Synthesis and biological evaluation of N-(4-phenylthiazol-2-yl)cinnamamide derivatives as novel potential anti-tumor agents

Article abstract of DOI:10.1039/c4md00573b

In this study, a series of novel N-(4-phenylthiazol-2-yl)cinnamamide derivatives (7a-8n) were synthesized and evaluated for their anti-proliferative activities in vitro by MTT assay and a possible antitumor mechanism was also explored. SAR analysis showed that steric effects played an important role on the anti-tumor activity. The most potent analogue 8f showed excellent inhibitions on the K562, Bel7402, A549 and Jurkat cells ranging from sub-micromolar to nanomolar concentration. Compound 8f inhibited Jurkat cells with an IC₅₀ value of 0.035 μM with no apparent toxicity in different non-cancerous cells. Furthermore, it was suggested that the possible mechanism of 8f might be associated with inducing cancer cell apoptosis following flow cytometer analysis and Hoechst 33358 staining assays.

Full text of DOI:10.1039/c4md00573b

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CONCISE ARTICLE
Synthesis and Biological Evaluation of N-(4-
phenylthiazol-2-yl) Cinnamamide Derivatives as
[Cite this: DOI: 10.1039/x0xx00000x
Novel Potential Anti-tumor Agents†
Yong Luo, ‡a Yongxia Zhu, ‡a Kai Ran, a Zhihao Liu, a Ningyu Wang, a Qiang Feng, a
c Jun Zeng, a Lidan Zhang, b Bing He, a c Tinghong Ye, a Shirui Zhu d, Xiaolong Qiu e
and Luoting Yua*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
In this study, a series of novel Nꢀ(4ꢀphenylthiazolꢀ2ꢀyl) cinnamamide derivatives (7a~8n) were
synthesized and evaluated for their antiꢀproliferative activities in vitro by MTT assay and the
possible antitumor mechanism was also explored. The SAR analysis showed that the steric effect
played an important role on the antiꢀtumor activity. The most potent analogue 8f showed
excellent inhibitions on the K562, Bel7402, A549 and Jurkat cells ranging from subꢀmicromolar
to nanomolar concentration. Compound 8f inhibited Jurkat cells with IC50 value of 0.035 ꢁM
with no apparent toxicity in different nonꢀcancerous cells. Furthermore, it was suggested that the
possible mechanism of 8f might be associated with inducing cancer cells apoptosis on the results
of flow cytometer analysis and Hoechst 33358 staining assays.
www.rsc.org/
on the antiꢀtumor effects of Nꢀ(4ꢀphenylthiazolꢀ2ꢀyl)
cinnamamide derivatives (Fig. 1).
Introduction
Cancer continues to be a major public health problem in
the world due to the highly cancer occurrence.1 As some
chemotherapy drugs had severely side effect or caused therapy
resistance,2, 3 efficiency and low toxicity drugs were imperative
needed. Cancer cell survival status was related to various
factors, including selfꢀsufficiency in growth signals, evasion of
programmed cell death (apoptosis), insensitivity to growthꢀ
inhibitory signals, sustained angiogenesis, limitless replicative
potential, the tissue invasion and metastasis, in which the
deregulation of apoptosis was believed to be a hallmark of most
types of cancer.4ꢀ6 Thus, compounds that restore apoptosis
could be effective drugs to address uncontrolled proliferation
cancer cells.7
Thiazole derivatives played a wide range of potential
applications in many areas such as antiꢀbacteria, antiꢀfungal,
antiꢀtubercular, antiꢀvirals, antiꢀepileptic and antiꢀcancer
activities.8ꢀ13 As a thiazolꢀ2ꢀamine derivative, particularly,
Dasatinib had been in clinical application successfully.14 Apart
from it, phenyl thiazoleꢀ2ꢀamine derivatives had also been
found potent antiꢀcancer activity, such as tubulin
polymerization inhibitor CKDꢀ516 which had significant
growth inhibition against CT26 colon cancer in vivo.15 In
addition, another phenyl thiazoleꢀ2ꢀamine derivative TRꢀ644
showed potent microtubule depolymerizing activity, caused cell
cycle arrest and inhibited angiogenesis.16 On the other hands,
some cinnamamide derivatives could also display potent antiꢀ
tumor effect through inducing apoptosis and coursing cell cycle
arrest.17ꢀ21 Conjugating different potent bioactivity structural
moiety together might exhibit unpredictable effect and it might
provide a method to find novel antiꢀcancer molecules.22
Therefore, these findings prompted our further investigations
Fig.1 The chemical structures of the representative
derivatives containing thiazolꢀ2ꢀamine, phenyl thiazoleꢀ2ꢀ
amine and cinnamamide groups and the conjugating moiety
designed.
From the conjugation ideal described above, we designed,
synthesized and screened some Nꢀ(4ꢀphenylthiazolꢀ2ꢀyl)
cinnamamide derivatives through our privileged small molecule
library.
acrylamide (compound
(
E
)ꢀ3ꢀ(4ꢀmorpholinophenyl)ꢀNꢀ(4ꢀphenylthiazolꢀ2ꢀyl)
) was first found moderate inhibition
1
(IC50=12.58 ꢁM) against chronic myeloid leukemia (CML)
K562 cells in MTT assay (Fig. 2). In order to develop more
potent antiꢀtumor agents, a series of novel Nꢀ(4ꢀphenylthiazolꢀ
2ꢀyl) cinnamamide derivatives compounds 7a~8n were
synthesized and evaluated for their antiꢀtumor activities.
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Moreover, the possible mechanism of the most potent inhibitor
8f) was further investigated by flow cytometer as well as
The Nꢀ(4ꢀphenylthiazolꢀ2ꢀyl) cinnamamide derivatives 1
(
and 7a~8o could be prepared according to Scheme1.
Bromination of 2a-2n with Tetrabutylammonium tribromide
afforded the αꢀbromination ketone 3a-3n, and FriedelꢀCrafts
acylation of commercial available 2o-2p generated αꢀ
bromination ketone 3o-3p. The crucial building block 4a-4p
was prepared by cyclizing 3a-3p with thiocarbamide in
refluxing alcohol.23 Another key intermediates 6a-6o were
synthesized in light of Knoevenagel reaction from different
Hoechst 33358 staining. The results implied that its activity
might be associated with inducing cancer cells apoptosis. To
our best knowledge, none of the Nꢀ(4ꢀphenylthiazolꢀ2ꢀyl)
cinnamamide derivatives were reported to trigger apoptosis
process as antiꢀcancer drugs.
aromatic aldehyde 5a-5o 24
Then condensation of various
.
cinnamic acids 6a-6o with 4a-4p afforded corresponding
products 7a-8o. Synthetic approaches of the 2l and 2n were
described in Scheme 2.25 With using 3, 5ꢀdimethylaniline as
starting material, 2l-2n could be prepared by five steps. All the
1
structures of these compounds were determined by HꢀNMR,
13CꢀNMR and HRꢀMS.
Fig.2 The structure of compound
1 and 8f
Scheme 2 Reagents and conditions: (vi) Acetyl chloride,
K2CO3, DCM, r.t., 2 h, 98.8%; (vii) Acetyl chloride, AlCl3,
DCM, 0
NaNO2, HCl, H2O, 0ꢀ100
Iodoethane, K2CO3, Me2CO, reflux, 99.6~99.8%.
℃
ꢀr.t., 3 h; (viii) 2N HCl, 80~100
℃, 2 h, 97.5%; (ix)
Results and discussion
℃
, 1.5 h, 33%; (x) Iodomethane or
Chemistry
Scheme 1 Reagents and conditions: (i) Tetrabutylammonium tribromide, acetonitrile, 12 h; (ii) Bromoacetyl bromide, AlCl3,
DCM, 0 , 5 min; (iii) Thiourea, EtOH, reflux, 3 h, 50~96%; (iv) Malonic acid, piperdine, pyridine, 115 , 8 h, 60~97%; (v)
℃
℃
EDCI, DMAP, DCM, r.t., 1 d, 29~80%.
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Table 2 The anti-proliferative activities of compounds 7p,
8a~8na
Biological evaluation
Cytotoxicity in vitro
The cytotoxicity of the synthesized compounds was tested
on chronic myeloid leukemia cell line (K562) by the MTT
assay,26 and Paclitaxel was used as a positive control. The IC50
were expressed and summarized in Table 1~3. All the
compounds exhibited activities ranging from 0.035 to 40.38 ꢁM,
IC50 (µM)
Cpd. R6
R7
R8
X
K562
0.61
4.16
2.48
1.49
11.75
7.88
0.18
13.98
4.59
32.18
0.48
3.06
0.38
4.06
9.39
40.38
1.26
and several compounds like 8f, 8j, 8l, 7p and 7l were much
more potent than Paclitaxel.
7p
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
H
H
H
H
Morpholino
OCH3
OCH2CH3
H
H
H
H
OCH3
H
H
H
H
H
H
CF3
H
H
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
C
The SAR study mainly focused on the two parts of the hit
compound . Compounds 7a-7p were synthesized to investigate
OCH2CH2OCH3
1
OCH3 OCH3
the influence of the phenyl group in region 1 on the potency. A
single substituent with suitable size on the phenyl ring could
improve the activity, as illustrated by the fluoro substituted
analogs 7d-7f and methyl substituted analogs 7h-7i, while a
much bulkier group like methoxy (7a-7c) was detrimental to
the potency. Substituent on orthoꢀposition of the phenyl ring
could improve the activity moderately, as illustrated by the
single substituted analogs 7f, 7i and diꢀsubstituted analogue 7j.
Triꢀsubstituted phenyl ring could improve the potency
substantially, especially the introduction of methyl on both
orthoꢀpositions of phenyl ring (7l, 7m and 7p). Optimization on
H
H
H
H
H
H
H
H
H
H
H
CH3
C(CH3)3
F
Br
NO2
CF3
Cl
Cyclopropane
Piperidine
ꢀ
H
H
H
region 1 showed that 2, 4, 6ꢀtrimethyl phenyl was the most
suitable group for antiꢀcancer activity.
Paclitaxel
a
IC50 value was average of three determinations and deviation from the
average was <5% of the average value.
Table 1 The anti-proliferative activities of compounds 1,
7a~7pa
Compounds 8a-8o were subsequently prepared to
investigate the SAR on the region 2. As shown in Table 2,
when the morpholino group was replaced by H atom (8o), a
sharp loss of activity was observed, suggesting the substituent
on C4’ꢀposition of phenyl ring was very important. Then we
introduced different substituents on this position to investigate
the electric and steric effects on the potency. A series of
electronꢀdonating alkyoxy substituted analogs were prepared
and the potency improved as the increasing of size on the
substituent (8a-8c), suggesting that a bulky group on this
position was favorable. The same tendency could be found
IC50 (µM)
Cpd.
R1
R2
R3
R4
R5
K562
12.58
14.59
25.16
>90
7.30
5.73
4.18
>90
7.51
3.74
5.38
>90
1.00
2.09
30.31
5.15
0.61
1.26
1
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
H
H
H
OCH3
H
H
F
H
H
CH3
CH3
H
CH3
CH3
F
H
H
OCH3
H
H
F
H
H
CH3
H
H
CH3
H
H
H
H
H
OCH3
H
H
F
H
H
CH3
H
H
CH3
H
OCH3
OCH2CH3
OCH3
F
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
F
F
CH3
from the alky substituted derivatives 8e, 8f and 8l. The
introduction of substituent in metaꢀposition was unfavorable
for the activity, which can be illustrated by the triꢀsubstituted
analogue 8d. The electronꢀwithdraw substituted analogs
exhibited comparable potency with electronꢀdonating
derivatives (8gꢀ8k), suggesting that different electric effect
group on this position was well tolerated. Altogether, the SAR
of region 2 showed that bulky groups or flexible long chain
groups on C4’ꢀposition could effectively increase the potency.
Especially, 8f got a 3ꢀfold and 70ꢀfold more potent activities
compared with 7p and 1, respectively.
Further studying on the antiꢀproliferative activity of Nꢀ(4ꢀ
phenylthiazolꢀ2ꢀyl) cinnamamide derivatives 8f, 8j, 8l and 7p
and 7l against a panel of human cancer cell lines were
evaluated, including leukemia cell lines K562, MV4ꢀ11, Jurkat,
breast cancer cell lines MDAꢀMBꢀ468, MCFꢀ7, lymphoma cell
line LYꢀ1, hepatocellular cell line Bel7402 and lung cancer cell
F
CH3
H
CH3
Paclitaxel
a
IC50 value was average of three determinations and deviation from the
average was <5% of the average value.
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DOI: 10.1039/C4MD00573B
line A549. As shown in Table 3, all these compounds exhibited (IC50=0.74 ꢁM). Moreover, all these compounds showed no
good inhibition on different cancer cells, especially on significant toxicity against the nonꢀcancerous cell lines,
leukemia cell lines. Among these compounds, 8f showed including LO2, VERO and HEK293. Hence, the excellent antiꢀ
significant inhibition activities on Jurkat (IC50=0.035 ꢁM), cancer efficiency and safety in vitro encouraged us to
MV4ꢀ11 (IC50=0.11 ꢁM) and K562 (IC50=0.18 ꢁM), apparently investigate the possible molecular mechanism of the lead
better than Paclitaxel. In addition, 8f also showed moderate compound 8f
.
inhibition against A549 (IC50=0.27 ꢁM) and Bel7402
Table 3 The anti-proliferation activities of selective compounds and Paclitaxel against various cancer cell lines and non-
cancerous cell lines a
IC50 (
7p
μ
M)a
Cell Lines
Cell Type
8f
8j
8l
7l
Paclitaxel
K562
MV4ꢀ11
Jurkat
0.18
0.11
0.035
>30
>30
1.54
0.74
0.27
>90
>90
>90
0.48
3.65
1.15
>30
1.53
3.69
34.13
0.20
>90
0.38
1.41
1.24
7.76
15.72
1.63
6.58
1.17
>90
0.61
6.42
9.05
19.96
>30
1.00
2.73
1.24
1.45
>30
>30
9.65
1.56
>90
>90
>90
1.26
0.75
0.69
9.66
0.31
0.18
>10
0.74
n.d*
n.d
Leukemia
MCFꢀ7
MDAꢀMBꢀ468
LYꢀ1
Breast cancer
Large B cell lymphoma
Hepatocellular carcinoma
Lung adenocarcinoma
11.65
10.60
4.29
>90
>90
>90
Bel7402
A549
LO2
VERO
HEK293
nonꢀcancerous cells
>90
>90
>90
>90
n.d
a
Cancer cells and nonꢀcancerous cells were all test for 96h. IC50 value was average of three determinations and deviation from the average was <5% of the
average value. *n.d. means no detection.
Analysis of apoptosis by Flow Cytometry (FCM) and Hoechst low glucose type RPMI 1640 medium (Gibco BRL, Grand
staining
Island, N.Y.) supplemented with 10 % fetal bovine serum (FBS;
Based on the antiꢀcancer activation of Nꢀ(4ꢀphenylthiazolꢀ Gibco, Auckland, N.Z.), 100 units/mL penicillin and 100ꢁL
2ꢀyl) cinnamamide derivatives, 8f was chosen for further study streptomycin in a humid chamber at 37
its possible mechanism against the most sensitive cell lines, atmosphere.
℃ under 5% CO2 in
including K562, A549, Jurkat and Bel7402. As indicated in Fig. (B)Cell viability assay
3A, when treated with 3.3 ꢁM 8f, the percentage of apoptotic
For all in vitro assays, the dosage was diluted in relevant
cells in K562, Jurkat, A549 and Bel7402 were 21.04%, 14.64%, medium with a final DMSO concentration of less than 0.1 %.
23.13% and 48.15%, respectively. As shown in Fig. 3B and 3C, The MTT assay was used to measure the cell viability after
8f induced apoptosis against Bel7402 cell line in
a
compounds treatment. Cells were seeded in 96ꢀwell microꢀ
concentrationꢀdependent manner, from 5.37%, 25.37%, 51.97% plates at a density of 2~5*103 cells per well, and then, cultured
and 61.35% after treated with 0.37, 1.1, 3.3 and 10 ꢁM 8f for for 24 h. After treatment with various concentrations of
48 h, respectively. The apoptosisꢀinducing effect was further compound for 96 h, 20 ꢁL of MTT solution(5 mg mL-1) was
confirmed by florescence microscopic Hoechst 33358ꢀstained added to each well and incubated 2~4 h at 37
℃. After that, the
Bel7402 cells, as indicated by bright blue fluorescent cells and supernatant fluid was removed and 150 ꢁL of DMSO was
condensed nuclei. These results implied that 8f inhibited the added to dissolve the formazan crystal produced by living cells
cancer cell proliferation by inducing apoptosis.
for 10~20 min. Then, 96ꢀwell microplates were read on Spectra
MAX M5 microplate spectrophotometer at 570 nm for O.D.
values. Statistical analyses were carried out in Graphpad Prism
5 (GraphPad Software Inc.).
Experimental
(A)Cell Culture
(C)Analysis of apoptosis by Flow Cytometry (FCM)
The human Belꢀ7402 cell line was obtained from the
China Centre for Type Culture Collection (CTCCC, Wuhan,
China). LO2 and VERO cell lines were purchased from
Shanghai Institute of Cell Resource Centre of Life Science
(Shanghai, China). All other cell lines were acquired from the
American Type Culture Collection. Cells were cultured in high
glucose type Dulbecco’s modified Eagle medium (DMEM) or
To investigate the apoptosis effect of 8f, we analysed the
percentage of apoptotic cells by FCM after propidium iodide
(PI) staining. Briefly, cells were seeded into 2 mL of
medium/well in 6ꢀwell plates for 24 h and treated with various
concentrations of 8f for another 48 h. Then the cells were
washed twice with cold PBS, and next stained PI solution
(containing 50 ꢁg mL-1 PI and 20ꢁg mL-1 RNAase in 0.1 %
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sodium citrate plus 0.1 % Triton Xꢀ100). The results were 8f treatment for another 48 h. The cells were fixed with
tested by FCM (BectonꢀDickinson, USA) and analysed by Flow paraformaldehyde 15 min and washed twice with PBS. Then,
Jo software.
(D)Morphological analysis by Hoechst staining
the cells were stained with Hoechst 33358 solutions (5 ꢁg mLꢀ
1, in PBS) and examined under fluorescence microscope to
Morphological changes associated with apoptosis in Bel7402 identify the nuclear morphology of the apoptotic cells.
cells were detected by Hoechst 33358 staining. Briefly, cells
were plated in 6ꢀwell plates and cultured for 24 h, followed by
Fig3. Effect of 8f on the induction of apoptosis: (A) Statistical results of apoptosis assays presented as surviving cells (percentage
of untreated control), inducing K562, Jurkat, A549, Bel7402, after treatment with 0.37 or 3.3 ꢁM 8f for 48 hours. (B) and (C) Flow
cytometric analysis and statistical results of PIꢀstained Bel7402 cells incubation with varying concentrations of 8f (0.37 ꢁM, 1.1
ꢁM, 3.3 ꢁM, 10 ꢁM) for 48 hours. Date are expressed as mean ± SD. for at least 3 independent experiments (*p<0.05;**p<0.01;
***p<0.001 vs. Vehicle control).
Fig4. Effect of 8f on cell morphology. The fluorescence microscopic appearance of Hoechst 33358ꢀstained Bel7402 cells which
incubated with 8f for 48 h
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Conclusions
In conclusion, we described the discovery and
optimization
10.
of
Nꢀ(4ꢀphenylthiazolꢀ2ꢀyl)
cinnamamide
derivatives as novel potential antiꢀtumor agents. These
compounds were synthesized and evaluated for their antiꢀ
cancer activities in vitro. The SAR analysis showed that
conformational restriction and steric effect played a crucial role
on the antiꢀproliferation activities. The most potent analogue 8f
displayed excellent inhibitory activities against several human
cancer cell lines at subꢀmicromolar to nanomolar
concentrations, including K562, Bel7402, A549, MV4ꢀ11 and
Jurkat, while no apparent toxicity to nonꢀcancerous cells was
observed. The further studies of the mechanism of action
implied that 8f might display its antiꢀcancer activity via
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13.
14.
15.
16.
In brief, our results provided interesting information for
the design of novel Nꢀ(4ꢀphenylthiazolꢀ2ꢀyl) cinnamamide
derivatives with better antiꢀcancer potency. Further studies on
the exact biological mechanisms and antiꢀtumor research in
vivo are underway.
17.
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Acknowledgements
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Notes and references
a Sichuan University, State Key Laboratory of Biotherapy/Collaborative
Innovation Center of Biotherapy and Cancer Center, West China Hospital,
West China Medical School, Sichuan University, Chengdu 610041, China. b
Department of Pharmaceutical and Bioengineering, School of Chemical
Engineering, Sichuan University, Chengdu, Sichuan 610065, China. c College
of Chemistry and Life Science, Chengdu Normal University, Chengdu
611130, China. d Department of Encephalopathy, The First Affiliated
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University of Traditional Chinese Medicine, Zhengzhou, 450004,China. e
Wisdom Pharmaceutical Co., Ltd, Haimen, 226123,China.
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‡These authors contributed equally to this work.
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J. Name., 2013, 00, 1-3 | 6

Page 7 of 7
MedChemComm
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DOI: 10.1039/C4MD00573B
A series of N-(4-phenylthiazol-2-yl) cinnamamide derivatives were synthesized and evaluated
bioactivity in vitro by MTT assay, further studies revealed that the activity might be associated
with inducing cancer cells apoptosis.
H
N
N
S
O
Region 2
Region 1
8f
K562 IC50(μM)=0.18
Jurkat IC50(μM)=0.035
Bel7402 IC50(μM)=0.74
A549 IC50(μM)=0.27