Design and synthesis of novel 2′-hydroxy group substituted 2-pyridone derivatives as anticancer agents

Article abstract of DOI:10.1016/j.ejmech.2013.06.046

We have synthesized a series of novel 2-pyridone derivatives with 1,2,3-triazole and evaluated their antitumor activities in vitro. The bioassays showed that the majority of the resultant compounds exerted inhibitory effects on six human cancer cell lines to various extents. In particular, compound 10k showed the best anti-tumor activities (IC₅₀ values of A549, HeLa and SW480 cancer cell lines were 0.86 ± 0.17 mM, 0.54 ± 0.23 mM and 0.21 ± 0.13 mM, respectively).

Full text of DOI:10.1016/j.ejmech.2013.06.046

European Journal of Medicinal Chemistry 67 (2013) 447e453
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Design and synthesis of novel 20-hydroxy group substituted
2-pyridone derivatives as anticancer agents
,
Zhiliang Lv a, Yikai Zhang a, Mingfeng Zhang a, Huan Chen a, Zhenliang Sun b
**
,
,
Dongping Geng a, Chunjuan Niu a, Ke Li a
*
a Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433,
People’s Republic of China
b Branch Hospital in Fengxian of Shanghai No. 6 People’s Hospital, 9588 NanFeng Road, Shanghai 201400, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
We have synthesized a series of novel 2-pyridone derivatives with 1,2,3-triazole and evaluated their anti-
tumor activities in vitro. The bioassays showed that the majority of the resultant compounds exerted
inhibitory effects on six human cancer cell lines to various extents. In particular, compound 10k showed
the best anti-tumor activities (IC50 values of A549, HeLa and SW480 cancer cell lines were
Received 10 April 2013
Received in revised form
16 June 2013
Accepted 19 June 2013
Available online 1 July 2013
0.86 ꢀ 0.17
m
M, 0.54 ꢀ 0.23
m
M and 0.21 ꢀ 0.13
m
M, respectively).
Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords:
2-Pyridone derivatives
Synthesis
Anti-cancer activity
Click chemistry
1. Introduction
form of a water-soluble phosphate prodrug, is currently in phase II
and III clinical trials for the treatment of solid tumors [7,9,10]
However, many of the currently available anticancer agents are
unable to differentiate between the normal cells and the tumor
cells. Thereby, it is hard to overcome primary or secondary resis-
tance mechanisms evolved in the cancer cells [11]. For these rea-
sons mentioned above, there is an urgent need to develop a new
kind of chemotherapeutic agent working on multiple targets or
novel single chemical entity that could modulate several targets of
a multi-factorial disease.
In our previously study, we have designed and synthesized a
series of 2-pyridone derivatives possessing good anti-HBV activity
[12]. In continuation of pursuing more potent anti-HBV agents,
we found that though the modification of 20-hydroxyl group
would reduce the anti-HBV activity of 2-pyridone derivatives,
they showed good to excellent antiproliferative against the hu-
man cancer cell lines. Consequently, we reported herein the
design and synthesis of 20-modified derivatives of novel 2-
pyridones and their evaluation as anticancer agents against six
human cancer cell lines, viz. A549 (human lung adenocarcinoma),
HeLa (Henrietta Lacks strain of cancer cell line), QGY (human
hepatocellular carcinoma cell line), SGC7901 (human gastric
cancer cells), MDA (human breast cancer cell line) and SW480
(colorectal cancer cell line).
Cancer is one of the leading causes of death and only second to
heart diseases [1]. The current treatment options for cancers are
unsatisfactory due to the poor efficacy and relatively significant
side effects [2]. Moreover, the growing incidence of drug resistance
also results in serious medical problems [3]. During decades of
research, several classes of small molecule drug have been studied
deeply as antiproliferative agents (Fig. 1). Colchicine, first isolated
in 1820 from Colchicum autumnale [4], was limited in the use of
anti-gout due to its severe side effects. Paclitaxel, which was iso-
lated in 1966 [5],is used in the treatment of non-small-cell lung
cancer (NSCLC) and other epithelial malignancies [6]. Furthermore,
CA-4 was a natural cis-stilbene product which was first isolated by
Pieet, etc. from the bark of African willow tree Combretum caffrum
[7]. This natural product strongly inhibits tubulin polymerization
by binding to the colchicines binding site which had drawn great
interests to the scientists round the world. A lot of CA-4 analogs had
been reported [1,8]. CA-4P, the most promising compound in the
* Corresponding author. Tel.: þ86 21 81871237.
** Corresponding author. Tel.: þ86 13472410688.
E-mail addresses: skeyan@yahoo.cn (Z. Sun), proflike@sina.com (K. Li).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.06.046

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Z. Lv et al. / European Journal of Medicinal Chemistry 67 (2013) 447e453
2. Chemistry
Furthermore, substituted phenyl derivatives (compounds 8a, 8c, 8d
and 8f) showed better anti-cancer potency than the alkyl group
ones (compounds 8b and 8e), which maybe the poor flexibility
affected the anti-cancer activity severely. Meanwhile, the resultant
compounds with propoxy or ethoxy group (compounds 8j or 8l),
did not show good anti-cancer performance. A simple conclusion
could be drawn that the flexibility and aromatic substituent were
important for the anti-cancer activity.
Based on the conclusion above, compounds 10ae10t were
designed and synthesized via click chemistry approach (Fig. 2).
Apparently, the issues about flexibility and aromatic substituent
could be realized easily. However, the drawback was that when the
1,2,3-triazole ring was between aromatic group and 20-oxygen
atom, it could affect the anti-cancer activity by forming excess
hydrogen bonds with receptor protein. Anyway, the anti-cancer
activity (Table 1) indicated that most of them showed good
activities.
Compound 10a, which had no substituted on the phenyl group,
was more potent than the positive control 5-Fu against A549, HeLa
and SW480 cancer cell lines. When a chloro-group was introduced
on the 4 position of the phenyl group, compound 10k showed 6.5,
30.6, and 74.8 folds more potent than 5-Fu against A549, HeLa and
SW480 cancer cells. When the chloro-group was replaced by fluoro-
and methyl group (compound 10o and 10r), the anti-cancer activity
also maintained. However, the antiproliferative activity of the ana-
logs was lost or decreased severely while the chloro-, fluoro-and
methyl groups were moved to 3 or 2 position (compounds 10i, 10j,
10m,10n,10p and 10q). The same regularity could also be seen from
compounds 10b to 10g. More interestingly, a tert-butyl substituent
on the 4 position of the phenyl group (compound 10t) showed best
antiproliferative against HeLa and SW480 cancer cell lines
The synthetic route of compound 7 was depicted in Scheme 1.
Compound 5 was synthesized by a reported procedure [13].
Coupling of compound 5 with methyl acrylate by a Heck reaction
afforded the intermediate 6. In the presence of triethylamine, the
key intermediate (KI) 7 was obtained by reacting compound 6 with
m-methylanline [12]. The KI 7 was reacted with substituted chlo-
rides or chloroformic esters to give the target compounds 8ae8l
(Scheme 2). Compound 9 was obtained by reacted KI 7 with 3-
bromoprop-1-yne and the target compounds 10ae10t were syn-
thesized through click reaction with substituted benzyl bromides
or benzyl chlorides (Scheme 3).
3. Pharmacology
The potential anticancer activity of all the synthesized target
compounds was tested in A549, HeLa, QGY7701, SGC7901, MDA-
MB-231 and SW480 using MTT assay, and 5-fluorouracil (5-Fu)
was used as a reference antiproliferative drug. The antiproliferative
activity of each compound was expressed as the concentration of
compound that achieved 50% inhibition (IC50).
4. Results and discussion
As showing in Table 1, all the synthesized compounds possessed
good to excellent antiproliferative activities against the six cell lines
and most of them were more active than the positive control (5-Fu)
and different substitutions were important for the anti-
proliferative activity. Compounds 8ae8l, 8k (IC50 against A549,
HeLa, and SW480 were 0.59 ꢀ 0.13
m
M, 0.46 ꢀ 0.06
mM and
0.52 ꢀ 0.23 M, respectively) possessed the best inhibitory effects
m
(0.34 ꢀ 0.23 and 0.11 ꢀ 0.08
mM, respectively) among all the target
against six human cancer cell lines, which were 9.5, 35.9 and 30.2
folds more potent than 5-Fu against A549, HeLa, and SW480 cancer
cells, respectively. When the benzyloxy (compound 8k) was
replaced by para- or ortho-chloro benzyl (compounds 8g and 8h),
the anticancer activity could be maintained except for the SGC7901
and MDA-MB-231 cell lines. Moreover, para-chloro substituted on
phenyl was preferable. Methyl derivative (compound 8e) showed
no anticancer activity against five cancer cell lines of all.
compounds, which were48.5 and 142.7 folds morepotentthan 5-Fu.
Thereby, a simple conclusion could be made that the substituent on
the 4 position was preferable for compounds 10ae10t.
5. Conclusion
In the present study, a library of novel 2-pyridone derivatives
were designed and synthesized and their anticancer activities
Fig. 1. The structures of anticancer agents and compounds 8 and 10.

Z. Lv et al. / European Journal of Medicinal Chemistry 67 (2013) 447e453
449
Scheme 1. Synthesis of the key intermediate compound 7. Reagents and conditions: a. Na, ether, ethyl formate, 0 ꢁC, yield 95%; b. CH3COOH, conc HCl, 100 ꢁC, 30 min, yield 98%; c.
piperidine, methanol, reflux, yield 99%; d. dichloromethane, I2, over night, yield 97%; e. PdCl2(Ph3P)2, CuI, K2CO3, THF/H2O, 100 ꢁC, yield 80%; f. 2-methylaniline, methanol, reflux,
yield 83%.
in vitro against six human cancer cell lines were evaluated. From the
structureeactivity relationship (SAR) of the substituents on the 20-
hydroxy group of the target compounds, the aromatic group, which
was linked through a flexible linker to the 20-hydroxy group, was
needed and substituents at the para-position of the aromatic group
were better for the anticancer activity (compounds 8g, 10k, 10o, 10r
and 10t). The further chemical and biological studies are under way.
Moreover, due to the solubility of the compounds was unsatisfac-
tory, some hydroxyl groups could be introduced to the molecule.
Our finding would provide very useful clues for the design and
development of more potent anticancer agents based on the novel
2-pyridone scaffold.
6.1.1.1.1. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl 4-methylbenzoate (8a). White solid, m.p.: 209e
211 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.547 (s, 3H), 3.765 (s, 3H),
3.878 (s, 3H), 6.608 (d,1H, J ¼ 9.6 Hz), 6.830 (d,1H, J ¼ 2.4 Hz), 6.888
(dd,1H, J1 ¼9 Hz, J2 ¼ 2.4 Hz), 7.019 (d,1H, J ¼ 7.5 Hz), 7.321 (m, 3H),
7.487 (m, 3H), 7.509 (m, 1H), 7.813 (d, 1H, J ¼ 1.8 Hz), 7.824 (dd, 1H,
J1 ¼ 9.9 Hz, J2 ¼ 4.2 Hz), 8.044 (m, 2H). ESI-MS (m/z): 470.3 [M þ 1].
6.1.1.1.2. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl 2-ethylhexanoate (8b). White powder, m.p.: 210e
211 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 0.966 (m, 6H), 1.257 (m, 4H),
1.577 (m, 2H), 1.678 (m, 2H), 2.180 (s, 3H), 2.237 (m, 1H), 3.854 (s,
3H), 6.597 (d, 1H, J ¼ 1.8 Hz), 6.633 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz),
6.656 (d,1H, J ¼ 2.6 Hz), 7.196 (d,1H, J ¼ 7.5 Hz), 7.342 (m, 3H), 7.427
(d, 1H, J ¼ 8.4 Hz), 7.794 (d, 1H, J ¼ 1.6 Hz), 7.949 (dd, 1H, J1 ¼ 6.6 Hz,
J2 ¼ 1.8 Hz). ESI-MS (m/z): 462.6 [M þ 1].
6. Experimental procedures
6.1.1.1.3. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl 4-chlorobenzoate (8c). White powder, m.p.: 185e
6.1. Chemistry
186 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.047 (s, 3H), 3.865 (s, 3H),
Melting points were measured on an uncorrected X-5 Digital
melting point apparatus (Gongyi City Yuhua Instrument Co., Ltd;
China). 1H NMR and 13C NMR spectra were recorded on a BRUKER
AVANCE 300 spectrometer (Bruker Company, Germany), using TMS
as an internal standard and CDCl3 as solvents. Chemical shift are
6.607 (d, 1H, J ¼ 9.6 Hz), 6.831 (d, 1H, J ¼ 2.4 Hz), 6.888 (dd, 1H,
J1 ¼ 9 Hz, J2 ¼ 2.4 Hz), 7.019 (d, 1H, J ¼ 7.5 Hz), 7.321 (m, 3H), 7.487
(m, 2H), 7.509 (m, 1H), 7.813 (d, 1H, J ¼ 1.8 Hz), 7.824 (dd, 1H,
J1 ¼ 9.9 Hz, J2 ¼ 4.2 Hz), 8.044 (m, 2H). ESI-MS (m/z): 474.2 [M þ 1].
6.1.1.1.4. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl 4-fluorobenzoate (8d). White crystal, m.p.: 95e
given in ppm (d). The mass spectra were recorded on an Esquire
3000 LC-MS mass spectrometer. Silica gel thin-layer chromatog-
raphy was performed on precoated plates GF-254 (Qingdao
Haiyang Chemical, China). All solvents and reagents were analytical
pure and no further purification is needed. All starting materials
were commercially available.
96 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.046 (s, 3H), 3.866 (s, 3H), 6.611
(d, 1H, J ¼ 9.6 Hz), 6.821 (d, 1H, J ¼ 2.4 Hz), 6.874 (dd, 1H, J1 ¼9.6 Hz,
J2 ¼ 2.4 Hz), 7.021 (d, 1H, J ¼ 7.5 Hz), 7.318 (m, 3H), 7.447 (m, 2H),
7.521 (m, 1H), 7.812 (d, 1H, J ¼ 1.8 Hz), 7.821 (dd, 1H, J1 ¼ 9.9 Hz,
J2 ¼ 4.2 Hz), 8.007 (m, 2H). ESI-MS (m/z): 458.5 [M þ 1].
6.1.1.1.5. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl acetate (8e). White powder, m.p.: 99e100 ꢁC; 1H
6.1.1. Synthesis of the target compounds
6.1.1.1. General procedure for the synthesis of compounds 8ae8l.
Substituted acyl chloride (4.5 mmol) was added dropwise into a
solution of triethylamine (0.3 g, 3.3 mmol) and compound 7 (1 g,
3 mmol) in dry CH2Cl2 (15 mL). The reaction mixture was stirred at
20 ꢁC for 1 h. 10% HCl solution (20 mL) was added to quench the
reaction. The CH2Cl2 layer was washed by saturated NaHCO3 solu-
tion (20 mL), water and dried with MgSO4. CH2Cl2 was removed
and the crude product was recrystallized in ethyl acetate to give the
target compound.
NMR (CDCl3, 300 MHz)
d 2.780 (s, 3H), 2.237 (s, 3H), 3.855 (s, 3H),
6.590 (d,1H, J ¼ 1.8 Hz), 6.626 (dd,1H, J1 ¼9.6 Hz, J2 ¼ 2.4 Hz), 6.652
(d, 1H, J ¼ 2.6 Hz), 7.196 (d, 1H, J ¼ 7.5 Hz), 7.442 (m, 3H), 7.428 (d,
1H, J ¼ 8.4 Hz), 7.797 (d, 1H, J ¼ 1.6 Hz), 7.951 (dd, 1H, J1 ¼ 6.6 Hz,
J2 ¼ 1.8 Hz). ESI-MS (m/z): 378.4 [M þ 1].
6.1.1.1.6. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl benzoate (8f). White crystal, m.p.: 76e78 ꢁC; 1H
NMR (CDCl3, 300 MHz)
d 2.023 (s, 3H), 3.878 (s, 3H), 6.608 (d, 1H,
Scheme 2. Synthesis of the target compounds 8ae8l. Reagents and conditions: a. substituted acyl chlorides, CH2Cl2, Et3N, 20 ꢁC, 1 h.

450
Z. Lv et al. / European Journal of Medicinal Chemistry 67 (2013) 447e453
Scheme 3. Synthesis of the target compounds 10ae10t. Reagents and conditions: a. 3-bromoprop-1-yne, K2CO3, CH2Cl2, 20 ꢁC, 6 h; b. substituted benzyl chlorides, NaN3,
CuSO4$5H2O, sodium ascorbate, acetone, r.t., 2 h.
J ¼ 9.6 Hz), 6.830 (d, 1H, J ¼ 2.4 Hz), 6.888 (dd, 1H, J1 ¼ 9 Hz,
J2 ¼ 2.4 Hz), 7.019 (d, 1H, 7.5 Hz), 7.321 (m, 3H), 7.487 (m, 3H), 7.509
(m, 1H), 7.813 (d, 1H, J ¼ 1.8 Hz), 7.824 (dd, 1H, J1 ¼ 9.9 Hz,
J2 ¼ 4.2 Hz), 8.044 (m, 2H). ESI-MS (m/z): 440.4 [M þ 1].
6.1.1.1.7. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl 2-(4-chlorophenyl)acetate (8g). White crystal,
m.p.: 79e80 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
2.120 (s, 3H), 3.578 (s,
2H), 3.898 (s, 3H), 6.618 (d, 1H, J ¼ 9.3 Hz), 6.748 (d, 1H, J ¼ 2.4 Hz),
Table 1
IC50 determination of cytotoxicity of target compounds against human cancer cell lines.
Compd.
R
Cytotoxicity IC50 ꢀ SEM (
m
M)b
A549a
HeLaa
QGY7701a
SGC7901a
MDA-MB-231a
SW480a
5-Fuc
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
e
5.62 ꢀ 0.72
3.24 ꢀ 0.59
2.95 ꢀ 0.21
5.23 ꢀ 0.62
3.68 ꢀ 0.66
>30
16.52 ꢀ 0.93
3.27 ꢀ 0.72
2.28 ꢀ 0.33
1.56 ꢀ 0.53
6.86 ꢀ 0.80
>30
14.30 ꢀ 0.055
>30
>30
6.04 ꢀ 0.83
3.96 ꢀ 0.77
1.48 ꢀ 0.70
5.79 ꢀ 0.43
3.62 ꢀ 0.02
6.21 ꢀ 0.83
1.42 ꢀ 0.43
3.48 ꢀ 0.33
1.45 ꢀ 0.49
2.44 ꢀ 0.43
4.18 ꢀ 0.72
0.69 ꢀ 0.43
3.35 ꢀ 0.46
6.94 ꢀ 0.49
1.25 ꢀ 0.44
1.23 ꢀ 0.13
5.68 ꢀ 0.63
2.29 ꢀ 0.03
>30
13.65 ꢀ 0.82
0.54 ꢀ 0.12
0.37 ꢀ 0.11
1.84 ꢀ 0.15
2.35 ꢀ 0.37
>30
1.18 ꢀ 0.41
2.44 ꢀ 0.49
2.97 ꢀ 0.83
3.28 ꢀ 0.67
2.11 ꢀ 0.99
0.75 ꢀ 0.58
>30
15.71 ꢀ 0.86
2.31 ꢀ 0.32
3.35 ꢀ 0.24
1.33 ꢀ 0.32
2.78 ꢀ 0.07
>30
3.12 ꢀ 0.11
0.58 ꢀ 0.33
1.17 ꢀ 0.43
2.75 ꢀ 0.74
5.97 ꢀ 0.09
0.52 ꢀ 0.23
4.56 ꢀ 0.83
5.33 ꢀ 0.36
2.51 ꢀ 0.43
3.62 ꢀ 0.41
2.32 ꢀ 0.46
>30
p-Methylphenyl
2-Ethylamyl
p-Chlorophenyl
p-Fluorophenyl
Methyl
>30
9.64 ꢀ 0.82
>30
Phenyl
4.47 ꢀ 0.72
0.49 ꢀ 0.13
1.94 ꢀ 0.83
3.89 ꢀ 0.40
6.13 ꢀ 0.23
0.59 ꢀ 0.13
5.83 ꢀ 0.41
7.59 ꢀ 0.93
3.64 ꢀ 0.73
5.35 ꢀ 0.09
4.46 ꢀ 0.33
5.45 ꢀ 0.72
8.32 ꢀ 0.83
7.28 ꢀ 0.77
4.31 ꢀ 0.43
3.61 ꢀ 0.40
0.69 ꢀ 0.09
1.53 ꢀ 0.07
0.86 ꢀ 0.17
2.56 ꢀ 0.73
3.96 ꢀ 0.63
3.06 ꢀ 0.43
0.48 ꢀ 0.44
3.21 ꢀ 0.83
3.25 ꢀ 0.11
0.61 ꢀ 0.33
1.54 ꢀ 0.08
1.73 ꢀ 0.49
7.29 ꢀ 0.59
0.58 ꢀ 0.43
0.87 ꢀ 0.08
5.33 ꢀ 0.93
7.03 ꢀ 0.47
0.46 ꢀ 0.06
7.44 ꢀ 0.77
7.82 ꢀ 0.59
4.23 ꢀ 0.59
5.22 ꢀ 0.31
4.52 ꢀ 0.13
4.25 ꢀ 0.43
8.05 ꢀ 0.89
9.62 ꢀ 0.52
0.89 ꢀ 0.03
3.12 ꢀ 0.48
1.70 ꢀ 0.33
3.71 ꢀ 0.59
0.54 ꢀ 0.23
3.51 ꢀ 0.13
4.83 ꢀ 0.81
5.75 ꢀ 0.82
8.48 ꢀ 0.59
4.86 ꢀ 0.53
3.27 ꢀ 0.18
0.38 ꢀ 0.03
0.99 ꢀ 0.43
0.34 ꢀ 0.23
>30
p-Chlorobenzyl
o-Chlorobenzyl
3,5-Dinitrophenyl
Propoxy
Benzyloxy
Ethoxy
5.68 ꢀ 0.52
6.05 ꢀ 0.59
>30
>30
4.33 ꢀ 0.59
>30
9
e
9.08 ꢀ 0.73
>30
>30
>30
>30
>30
>30
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
10s
10t
H
o-Bromo
m-Bromo
p-Bromo
o-Cyano
m-Cyano
p-Cyano
m-Nitro
o-Chloro
m-Chloro
p-Chloro
2,4-Dichloro
o-Fluoro
>30
4.99 ꢀ 0.83
2.47 ꢀ 0.08
>30
>30
>30
>30
>30
>30
>30
>30
>30
2.87 ꢀ 0.72
3.01 ꢀ 0.43
4.72 ꢀ 0.11
>30
0.43 ꢀ 0.33
1.39 ꢀ 0.93
0.38 ꢀ 0.33
0.38 ꢀ 0.02
0.32 ꢀ 0.72
1.19 ꢀ 0.43
1.14 ꢀ 0.33
1.24 ꢀ 0.43
1.46 ꢀ 0.62
1.34 ꢀ 0.05
0.21 ꢀ 0.45
0.49 ꢀ 0.08
0.59 ꢀ 0.06
3.35 ꢀ 0.45
0.55 ꢀ 0.06
4.42 ꢀ 0.72
0.39 ꢀ 0.05
1.37 ꢀ 0.19
0.21 ꢀ 0.13
2.22 ꢀ 0.40
3.28 ꢀ 0.83
2.23 ꢀ 0.13
2.37 ꢀ 0.93
3.07 ꢀ 0.43
2.45 ꢀ 0.09
0.48 ꢀ 0.13
>30
>30
>30
>30
1.10 ꢀ 0.59
0.41 ꢀ 0.55
>30
6.43 ꢀ 0.72
>30
m-Fluoro
p-Fluoro
>30
>30
5.44 ꢀ 0.39
4.63 ꢀ 0.22
6.38 ꢀ 0.23
>30
>30
3.39 ꢀ 0.07
0.19 ꢀ 0.43
o-Methyl
m-Methyl
p-Methyl
p-Methoxyl
p-tert-Butyl
>30
>30
5.48 ꢀ 0.59
1.28 ꢀ 0.63
3.52 ꢀ 0.44
0.11 ꢀ 0.08
a
Abbreviations: A549: human lung adenocarcinoma cell line; HeLa: human cervical carcinoma cell line; QGY7701: human hepatoma cell line; SGC7901: human gastric
adenocarcinoma cell line; MDA-MB-231: human breast carcinoma cell line; SW480: human colon carcinoma cell line.
b
The IC50 value was defined as the concentration at which 50% survival of cells was observed.
Used as a positive control.
c

Z. Lv et al. / European Journal of Medicinal Chemistry 67 (2013) 447e453
451
Fig. 2. The design of the target compounds 10ae10t.
6.842 (dd, 1H, J1 ¼ 8.7 Hz, J2 ¼ 2.4 Hz), 7.121 (d, 1H, J ¼ 8.6 Hz), 7.351
(m, 7H), 7.496 (d, 1H, J ¼ 8.7 Hz), 7.740 (d, 1H, J ¼ 2.4 Hz), 7.875 (dd,
1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz). ESI-MS (m/z): 488.6 [M þ 1].
(CDCl3, 300 MHz)
d
2.180 (s, 3H), 2.383 (t, 1H, J ¼ 2.4 Hz), 3.854 (s,
3H), 4.658 (d, 2H, J ¼ 2.4 Hz), 6.597 (d, 1H, J ¼ 1.8 Hz), 6.633 (d, 1H,
J ¼ 2.4 Hz), 6.656 (d, 1H, J ¼ 9.6 Hz), 7.196 (d, 1H, J ¼ 7.5 Hz), 7.342
(m, 3H), 7.427 (d, 1H, J ¼ 7.4 Hz), 7.794 (d, 1H, J ¼ 1.6 Hz), 7.949 (dd,
1H, J1 ¼ 6.6 Hz, J2 ¼ 1.8 Hz). ESI-MS(m/z): 374.1 [M þ 1].
6.1.1.1.8. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl 2-(2-chlorophenyl)acetate (8h). White crystal,
m.p.: 84e85 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.121 (s, 3H), 3.573 (s,
2H), 3.899 (s, 3H), 6.618 (d, 1H, J ¼ 9.3 Hz), 6.750 (d, 1H, J ¼ 2.4 Hz),
6.838 (dd, 1H, J1 ¼ 8.7 Hz, J2 ¼ 2.4 Hz), 7.109 (d, 1H, J ¼ 8.6 Hz), 7.551
(m, 7H), 7.516 (d, 1H, J ¼ 8.7 Hz), 7.738 (d, 1H, J ¼ 2.4 Hz), 7.785 (dd,
1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz). ESI-MS (m/z): 488.3 [M þ 1].
6.1.3. General procedure for the synthesis of compounds 10ae10t
To a solution of substituted benzyl chloride (3.3 mmol) in
acetone (9 mL) with stirring at r.t. for 30 min. Then NaN3 (0.24 g,
3.6 mmol), compound 9 (1.12 g, 3 mmol), saturated CuSO4 solution
(10 mL) and catalytic amount of sodium ascorbate were added. The
mixture was stirred at room temperature for 2 h. The mixture was
poured into ice-water (200 mL) with severe stirring. The solution
was extracted with EtOAc and the EtOAc layer was washed with
brine, dried with MgSO4 and concentrated to afford target
compound.
6.1.1.1.9. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl 2-(3,5-dinitrophenyl)acetate (8i). Yellow crystal,
m.p. 68e70 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.178 (s, 3H), 3.917 (s,
3H), 6.669 (d, 1H, J ¼ 9.6 Hz), 6.882 (d, 1H, J ¼ 2.4 Hz), 6.921 (dd, 1H,
J1 ¼ 8.4 Hz, J2 ¼ 1.6 Hz), 7.186 (m, 1H), 7.367 (m, 3H), 7.557 (d, 1H,
J ¼ 8.4 Hz), 7.83 (m, 2H), 9.277 (m, 3H). ESI-MS (m/z): 530.6 [M þ 1].
6.1.1.1.10. 5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-3-
carbonyl)phenyl propyl carbonate (8j). Yellow powder, m.p.: 97e
6.1.3.1. 5-(2-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-4-
98 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
2.180 (s, 3H), 2.383 (t, 1H,
methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10a). White crystal,
J ¼ 2.4 Hz), 3.854 (s, 3H), 4.658 (d, 2H, J ¼ 2.4 Hz), 6.597 (d, 1H,
J ¼ 1.8 Hz), 6.633 (d, 1H, J ¼ 2.4 Hz), 6.656 (d, 1H, J ¼ 9.6 Hz), 7.196
(d, 1H, J ¼ 7.5 Hz), 7.342 (m, 3H), 7.427 (d, 1H, J ¼ 7.4 Hz), 7.794 (d,
1H, J ¼ 1.6 Hz), 7.949 (dd, 1H, J1 ¼ 6.6 Hz, J2 ¼ 1.8 Hz). ESI-MS (m/z):
422.2 [M þ 1].
m.p.: 85e86 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.045 (s, 3H), 3.843 (s,
3H), 5.164 (s, 2H), 5.484 (s, 2H), 6.563 (m, 2H), 6.657 (s, 1H), 6.993
(d, 1H, J ¼ 9.3 Hz), 7.254 (m, 2H), 7.387 (m, 7H), 7.736 (d, 1H,
J ¼ 2.4 Hz), 7.845 (d, 1H, J1 ¼9.6 Hz, J2 ¼ 2.7 Hz). ESI-MS (m/z): 507.3
[M þ 1].
6.1.1.1.11. Benzyl 5-methoxy-2-(6-oxo-1-o-tolyl-1,6-
dihydropyridine-3-carbonyl)phenyl carbonate (8k). Yellow powder,
6.1.3.2. 5-(2-((1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-
m.p.: 108e109 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
2.131 (s, 3H), 3.839
methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10b). White crystal,
(s, 3H), 5.198 (s, 2H), 6.618 (d, 1H, J ¼ 9.3 Hz), 6.748 (d, 1H,
J ¼ 2.4 Hz), 6.842 (dd, 1H, J1 ¼ 8.7 Hz, J2 ¼ 2.4 Hz), 7.121 (d, 1H,
J ¼ 8.6 Hz), 7.351 (m, 8H), 7.496 (d, 1H, J ¼ 8.7 Hz), 7.740 (d, 1H,
J ¼ 2.4 Hz), 7.875 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz). ESI-MS (m/z):
470.3 [M þ 1].
m.p.: 97e98 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 1.879 (s, 3H), 3.789 (s,
3H), 5.178 (s, 2H), 5.775 (s, 2H), 6.494 (d, 1H, J ¼ 9.6 Hz), 6.609 (dd,
1H, J1 ¼ 8.4 Hz, J2 ¼ 2.1 Hz), 6.853 (d, 1H, J ¼ 1.8 Hz), 7.251 (m, 3H),
7.455 (m, 3H), 7.558 (m, 1H), 7.635 (m, 2H), 7.805 (dd, 1H,
J1 ¼9.6 Hz, J2 ¼ 1.8 Hz), 7.882 (d,1H, J ¼ 1.2 Hz), 7.908 (s,1H). ESI-MS
(m/z): 585.1 [M þ 1].
6.1.1.1.12. Ethyl 5-methoxy-2-(6-oxo-1-o-tolyl-1,6-
dihydropyridine-3-carbonyl)phenyl carbonate (8l). Light yellow
powder, m.p.: 116e118 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
1.331 (t, 3H,
6.1.3.3. 5-(2-((1-(3-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-
J ¼ 7.2 Hz), 2.192 (s, 3H), 3.856 (s, 3H), 4.219 (q, 2H, J ¼ 7.2 Hz), 6.678
(d, 1H, J ¼ 9.6 Hz), 6.763 (d, 1H, J ¼ 2.4 Hz), 6.847 (dd,1H, J1 ¼8.7 Hz,
J2 ¼ 2.4 Hz), 7.218 (m, 1H), 7.367 (m, 3H), 7.506 (d, 1H, J ¼ 8.7), 7.784
(m, 1H), 7.938 (dd, 1H, J1 ¼ 9.9 Hz, J2 ¼ 2.7 Hz). ESI-MS (m/z): 408.9
[M þ 1].
methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one 10c. White crystal,
m.p.: 85e86 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.138 (s, 3H), 3.849 (s,
3H), 5.166 (s, 2H), 5.732 (s, 2H), 6.195 (d, 1H, J ¼ 9.4 Hz), 6.664 (dd,
1H, J1 ¼ 9.4 Hz, J2 ¼ 2.4 Hz), 6.884 (d, 1H, J ¼ 1.8 Hz), 7.685 (m, 2H),
7.395 (m, 4H), 7.448 (m, 1H), 7.586 (m, 2H), 7.811 (dd, 1H,
J1 ¼9.6 Hz, J2 ¼ 1.8 Hz), 7.888 (d,1H, J ¼ 1.2 Hz), 7.877 (s,1H). ESI-MS
(m/z): 585.1 [M þ 1].
6.1.2. Synthesis of 5-(4-methoxy-2-(prop-2-ynyloxy)benzoyl)-1-o-
tolylpyridin-2(1H)-one (9)
A solution of compound 7 (1 g, 3mmol), K2CO3 (0.4 g, 3 mmol)
and 3-bromoprop-1-yne (0.4 g, 3.3 mmol) in CH2Cl2 (15 mL) was
stirred at 20 ꢁC for 6 h. 10% HCl solution (20 mL) was added to
quench the reaction after which completed when monitored by
TLC. Consequently, the CH2Cl2 layer was washed by NaHCO3 solu-
tion (20 mL), water and dried with MgSO4. CH2Cl2 was removed
and the crude product was re-crystallized in ethyl acetate. White
crystal was obtained, 0.98 g, yield 87.6%, m.p.: 148e149 ꢁC; 1H NMR
6.1.3.4. 5-(2-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-
methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one 10d. White crystal,
m.p.: 148e150 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 1.889 (s, 3H), 3.788
(s, 3H), 5.155 (s, 2H), 5.547 (s, 2H), 6.499 (d, 1H, J ¼ 9.6 Hz), 6.531
(dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 6.849 (d, 1H, J ¼ 2.1 Hz), 7.210 (m,
2H), 7319 (m, 5H), 7.533 (m, 2H), 7.696 (d, 1H, J ¼ 1.8 Hz), 7.803 (dd,
1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 8.091 (s, 1H). ESI-MS (m/z): 585.2
[M þ 1].

452
Z. Lv et al. / European Journal of Medicinal Chemistry 67 (2013) 447e453
6.1.3.5. 2-((4-((5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-
3-carbonyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzoni-
trile (10e). White crystal, m.p.: 192e193 ꢁC; 1H NMR (CDCl3,
White crystal, m.p.: 139e140 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 1.899
(s, 3H), 3.790 (s, 3H), 5.168 (s, 2H), 5.649 (s, 2H), 6.495 (d, 1H,
J ¼ 9.6 Hz), 6.611 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 6.850 (d, 1H,
J ¼ 1.4 Hz), 7.221 (m, 2H), 7.331 (m, 4H), 7.423 (dd, 1H, J1 ¼ 8.1 Hz,
J2 ¼ 2.1 Hz), 7.674 (m, 2H), 7.807 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.7 Hz),
8.042 (s, 1H). ESI-MS (m/z): 575.4 [M þ 1].
300 MHz)
d 1.881 (s, 3H), 3.789 (s, 3H), 5.178 (s, 2H), 5.775 (s, 2H),
6.494 (d,1H, J ¼ 9.6 Hz), 6.609 (dd,1H, J1 ¼8.4 Hz, J2 ¼ 2.1 Hz), 6.853
(d, 1H, J ¼ 1.8 Hz), 7.251 (m, 3H), 7.355 (m, 3H), 7.538 (m, 1H), 7.682
(m, 2H), 7.805 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 1.8 Hz), 7.882 (d, 1H,
J ¼ 1.2 Hz), 7.908 (s, 1H). ESI-MS (m/z): 532.3 [M þ 1].
6.1.3.13. 5-(2-((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-
4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10m). White crys-
6.1.3.6. 3-((4-((5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-
3-carbonyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzoni-
trile (10f). White crystal, m.p.: 167e168 ꢁC; 1H NMR (CDCl3,
tal, m.p.: 123e124 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 1.887 (s, 3H),
3.789 (s, 3H), 5.159 (s, 2H), 5.620 (s, 2H), 6.502 (d, 1H, J ¼ 9.6 Hz),
6.609 (dd, 1H, J1 ¼8.4 Hz, J2 ¼ 1.4 Hz), 6.850 (d, 1H, J ¼ 2.4 Hz), 7.228
(m, 5H), 7.339 (m, 4H), 7.697 (d, 1H, J ¼ 2.4 Hz), 7.806 (dd, 1H,
J1 ¼ 9.6 Hz, J2 ¼ 2.7 Hz), 8.038 (s, 1H). ESI-MS (m/z): 524.3[M þ 1].
300 MHz)
d 2.138 (s, 3H), 3.849 (s, 3H), 5.166 (s, 2H), 5.732 (s, 2H),
6.195 (d,1H, J ¼ 9.4 Hz), 6.664 (dd,1H, J1 ¼9.4 Hz, J2 ¼ 2.4 Hz), 6.884
(d, 1H, J ¼ 1.8 Hz), 7.685 (m, 2H), 7.395 (m, 4H), 7.448 (m, 1H), 7.586
(m, 2H), 7.811 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 1.8 Hz), 7.888 (d, 1H,
J ¼ 1.2 Hz), 7.877 (s, 1H). ESI-MS (m/z): 532.6 [M þ 1].
6.1.3.14. 5-(2-((1-(3-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-
4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10n). White crys-
tal, m.p.: 81e83 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.138 (s, 3H), 3.849
6.1.3.7. 4-((4-((5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-
3-carbonyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzoni-
trile (10g). White crystal, m.p.: 194e196 ꢁC; 1H NMR (CDCl3,
(s, 3H), 5.166 (s, 2H), 5.732 (s, 2H), 6.195 (d, 1H, J ¼ 9.4 Hz), 6.664
(dd, 1H, J1 ¼ 9.4 Hz, J2 ¼ 2.4 Hz), 6.884 (d, 1H, J ¼ 1.8 Hz), 7.685 (m,
2H), 7.395 (m, 4H), 7.448 (m, 1H), 7.586 (m, 2H), 7.811 (dd, 1H,
J1 ¼9.6 Hz, J2 ¼ 1.8 Hz), 7.888 (d,1H, J ¼ 1.2 Hz), 7.877 (s,1H). ESI-MS
(m/z): 524.1 [M þ 1].
300 MHz)
d 1.889 (s, 3H), 3.788 (s, 3H), 5.155 (s, 2H), 5.547 (s, 2H),
6.499 (d,1H, J ¼ 9.6 Hz), 6.531 (dd,1H, J1 ¼9.6 Hz, J2 ¼ 2.4 Hz), 6.849
(d, 1H, J ¼ 2.1 Hz), 7.210 (m, 2H), 7319 (m, 5H), 7.533 (m, 2H), 7.696
(d, 1H, J ¼ 1.8 Hz), 7.803 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 8.091 (s,
1H). ESI-MS (m/z): 532.1 [M þ 1].
6.1.3.15. 5-(2-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-
4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10o). White crys-
tal, m.p.: 86e87 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 1.878 (s, 3H), 3.789
6.1.3.8. 3-((4-((5-Methoxy-2-(6-oxo-1-o-tolyl-1,6-dihydropyridine-
3-carbonyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl ni-
trate (10h). Yellow crystal, m.p.: 123e124 ꢁC; 1H NMR (CDCl3,
(s, 3H), 5.150 (s, 2H), 5.548 (s, 2H), 6.503 (d, 1H, J ¼ 9.6 Hz), 6.611
(dd, 1H, J1 ¼ 11.4 Hz, J2 ¼ 1.8 Hz), 6.849 (d, 1H, J ¼ 2.1 Hz), 7.208 (m,
3H), 7.332 (m, 6H), 7.696 (d, 1H, J ¼ 2.4 Hz), 7.808 (dd, 1H,
J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 8.072 (s, 1H). ESI-MS (m/z): 524.6 [M þ 1].
300 MHz)
d 1.869 (s, 3H), 3.784 (s, 3H), 5.172 (s, 2H), 5.743 (s, 2H),
6.469 (d,1H, J ¼ 9.6 Hz), 6.607 (dd,1H, J1 ¼8.4 Hz, J2 ¼ 1.4 Hz), 6.848
(d, 1H, 1.4 Hz), 7.187 (d, 1H, J ¼ 0.9 Hz), 7.313 (m, 4H), 7.671 (m, 3H),
7.798 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.7 Hz), 8.173 (m, 3H). ESI-MS (m/z):
552.5 [M þ 1].
6.1.3.16. 5-(2-((1-(2-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-
4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10p). White crys-
tal, m.p.: 146e147 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.281 (s, 3H),
2.321 (s, 3H), 3.789 (s, 3H), 5.174 (s, 2H), 5.765 (s, 2H), 6.492 (d, 1H,
J ¼ 9.6 Hz), 6.612 (dd, 1H, J1 ¼ 9.4 Hz, J2 ¼ 2.1 Hz), 6.851 (d, 1H,
J ¼ 1.8 Hz), 7.256 (m, 3H), 7.555 (m, 3H), 7.568 (m, 1H), 7.684 (m,
2H), 7.815 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 1.8 Hz), 7.862 (d, 1H, J ¼ 1.2 Hz),
7.918 (s, 1H). ESI-MS (m/z): 521.5 [M þ 1].
6.1.3.9. 5-(2-((1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-
methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10i). White crystal,
m.p.: 95e96 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 1.882 (s, 3H), 3.787 (s,
3H), 5.177 (s, 2H), 5.772 (s, 2H), 6.491 (d, 1H, J ¼ 9.6 Hz), 6.610 (dd,
1H, J1 ¼ 8.4 Hz, J2 ¼ 2.1 Hz), 6.853 (d, 1H, J ¼ 1.8 Hz), 7.251 (m, 3H),
7.364 (m, 3H), 7.538 (m, 1H), 7.677 (m, 2H), 7.805 (dd, 1H,
J1 ¼9.6 Hz, J2 ¼ 1.8 Hz), 7.882 (d,1H, J ¼ 1.2 Hz), 7.910 (s,1H). ESI-MS
(m/z): 541.2 [M þ 1].
6.1.3.17. 5-(2-((1-(3-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-
4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10q). White crys-
tal, m.p.: 83e85 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.253 (s, 3H), 2.332
(s, 3H), 3.889 (s, 3H), 5.178 (s, 2H), 5.764 (s, 2H), 6.493 (d, 1H,
J ¼ 9.6 Hz), 6.622 (dd, 1H, J1 ¼ 9.4 Hz, J2 ¼ 2.1 Hz), 6.855 (d, 1H,
J ¼ 1.8 Hz), 7.266 (m, 3H), 7.532 (m, 3H), 7.568 (m, 1H), 7.684 (m,
2H), 7.812 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 1.8 Hz), 7.867 (d, 1H, J ¼ 1.2 Hz),
7.915 (s, 1H). ESI-MS (m/z): 521.1 [M þ 1].
6.1.3.10. 5-(2-((1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-
4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10j). White crystal,
m.p.: 83e84 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 2.135 (s, 3H), 3.889 (s,
3H), 5.168 (s, 2H), 5.734 (s, 2H), 6.191 (d, 1H, J ¼ 9.6 Hz), 6.654 (dd,
1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 6.856 (d, 1H, J ¼ 1.8 Hz), 7.674 (m, 2H),
7.368 (m, 4H), 7.436 (m, 1H), 7.586 (m, 2H), 7.811 (dd, 1H,
J1 ¼9.6 Hz, J2 ¼ 1.8 Hz), 7.863 (d, 1H, J ¼ 1.2 Hz), 7.874 (s,1H). ESI-MS
(m/z): 541.5 [M þ 1].
6.1.3.18. 5-(2-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-
4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10r). White crystal,
m.p.: 85e86 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 1.889 (s, 3H), 2.543 (s,
3H), 3.788 (s, 3H), 5.155 (s, 2H), 5.547 (s, 2H), 6.499 (d, 1H,
J ¼ 9.6 Hz), 6.531 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 6.849 (d, 1H,
J ¼ 2.1 Hz), 7.210 (m, 2H), 7319 (m, 5H), 7.533 (m, 2H), 7.696 (d, 1H,
J ¼ 1.8 Hz), 7.803 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 8.091 (s, 1H). ESI-
MS (m/z): 521.4 [M þ 1].
6.1.3.11. 5-(2-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-
4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one (10k). White crys-
tal, m.p.: 132e133 ꢁC 1H NMR (CDCl3, 300 MHz)
d 1.887 (s, 3H),
3.786 (s, 3H), 5.157 (s, 2H), 5.547 (s, 2H), 6.501 (d, 1H, J ¼ 9.6 Hz),
6.531 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 6.849 (d,1H, J ¼ 2.1 Hz), 7.233
(m, 2H), 7332 (m, 5H), 7.533 (m, 2H), 7.697 (d, 1H, J ¼ 1.8 Hz), 7.805
(dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 8.091 (s, 1H). ESI-MS (m/z): 541.8
[M þ 1].
6.1.3.19. 5-(2-((1-(4-Methoxylbenzyl)-1H-1,2,3-triazol-4-yl)
methoxy)-4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one
(10s).
1.889 (s,
White crystal, m.p.: 98e99 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
3H), 3.743 (s, 3H), 3.788 (s, 3H), 5.155 (s, 2H), 5.547 (s, 2H), 6.499 (d,
1H, J ¼ 9.6 Hz), 6.531 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 6.849 (d, 1H,
J ¼ 2.1 Hz), 7.210 (m, 2H), 7319 (m, 5H), 7.533 (m, 2H), 7.696 (d, 1H,
6.1.3.12. 5-(2-((1-(2,4-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl)
methoxy)-4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one
(10l).

Z. Lv et al. / European Journal of Medicinal Chemistry 67 (2013) 447e453
453
J ¼ 1.8 Hz), 7.803 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.4 Hz), 8.091 (s, 1H). ESI-
Acknowledgments
MS (m/z): 537.2 [M þ 1].
This work was supported by the National Natural Science
Foundation of China (grant no. 21172259). We also thank staffs at
the Key Laboratory of Drug Research for Special Environments of
PLA.
6.1.3.20. 5-(2-((1-(4-tert-Butylbenzyl)-1H-1,2,3-triazol-4-yl)
methoxy)-4-methoxybenzoyl)-1-o-tolylpyridin-2(1H)-one
(10t).
White crystal, m.p.: 83e84 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
1.232 (s,
9H), 1.896 (s, 3H), 3.785 (s, 3H), 5.144 (s, 2H), 5.501 (s, 2H), 6.491 (d,
1H, J ¼ 9.6 Hz), 6.607 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.1 Hz), 6.844 (d, 1H,
J ¼ 2.1 Hz), 7.207 (m, 2H), 7.337 (m, 7H), 7.700 (d, 1H, J ¼ 2.4 Hz),
7.803 (dd, 1H, J1 ¼ 9.6 Hz, J2 ¼ 2.7 Hz), 8.040 (s, 1H). ESI-MS (m/z):
563.7 [M þ 1].
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2013.06.
046.
6.2. Biological assay
6.2.1. Screening of the in vitro anti-cancer activities
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