Synthesis and structure-activity relationships of chalcone derivatives as inhibitors of ovarian cancer cell growth

Article abstract of DOI:10.2174/1570180814666170505120258

Background: Ovarian cancer remains a disease with a poor five year survival rate. As such, novel therapies are needed. Natural chalcones as well as their synthetic derivatives have shown biological activity in a number of areas including the inhibition of cancer cell growth. Objective: To synthesize a library of chalcone derivatives, including novel structures, and determiner the inhibition of ovarian cancer cell growth and Structure-activity-relationships. Methods: The Claisen-Schmidt condensation reaction between substituted acetophenones and aromatic aldehydes was used to produce a series of novel chalcones in moderate to excellent yields and good purity. Cellular proliferation of CA-OV3 cells was measured with a MTS assay. Results: Out of the thirty-four synthesized compounds, eight are new derivatives. The synthesized compounds were characterized by ¹H NMR, ¹³C NMR, and HRMS. Biological evaluation of these β-phenylacrylophenone derivatives in CA-OV3 cells showed interesting antiproliferative activities providing initial structure – activity information. Conclusion: Fourteen of the thirty-four tested compounds showed significant activity, with several showing near complete inhibition of growth at 100 μM. The structure-activity relationships suggest that modification to the A ring is widely tolerated and that electron-donating modifications to the B ring are beneficial to activity. Electron-withdrawing modifications to the B ring did not show inhibition of cell growth.

Full text of DOI:10.2174/1570180814666170505120258

1259
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Letters in Drug Design & Discovery, 2017, 14, 1259-1266
RESEARCH ARTICLE
ISSN: 1570-1808
eISSN: 1875-628X
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Synthesis and Structure-activity Relationships of Chalcone
Derivatives as Inhibitors of Ovarian Cancer Cell Growth
BENTHAM
S
CIENCE
Zachary D. Tucker, Francis J. Barrios and Amanda J. Krzysiak*
Department of Chemistry and Physics, Faculty of Chemistry, Bellarmine University, Louisville, KY, USA
Abstract: Background: Ovarian cancer remains a disease with a poor five year survival rate. As
such, novel therapies are needed. Natural chalcones as well as their synthetic derivatives have
shown biological activity in a number of areas including the inhibition of cancer cell growth.
Objective: To synthesize a library of chalcone derivatives, including novel structures, and deter-
miner the inhibition of ovarian cancer cell growth and Structure-activity-relationships.
Methods: The Claisen-Schmidt condensation reaction between substituted acetophenones and aro-
matic aldehydes was used to produce a series of novel chalcones in moderate to excellent yields and
A R T I C L E H I S T O R Y
good purity. Cellular proliferation of CA-OV3 cells was measured with a MTS assay.
Received: December 22, 2016
Revised: March 23, 2017
Accepted: April 03, 2017
Results: Out of the thirty-four synthesized compounds, eight are new derivatives. The synthesized
1
compounds were characterized by H NMR, 13C NMR, and HRMS. Biological evaluation of these
DOI:
10.2174/1570180814666170505120258
β-phenylacrylophenone derivatives in CA-OV3 cells showed interesting antiproliferative activities
providing initial structure – activity information.
Conclusion: Fourteen of the thirty-four tested compounds showed significant activity, with several
showing near complete inhibition of growth at 100 µM. The structure-activity relationships suggest
that modification to the A ring is widely tolerated and that electron-donating modifications to the B
ring are beneficial to activity. Electron-withdrawing modifications to the B ring did not show inhi-
bition of cell growth.
Keywords: Synthesis, chalcones, claisen-schmidt condensation, structure-activity, ovarian cancer, growth inhibition.
1. INTRODUCTION
characterized by an ɑ,β-unsaturated carbonyl bridge between
the two aryl rings (Fig. 1). Their simple scaffold, as well as
their ease and affordability of synthesis, make this class of
natural products attractive for the design and synthesis of
analogues enabling the study of biological activities with
different functional groups. A diverse set of chalcone struc-
tures has been found to possess a large number of biological
activities, including anti-inflammatory, anti-bacterial, and
anti-cancer [4, 5]. Recently, the interest in these compounds
has dramatically increased due to reports on their anti-cancer
properties, and this work has been reviewed [6, 7].
Cancer remains the second leading cause of death despite
significant therapeutic advances in the past 20 years. While
great strides have been made toward improving the five-year
survival after a cancer diagnosis, many cancers still have
survival rates below fifty percent at the five-year mark.
Ovarian cancer is one such disease with forty-six percent of
patients surviving to five years. Early detection continues to
remain a crucial problem as survival drops from 92% for
localized cancers to 29% for metastatic ovarian cancer [1].
Until improved detection methods are available, novel thera-
peutic approaches are needed.
O
Natural products have shown great utility as chemothera-
peutic agents [2]. Flavonoids, a class of natural products and
a subset of phenylpropanoids, have provided a rich source of
structural analogues for structure-activity investigation
against cancer [3]. Chalcones, a subclass of flavonoids, are
R1
A
B
R2
Fig. (1). The general structure of a chalcone scaffold.
While chalcones have shown utility against ovarian can-
cer, their development is still relatively unexplored. As part
of our drug discovery program we have been investigating
important features and searching for novel anti-cancer agents
that show growth inhibitory activity against ovarian cancer
*Address correspondence to this author at the Department of Chemistry and
Physics, Faculty of Chemistry, Bellarmine University, 2001 Newburg Rd.,
Louisville, KY, USA; Tel/Fax: +1-502-272-7755, +1-502-272-8055;
E-mail: akrzysiak@bellarmine.edu
1570-1808/17 $58.00+.00
©2017 Bentham Science Publishers

1260 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 11
Tucker et al.
cells. Here, we report the synthesis of a series of chalcone
derivatives modified with a variety of functional groups and
their inhibition of CA-OV3 cell growth.
Hz, 1H), 8.05 (d, J = 7.3 Hz, 2H), 7.92 (d, J = 7.8 Hz, 1H),
7.83 (d, J = 15.7 Hz, 1H), 7.70 – 7.49 (m, 5H).
1-(4-ethoxyphenyl)-3-(3-nitrophenyl)-2-propen-1-one (9)
1
Lit. mp: 113 °C; Experimental mp: 112.5–113.4 °C; H
2. MATERIALS AND METHODS
2.1. Chemistry
NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.22 (d, J = 8.2 Hz,
1H), 8.07 – 8.01 (m, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.79 (d, J
= 15.7 Hz, 1H), 7.70 – 7.56 (m, 2H), 6.97 (d, J = 8.9 Hz,
2H), 4.12 (q, J = 7.0 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 187.6, 163.2, 148.6, 140.6,
136.8, 134.2, 130.9 (2), 130.2, 129.9, 124.4, 124.4, 122.2,
114.4 (2), 63.8, 14.6; IR (KBr) νmax 3083, 2932, 1655, 1595,
1530, 1449, 1347, 1224, 814 cm-1; HRMS (ESI) m/z calcd
for C17H15O4N (M+H)+ 298.1080, found 298.1069.
All reagents used were commercially available unless
otherwise specified. Melting points were measured with
Digimelt melting point devices. NMR spectra were recorded
on a Varian 400 MR system (400 MHz) with automated
sampling, locking, shimming and tuning.
2.1.1. General Procedure for the Synthesis of Compounds
1, 3-7, 9-13, 15-19, 21-24
1-(4-phenoxyphenyl)-3-(3-nitrophenyl)-2-propen-1-one
(10)
To a solution of equimolar amounts of acetophenone and
aromatic aldehyde derivatives in MeOH (2 mL/1 mmol of
substrate), 6M NaOH (3 equiv.) was added. The reaction
mixture was stirred for 1 h at room temperature and then
refrigerated for a minimum of 24 h. The precipitate was col-
lected by vacuum filtration, washed with cold water and re-
crystallized with 95% ethanol. The pure product was
collected by vacuum filtration, dried under a high vacuum
for 24 h, and then stored in a desiccator at room temperature.
1
Experimental mp: 146.0–147.3 °C; H NMR (400 MHz,
CDCl3) δ 8.47 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.07 – 8.01
(m, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 15.7 Hz, 1H),
7.70 – 7.56 (m, 2H), 6.97 (d, J = 8.9 Hz, 2H), 4.12 (q, J = 7.0
Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H).
1-(4-bromophenyl)-3-(3-nitrophenyl)-2-propen-1-one (11)
1
Experimental mp: 157.9–159.3 °C; H NMR (400 MHz,
CDCl3) δ 8.50 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.91 (d, J =
8.4 Hz, 3H), 7.83 (d, J = 15.7 Hz, 1H), 7.67 (d, J = 8.5 Hz,
2H), 7.65 – 7.55 (m, 2H).
1,3-Diphenyl-2-propen-1-one (1)
1
Lit. mp: 54‒55 °C; Experimental mp: 54.2–55.3 °C; H
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.83 (d,
J = 15.7 Hz, 1H), 7.67 – 7.61 (m, 2H), 7.57 (d, J = 5.3 Hz,
2H), 7.54 – 7.46 (m, 2H), 7.44 – 7.38 (m, 3H).
1-(2-naphthyl)-3-(3-nitrophenyl)-2-propen-1-one (12)
1
Lit. mp: 147 °C; Experimental mp: 142.9–144.6 °C; H
NMR (400 MHz, CDCl3) δ 8.55 (d, J = 9.1 Hz, 2H), 8.25 (d,
J = 9.1 Hz, 1H), 8.06 (dd, J = 35.7, 8.9 Hz, 2H), 7.97 – 7.76
(m, 5H), 7.60 (dd, J = 13.9, 6.6 Hz, 3H).
1-(4-ethoxyphenyl)-3-phenyl-2-propen-1-one (3)
1
Lit. mp: 74‒76 °C; Experimental mp: 75.4–76.9 °C; H
NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.9, 1.0 Hz, 2H),
7.79 (d, J = 15.6 Hz, 1H), 7.66 – 7.59 (m, 2H), 7.54 (d, J =
15.6 Hz, 1H), 7.39 (d, J = 5.5 Hz, 3H), 6.95 (d, J = 7.9 Hz,
2H), 4.08 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H).
3-(1-naphthyl)-1-phenyl-2-propen-1-one (13)
1
Lit. mp: 87.0 °C; Experimental mp: 85.6–87.0 °C; H
NMR (400 MHz, CDCl3) δ 8.62 (dd, J = 15.4, 10.9 Hz, 1H),
8.18 (t, J = 9.2 Hz, 1H), 8.03 (t, J = 9.0 Hz, 2H), 7.83 (dd, J
= 12.4, 6.6 Hz, 3H), 7.62 – 7.38 (m, 7H).
1-(4-phenoxyphenyl)-3-phenyl-2-propen-1-one (4)
1
Lit. mp: 87‒88 °C; Experimental mp: 86.1–87.2 °C; H
1-(4-ethoxyphenyl)-3-(1-naphthyl)-2-propen-1-one (15)
NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.7 Hz, 2H), 7.81 (d,
J = 15.7 Hz, 1H), 7.62 (dd, J = 6.5, 2.9 Hz, 2H), 7.52 (d, J =
15.7 Hz, 1H), 7.43 – 7.33 (m, 5H), 7.18 (t, J = 7.4 Hz, 1H),
7.05 (dd, J = 16.2, 8.4 Hz, 4H).
1
Experimental mp: 115.5–116.7 °C; H NMR (400 MHz,
CDCl3) δ 8.63 (d, J = 15.4 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H),
8.06 (d, J = 8.9 Hz, 2H), 7.90 – 7.81 (m, 3H), 7.63 – 7.44
(m, 4H), 6.94 (d, J = 8.9 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H),
1.41 (t, J = 7.0 Hz, 3H).
1-(4-bromophenyl)-3-phenyl-2-propen-1-one (5)
Lit. mp: 102–104 °C; Experimental mp: 100.3–103.9 °C;
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 2H), 7.81
(d, J = 15.7 Hz, 1H), 7.63 (d, J = 8.4 Hz, 4H), 7.47 (d, J =
15.7 Hz, 1H), 7.44 – 7.38 (m, 3H).
1-(4-phenoxyphenyl)-3-(1-naphthyl)-2-propen-1-one (16)
1
Colorless solid; mp: 108.5‒110.2 °C; Yield: 57%; H
NMR (400 MHz, CDCl3) δ 8.64 (d, J = 15.3 Hz, 1H), 8.21
(d, J = 7.6 Hz, 1H), 8.04 (d, J = 7.3 Hz, 2H), 7.83 (t, J = 7.9
Hz, 3H), 7.62 – 7.41 (m, 4H), 7.36 (s, 2H), 7.17 (d, J = 6.6
Hz, 1H), 7.04 (dd, J = 16.4, 8.6 Hz, 4H); 13C NMR (100
MHz, CDCl3) δ 188.52, 161.9, 155.6, 141.3, 133.7, 132.7,
132.4, 131.8, 130.9 (2), 130.8, 130.1 (2), 128.8, 127.0,
126.3, 125.5, 125.1, 124.7, 124.4, 123.5, 120.2 (2), 117.5
(2); IR (KBr) νmax 3057, 1940, 1653, 1593, 1486, 1243, 775
cm-1; HRMS (ESI) m/z calcd for C25H18O2 (M+H)+
351.1385, found 351.1379.
1-(2-naphthyl)-3-phenyl-2-propen-1-one (6)
Lit. mp: 105–107 °C; Experimental mp: 105.0–106.2 °C;
1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.12 (d, J = 7.1
Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.96 – 7.84 (m, 3H), 7.74
– 7.65 (m, 3H), 7.64 – 7.53 (m, 2H), 7.48 – 7.40 (m, 3H).
3-(3-nitrophenyl)-1-phenyl-2-propen-1-one (7)
Lit. mp: 144–145 °C; Experimental mp: 143.4‒144.3 °C;
1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.25 (d, J = 8.2

Synthesis and Structure-activity Relationships of Chalcone Derivatives
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 11 1261
1-(4-bromophenyl)-3-(1-naphthyl)-2-propen-1-one (17)
collected by vacuum filtration, dried under a high vacuum
for 24 hours, and then stored in a desiccator at room tem-
perature.
Lit. mp: 110–111 °C; Experimental mp: 110.2–111.7 °C;
1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 15.4 Hz, 1H),
8.20 (d, J = 8.2 Hz, 1H), 7.88 (dd, J = 16.7, 7.8 Hz, 5H),
7.61 (d, J = 8.4 Hz, 2H), 7.58 – 7.42 (m, 4H).
1-(3-hydroxyphenyl)-3-phenyl-2-propen-1-one (2)
1
Lit. mp: 126 °C; Experimental mp: 127.7–128.8 °C; H
1-(2-naphthyl)-3-(1-naphthyl)-2-propen-1-one (18)
NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 7.94 – 7.82 (m,
3H), 7.76 (d, J = 15.7 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.50
(d, J = 24.5 Hz, 4H), 7.41 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.7
Hz, 1H).
Lit. mp: 158–160 °C; Experimental mp: 160.0–161.7 °C;
1H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 15.4 Hz, 1H),
8.57 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.6 Hz,
1H), 7.93 (ddd, J = 22.7, 15.5, 8.0 Hz, 6H), 7.76 (d, J = 15.4
Hz, 1H), 7.63 – 7.47 (m, 5H).
1-(3-hydroxyphenyl)-3-(3-nitrophenyl)-2-propen-1-one (8)
1
Experimental mp: 212.0–214.3 °C; H NMR (400 MHz,
3-(2-naphthyl)-1-phenyl-2-propen-1-one (19)
DMSO-d6) δ 9.86 (s, 1H), 8.72 (s, 1H), 8.28 (d, J = 25.0 Hz,
1H), 8.07 (s, 1H), 7.77 (d, J = 45.3 Hz, 3H), 7.59 – 7.29 (m,
2H), 7.11 (d, J = 5.3 Hz, 1H), 3.44 (s, 1H).
1
Lit. mp: 90–92 °C; Experimental mp: 89.5–91.1 °C; H
NMR (400 MHz, CDCl3) δ 8.62 (d, J = 15.4 Hz, 1H), 8.17
(d, J = 7.9 Hz, 1H), 8.03 (d, J = 7.2 Hz, 2H), 7.86 – 7.76 (m,
3H), 7.60 – 7.38 (m, 7H).
1-(3-hydroxyphenyl)-3-(1-naphthyl)-2-propen-1-one (14)
Lit. mp: 174–175 °C; Experimental mp: 174.9–176.5 °C;
1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.58 (d, J =
15.4 Hz, 1H), 8.37 – 8.17 (m, 2H), 7.99 (dd, J = 35.9, 17.2
Hz, 2H), 7.75 – 7.37 (m, 6H), 7.13 (d, J = 8.2 Hz, 1H), 3.43
(s, 1H).
1-(4-ethoxyphenyl)-3-(3-naphthyl)-2-propen-1-one (21)
1
Experimental mp: 113.6–115.0 °C; H NMR (400 MHz,
CDCl3) δ 8.63 (d, J = 15.2 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H),
8.05 (d, J = 6.7 Hz, 2H), 7.84 (s, 3H), 7.64 – 7.42 (m, 4H),
6.93 (d, J = 6.6 Hz, 2H), 4.04 (dd, J = 6.4, 2.6 Hz, 2H), 1.41
(t, J = 7.9 Hz, 3H).
1-(3-hydroxyphenyl)-3-(2-naphthyl)-2-propen-1-one (20)
1
Red solid; mp: 174.2‒175.5 °C; Yield: 95%; H NMR
1-(4-phenoxyphenyl)-3-(2-naphthyl)-2-propen-1-one (22)
(400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.35 (s, 1H), 8.13 (dd,
J = 8.6, 1.6 Hz, 1H), 8.07 – 7.88 (m, 5H), 7.73 (d, J = 7.7
Hz, 1H), 7.59 (q, J = 3.7, 2.9 Hz, 3H), 7.44 (t, J = 7.9 Hz,
1H), 7.14 (dd, J = 8.0, 2.5 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 189.4, 158.2, 140.1, 139.4, 133.8, 131.7, 131.6,
131.2, 130.3, 129.2, 127.6, 126.7, 126.1, 126.0, 125.1, 123.4,
120.8, 120.1, 115.1; IR (KBr) νmax 3252, 3053, 1637, 1561,
1472, 781 cm-1; HRMS (ESI) m/z calcd for C19H14O2
(M+H)+ 275.1072, found 275.1066.
1
Colorless solid; mp: 108.1‒109.9 °C; Yield: 71%; H
NMR (400 MHz, CDCl3) δ 8.11 – 7.93 (m, 4H), 7.93 – 7.74
(m, 4H), 7.62 (dd, J = 15.5, 8.5 Hz, 1H), 7.56 – 7.46 (m,
2H), 7.40 (t, J = 8.0 Hz, 2H), 7.26 – 7.16 (m, 1H), 7.08 (dd,
J = 14.1, 8.7 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 188.8,
161.8, 155.6, 144.5, 134.3, 133.4, 132.8, 132.4, 130.8 (2),
130.6, 130.1 (2), 128.7, 128.6, 127.8, 127.3, 126.8, 124.6,
123.7, 121.9, 120.1 (2), 117.5 (2); IR (film) νmax 3053, 1657,
1604, 1474, 1264 cm-1; HRMS (ESI) m/z calcd for C25H18O2
(M+Na)+ 373.1205, found 373.1196.
2.1.3. General Procedure for the Synthesis of 3,4-
bis(methoxymethoxy)benzaldehyde
1-(4-bromophenyl)-3-(2-naphthyl)-2-propen-1-one (23)
To a solution of 3,4-dihydroxybenzaldehyde (11 mmol)
in CH2Cl2 (22 mL) was added N, N-diisopropylethylamine
(4.4 equiv.) After stirring for 20 minutes, MOMCl (3 equiv.)
was added at 0°C, under N2 atm. The reaction was monitored
by TLC and quenched with a saturated aqueous solution of
NH4Cl (20 mL). The reaction mixture was extracted with
CH2Cl2 (3 × 20 mL), washed with brine (3 × 15 mL) and
dried over Na2SO4. The solvents were removed under reduce
pressure and the crude product purified via column chroma-
tography over silica gel (8:2 hexane: ethyl acetate).
1
Experimental mp: 109.7–111.3 °C; H NMR (400 MHz,
CDCl3) δ 8.63 (d, J = 15.4 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H),
7.92 – 7.80 (m, 5H), 7.60 (d, J = 8.4 Hz, 2H), 7.57 – 7.42
(m, 4H).
1-(2-naphthyl)-3-(2-naphthyl)-2-propen-1-one (24)
1
Experimental mp: 160.0–162.2 °C; H NMR (400 MHz,
CDCl3) δ 8.72 (d, J = 15.4 Hz, 1H), 8.57 (s, 1H), 8.27 (d, J =
8.2 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.93 (ddd, J = 22.7,
15.2, 8.0 Hz, 6H), 7.76 (d, J = 15.4 Hz, 1H), 7.63 – 7.46 (m,
5H).
2.1.4. General Procedure for the Synthesis of Compounds
25-29
2.1.2. General Procedure for the Synthesis of Compounds
2, 8, 14 and 20
To a solution of equimolar amounts of acetophenone and
3,4-bis(methoxymethoxy)benzaldehyde in MeOH (2 mL/1
mmol of substrate), 6M NaOH (3 equiv.) was added. The
reaction mixture was stirred for 1 h at room temperature and
then refrigerated for a minimum of 24 h. The precipitate was
collected by vacuum filtration, washed with cold water and
recrystallized with 95% ethanol. The pure product was
collected by vacuum filtration, dried under a high vacuum
for 24 h, and then stored in a desiccator at room temperature.
To a solution of equimolar amounts of acetophenone and
aromatic aldehyde in EtOH (2 mL/1 mmol of substrate), 6M
NaOH (6 equiv.) was added. The reaction mixture was
stirred for 24 h, quenched with concentrated HCl, and refrig-
erated for a minimum of 24 h. The precipitate was collected
by vacuum filtration, washed with cold water and recrystal-
lized with methanol and water. The pure product was

1262 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 11
Tucker et al.
2.1.5. General Procedure for the Synthesis of Compounds
30-34
3-(3,4-dimethoxymethoxy)-1-phenyl-2-propen-1-one (25)
1
Experimental mp: 65.5–66.2 °C; H NMR (400 MHz,
To a heated (60 °C) solution of MOM-protected chal-
cones (1 equiv.) in EtOH (2mL/ 1mmol of the substrate) a
solution of 10% HCl (2.5 equiv.) was added. The reaction
mixture was stirred for 40 minutes, diluted with 10 mL of
water, and brought to a pH of 5.5 with 1M NaOH. The mix-
ture was extracted with EtOAc (3 × 10 mL), washed with
brine (2 × 15 mL) and dried over Na2SO4. The solvent was
removed under pressure, and the crude product was purified
by column chromatography. The pure product was dried
under a high vacuum for 24 h and then stored in a desiccator
at room temperature.
CDCl3) δ 8.00 (d, J = 7.3 Hz, 2H), 7.74 (d, J = 15.7 Hz, 1H),
7.53 (dt, J = 30.7, 7.1 Hz, 4H), 7.40 (d, J = 15.7 Hz, 1H),
7.27 (dd, J = 8.4, 1.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.29
(s, 2H), 5.28 (s, 2H), 3.55 (s, 3H), 3.52 (s, 3H).
1-(3-hydroxyphenyl)-3-(3,4-dimethoxymethoxy)-2-propen-
1-one (26)
Yellow solid; mp: 112.2‒113.9 °C; Yield: 86%; 1H NMR
(400 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.77 – 7.59 (m, 4H),
7.50 – 7.45 (m, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.18 (d, J = 8.5
Hz, 1H), 7.08 (d, J = 10.5 Hz, 1H), 5.31 (s, 2H), 5.28 (s,
2H), 3.46 (s, 3H), 3.43 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 189.4, 158.1, 149.8, 147.2, 144.2, 139.6, 130.2,
129.3, 124.9, 121.1, 120.6, 119.9, 117.1, 116.8, 115.0, 110.0,
95.3, 94.9, 56.3; IR (KBr) νmax 3464, 2947,1659, 1451, 1366,
1074, 781 cm-1; HRMS (ESI) m/z calcd for C19H20O6
(M+Na)+ 367.1158, found 367.1143.
3-(3,4-dihydroxyphenyl)-1-phenylprop-2-en-1-one (30)
1
Lit. mp: 212–213 °C; Experimental mp: 210–212 °C; H
NMR (400 MHz, acetone-d6) δ 8.44 (s, 1H), 8.12 (d, J = 7.6
Hz, 2H), 7.72‒7.54 (m, 5H), 7.35 (s, 1H), 7.22 (d, J = 8.3
Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 3.08 (s, 1H).
1-(3-hydroxyphenyl)-3-(3,4-dihydroxyphenyl)-2-propen-1-
one (31)
1-(4-ethoxyphenyl)-3-(3,4-dimethoxymethoxy)-2-propen-1-
one (27)
Orange oil; 91% yield; 1H NMR (400 MHz, DMSO-d6) δ
9.77 (s, 1H), 9.72 (s, 1H), 9.15 (s, 1H), 7.62 – 6.99 (m, 7H),
6.83 (d, J = 7.9 Hz, 1H), 3.42 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 188.9, 157.7, 148.7, 145.6, 144.8, 139.5, 129.8,
126.3, 122.2, 119.9, 119.3, 118.6, 115.8, 115.4, 114.5; IR
(neat) νmax 3353, 3054, 2986, 1616, 1578, 1422, 1160 cm-1;
HRMS (ESI) m/z calcd for C15H12O4 (M‒H)+ 255.0657,
found 255.0662.
Colorless solid; mp: 75.3‒76.6 °C; Yield: 95%; 1H NMR
(400 MHz, CDCl3) δ 8.01 (s, 2H), 7.73 (d, J = 15.4 Hz, 1H),
7.51 – 7.37 (m, 1H), 7.30 – 7.13 (m, 2H), 7.05 – 6.78 (m,
3H), 5.29 (dd, J = 4.6, 2.3 Hz, 4H), 4.11 (dd, J = 12.6, 5.8
Hz, 2H), 3.53 (dd, J = 11.9, 2.7 Hz, 6H), 1.47 – 1.39 (t, 3H);
13C NMR (100 MHz, CDCl3) δ 188.6, 162.7, 149.2, 147.3,
143.5, 130.9, 130.7 (2), 129.5, 123.7, 120.5, 116.1, 114.2
(2), 95.5, 95.1 (2), 63.7, 56.2 (2), 14.6; IR (KBr) νmax 3064,
2977, 1656, 1597, 1448, 1391, 1255, 1079 cm-1; HRMS
(ESI) m/z calcd for C21H24O6 (M+Na)+ 395.1471, found
395.1458.
1-(4-ethoxyphenyl)-3-(3,4-dihydroxyphenyl)-2-propen-1-
one (32)
Yellow solid; mp: 131.8–131.8 °C; Yield: 56%;1H NMR
(400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.10 (s, 1H), 8.09 (d, J
= 8.9 Hz, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 6.8 Hz,
1H), 7.25 (s, 1H), 7.20 – 7.13 (m, 1H), 7.02 (d, J = 8.8 Hz,
1H), 6.97 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.10
(dt, J = 12.8, 6.8 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 187.6, 162.6, 149.0, 146.0, 144.4,
131.1 (2), 131.0, 126.8, 122.4, 118.7, 116.1, 115.9, 114.7
(2), 63.9, 14.9; IR (KBr) νmax 3454, 3144, 2922, 1644, 1596,
1440, 1166 cm-1; HRMS (ESI) m/z calcd for C17H16O4
(M‒H)+ 283.0970, found 283.0977.
1-(4-bromophenyl)-3-(3,4-dimethoxymethoxy)-2-propen-1-
one (28)
1
Yellow solid; mp: 98.0‒99.5 °C; Yield: 66%; H NMR
(400 MHz, CDCl3) δ 7.86 (s, 2H), 7.73 (d, J = 15.7 Hz, 1H),
7.54 (d, J = 57.6 Hz, 3H), 7.28 (dd, J = 47.4, 19.8 Hz, 3H),
5.28 (s, 4H), 3.52 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
189.2, 149.6, 147.3, 145.1, 137.0, 131.8 (2), 129.9 (2),
129.0, 127.6, 124.0, 120.0, 116.1, 95.4, 95.0 (2), 56.3 (2); IR
(KBr) νmax 3077, 2951,1660, 1594, 1509, 1447, 1258, 800,
597 cm-1; HRMS (ESI) m/z calcd for C19H19O5Br (M+Na)+
429.0314, found 429.0299.
1-(3-bromophenyl)-3-(3,4-dihydroxyphenyl)-2-propen-1-
one (33)
1-(2-naphthyl)-3-(3,4-dimethoxymethoxy)-2-propen-1-one
(29)
Orange solid; mp: 135.8‒136.7 °C; Yield: 94%; 1H NMR
(400 MHz, DMSO-d6) δ 8.05 (d, J = 8.6 Hz, 2H), 7.76 (d, J
= 8.6 Hz, 2H), 7.61 (s, 2H), 7.27 (s, 1H), 7.20 (d, J = 9.7 Hz,
1H), 6.82 (d, J = 8.2 Hz, 1H), 3.34 (s, 2H); 13C NMR (100
MHz, DMSO-d6) δ 187.9, 148.8, 145.5, 145.4, 136.9, 131.6
(2), 130.2 (2), 126.7, 126.0, 122.3, 117.8, 115.6, 115.5; IR
(KBr) νmax 3473, 2919, 1646, 1588, 1574, 1173, 520 cm-1;
HRMS (ESI) m/z calcd for C15H11BrO3 (M‒H)+ 316.9813,
found 316.9828.
Colorless solid; mp: 70.9‒72.1 °C; Yield: 76%; 1H NMR
(400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.22 – 8.14 (m, 2H),
8.11 – 7.97 (m, 3H), 7.79 (d, J = 15.5 Hz, 1H), 7.74 – 7.63
(m, 3H), 7.57 (d, J = 6.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H),
5.34 (s, 2H), 5.31 (s, 2H), 3.49 (s, 3H), 3.45 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 188.8, 149.4, 146.7, 143.8,
135.0, 134.9, 132.2, 130.1, 129.5, 128.9, 128.5, 128.3, 127.6,
126.8, 124.3, 124.2, 120.5, 117.2, 116.4, 94.9, 94.4, 55.9 (2);
IR (KBr) νmax 3065, 2920,1656, 1591, 1508, 1447,1258, 755
cm-1; HRMS (ESI) m/z calcd for C23H22O5 (M+Na)+
401.1365, found 401.1354.
1-(2-naphthyl)-3-(3,4-dihydroxyphenyl)-2-propen-1-one (34)
Yellow solid; mp: 198.0–199.9 °C; Yield: 82%; 1H NMR
(400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.21 – 7.96 (m, 5H),

Synthesis and Structure-activity Relationships of Chalcone Derivatives
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 11 1263
7.93 – 7.58 (m, 5H), 7.40 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H),
6.90 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ
188.6, 148.7, 145.6, 144.8, 135.2, 134.8, 132.3, 129.9, 129.4,
128.3, 128.2, 127.6, 126.7, 126.3, 124.1, 122.2, 118.4, 115.7,
115.5; IR (KBr) νmax 3452, 2920, 1645, 1567, 1508, 1125
cm-1; HRMS (ESI) m/z calcd for C19H14O3 (M‒H)+
289.0865, found 289.0872.
chloromethyl methyl ether (MOMCl). The base‒catalyzed
condensation
reaction
of
3,4-bis(methoxymethoxy)
benzaldehyde with acetophenone derivatives afforded
MOM-protected chalcones 25-29 in good to excellent yields
(66%‒95%). Successful deprotection of the alcohols with
HCl in EtOH generated the dihydroxychalcones 30-34 from
moderated to excellent yields (54%‒94%). Unfortunately,
the condensation of 4-phenoxyacetophenone with either the
MOM-protected or 3,4‒dihydroxybenzaldehyde did not pro-
ceed, and this compound has yet to be reported in the litera-
ture. The structures of the compounds synthesized are shown
in Fig. (2). To the best of our knowledge, eight of the
thirty‒four (24%) chalcone derivatives synthesized are
unique structures, and none of the chalcones in the library
have been tested for their ability to inhibit CA-OV3, ovarian
cancer cell growth. Of the compounds that have been
previously synthesized, a variety of biological activities has
been shown including antibacterial [8-11], anti-prion [12],
anti-oxidant [13], and anti-diabetic [14]. Selected com-
pounds have also been screened for certain cancers including
breast [15], cervical [16], liver [17], and leukemia [18].
Compounds 6, 12, and 24 have been screened against the
OVCAR cell line showing mild inhibition of growth [19].
The resulting library (1‒34) served as a platform to identify
structure‒activity relationships between the chalcone deriva-
tives and their inhibition of ovarian cancer cell proliferation
(CA-OV3).
2.2. Biology
CA-OV3 cells were grown at 37oC with 5% CO2 in D-
MEM (ATCC) supplemented with 10% FBS (Life Tech-
nologies). The proliferation of compounds on CA-OV3 cells
was measured using the CellTiter® Aqueous One Cell Prolif-
eration Assay (MTS) (Promega). 7,000 cells were plated in
96 well plates. 48 hours later, media was changed, and chal-
cone or DMSO vehicle (1% final concentration) was added
to the media. 48 h post treatment, the media was removed by
vacuum, and 100 µL of media with 20µL of the MTS reagent
was added. The plates were incubated at 37oC for one hour.
The absorbance was read at 490nM according to the manu-
facturer protocol. For general screening cells were treated
with 100 µM chalcone. To determine the IC50 values, cells
were treated with 7 concentrations of chalcone ranging from
0.01-100µM. Data were fitted with a non-linear regression
analysis for inhibition using Graphpad Prism.
3. RESULTS AND DISCUSSION
3.1. Chemistry
3.2. Biology
Because chalcones are bioactive natural products, we
screened the library for the inhibition of cell growth in CA-
OV3 ovarian cancer cells and found a broad range of activi-
ties as the ring substituents were varied. Fig. (3) illustrates
that fourteen from the thirty-four tested compounds had good
activity against CA-OV3 cells. The library contains several
compounds showing strong inhibition of CA-OV3 cell
growth at 100µM. The growth inhibition of the library
ranged from total inhibition (compounds 2, 4 and 5) to no
inhibition (compounds 8, 10). Quantitative values of the in-
hibition at 100 µM are reported in Supplemental Table 1.
The analysis of the structure‒activity data shows that chal-
cones analogues with substitution on the A ring retained
some activity and showed no significant trend in the biologi-
cal activity. The analysis for subtle effects resulting from the
A ring modification did not yield any consistent change in
activity pattern. However, modification to the B ring did
cause changes in the inhibitory potential of the compounds.
Almost all derivatives containing a nitro (NO2) electron-
withdrawing substituent on the B ring show little to no activ-
ity in the assay. Also, the naphthalene derivatives were inac-
tive. In contrast, electron‒donating groups on the B ring displayed
a dramatic range of activity Both, the 3’,4’ ‒methoxymethyl
ethers (25, 27-29) as well as the 3’,4’-dihydroxy (30-34)
inhibited growth at greater than 70% inhibition of cell
We began our investigation by generating a library of
compounds utilizing six substituted acetophenones crossed
with five aromatic aldehyde derivatives. Specifically, the
Claisen‒Schmidt condensation of benzaldehyde with aceto-
phenone afforded chalcone 1 in 77% yield (Scheme 1).
Using chalcone 1 as a representative structure, we con-
ducted a series of condensations with readily available aro-
matic aldehyde and acetophenones analogues in the presence
of a base (Fig. 2). The trans-conformation was isolated in
each case after purification in moderate to excellent yields
(56% ‒100%). The substituents on the aromatic rings were
strategically selected with varying chemical properties
including halogens as well as electron‒donating and -
withdrawing substituents to understand the structure-activity
relationships of the groups of the synthesized chalcones.
Interestingly, compounds with any electronic effects on the
B ring produced lower yields. With the successful synthesis
of chalcones 1-24, we turned our attention to the synthesis of
hydroxy substituted chalcones.
Because the synthesis of the hydroxy chalcone deriva-
tives from the condensation of dihyroxybenzaldehyde with
acetophenone derivatives proved to be challenging, we stra-
tegically decided to protect the hydroxyl groups with
O
O
O
NaOH, EtOH
+
H
rt, 24 h
77%
Scheme 1. General scheme for the synthesis of chalcones.

1264 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 11
Tucker et al.
O
O
O
O
O
O
OH
OH
NO2
OMOM
OMOM
19, 81%
25, 72%
7, 72%
13, 86%
30, 62%
1, 77%
O
O
O
O
O
O
HO
HO
NO2
HO
HO
OH
OH
HO
OMOM
OMOM
HO
20*, 95%
2, 65%
14, 61%
31, 91%
26*, 86%
8, 64%
O
O
O
O
O
O
OH
OH
OMOM
OMOM
NO2
O
O
O
O
O
PhO
Br
O
PhO
Br
27*, 95%
32, 56%
15, 99%
21, 75%
9, 60%
3, 72%
O
O
O
O
O
O
OMOM
OMOM
OH
OH
NO2
Br
Br
PhO
PhO
28*, 66%
33*, 94%
22*, 71%
16*, 57%
4, 66%
10, 87%
O
O
O
O
O
O
OH
OH
NO2
OMOM
OMOM
Br
Br
29*, 76%
34, 82%
11, 78%
23, 99%
17, 89%
5, 93%
O
O
O
O
NO2
24, 66%
18, 70%
12, 64%
6, 100%
Fig. (2). Structures of the synthesized chalcones. Compound numbers are in bold. All percent yields refer to isolated, pure products.
*Designates novel compound.
B
1
2
3
4
5
6
30
31
32
NS
33
34
25
26
27
NS
28
29
7
8
13
14
15
16
17
18
19
20
21
22
23
24
A
9
10
11
12
Fig. (3). The effect of chalcone substituents on CA-OV3 cell proliferation. Modifications to the A ring are along the Y axis. Modifications to
the B ring are along the X-axis. Proliferation, measured as the absorbance at 490nm, is expressed in color as % of 100 µM treatment com-
pared to DMSO alone. Green (0-25% cell growth), Yellow (26-60% cell growth), Red (61-100% cell growth). Compound numbers are in the
grid for reference (NS, not synthesized). (The color version of the figure is available in the electronic copy of the article).
growth at 100 µM with the methoxymethyl ethers performing
marginally better than the dihydroxy counterparts. Because
all of the methoxymethyl ethers showed significant activity,
further exploring the space of the B ring, particularly with
electron-donating groups is a worthy next step. Overall, the
synthesized chalcone derivatives with electron‒withdrawing
group showed no activity. However, some of the analogues
with electron-donating substituents retain activity suggesting
that analogues with multiple groups at this site could provide
additional improvements in biological activity.

Synthesis and Structure-activity Relationships of Chalcone Derivatives
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 11 1265
Table 1. Inhibition of cell proliferation in CAOV3 cells.
CONSENT FOR PUBLICATION
Not applicable.
Compound
IC50 (µM)
CONFLICT OF INTEREST
1
6.99 ± 1.9
8.67 ± 3.3
69.9 ± 3.6
73.1 ± 4.7
93.3 ± 30
25.3 ± 1.9
146 ± 12.6
5.83 ± 2.8
80.9 ± 7.8
6.69 ± 1.5
10.29 ± 1.6
6.19 ± 1.2
95.5 ± 23.3
92.7 ± 3.0
The authors declare no conflict of interest, financial or
otherwise.
2
4
ACKNOWLEDGEMENTS
5
Authors are thankful to the Department of Chemistry and
Physics at Bellarmine University for its financial support.
The authors are also grateful to the Department of Chemistry
at the University of Louisville for the use of their NMR
facilities.
6
13
24
25
27
28
29
30
31
32
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher’s
web site along with the published article.
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