Antimitotic and antiproliferative activities of chalcones: Forward structure-activity relationship

Article abstract of DOI:10.1021/jm0708331

A series of 59 chalcones was prepared and evaluated for the antimitotic effect against K562 leukemia cells. The most active chalcones were evaluated for their antiproliferative activity against a panel of 11 human and murine cell cancer lines. We found that three chalcones were of great interest as potential antimitotic drugs. In vivo safety studies conducted on one of the most active chalcones revealed that the compound was safe, allowing further in vivo antitumor evaluation.

Full text of DOI:10.1021/jm0708331

J. Med. Chem. 2008, 51, 2307–2310
2307
Antimitotic and Antiproliferative Activities of Chalcones: Forward Structure–Activity
Relationship
Ahcène Boumendjel,*,† Julien Boccard,‡ Pierre-Alain Carrupt,‡ Edwige Nicolle,† Madeleine Blanc,† Annabelle Geze,†
Luc Choisnard,† Denis Wouessidjewe,† Eva-Laure Matera,§ and Charles Dumontet§
Département de Pharmacochimie Moléculaire, UMR 5063, ICMG-FR 2607-UniVersité Joseph Fourier Grenoble I, 470, rue de la Chimie,
38240 St Martin d’Hères France, Unité de Pharmacochimie, Section des Sciences Pharmaceutiques, UniVersité de GenèVe, UniVersité de
Lausanne, 30 Quai Ernest-Ansermet, CH-1211 GenèVe 4, Switzerland, UniVersité de Lyon, Lyon, F-69008, France, and INSERM,
U590, F-69008, France
ReceiVed July 10, 2007
A series of 59 chalcones was prepared and evaluated for the antimitotic effect against K562 leukemia cells.
The most active chalcones were evaluated for their antiproliferative activity against a panel of 11 human
and murine cell cancer lines. We found that three chalcones were of great interest as potential antimitotic
drugs. In vivo safety studies conducted on one of the most active chalcones revealed that the compound
was safe, allowing further in vivo antitumor evaluation.
Introduction
Interfering with the dynamic instability of microtubules,
spindle poisons arrest dividing cells in G2/M phase of the cell
cycle, causing apoptotic cell death. Many clinically successful
anticancer drugs acting as antimitotics are being used worldwide.
Most of these molecules are derived from naturally occurring
compounds and act by stabilization or destabilization of
microtubules.1 Among the natural products affecting microtubule
Figure 1. General structure of targeted chalcones.
dynamics are colchicines, the vinca alkaloids, combrestatin A4,
epothilone, and taxanes.2 Flavonoids are naturally occurring
polyphenols possessing a variety of biological activities.3 The
health benefits of fruits and vegetables is partially due to the
presence of flavonoids in substantial amounts.4 The anticancer
potential of flavonoids and their biogenetic precursors have been
investigated.5 In this regard, the example of flavopiridol, a
synthetic flavone acting as a cyclin-dependent kinase inhibitor
with potent activity in chronic lymphocytic leukemia, is
illustrative.6 Chalcones that are flavone precursors have been
investigated for their antiproliferative effect.7 Recent and evident
structure–activity relationship studies are being emerged.8–10
As part of a subsequent study to determine the important
features of flavone precursors influencing their anticancer
activity, we disclose here additional structural requirements for
the antimitotic activity of chalcones. Combined with recently
reported data, this study will aid in the design of more active,
selective, and safe chalcones.8–10
Scheme 1. Synthesis of Chalcones; R2-R6 are Shown in Tables
1 and 2
in the presence of KOH (50%) (Scheme 1). The 4′-N-acetyl-
2′,6′-dimethoxyacetophenone needed for the preparation of
chalcone 56 (Table 1) was prepared according to an earlier
report.18 Chalcones bearing ethoxy groups were prepared by
condensation of the appropriate ethoxyacetophenone with the
required ethoxybenzaldehyde. In this case, ethoxyacetophenones
and ethoxybenzaldehydes were obtained by alkylation of
hydroxylated derivatives with bromoethane in the presence of
NaH in DMF.
The activity of chalcones was found to be dependent on the
presence, the number, and the positions of hydroxy and methoxy
groups in both A and B rings.11–17 The present article is mostly
focused on the synthesis of chalcones bearing hydroxy, methoxy,
and halogens and effects on cell cycle and cell growth to address
additional elements of structure-anticancer activity (Figure 1).
Results
Overall, 59 chalcones were obtained and tested in vitro
for the antimitotic activity on human leukemic K562 cell line.
Their structures and the corresponding cell cycle arrest are
presented in Tables 1 and 2. Cells were exposed to test
compounds at a concentration of 10 µM for 24 h and stained
with propidium iodide and analyzed by flow cytometry to
determine the distribution of the total population in the
different phases (G0/G1, S, and G2/M). Compounds inducing
G2/M arrest equal to or higher than our reference compound,
vincristine (VCR) were evaluated for the antiproliferative
effect against a panel of cell lines representing different types
of cancer. Chalcones 3, 6, 13, and 39 induce G2/M arrest
Chemistry
Chalcones are prepared by the Claisen-Schmidt condensation
of an acetophenone derivative with substituted benzaldehydes
* To whom correspondence should be addressed. Département de
Pharmacochimie Moléculaire, Bâtiment E, André Rassat, Pole Chimie -
BP 5338041 Grenoble Cedex 9, France. Tel.: (33) 4 76 63 53 11. Fax: (33)
4 76 63 52 98. E-mail: ahcene.boumendjel@ujf-grenoble.fr.
†
ICMG-FR 2607-Université Joseph Fourier Grenoble I.
Université de Genève, Université de Lausanne.
Université de Lyon, INSERM.
‡
§
10.1021/jm0708331 CCC: $40.75
2008 American Chemical Society
Published on Web 02/23/2008

2308 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7
Brief Articles
Table 2. Cell Cycle Arrest Induced by Chalcones 50–59 at 10 µM
against K562 Cell Line
higher than vincristine, whereas chalcones 52 and 56 are
equally potent than the reference compound. Based on the
Table 1. Cell Cycle Arrest Induced by Chalcones 1–49 at 10 µM
against K562 Cell Linea
cmpd
R2′
R4′
R6′
R2 R3 R4 R5 R6 G2/M ClogP
50
51
52
53
54
55
56
57
H
3′-Cl
3′-OMe OMe
OEt
OEt
OEt
OMe
OEt
H
H
Cl
H
H
H
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe 34
OMe 30
OMe 72
OMe 10
OMe 14
3.63
5.03
3.52
4.93
4.94
6
2.95
7
5.05
3.97
4.01
OMe
OMe
OMe
H
OEt
OMe
OEt
H
cmpd
R2
R3
R4
R5
R6
G2/M
ClogP
H
H
H
OEt OMe
OEt OMe
OEt OEt
1
2
3
4
5
6
7
8
H
Cl
F
H
H
H
H
H
H
H
OMe
F
Cl
H
H
H
H
H
OMe
H
OMe
F
H
H
OMe
OMe
H
H
H
H
H
H
H
H
OMe
H
CF3
OEt
OMe
OMe
OMe
OMe
Me
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
OMe
H
H
H
H
H
H
OMe
Cl
H
OEt
H
H
32
42
86
25
45
78
38
23
29
27
19
18
84
39
23
12
19
49
25
46
23
22
4.01
4.58
3.87
3.88
3.87
3.88
4.01
4.58
3.79
4.01
4.58
3.79
3.87
5.3
4.75
5.46
3.17
3.52
3.17
3.61
5.37
3.88
H
11
OMe
OMe
H
OMe
F
Cl
H
H
H
NH2 OMe OMe
OEt OEt OEt
H
OMe 74
OEt
Cl
18
28
13
72
58
59
VCR
H
Cl
OH
OMe OMe 3,4-methylendioxy
9
10
11
12
13
14
15
16
17
18
19
20
21
22
results obtained from cell cycle arrest, chalcones 6, 13, and
39 were selected and screened for their ability to inhibit cell
growth using the MTT assay on a series of 11 human and
murine cell lines representative of various solid tumors and
hematological malignancies (Table 3). The IC50 concentration
was calculated as the drug concentration resulting in 50%
loss of cell viability with reference to untreated cells after
24 h incubation.
OMe
OMe
Cl
H
OEt
OMe
OMe
H
OMe
Me
OMe
H
OMe
OMe
F
H
H
H
OMe
Me
H
H
H
Chalcone 13 was selected for in vivo studies to check its
toxicity on healthy animals before proceeding to efficacy testing.
The compound was formulated in a H2O-PEG system to reach
a solubility of 0.35 g ·L-1. Toxicity studies were performed on
groups of five animals treated at different dose levels. Intrap-
eritoneal injections were administered three times a week up to
a total of 8 injections. This molecule was well tolerated up to
the maximum dose level tested, 1 mg/kg. Tolerance was
considered satisfactory because none of the animals died and
animal weight did not vary by more than 10%.
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
Cl
H
Cl
Cl
H
H
OMe
H
OMe
OMe
OMe
H
OMe
OMe
OMe
H
H
H
H
H
H
Cl
H
H
H
H
H
OMe
OMe
H
H
H
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
OMe
H
OMe
H
OMe
H
H
H
OMe
F
H
H
H
H
H
H
OMe
H
H
H
67
4.74
4.74
4.8
10
45
19
40
26
22
18
18
32
18
40
20
15
19
20
4.89
4.17
3.95
3.69
3.69
4.04
4.04
4.04
4.04
3.33
3.68
4.03
3.33
F
OMe
OMe
OMe
H
H
H
OMe
OMe
H
H
OMe
Discussion
The present article is focused on the synthesis of specific
chalcones, notably methoxylated and to less extent hydroxylated
derivatives. This choice was motivated by a recent report
disclosing a natural chalcone, 2′-hydroxy-2,3,4′,6′-tetramethoxy-
chalcone as an agent against the cancer cell.19 On the other hand,
a polymethoxyphenyl moiety is frequently met in the number
of naturally occurring anticancer agents such as colchicine and
combretastatin A. In an effort to contribute to robust SAR studies
and develop potential anticancer drugs, we targeted chalcones
possessing hydroxy and methoxy groups at the 2′,4′,6′-positions
of the A-ring and methoxy groups at different positions of the
B-ring. The results shown in Tables 1 and 2 indicate that the
most potent chalcones belong to the series with an optimum of
lipophilicity (CLOGP around 4), suggesting that higher lipo-
philicity lowered the cell permeation and thus reduced dramati-
cally the cell arrest activity of the resulting derivatives. This
phenomenon is particularly evident for the replacement of the
methoxy groups by ethoxyl or methyl groups (13 vs 16 and 21
or 6 vs 54). We also observed a clear correlation between the
cell cycle arrest and the methoxylation pattern. The methoxy-
lation did not affect greatly the lipophilicity of examined
chalcones but reflected modifications in their pharmacodynamic
interactions with biological targets. Indeed, it appeared that
dimethoxylation and trimethoxylation at 2′,4′,6′-carbons are
highly beneficial (compounds 3, 6, 13, 39, 41, 52). The
OMe
H
OMe
39
40
41
42
43
44
45
46
47
48
49
OMe
H
H
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
OMe
H
OMe
OMe
H
H
H
H
Cl
H
86
15
64
12
43
48
11
28
26
41
52
3.83
3.83
3.83
4.01
4.72
4.15
4.01
4
OMe
OMe
OMe
Cl
H
H
H
Cl
OMe
H
H
F
OMe
H
H
H
OMe
5.43
3.92
3.92
H
H
H
H
H
a Compounds that induced equal or higher G2/M arrest than vincristine
are in bold.

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7 2309
Table 3. Cytotoxicity of Chalcones 6, 13, and 39 against Different Cell
Lines
Chalcone 6, one of the most active chalcones reported by
Bowen and co-workers,12 was prepared and its growth inhibition
against 11 cancer cell lines was compared to chalcones 13 and
39. As shown in Table 3, it is clear that higher antimitotic
activity is correlated to strong antiproliferative effect. The IC50
values observed, in the micromolar range, are in keeping with
those observed in human serum with a number of commercially
active anticancer agents, such as cytarabine, methotrexate, or
cyclophosphamide.
Although additional data, such as clearance studies, are
required, the preliminary toxicity data obtained on chalcone 13
suggest that it is a good candidate for further in vivo development.
The present investigation allowed the identification of active
chalcones with anticancer activities and brings new structural
elements that will aid in the design of more active chalcones.
One of the most active chalcones (chalcone 13) was formulated
and evaluated in vivo for toxicity in healthy animals. The lack
of toxicity makes this compound and probably its analogs
(chalcones 3 and 39) good candidates for in vivo evaluation
for antitumor chemotherapy.
chalcone (IC50, µM)a
cell line
6
13
60
2.2
30
0.25
1.3
0.45
1
0.65
39
52
4
30
0.8
10
1
2.2
1.9
50
MCF7
N2A
75
55
60
10
62
9
10
6
80
40
34
NIH3T3
SW48
HNO150
HCT116
Messa
CEM
K562
RL
L1210
50
0.8
7
0.9
8.5
a IC50 was determined with reference to a standard curve constructed
for control cells and represents the concentration that results in a 50%
decrease in cell growth after 24 h incubation.
importance of methoxylation on the A-ring was previousley
reported and discussed by Ducki and co-workers.10,14 Indeed,
a number of potent anticancer chalcones having three methoxy
groups at 3′,4′,5′-positions were reported (IC50 within the nM
range). The presence of a hydrogen-bond donor such as an NH2
at 4′-position (compound 56) did not affect the cell cycle arrest
showing that this position may tolerate a variety of substituents.
The beneficial effect of a NH2 group at 4′-position has been
recently pointed out by Robinson and co-workers.11 The
enhanced activity of 2′,6′-dimethoxy derivatives indicates that
the conformation of the acyl substituent is an important
parameter for the binding to biological targets because di-ortho-
substitution drives by electrostatic repulsion the dihedral angle
between the A-ring and the carbonyl group to 90°. The issue
related to the conformation of chaclcones versus anticancer
activity has been adressed by Ducki et al.14,20
The hydroxylation at 2′ is generally undesirable (e.g., 41 vs
42 and 3 vs 37). It is conceivable that the negative effect of a
hydroxy group at 2′-position is due to a flat geometry induced
by the intramolecular hydrogen bond between the hydroxyl and
carbonyl groups. This observation is in contrast with the results
reported by Rao and co-workers,13 showing high cytotoxic 2′-
hydroxylated chalcones against Jurkat and U937 cancer cells.
In the case of dimethoxylated chalcones on the A-ring, it is
shown that the most suitable positions for methoxylation are
2′,4′ or 2′,6′ (derivatives 3 and 13 vs 52).
At the B-ring, it is clear that 2-, 4-, and 6-positions are the
most suitable positions for substitution (compounds 3, 6, 13,
39, 41, 52, 56). The substitution pattern can include two or three
methoxy groups at the above positions. For dimethoxylated
derivatives on the B-ring, the methoxy groups should preferably
be linked to carbons 2 and 6 (6 vs 22). However, the topological
requirements for methoxy substitution on the B-ring are less
demanding than those of the A-ring, suggesting that this phenyl
ring is not a strong pharmacophoric element for the pharma-
codynamic behavior of these compounds. Several attempts to
drive 2D or 3D quantitative relationships were performed using
a wide panel of recently developed in silico methods. Unfor-
tunately, no predictive model was obtained with regard to the
low internal predictive power. We believe that, to interfere with
the different phases of the cell cycle, the compounds have to
permeate the cell and the nucleus membranes. Variations of
molecular structure of examined chalcones influence differently
pharmacodynamics and permeation mechanisms, and these
complex mechanisms, quantified by cell growth inhibition
results, are presumably responsible for the lack of global QSAR
models.
Experimental Section
Chemistry. Melting points were measured on a Fisher mi-
cromelting point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded on Bruker Avance 400. Mass spectra were
obtained on a JEOL HX-110 spectrometer. Elemental analysis were
performed by the Analytical Department of CNRS, Vernaison,
France. Chemicals and reagents were obtained either from Aldrich
or Acros companies. PEG 300 (Lutrol E300) was kindly donated
by BASF (Germany).
Synthesis of Chalcones: Typical Procedure. To a stirred
solution of acetophenone (1 mmol) and a benzladehyde derivative
(1 mmol) in MeOH (10 mL) was added KOH (50% aqueous
solution, 1 mL). The solution was heated at 70 °C for 3-5 h, MeOH
was evaporated, and the residue was dissolved in CH2Cl2/H2O (50
mL, 4:1). The organic layer was washed with brine and evaporated.
After this, column chromatography was carried out over silica gel
(AcOEt/hexane 1:2). In the case of fluorinated chalcones, KOH
(25%) was used.
Formulation of 13 for Animal Experiments. Chalcone 13 was
dissolved in a mixture of 50/50 PEG 300/injectable water (% v/v).
The solution was magnetically stirred at ambient temperature in a
sealed container for 4 h. A volume of 25 mL of the formulated
solution was filtered using sterile 0.22 µm PVDF filtration devices
(Roth Sochiel, Germany) and introduced into 50 mL glass vials,
previously sterilized by autoclaving. The amount of dissolved 13
was assayed spectrophotometrically at 347 nm in absolute ethanol.
Solutions without 13 were similarly prepared as references.
Flow Cytometry Analysis of Cell Cycle. Cells were treated with
the test compound at 10 µM for 24 h. After drug exposure, 106
cells/mL were resuspended in 2 mL of propidium iodide solution
(50 µL/mL), incubated at 4 °C overnight, and then analyzed by
flow cytometry. The G2/M fraction of cells exposed to different
compounds was performed on a FACScalibur (Becton Dickinson,
San Jose, U.S.A.). Cell cycle distribution was calculated after
exclusion of cell doublets and aggregates on a FL2-area/FL2-width
dot plot using Modfit LT 2.0 software (Verity Software Inc.,
Topsham, U.S.A.).
MTT Cytotoxicity Assays. Cell viability was determined on
exponentially growing K562 cells using the MTT assay, as
previously described.21 This assay is based on the conversion by
metabolically active cells of 3-(4,5-dimethylthiazol-2-yl)-2,5-di-
phenyl tetrazolium bromide (MTT) into formazan crystals, which
are then dissolved in an isopropanol solution. Optical density is
measured by spectrometry. Briefly, asynchronously growing cells
were transferred into 96-well cultures plates (Costar, Corning Inc.,
NY) in 100 µL of medium, with a final cell concentration of 3 ×
103 cells/well and incubated in media for 24 h. Corresponding drug
concentrations were then added to each plate. After 72 h of drug
exposure (10 µM), 20 µL of MTT reagent (5 mg/ml) were added

2310 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7
Brief Articles
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Chalcone and its analogs as agents for the inhibition of angiogenesis
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cell cycle phase distribution. Bioorg. Med. Chem. 2004, 12, 2679–
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advances in the discovery of flavonoids and analogs with high-affinity
binding to P-gp responsible for cancer cell multidrug resistance. Med.
Res. ReV. 2002, 22, 512–529.
(16) Hadjeri, M.; Peiller, E.-L.; Beney, C.; Deka, N.; Lawson, M.-A.;
Dumontet, C.; Boumendjel, A. Antimitotic activity of 5-hydroxy-7-
methoxy-2-phenyl-4-quinolones. J. Med. Chem. 2004, 47, 4964–4970.
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to each well. Cell viability was expressed as the percent of
absorbance of treated wells relative to the untreated control wells.
Assays were performed in triplicate in at least three separate
experiments. Cell lines used for cytotoxicity assays included MCF7,
a human breast cancer line; N2A, a murine neuroblastoma line;
NIH3T3, a murine fibroblastic line; HNO150, a human ENT line;
HCT 116 and SW48, human colorectal cancer lines; Messa, a
human sarcoma line; K562 and CEM, human leukemic lines; RL,
a human lymphoma line; and L1210, a murine leukemic line.
Supporting Information Available: Physical (melting points
and elemental analysis) and spectral data (1H NMR). This material
is available free of charge via the Internet at http://pubs.acs.org.
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JM0708331