Synthesis, biological evaluation, and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site

Article abstract of DOI:10.1080/14756366.2019.1690479

A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC₅₀ value of 1.42 ± 0.15 μM, as compared to cisplatin (IC₅₀ = 15.24 ± 1.27 μM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G₂/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC₅₀ value of 8.4 μM, which was slightly more active than the reference compound colchicine (IC₅₀ = 10.6 μM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.

Full text of DOI:10.1080/14756366.2019.1690479

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: https://www.tandfonline.com/loi/ienz20
Synthesis, biological evaluation, and molecular
modelling of new naphthalene-chalcone
derivatives as potential anticancer agents on
MCF-7 breast cancer cells by targeting tubulin
colchicine binding site
Guangcheng Wang, Wenjing Liu, Zipeng Gong, Yong Huang, Yongjun Li &
Zhiyun Peng
To cite this article: Guangcheng Wang, Wenjing Liu, Zipeng Gong, Yong Huang, Yongjun Li &
Zhiyun Peng (2020) Synthesis, biological evaluation, and molecular modelling of new naphthalene-
chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting
tubulin colchicine binding site, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1,
139-144, DOI: 10.1080/14756366.2019.1690479
To link to this article: https://doi.org/10.1080/14756366.2019.1690479
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
020, VOL. 35, NO. 1, 139–144
2
https://doi.org/10.1080/14756366.2019.1690479
SHORT COMMUNICATION
Synthesis, biological evaluation, and molecular modelling of new naphthalene-
chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells
by targeting tubulin colchicine binding site
a,b
c,d
a
a
c
b,e
Guangcheng Wang , Wenjing Liu , Zipeng Gong , Yong Huang , Yongjun Li and Zhiyun Peng
a
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical
b
c
University, Guiyang, China; College of Chemistry and Chemical Engineering, Jishou University, Jishou, China; Engineering Research Center for
the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang, China; School of
Pharmacy, Guizhou Medical University, Guiyang, China; College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
d
e
ABSTRACT
ARTICLE HISTORY
A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisa-
tion inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative
activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among
them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of
Received 17 August 2019
Revised 29 October 2019
Accepted 29 October 2019
KEYWORDS
Chalcone; tubulin inhibitor;
anticancer; synthesis
1
.42 ± 0.15 mM, as compared to cisplatin (IC50 ¼ 15.24 ± 1.27 mM). Additionally, the promising compound 3a
demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line.
Furthermore, compound 3a was found to induce significant cell cycle arrest at the G /M phase and cell
apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of
2
8
.4 mM, which was slightly more active than the reference compound colchicine (IC50 ¼ 10.6 mM).
Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of
the tubulin.
0
0
1
. Introduction
synthesis of 2-hydroxy-4-methoxy-2 ,3 -benzochalcone (HymnPro)
which exhibited antiproliferative activity in several human solid
tumour cell lines and suppressed xenografted tumour growth in
nude mice (Figure 1(I)). Additionally, mechanistic studies showed
that it can induced cell cycle arrest at the G2/M phase and
increased in apoptotic cell death through the inhibition of tubulin
Microtubules (composed of a-tubulin and b-tubulin heterodimers)
are essential components of the cytoskeleton of eukaryotic cells,
and they play important roles in a series of cellular processes such
as determination and maintenance of cell shape, regulation of
motility, organisation of intracellular architecture, secretion, cellu-
lar transport, and cell division . Over the past two decades,
microtubule has been recognised as an attractive target for devel-
oping chemotherapeutic drugs to treat cancer due to its import-
ant roles in the life cycle of the cell . Therefore, discovery and
development of new tubulin polymerisation inhibitors has
attracted great attention in recent years.
Chalcones are an important class of natural compounds
belonging to the flavonoid family, which have two aromatic rings
1
6
0
1
,2
polymerization . Lee et al reported the synthesis of 2 -hydroxy-
0
0
5
,6 -naphthochalcone derivatives and the most active compound
HMNC-74) was found to be strongly inhibited the clonogenicity
of SW620 colon cancer cells (Figure 1(II)). Mechanistically, HMNC-
4 triggered cell cycle arrest at G2/M phase and apoptosis by dis-
(
3
–6
7
1
4
rupting the microtubular network .
One the other hand, many researchers think that chalcones
possessed significant anticancer activity due to their have a similar
mode of action to the structurally related natural combretastatin
A-4 , and the methoxy substituent in A ring is a crucial pharma-
cophoric group for the anticancer potency by inhibition of tubulin
(A-ring and B-ring) are linked by a three carbon a, b-unsaturated
1
7
carbonyl system (Figure 1). Chalcones and derivatives received
significant attention since their have diverse and interesting
biological properties such as antifungal, anti-inflammatory, antitu- polymerisation (Figure 1(III–V))
18–23
. Moreover, introduction of dif-
berculosis, antihyperglycemic, antimalarial, antileishmanial, and ferent substituents on aromatic rings of chalcone can bring the
7
–9
anticancer . More particularly, a number of synthetic and natural significant changes in anticancer activity.
chalcones exhibited potent anticancer activity against many
Based on the studies discussed above, we decided to report
. Many the the synthesis of naphthalene-chalcone derivatives containing
previous studies have shown that the presence of a 2 -hydroxyl 2 -methoxyl in the A ring based on lead compound HMNC-74
group on the A-ring is important for the antitumor activity of (Figure 2). The synthesised compounds were evaluated for their
1
0–12
cancer cell lines via inhibition of tubulin polymerization
0
0
1
3–15
chalcone derivatives
. For example, Shin et al. reported the anticancer activity.
CONTACT Guangcheng Wang
Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, 550004, China; Zhiyun Peng
Chemical Engineering, Jishou University, Jishou, 416000, China
wanggch123@163.com
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key
pengzhiyun1986@163.com
College of Chemistry and
Supplemental data for this article can be accessed here.
ß 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

1
40
G. WANG ET AL.
Figure 1. Structures of chalcone and compounds I–V.
yl]-2,5-diphenyltetrazolium bromide (MTT) assay method against
human breast carcinoma cell line MCF-7. Cisplatin was used as a
reference drug. The results were expressed as the IC50 (50% inhibi-
tory concentration). As shown in Table 1, most of the tested com-
pounds displayed potent antiproliferative activity with IC50 values
ranging from 1.42 ± 0.15 to >10 mM. Among these compounds,
compounds 3c and 3j were found to be inactive toward MCF-7
cell line (IC50 > 10 mM). All other tested compounds shown low-
micromole IC50 values (IC50 < 10 mM). Particularly, compounds 3a
and 3t displayed the most potent antiproliferative activity with
Figure 2. Rationale design of the title compounds of this study.
2
. Chemistry
The synthesis route of naphthalene-chalcone derivatives 3a–3t was
shown in Scheme 1 (see Supplementary material). Compound 2 was IC50 values of 1.42 ± 0.15 and 2.75 ± 0.26 mM, respectively.
Analysis of structure-activity relationship (SAR) of this class of
compounds revealed that the substituents of aryl ring have influ-
Cs CO in dry acetone. Condensation of 2 with a variety of commer- ences on their antiproliferative activities. Introduction of halogen
prepared by alkylation of 1–(2-hydroxynaphthalen-1-yl)ethan-1-one
1) in classical conditions using methyl iodide in the presence of
(
2
3
cially available aryl aldehydes in the presence of KOH at room tem- group (Cl or Br) at para position of phenyl ring results in a slight
perature to provide the target compounds 3a–3t, which were increase of the biological activity (3b and 3k). However, shifting
1
13
1
characterised by H NMR, C NMR, and HRMS. The H NMR of com- these group to the 2- or 3- position decreased the biological activ-
pound 3a shows two doublets (d ¼ 6.96 and 7.21 ppm) with cou- ity (3d, 3m, and 3o). Furthermore, the replacement of the 4-Br or
pling constants J¼ 16.0 Hz for the olefin hydrogen of 4-Cl substitutes with dialkylamine group (3r and 3s) resulted in a
a,b-unsaturated ketone. The protons of 3-hydroxyl-4-methoxy phenyl decrease of the inhibitory activity. The replacement of the right
moiety were appeared as two doublets for one proton each at d phenyl ring with thiophene (3j) resulted in dramatically decrease
6
2
6
.78 ppm and d 7.16 ppm with the coupling constants J ¼ 8.0 Hz and of antiproliferative activity. Among the series, 3-OH-4-OMe deriva-
.0 Hz, respectively and a doublet of doublets of one proton at d tive (3a) and 3-NH -4-OMe derivative (3t) were found to be the
.95 ppm (J ¼ 8.0 Hz and 2.0 Hz). The remaining aryl protons were most active compound, with IC50 values of 1.42 ± 0.15 and
2.75 ± 0.26 mM, respectively. Additionally, compound 3a
.35–7.44 ppm and four doublets for one proton each at d 7.31, (IC50 ¼ 1.42 ± 0.15 mM) with 3-hydroxyl-4-methoxy phenyl moiety
.66, 7.80 and 7.91 ppm with the J values 8.8, 8.4, 8.0, and 8.8 Hz, was found to be the most active compound.
2
appeared as two multiplets for two protons between
7
7
d
respectively. The methoxyl protons of OCH3 appeared as two sin-
In order to verify the safety profile of this class of compounds,
glets at 3.89 and 3.91 ppm. The single peak of OH proton was the most potent compound 3a was selected to test its cytotoxicity
13
observed at d 5.64 ppm. The C NMR of compound 3a shows the against human embryonic kidney (HEK293) cell line in comparison
carbonyl carbon appeared at 197.53 ppm. The signals of two to reference drug cisplatin. As presented in Table 2, compound 3a
methoxyls appeared at d 56.10 and 56.75 ppm. The remaining aro- exhibited cytotoxic activity against normal HEK293 cells with IC50
matic and olefin carbons resonates around d 110.55–154.09 ppm. value of 18.3 ± 1.3 mM, as compared to cisplatin (IC50
¼
The high-resolution mass spectrum of compound 3a showed a
5.3 ± 0.4 mM). Hence, we could conclude that these compounds
þ
molecular ion peak at m/z 389.0149 as [M þ Na] which also sup- have good safety for potential application in the treatment of
ports the proposed structure of the compound. Similar pattern was tumour cells.
1
13
observed in H NMR and C NMR spectroscopy of all the title com-
pounds 3a–3t. The HRMS (TOF) of all the compounds 3a–3t showed
a molecular ion peak equivalent to their molecular formulae.
3.2. In vitro tubulin polymerisation inhibitory assay
To evaluate whether this class of compounds target the tubulin–-
microtubule system, compound 3a, one of the most active com-
pounds in this series of chalcone derivatives, was chosen to
investigate its ability to block microtubule assembly, with colchi-
cine as the reference compound. As shown in Figure 3, compound
3
. Biological evaluation
3.1. In vitro anticancer activity against breast cancer cell line
(
MCF-7)
All the synthesised naphthalene-chalcone derivatives 3a–3t were 3a inhibited the polymerisation of tubulin in a concentration-
evaluated for their anticancer activity by 3-[4,5-dimethylthiazole-2- dependent manner, which suggests that this class of compounds

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
141
ꢀ
Scheme 1. Scheme of synthesis of target compounds 3a–3t. Reagents and conditions: (a) Cs
2
CO
3
, acetone, r.t. 12 h; (b) 50% KOH (aq), MeOH, 0 C, 0.5 h to r.t., 24 h.
Table 1. Anticancer activity of compounds 3a–3t against MCF-7 cell line.
No.
Ar
IC50 (lM)
No.
Ar
IC50 (lM)
3
a
1.42 ± 0.15
3k
4.74 ± 0.19
3
b
4.10 ± 0.25
3l
7.68 ± 0.32
6.66 ± 0.27
3
c
>10
3m
3
3
d
e
7.63 ± 0.45
7.13 ± 0.33
3n
3o
7.62 ± 0.36
7.11 ± 0.47
3
f
6.87 ± 0.26
3p
7.23 ± 0.38
3
3
g
h
7.11 ± 0.40
6.67 ± 0.25
3q
3r
7.67 ± 0.39
8.91 ± 0.52
(continued)

1
42
G. WANG ET AL.
Table 1. Continued.
No.
Ar
IC50 (lM)
No.
Ar
IC50 (lM)
3
i
7.82 ± 0.35
3s
7.62 ± 0.30
3
j
>10
3t
2.75 ± 0.26
Cisplatin
15.24 ± 1.27
26
Table 2. Cytotoxic activity (IC50, mM) of selected compound 3a and cisplatin first studied its effect on cell cycle progression in MCF-7 cells . As
against human embryonic kidney (HEK293) cell line.
shown in Figure 4, control group show a typical pattern of
Compound
Structure
IC50 (lM)
cell cycle in G1, S and G2/M phase. In contrast, after treatment of
MCF-7 cells with compound 3a at concentrations of 2.0 mM, the accu-
mulation of cancer cells was detected at G2/M phase by 5.5 folds
compared to the control group, from 15.19% in the control group to
3
a
18.3 ± 1.3
84.55% in the compound 3a treated group (Figure 4). The result indi-
cates that compound 3a could arrest cells in G2/M phase and halt
cell mitosis, which leads to inhibited MCF-7 cells proliferation.
Cisplatin
5.3 ± 0.4
3.4. Cell apoptosis analysis
To investigate whether compound 3a could induces apoptosis,
the apoptotic effect of compound 3a and DMSO (control) were
2
7
evaluated by an annexin V FITC/PI (AV/PI) dual staining assay .
After treatment MCF-7 cells with compound 3a at the concentra-
tion of 2.0 mM for 24 h, the cells were labelled with the two dyes
and analysed by flow cytometry. In comparison to the DMSO con-
trol group, it was observed that compound 3a could induce an
increase in the late/secondary cellular apoptosis from 0.68% to
6
.34%. In addition, an increase in the early/primary apoptosis was
also observed from 1.85% to 20.0% (Figure 4). Collectively, these
results confirmed that this series of compounds could arrest cells
in G2/M phase and induce apoptotic cell death.
3.5. Molecular modelling studies
To explain the binding modes of this class of compounds with
tubulin, we performed a docking study of the most active com-
pound 3a into the colchicine binding pocket of tubulin (PDB
Figure 3. Tubulin polymerisation inhibitory activity of compound 3a (3.0 lM,
.0lM, 12.5 lM, and 25.0 lM) and colchicine (12.5 lM).
6
2
8
code: 1SA0) by using the Autodock vina 1.1.2 software . The
interfere with the microtubule polymerisation. Treatment with 3.0, result was shown in Figure 5 and the estimated binding energy
ꢁ
1
6
.0, 12.5, and 25 mM of compound 3a inhibited tubulin polymer- was ꢁ8.8 kcalꢂmol . Compound 3a adopted a “L-shaped” con-
isation by 21%, 41%, 60%, and 82%, respectively. Compound 3a formation in the pocket of the tubulin. The 2-methoxynaphthyl
was slightly more active than the reference compound colchicine, group of 3a located at the hydrophobic pocket, surrounded by the
with the IC50 values of 8.4 and 10.6 mM, respectively. These results residues Cys-241, Leu-248, Ala-250, Leu-252, and Leu-255, forming a
indicated that compound 3a is a tubulin polymerisation inhibitor, strong hydrophobic binding. Detailed analysis showed that the phe-
which can bind to tubulin and induces microtubule nyl group in the middle of 3a formed a cation-p interaction with
polymerisation.
the residue Lys-254. It was shown that the residues Gln-11 (bond
length: 3.4 Å), Leu-248 (bond length: 3.0 Å), and Leu-255 (bond
length: 3.1 Å) formed three hydrogen bond interactions with 3a,
which was the main interaction between 3a and tubulin.
3.3. Cell cycle arrest
Many studies have reported that tubulin polymerisation inhibitors
24,25
can arrest cancer cells in G2/M phase and lead to apoptosis
The potent tubulin polymerisation inhibitory activity of compound
a promoted us to further investigate its cellular mechanisms of In summary, we designed and synthesised a series of naphtha-
.
4. Conclusion
3
action in MCF-7 cancer cells by using flow cytometry analysis. In lene-chalcone derivatives (3a–3t) as tubulin polymerisation inhibi-
order to elucidate the molecular mechanism of compound 3a, we tors for the treatment of breast cancer. Among them, compound

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
143
Figure 4. Cell cycle analysis and cell apoptosis analysis for MCF-7 cells. (A,B) Induction of apoptosis by DMSO (control) and compound 3a (2.0 lM); (C,D) Cell cycle ana-
lysis of MCF-7 cells after treated with DMSO (control) or compound 3a (2.0 lM) for 24 h.
3a bearing 3-hydroxyl-4-methoxy phenyl moiety was found to be
the most active compound, with an IC50 value of 1.42 ± 0.15 mM
against MCF-7 breast cancer cell line. The promising compound
3a demonstrated relatively lower cytotoxicity on normal cell line
(HEK293) compared to tumour cell line. Additionally, in mechanis-
tic studies, the representative compound 3a was found to induce
significant cell cycle arrest at the G2/M phase and cell apoptosis
in MCF-7 cell lines. Notably, compound 3a also displayed potent
tubulin polymerisation inhibitory activity with an IC50 value of 8.4
mM, which was slightly more active than the reference compound
colchicine (IC50 ¼ 10.6 mM). Furthermore, molecular docking studies
revealed that these compounds can bind at the colchicine binding
site of the tubulin.
Figure 5. The binding mode of compound 3a (green) with colchicine binding
site (magenta) of tubulin (PDB code 1SA0). Hydrogen bonding was depicted as
yellow dotted lines.
Disclosure statement
No potential conflict of interest was reported by the authors.

1
44
G. WANG ET AL.
0
14. Lee JM, Lee MS, Koh D, et al. A new synthetic 2 -hydroxy-
Funding
0 0
2
,4,6-trimethoxy-5 ,6 -naphthochalcone induces g2/m cell
This work was supported by National Natural Science Foundation
of China (81660574), One Thousand Talents Programme of
Guizhou Province (the fifth group), Basic Research Plan of Guizhou
Province ([2019]1256), Guizhou province administration of trad-
itional Chinese medicine (QZYY-2019–057), the Doctor Foundation
of Guizhou Medical University ([2018]004), Guizhou Science and
Technology Department ([2016]5613\5677), Local Science and
Technology Project Guided by Central administration ([2018]4006),
Guizhou Science and Technology Department ([2017]5601),
Guiyang Science and Technology Bureau ([2017]30–29).
cycle arrest and apoptosis by disrupting the microtubular
network of human colon cancer cells. Cancer Lett 2014;354:
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