Synthesis of pyrazole peptidomimetics and their inhibition against A549 lung cancer cells

Article abstract of DOI:10.1016/j.bmcl.2012.09.032

A series of novel pyrazole peptidomimetics was synthesized from 3-aryl-1-arylmethyl-1H-pyrazole-5-carboxylic acid and amino acid ester. Structures of the compounds were characterized by means of IR, ¹H NMR and mass spectroscopy. Compounds 5e and 5k suppress effectively the growth of A549 lung cancer cells. Preliminary research on the mechanism of action showed that the inhibition might perform through combination of apoptosis, autophagy and cell cycle arrest.

Full text of DOI:10.1016/j.bmcl.2012.09.032

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6882–6887
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of pyrazole peptidomimetics and their inhibition against A549
lung cancer cells
Ying-Rui Liu a, , Ji-Zhuang Luo b, , Pan-Pan Duan a, Jing Shao b, Bao-Xiang Zhao a, , Jun-Ying Miao b,
⇑
⇑
a Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China
b Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2012
Revised 20 August 2012
Accepted 11 September 2012
Available online 18 September 2012
A series of novel pyrazole peptidomimetics was synthesized from 3-aryl-1-arylmethyl-1H-pyrazole-5-
carboxylic acid and amino acid ester. Structures of the compounds were characterized by means of IR,
1H NMR and mass spectroscopy. Compounds 5e and 5k suppress effectively the growth of A549 lung
cancer cells. Preliminary research on the mechanism of action showed that the inhibition might perform
through combination of apoptosis, autophagy and cell cycle arrest.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Pyrazole
Peptidomimetics
Anticancer
A549
Cancer is one of the leading causes of death. Lung cancer contin-
ues to be the major cause of cancer-related mortality in the world.
Chemotherapy is still one of the primary modalities for the treat-
ment of cancer. Many of the available anticancer agents exhibit
undesirable side effects such as reduced bioavailability, toxicity
and drug-resistance. Therefore, the search for novel and selective
anticancer agents is urgently required.
Pyrazoles, with several sites for modification, offer the flexibility
to design and construct structural analogs of biomedical interest.
General and classical syntheses of substituted pyrazoles involve
strategies based on the condensation of 1,3-dicarbonyl com-
pounds.1,2 The pyrazole scaffold represents a common motif in
many pharmaceutical active and remarkable compounds
demonstrating a wide range of pharmacological activities such as
anticancer activity,3–5 cyclooxygenase-2 inhibitor,6–11 PDE4 inhibi-
tors,12 anti-inflammatory,13,14 anti-angiogenic,15,16 anti-bacterial17
and anti-microbial.18 Pyrazoles can also be used as chelating
ligands to form metal complexes which possess bioactivities.19–24
Pyrazole-fused heterocycle has been received much attention.25–28
Peptides have received much attention due to their antitumor
activity.29–35 Mimetic peptides are also of interest in drug discov-
ery.36–38 Drug–peptide conjugates have been explored to improve
drug efficacy and lower side effects by directing the drug to a
specific cell type.39,40
In our effort to discover and develop potential new anticancer
agents, we reported a series of novel pyrazole derivatives with
anticancer activity.41–48 As an extension of our work on the synthe-
sis and biological evaluation for pyrazole derivatives with structure
diversity, we struggled to modify the structures of pyrazole deriv-
atives with amino acid to form peptidomimetics.
Chemistry: The synthesis of 3-aryl-1-arylmethyl-1H-pyrazole-5-
carboxylic peptidomimetics (5) has been accomplished as outlined
in Scheme 1 from 3-aryl-1-arylmethyl-1H-pyrazole-5-carboxylic
acid (4). The reaction of starting material pyrazole (1) and substi-
tuent benzyl chloride (2) afforded ethyl 3-aryl-1-arylmethyl-1H-
pyrazole-5-carboxylate (3) according to our previous report.49
The compounds 3 converted to 3-aryl-1-arylmethyl-1H-pyrazole-
5-carboxylic acid (4) by the alkali hydrolysis. The condensation
of 3-aryl-1-arylmethyl-1H-pyrazole-5-carboxylic acid (4) with
amino acid ester under the presence of EDCI afforded 3-aryl-1-
arylmethyl-1H-pyrazole-5-carboxylic peptidomimetics (5) in
18–73% yield. When ethyl 2-amino-3-mercaptopropanoate was
used, the yield of desired compound is low, which attributed to
competition reactions as shown in Scheme 2. 1-Benzyl-3-phenyl-
1H-pyrazole-5-carboxylic acid reacts with ethyl 2-amino-3-merca-
ptopropanoate to form desired peptidomimetics 5c. However, thiol
in 5c reacts with another 1-benzyl-3-phenyl-1H-pyrazole-5-car-
boxylic acid to afford carbothioate 6. In addition, thiol in 5c can
oxidized to yield disulfide 7. The structures of compounds 5a–l, 6
and 7 were determined by IR, 1H NMR and HRMS spectroscopy.
Inhibition of the compounds on the growth of A549 lung cancer
cells: To define the biological activity, in terms of cell proliferation
⇑
Corresponding authors. Tel.: +86 531 88366425; fax: +86 531 88564464.
E-mail addresses: bxzhao@sdu.edu.cn (B.-X. Zhao), miaojy@sdu.edu.cn
(J.-Y. Miao).
inhibition, compounds 5a–l were tested in A549 cells at 40 lM
These authors equally contributed to this work.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.032

Y.-R. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6882–6887
6883
Scheme 1. Synthesis of 3-aryl-1-arylmethyl-1H-pyrazole-5-carboxylic peptidomimetics.
Scheme 2. The proposed route to form byproducts.
using Sulforhodamie B (SRB) colorimetric assay. Evaluating the
number of viable cells at 48 h after treatment, a decrease of total
cell number was observed with most compounds, in particular
the effect on cell proliferation results more evident for 5e and
5k, comparing the number of viable cells to the control cells
(Fig. 1).
The compounds 5b, 5e, 5g–k possessed considerable activity
and they were selected for an advanced assay against A549 cells
at 40, 60 and 80 concentrations. It can be found that inhibitory is
obviously dose-dependent for compounds 5b, 5e, 5h, 5j and 5k
(Fig. 2). Table 1 presents IC50 of compounds 5b, 5e, 5h, 5j and 5k,
which corresponds to concentration of the compounds causing
50% decrease in net cell growth. The antitumor activities of these
compounds appear to relate to the pyrazole substituents and ami-
no acid ester. The presence of tert-butyl group in benzyl moiety re-
sults in strong inhibition for cell growth. The compounds 5b, 5e, 5h
and 5k, derived from serine ester, have more effective inhibitory
Figure 1. Effects of the compounds 5a–l at 40
l
M on A549 cell viability at 48 h.
effects comparing with compounds derived from glycine and
cysteine ester. In addition, the chlorine group in benzene moiety

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Y.-R. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6882–6887
by most anticancer agents is apoptotic cell death. To shed more
light on the mechanisms responsible for the cytotoxic effect of se-
lected compounds, we analyzed first the cellular effects of the com-
pounds on nuclear condensation by Hoechst 33258 staining. The
morphology of apoptotic cells, including chromatin condensation
and the formation of apoptotic bodies, can be determined after
staining with Hoechst 33258, which binds to specific sites on dou-
ble-stranded DNA. Hoechst 33258-stained A549 cells that were
subsequently treated with selected compounds 5b, 5e, 5g–k
(80 lM) for 48 h showed intense fluorescence in the nuclei
(Fig. 3), thereby indicating chromatin condensation. Apoptosis cells
in groups treated with selected compounds significantly increased
comparing with the control group. Among them, compounds 5e, 5i
and 5k caused a significant induction of apoptotic cells after 48 h.
Autophagy exerts dual functions in cancer, acting as both a tu-
mor suppressor, for example, by preventing the accumulation of
damaged proteins and organelles, and as a tumor promoter that
supports tumor growth. Recent studies have suggested that, like
apoptosis, autophagy is important in the regulation of cancer
development and progression and in determining the response of
tumor cells to anticancer therapy.50,51 We next evaluated the effect
of selected compounds on the induction of autophagy. LC3 is be-
lieved to be a credible marker of the autophagosome in mamma-
lian cells. Enhancement of the conversion of LC3-I to LC3-II and
upregulation of LC3 expression occurs when autophagy is induced.
Thus, induction or suppression of autophagy can be easily moni-
tored by examining the levels of LC3-II by immunoblot. The results
showed an elevated protein level of LC3-II in the A549 cells treated
with these compounds at 48 h (p < 0.05) (Fig. 4).
Figure 2. Effects of the selected compounds on A549 cell viability. A549 cells were
treated with compounds 5b, 5e, 5g–k at the concentration of 40, 60 or 80 lM or left
untreated (control) for 48 h. Cell viability was analyzed by SRB assay and illustrated
in the labeled column. Results are presented as mean SE; (n = 3, ⁄p < 0.05 vs
control; ⁄⁄p < 0.01 vs control).
Table 1
IC50 of the selected compounds and 5-FU for A549 cells at 48 h
Compounds
IC50 ( M)
5-FU
4.21
5b
5e
5h
5j
5k
l
56.07
36.12
56.81
63.41
38.77
affects also the inhibition of compounds for cell growth. Taken
together, compounds 5e and 5k with both tert-butyl in benzyl
moiety and serine ester moiety have most effective growth
inhibition.
Modulation of the compounds 5b, 5e, 5g–k for apoptosis and
autophagy in A549 lung cancer cells: The mode of cell killing induced
Taken together, compounds 5e, 5i and 5k can induce both apop-
tosis and autophagy. However, 5e and 5k can lead to cell autoph-
Figure 3. The compounds 5b, 5e, 5g–k induced apoptosis in A549 cells at 80
fluorescent microscope (Nikon).
lM for 48 h (p < 0.01 vs ctr, n = 3). Microscopic photographs (200Â) were taken under a

Y.-R. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6882–6887
6885
Table 2
Effects of treatment with molecules at 80 lM after 48 h on cell cycle distribution
%
ctr
5b
5e
5g
5h
5i
5j
5k
G1
G2
S
55.94
9.39
34.67
57.48
8.08
34.44
72.31
6.06
21.63
57.39
8.57
34.04
59.23
0.69
40.08
60.20
7.25
32.55
76.06
4.04
19.91
79.54
0.92
19.53
agy in a high level which causes cell autophagic death, but 5i in-
duces cell apoptosis in a high level. A growing number of publica-
tions on the cross-regulation between apoptosis and autophagy
show the interplay between these two important cellular events.
However, the mechanisms mediating the complex regulation of
apoptosis and autophagy are not yet fully understood. Therefore,
continued investigation of crosstalk between apoptosis and
autophagy is necessary.52 In this study, we found compounds 5e
and 5k suppress effectively the growth of A549 lung cancer cells
through combination of apoptosis and autophagy, suggesting that
these small molecules will be potential tools for investigating the
mechanisms of the cross-regulation between apoptosis and
autophagy.
Figure 4. Western blot to test the protein level of LC3-II upon compounds
treatment. A549 cells were treated with 80 M 5b, 5e, 5g–k for 48 h. The protein
l
levels of LC3-II were detected by Western blot analysis (A). The relative levels of
LC3-II were normalized by the level of b-actin, and represented as percent of control
(B). (⁄p < 0.05 vs control, n = 3).
Flow cytometry analysis of cell cycle distribution: Cell-cycle arrest
in cancer cells has become a major indicator of anticancer effects.
Figure 5. Effects of the selected compounds 5b, 5e, 5g–k on cell cycle distribution of A549 lung cancer cells. Cells were exposed to DMSO, 5b, 5e, 5g–k at 80
incubated for 48 h.
lM and

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Y.-R. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6882–6887
Figure 6. Effects of the compounds on LDH release in A549 cells. A549 cells were treated with compounds 5b, 5e, 5g–k at the concentration of 80
(control) for 48 h. LDH release was determined. Results are presented as mean SE; n = 3.
lM or left untreated
7. Thaher, B. A.; Arnsmann, M.; Totzke, F.; Ehlert, J. E.; Kubbutat, M. H. G.;
Schächtele, C.; Zimmermann, M. O.; Koch, P.; Boeckler, F. M.; Laufer, S. A. J. Med.
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Anticancer agents may alter the regulation of the cell-cycle result-
ing in an arrest of cells in various phases of the cell cycle, thereby
reducing the growth and proliferation of cancerous cells. Accord-
ingly, we also inspected the cell cycle profiles of untreated A549
cells or cells subjected to 48 h treatment with the selected com-
pounds. Compounds 5e, 5j and 5k highly increased the G1 popula-
tion. However, 5b, 5g, 5h and 5i increased slightly the G1
population (Fig. 5 and Table 2). Therefore, cell death induced by
the selected compounds 5e, 5j and 5k was associated with signif-
icant changes in the cell cycle distribution.
Compounds 5b, 5e, 5g–k do not cause necrosis in A549 lung cancer
cells: In order to determine if the growth inhibitory effects were
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centration did not cause necrosis in the cells (Fig. 6).
In summary, we synthesized a series of novel pyrazole pepti-
domimics by the condensation of 3-aryl-1-arylmethyl-1H-pyra-
zole-5-carboxylic acid and amino acid ester. Preliminary
biological evaluation indicates that some compounds suppress
the growth of A549 lung cancer cells. Structure–activity relation-
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tyl in benzyl moiety and serine ester moiety have most effective
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This work was supported by National Natural Science Founda-
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