3-Acyl-5-hydroxybenzofuran derivatives as potential anti-estrogen breast cancer agents: A combined experimental and theoretical investigation

Article abstract of DOI:10.1016/j.bmcl.2013.06.022

We first report the application of 3-acyl-5-hydroxybenzofurans as a scaffold to develop potential drugs for breast cancer. Seven novel derivative compounds were synthesized by using a microwave-assisted synthesis method. Those compounds exhibited different antiproliferation against human breast cancer MCF-7 cells, with the best activity of IC₅₀ = 43.08 μM for compound 1. A Quantum Mechanics Polarized Ligand Docking (QPLD) study was carried out to investigate the binding interactions between these compounds and estrogen receptor alpha (ERα). The simulation results showed that the trend of receptor-ligand binding interactions was same as that of their antiproliferative activities. A detailed analysis indicated that compound 1 possesses the highest Van der Waals and hydrogen bond interactions compared to the other six compounds and better inhibitors are achievable by enhancing the hydrogen bond interactions. Based on these results, we addressed that 3-acyl-5-hydroxybenzofuran is an attractive scaffold for designing drugs against breast cancer.

Full text of DOI:10.1016/j.bmcl.2013.06.022

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4617–4621
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
3-Acyl-5-hydroxybenzofuran derivatives as potential anti-estrogen
breast cancer agents: A combined experimental and theoretical
investigation
Xiao-Yan Li a,b, Bi-Feng He a, Hua-Jun Luo a, Nian-Yu Huang a, Wei-Qiao Deng b,
⇑
a Hubei Key Laboratory of Natural Products Research and Development, College of Chemistry and Life Sciences, China Three Gorges University, Yichang 443002, China
b State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Dalian National Laboratory for Clean Energy, Chinese Academy of Sciences,
Dalian 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We first report the application of 3-acyl-5-hydroxybenzofurans as a scaffold to develop potential drugs
for breast cancer. Seven novel derivative compounds were synthesized by using a microwave-assisted
synthesis method. Those compounds exhibited different antiproliferation against human breast cancer
Received 19 April 2013
Revised 30 May 2013
Accepted 10 June 2013
Available online 19 June 2013
MCF-7 cells, with the best activity of IC50 = 43.08
Ligand Docking (QPLD) study was carried out to investigate the binding interactions between these
compounds and estrogen receptor alpha (ER ). The simulation results showed that the trend of recep-
lM for compound 1. A Quantum Mechanics Polarized
a
Keywords:
3-Acyl-5-hydroxybenzofuran
Breast cancer
Estrogen receptor
Quantum Mechanics Polarized Ligand
Docking (QPLD)
tor–ligand binding interactions was same as that of their antiproliferative activities. A detailed analysis
indicated that compound 1 possesses the highest Van der Waals and hydrogen bond interactions com-
pared to the other six compounds and better inhibitors are achievable by enhancing the hydrogen bond
interactions. Based on these results, we addressed that 3-acyl-5-hydroxybenzofuran is an attractive scaf-
fold for designing drugs against breast cancer.
a (ERa)
Ó 2013 Elsevier Ltd. All rights reserved.
Cancer is accounted for 13% of all worldwide deaths in 2007 and
it is projected to continue rising, with an estimated 12 million
deaths in 2030.1 Breast cancer is the most frequently diagnosed
cancer and the second leading cause of cancer deaths among wo-
men which is after lung cancer, accounting for 23% of total cancer
cases in women, and 14% of cancer deaths.2
Estrogen receptor (ER) and aromatase are two major targets
in the treatment of breast cancer. CYP19 enzyme is one of the
important targets in breast cancer treatment and estrogen bio-
synthesis.3 It is a crucial aromatase catalyzing the final forma-
tion step of estrogens from corresponding androgen precursors
such as testosterone and androstenedione.4 By inhibiting CYP19
enzyme, the estrogen production can be blocked and conse-
quently the breast cancer cells are prevented from proliferation.
to the estrogen response element (ERE) on DNA to activate the
target genes regulating transcription. As a result, several effects
are stimulated, for instance, cell proliferation in the breast.5 As
a ligand inducible nuclear receptor, ER
a plays a critical physio-
logical role as mediator of the actions of the estrogen hor-
mones.6 Therefore, it is an attractive pharmaceutical target for
the development of novel therapeutic agents for the treatment
of breast cancer.
The link between estrogen and breast cancer suggested that
‘antiestrogenic strategies’7 might have potential as therapeutic
agents.8 In fact, many existing chemotherapies are ER
a antago-
nists. Tamoxifen9 is well known to remain the first line therapy
for estrogen receptor positive breast cancer since the 1980s,10,11
and it has been used successfully by more than 10 million pa-
tients.12 However, the extensive evaluation of tamoxifen treatment
revealed small but significant side effects such as endometrial can-
cer, blood clots and the development of acquired resistance.13
More than that, many current breast cancer chemotherapy treat-
ments are often associated with severe side effects, and according
to statistics, up to approximate 50% of patients with ER-positive tu-
mors either initially do not respond or become resistant to these
drugs.14 Thus contributing to a significant obstacle towards breast
cancer treatment. Hence, there is a great need for the improvement
of existing therapies and the development of new ones for the pre-
vention and treatment of breast cancer.
The ER subtype ER
cancer cells is another important target. Different from the
mechanism of CYP19 enzyme, ER antagonists directly block
the active site of ER to prevent any estrogen from binding to
it as well as to stop the function of hormone. In breast cancer
cell, estrogen activates ER by binding to its active site, which
induces conformational changes that allow co-activators to at-
a which is predominantly expressed in breast
a
a
a
tach on the complex. The estrogen–ERa complex further binds
⇑
Corresponding author. Tel.: +86 411 8437 9571; fax: +86 411 8467 5584.
E-mail address: dengwq@dicp.ac.cn (W.-Q. Deng).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.06.022

4618
X.-Y. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4617–4621
The significance of the hydroxylated benzofuran scaffold in
medicinal chemistry is widely known.15 Many of those compounds
are serving as anticancer agent,16 antifungal agents,17 and anti-
inflammatory agents.18 For instance, 5-hydroxybenzofurans, are
well-known on account of their reported inhibition of human leu-
kocyte 5-lipoxygenase inhibitors.
Herein, we first report the application of 3-acyl-5-hydrox-
ybenzofurans as a scaffold to develop potential drugs for breast
cancer. Seven derivative compounds were synthesized (Scheme 1)
by using a microwave-assisted synthesis method. The antiprolifer-
ative effects of these derivatives were evaluated on the human
breast cancer MCF-7 cells using the MTT colorimetric assay.19
The results demonstrated different concentrations in antiprolifera-
tive assays against the cell line with the best activity of IC50 values
Scheme 2. Synthesis routines of compounds. Reagents and conditions: (a) micro-
wave irradiation, DMF, 190 °C, 30 min; (b) microwave irradiation, DMF, acetic acid,
60 °C, 30 min.
below 50 lM. To rationalize the observed ERa binding selectivity
We evaluated the activity against breast cancer in vitro.22 The
antiproliferative activities of all compounds on MCF-7 human
mammary carcinomas cell line are in micromolar range. Here we
used tamoxifen as a positive control and its IC50 value measured
of the benzofuran products, a detailed Quantum Mechanics Polar-
ized Ligand Docking (QPLD) study20 was undertaken involving cal-
culation of receptor–ligand interactions between those compounds
and estrogen receptor alpha (ERa). The trends of receptor–ligand
in this test was 12.35 lM. The IC50 values are presented in Figure 1.
binding interactions and antiproliferative activity are presented
The general order of antiproliferative activities is as follows: com-
pound 1 > 2 > 3 > 4 > 5 > 6 > 7. Compound 1 shows much better
activity than the others, and its IC50 value was comparable to that
of tamoxifen.
into good linear relationship. We further analyzed the interactions
between the seven compounds and ERa and found out that com-
pound 1 possesses the highest Van der Waals and hydrogen bond
interactions compared to the other six compounds. Better inhibi-
tors can be achievable by enhancing the hydrogen bond interac-
tions. We addressed that 3-acyl-5-hydroxybenzofuran is an
attractive scaffold for designing drugs against breast cancer.
The synthetic route is displayed in Scheme 2. We used the syn-
thetic method reported by our laboratory shortly before.21 The
starting materials are different ketones and quinines. A mixture
of 1,1-dimethoxy-N,N-dimethylmethanamine, ketone and DMF
first reacted under microwave irradiation. After the reaction mix-
ture was cooling and analyzed by TLC, the quinine was added into
the system. Then the system was exposure to microwave irradia-
tion again. We finally got the desired compounds after cooling,
separating, extracting, drying, filtering, and purifying. The detailed
synthetic process can be found in the Supplementary data.
Schrödinger Suite 2010 containing Maestro 9.1,23 Glide 5.6,24
and QM-Polarized Ligand Docking25 was the principal software
used in this simulation. The crystal structure of the complex
(PDB code: 1A52)26 formed by 17b-estradiol (E2) and the human
estrogen receptor
a (ERa) ligand binding domain (hERaLBD) was
selected for the calculation.27–29 The detailed simulation process
can also be found in the Supplementary data. The best Gscore val-
ues (Fig. 1) obtained from the Quantum Mechanics Polarized Li-
gand Docking30,31 were À10.138 kcal/mol for compound 1,
À9.512 kcal/mol for compound 2, À8.715 kcal/mol for compound
3, À7.961 kcal/mol for compound 4, À7.706 kcal/mol for com-
pound 5, À7.370 kcal/mol for compound 6 and À6.862 kcal/mol
for compound 7, respectively. The numerical order of the above
Scheme 1. Core structure of 3-acyl-5-hydrogenbenzofuran and chemical structures of 3-acyl-5-hydrogenbenzofuran derivatives synthesized in this project.

X.-Y. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4617–4621
4619
Leu346
Lue410
Ala350
Thr347
Met342
Met343
Phe404
Lue403
Lue402
Lue384
Lue525
Gly415
Met388
A
Ala350 Leu346
Leu346
Met342
Met342
Thr347
Ala350
Phe404
Thr347
Figure 1. Linear relation comparison between Gscores of QPLD simulation and
Phe404
Met343
Met343
log(IC50) of the seven compounds.
Lue403
Lue410
Lue403
Lue410
Lue402
Lue384
Lue525
Lue402
Lue384
Lue525
Gscore values is completely the same as that of the IC50 values of
the seven compounds against the ERa in vitro: compound 7 > 6 >
Gly415
Gly415C
B
5 > 4 > 3 > 2 >1 (Gscores are negative and a low value indicates
a good result).
Leu346
Leu346
Ala350
Phe404
Ala350
Phe404
Lue403
Met342
Met343
Met342
Met343
Thr347
Lue410
Thr347
Lue410
In order to reveal the relationship between docking calculation
and antiproliferative activity, we conducted a diagram based on
the data of Gscores of QPLD simulation32 and IC50 values (Fig. 1).
For the sake of reflecting the relationship more clearly in the
pattern, here we adopted the logarithms of the IC50 values
(log(IC50) = log10 (IC50)). This figure shows that the results of recep-
tor–ligand binding interactions and antiproliferative activity are
presented into a good linear relationship. The linear relationship
can be written as a mathematical equation IC50 = b0 + b1*Gscore,
where b0 = 6.73, b1 = 0.49 with correlation R2 = 0.95.
Lue402
Lue384
Lue525
Lue402
Lue384
Lue525
Gly415
Met522
Thr347
Leu346
E
D
Ala405
Glu353
Leu346
Ala350
Thr347
Ala350
Met342
Met343
Met342
Met343
Phe404
Phe404
Lue403
Lue410
Lue410
Lue402
Lue384
We further analyzed the interactions between the seven com-
Lue525
Gly415
Met522
Lue402
Lue384
Lue525
pounds and ER
pounds 1–7 docked into the binding sites to ER
a
. Figure 2 showed the simulation results of com-
. The main
Met388
a
Gly415 F
G
binding modes in these complexes can be described as following.
One major interaction is hydrogen bond. Compound 1 formed
hydrogen bonds with the amino acid residues 5-OH/Leu346, N–
Figure 2. Schematic 3-dimensional diagrams of compound 1–7 in ER
Hydrogen bonds are indicated by yellow dotted lines between ligand and protein.
a
active site.
Binding site of ligands to Er . (A) compound 1. (B) compound 2. (C) compound 3 (D)
a
H/Thr347 of ER
bond with 5-OH/Leu346 of ER
a
(Fig. 2A). Compounds 2 and 3 formed a hydrogen
(Fig. 2B and C), respectively. Com-
compound 4 (E) compound 5 (F) compound 6 (G) compound 7. (The yellow dashed
lines show the formation of the H-bonds. Active site residues are represented by
wires and colored by element. Atoms in the ligand are colored as follows: O, red; C,
brown; H, white; N, blue; F, bright green; Cl, dark green.)
a
pound 6 formed a hydrogen bond with 5-OH/Glu353 (Fig. 2F) and
compound 7 form a hydrogen bond with 5-OH/His524 (Fig. 2G).
Another major interaction is p–p interaction. We got the 2-dimen-
sional diagrams from the ligand interaction diagram module in
Schrodinger Suite 2010. From the 2-dimensional diagrams of li-
gand–receptor interactions (Fig. 3), we found that the benzene
rings of Phe 404, Trp383, His524 were able to coordinate the li-
der Waals interations (a*vdW = À2.320 kcal/mol) and hydrogen
bond interactions (Hbond = À1.297 kcal/mol) compared to the
other six compounds (Fig. 4), and thus contributed to its best QM
calculation score (Gscore = À10.138 kcal/mol). Though compound
gands position in the active site of ER
intercations. Compound 1 formed
tween the two rings of benzofuran skeleton and Phe404 (Fig. 3A).
Compounds 2 and 6 formed conjugate interactions between
a
throught Van der Waals
2 formed p–p conjugate interactions with Phe404 similar to com-
p–p conjugate interactions be-
pound 1, but lacked the hydrogen bond with N–H (Fig. 3A and B).
Therefore its hydrogen bond interaction (Hbond = À0.698 kcal/
mol) was much weaker than compound 1 (Hbond = À1.297 kcal/
mol). Similarly, its coulomb force with protein (b*Coul = À0.236
p–p
the two rings of benzofuran skeleton and Phe404, the ring of side
chain and Trp383, respectively (Fig. 3B and F). Compound 3 formed
kcal/mol) was also weaker than that of compound
1
p–p
conjugate interactions between the six-membered ring of
benzofuran skeleton and Phe404, the ring of side chain and
Trp383, respectively (Fig. 3C). Compounds 4 and 5 formed
(b*Coul = À0.538 kcal/mol). Compounds 2 and 3 both formed
hydrogen bonds with Leu346, but the hydrogen bond interaction
p–p
of compound
(Hbond = À0.480 kcal/mol). They also shaped
2
was stronger than that of the latter
conjugate inter-
conjugate interactions between the five-membered ring of benzo-
furan skeleton and His524, the ring of side chain and Phe404,
respectively (Fig. 3D and E).
p–p
actions with Phe404 and Trp383, but Phe404 was merely affected
the six-membered ring of benzofuran skeleton for compound 3
(Fig. 3C), thus brought about a weaker Van der Waals interaction
(a*vdW = À1.367 kcal/mol) compared to compound 2 (a*vdW =
À1.553 kcal/mol). This leads to a lower Gscore for compound 2
Figure 4 displayed the results of QPLD. (GScore = a*vdW +
b*Coul + Lipo + Hbond + Metal + Buryp + RotB + Site,
a = 0.065,
b = 0.130, here we only discussed the main items which are vdW,
Coul and Hbond). Compound 1 possesses the lowest score of Van
(Gscore = À9.512 kcal/mol) than that for compound
3

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X.-Y. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4617–4621
Figure 3. Schematic 2-dimensional diagrams of ligand–receptor interactions of compound 1–7 and ER
a. (A) compound 1 (B) compound 2 (C) compound 3 (D) compound 4
(E) compound 5 (F) compound 6 (G) compound 7 (hydrogen-bonds are indicated by red lines. Aromatic
p–p
interactions are displayed by green lines. Green residues are
hydrophobic contacts, cyan residues are polar contacts, blue residues are positively charged contacts, and red residues are negatively charged contacts. The residue font size
indicates the distance (larger letters are closer).
(Gscore = À8.715 kcal/mol). Despite the
p–p conjugate interac-
tions with Phe 404 and His524, compound 4 did not show any
strong hydrogen bonds (Fig. 3D). Hence compound 4 (Gscor-
e = À7.961 kcal/mol) was weaker interaction (Hbond = À0.264 k-
cal/mol) and coulombian force (b*Coul = À0.025 kcal/mol) to the
receptor. The ligand–receptor ligand than compound 3 because
of its poor hydrogen bond interactions for compound 4 and 5 are
very similar (Fig. 3D and F). They both shaped p–p conjugate inter-
actions between the five-membered ring of benzofuran skeleton
and His524, the benzene ring and Phe404, but the distance be-
tween compound and His524 was much shorter for compound 4.
So it has a better Van der Waals interaction (a*vdW = À2.087
kcal/mol) compared to compound 5 (a*vdW = À1.850 kcal/mol).
This leads to a weaker ligand–receptor interaction for compound
5 (Gscore = À7.706 kcal/mol). Regardless of the strong coulombian
force (b*Coul = À0.944 kcal/mol) and slightly stronger hydrogen
bond interactions (Hbond = À0.733 kcal/mol), compound 6 did not
gain a considerable QM docking score (Gscore = À7.370 kcal/mol)
on account of the considerably poor Van der Waals interactions
(a⁄vdW = À0.835 kcal/mol). Although compound 6 formed more
p–p
conjugate interactions with ER
a than other compounds, the
Figure 4. Part of Quantum mechanism calculation results. Final selection of top
docking scores was ranked based on GScore.
binding affinities were weaker, which is due to farther distance

X.-Y. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4617–4621
4621
3. Yang, L. J.; Lu, D. F.; Guo, J. J.; Meng, X. L.; Zhang, G. L.; Wang, F. J.
Ethnopharmacol. 2013, 145, 715.
between compound 6 and the amino acids. Compound 7 did not
show any apparent Van der Waals intercations in the 2-dimen-
sional diagram (Fig. 3G), in spite of the hydrogen bond between
His524 and the benzofuran skeleton, it gained a comparative poor
QM calculation score (Gscore = À6.862 kcal/mol). From discussion
above, we found that the hydrogen bonds and Van der Waals inter-
actions are key factors of ligand–receptor interactions. Thus we
proposed that a better candidate can be achieved with the methyl
of N-methylacetamide replaced by chlorine or bromine, which en-
hances the hydrogen bond interactions.
In summary, we synthesized seven compounds as drug
candidates against breast cancer based on the core structure of
3-acyl-5-hydroxybenzofuran. We evaluated their antiproliferative
activities in vitro and they showed different antiproliferation
against human breast cancer MCF-7 cell with the best activity of
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IC50 = 43.08
of the receptor–ligand binding interactions and their differential
inhibitory activity against ER , we carried out a Quantum Mechan-
ics Polarized Ligand Docking (QPLD) study for docking these seven
compounds in ER receptor. The simulation results show that the
lM for compound 1. In order to clarify the mechanism
a
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hydroxybenzofuran is an attractive scaffold for designing drugs
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Acknowledgment
This work was supported by ‘talent 100’ program of Chinese
Academy of Sciences and ‘Chutian’ project of China Three Gorges
University.
Supplementary data
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Supplementary data associated with this article can be found, in
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06.022.
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