Biomedicine & Pharmacotherapy 67 (2013) 215217

Original article

Synthesis and antitumor activity of novel chalcone derivatives

Chuanfei Jin a, Yong-Ju Liang b, Hongwu He a,*, Liwu Fu b
a
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152, Luoyu Road, Wuhan 430079, PR China
b
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China

A R T I C L E I N F O A B S T R A C T

Article history: A novel series of chalcone derivatives containing pyrimidinyl group were synthesized and evaluated for
Received 16 October 2010 their cytotoxic activities in vitro against various human cancer cell lines. Most of the prepared
Accepted 7 December 2010 compounds showed potential cytotoxicity against several human cancer cell lines. The compound 5g
displayed more potent cytotoxic activities against human cancer cell lines in comparison with Curcumin.
Keywords: 2013 Published by Elsevier Masson SAS.
Chalcone
Pyrimidine
Synthesis
Antitumor activity

1. Introduction 2. Materials and methods

Many clinically successful anticancer drugs are either natural
products or have been developed from naturally occurring lead
compounds, such as taxol, topotecan and irinotecan. Chalcones
constitute an important group of natural products and serve as
precursors for the synthesis of different classes of avonoids,
which are common substances in plants [1]. Chalcone derivatives
have received a great deal of attention due to their relatively
simple structures, and wide variety of pharmacological activities
reported for these compounds include anti-inammatory [2],
antifungal [3,4], antibacterial [5] antimalarial [6] and antitumor
activities [7]. For these reasons, the synthesis of chalcones and
their functionalized derivatives is a primary objective.
Pyrimidine nucleus is a pharmacophoric scaffold and repre-
sents a class of heterocyclic compounds with a wide range of
biological applications. Many of them are widely used as
anticonvulsant [8], and analgesic [9]. Some compounds containing
pyrimidine moiety were reported to possess anti-inammatory
[10], antimicrobial [11], and antitumor activities [1214]. It has
been noticed that introduction of an additional pyrimidinyl group
to the chalcone core tends to exert profound inuence in
conferring novel biological activities in these molecules. Herein,
a series of novel chalcone analogues containing the pyrimidinyl
group were designed and synthesized. The antitumor activity of
the new compounds was evaluated.
* Corresponding author. Tel.: +86 0 27 67867960; fax: +86 0 27 67867960.
E-mail addresses: he1208@yahoo.com (H. He), fulw@mail.sysu.edu.cn (L. Fu).
2.1. Chemicals
Synthesis of these novel compounds was carried out in a
straightforward manner. 4,6-dimethoxy-2-(methylsulfonyl)pyr-
imidine 1 was prepared according to the method in the literature
[15]. Compound 3 could be synthesized in 6772% yield starting
from 3-substituted-4-hydroxybenzaldehyde 2 and compound 1
in presence of K2CO3 in DMF. The chalcone derivatives (5a5k)
were prepared in 5983% yield from substituted acetophenone 4
and compound 3 using a catalytic amount of KOH in ethanol
(Scheme 1).
2.2. Cell lines
KB cells were the drug sensitive human oral carcinoma cells,
CNE2 cells were the drug sensitive human nasopharyngeal
carcinoma cells, MGC-803 cells were the drug sensitive human
gastric carcinoma cells and MCF-7 cells were the drug sensitive
human breast adenocarcinoma cells and K562 cells were the drug
sensitive human leukemia cells.
2.3. In vitro cytotoxicity assay
The in vitro cytotoxicity of the synthesized compounds against
different cancer cell lines was performed with the MTT assay
according to the Mosmanns method [16]. The MTT assay is based
on the reduction of the soluble 3-(4,5-dimethyl-2-thiazolyl)-2,5-
diphenyl-2H-tetrazolium bromide (MTT) into a blue-purple
formazan product, mainly by mitochondrial reductase activity

0753-3322/$ see front matter 2013 Published by Elsevier Masson SAS.

doi:10.1016/j.biopha.2010.12.010
[(Schem_1)TD$FIG]
216 C. Jin et al. / Biomedicine & Pharmacotherapy 67 (2013) 215217

OMe OMe Table 1

N K2CO3 N Cytotoxic activity of chalcones 5a5k against human tumor cells. [TD$INLE]
MeO2S OHC OH OHC O
N DMF N O OMe
OMe R1 R1 OMe
2 B A N
1 2 3 R
1 O N OMe
2a R = H R1
2b R1 = OMe
2c R1 = Cl 5
O OMe
KOH, EtOH N
O R2 Compound In vitro cytotoxicity IC50 (mM)
O N OMe
R 2 R1 KB CNE2 MGC-803 MCF-7 K562

4 5 5a 14.7 35.7 15.6 18.2 -a

5b 5.55 32.1 22.2 > 50 -
5a R1 = H; R2= H 5b R1 = H; R2= 4-Me 5c 13.7 32.4 14.0 30.8 -
5c R1 = H; R2= 4-OMe 5d R1 = H; R2= 4-NO2 5d > 50 > 50 > 50 > 50 > 50
5e R1 = H; R2= 2-OH 5f R1 = OMe; R2= H 5e 19.2 24.2 18.3 32.6 35.7
5g R1 = OMe; R2=4-OMe 5h R1 = OMe; R2= 2-OH 5f 11.7 15.8 13.5 18.6 19.2
5i R1 = Cl; R2= H 5j R1 = Cl; R2= 4-OMe 5g 12.9 14.0 12.5 15.9 21.7
5k R1 = Cl; R2= 2-OH 5h 13.4 33.2 21.0 22.7 -
5i 12.4 10.7 47.4 20.0 24.6
Scheme 1. General synthetic route for compounds 5a5k. 5j 15.0 17.8 18.2 17.8 18.6
5k 15.9 19.3 15.7 17.2 19.3
Curcumin 20.1 16.1 9.68 16.8 28.8
5-FU 10.5 13.1 12.6 10.4 > 50

inside living cells. The cells used in cytotoxicity assay were
cultured in RPMI 1640 medium supplemented with 10% fetal calf
serum. Cells suspended in the medium (2Y0 104/mL) were plated
in 96-well culture plates and incubated at 37 C in a 5% CO2
incubator. After 12 h, the test sample (2 mL) was added to the cells
(2Y0 104) in 96-well plates and cultured at 37 C for 3 days. The
cultured cells were mixed with 20 mL of MTT solution and
incubated for 4 h at 37 C. The supernatant was carefully removed
from each well and 100 mL of DMSO was added to each well to
dissolve the formazan crystals, which were formed by the cellular
reduction of MTT. After mixing with a mechanical plate mixer, the
absorbance of each well was measured by a microplate reader
using a test wavelength of 570 nm. The results were expressed as
the IC50, which is the concentration of the drugs inducing a 50%
inhibition of cell growth of treated cells when compared to the
growth of control cells. Each experiment was performed at least
three times. There was a good reproducibility between replicate
wells with standard errors below 10%. 5-FU and Curcumin were
used as the reference drug.
KB cells: drug sensitive human oral carcinoma cells; CNE2 cells: drug sensitive
human nasopharyngeal carcinoma cells; MGC-803 cells: drug sensitive human
gastric carcinoma cells; MCF-7 cells: drug sensitive human breast adenocarcinoma
cells; K562 cells: drug sensitive human leukemia cells.
a
Not tested.
against the tumor cells. However, substitution of 4-NO2 in B-ring
(5d) decreased the inhibitory activity. The compound 5d displayed
very weak antitumor activity against the tumor cells. Still, the
change of R1 group, also had a little inuence on their activity.
Introduction of one methoxy group in A-ring, (5f, 5g and 5h)
increased the inhibitory activity. It had been observed from Table 1
that most of the derivatives with strong electron-donating
substituent groups such as methoxyl, had signicantly higher
cytotoxicities than those with electron-absorbing groups or with
no substitution.
4. Conclusion

In summary, we had synthesized a novel series of chalcone

3. Results and discussion
The results indicated that the pyrimidinyl group introduced to
chalcones structure was useful for the improvement of antitumor
activity. As seen from Table 1, most of the compounds showed
potential cytotoxicity against several human cancer cell lines.
Some compounds were found to be more potent cytotoxic
activities against certain human cancer cell lines than 5-FU. The
compound 5g displayed more potent cytotoxic activities against
human cancer cell lines in comparison with Curcumin. Generally,
most of the compounds tended to be more active against KB, than
against other tested tumor cells. The compound 5b showed the
best inhibitory activity against KB with IC50 5.55 mM. The
compound 5i showed the best inhibitory activity against CNE2
with IC50 10.7 mM. The compound 5g showed the best inhibitory
activity against MGC-803 and MCF-7 with IC50 12.5 and 15.9 mM
respectively. Most of the compounds displayed moderate cytotox-
icity against K562. The cytotoxicities of the resulting chalcone
derivatives appeared to be related to the electronic effect of the
substituent group on the benzene rings. Substitution pattern (R2)
in B-ring was changed simultaneously with 4-Me, 4-OMe, H, and 2-
OH groups (5a, 5b, 5c and 5e) showed potential antitumor activity
derivatives. Most of the prepared compounds showed potential
cytotoxicity against several human cancer cell lines. Some
compounds were found to be more potent cytotoxic activities
against certain human cancer cell lines than 5-FU. From the
structure-activity relationships, we may conclude that the
introduction of pyrimidinyl group in chalcone is associated with
enhanced cytotoxic activity. The compound 5g displayed more
potent cytotoxic activities against human cancer cell lines in
comparison with Curcumin. This study may provide valuable
information for further designing and developing more potent
anticancer agents.
Disclosure of interest
The authors declare that they have no conicts of interest
concerning this article.
Acknowledgement
This work was supported by the National Natural Science
Foundation of China (20772042).
 C. Jin et al. / Biomedicine & Pharmacotherapy 67 (2013) 215217
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