substitution pattern and
following the known guidelines for the design of ER
ligands. e formation of amide bond is simple, reliable
and easily automated, opening the possibility for large
combinatorial screening on this scaffold. Pharmacology
benefits from the use of combinatorial chemistry and
high throughput assay screen exploited to find new
e authors report no conflicts of interest.
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