Design, synthesis and cytotoxicity evaluation of novel (E)-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-ones as anticancer agents

Article abstract of DOI:10.1515/hc-2016-0042

(E)-3-(3-Aryl-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-ones 4a-i have been synthesized and evaluated for their in vitro cytotoxicity against a panel of three human cancer cell lines Caco-2, MIA PaCa-2, MCF-7 and a normal NIH-3T3 cell line. Compound 4g is cytotoxic with the IC₅₀ value of 15.32±0.62 μm against the Caco-2 cell line.

Full text of DOI:10.1515/hc-2016-0042

Heterocycl. Commun. 2016; aop
Preliminary Communication
Raquib Alam, Md. Aftab Alam, Amulya K. Panda and Rahis Uddin*
Design, synthesis and cytotoxicity evaluation of
novel (E)-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-
(pyridin-3-yl)prop-2-en-1-ones as anticancer agents
DOI 10.1515/hc-2016-0042
[11–28] apparently due to their inhibition of tubulin [15],
thioredoxin reductase [17], VEGF [18], mTOR [19] topoi-
somerase-I/II [20], 5α-reductase [21], sirtuin-1 [22], JAK/
STAT signaling pathways [23], MMP-2 [24], cathepsin-K
[25], Wnt [26], B-Raf [27] and NF-κB [28], among others.
On the basis of the interesting biological activity pro-
files of pyrazoles and chalcones, we were inspired to syn-
thesize some pyrazolic chalcones as potential anticancer
agents. Synthesis is outlined in Scheme 1. Pyrazolic chal-
Received March 16, 2016; accepted June 1, 2016
Abstract: (E)-3-(3-Aryl-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-
3-yl)prop-2-en-1-ones 4a–i have been synthesized and eval-
uated for their in vitro cytotoxicity against a panel of three
human cancer cell lines Caco-2, MIA PaCa-2, MCF-7 and a
normal NIH-3T3 cell line. Compound 4g is cytotoxic with
the IC50 value of 15.32 0.62 μm against the Caco-2 cell line.
Keywords: chalcones; Claisen-Schmidt condensation; cones were prepared from the corresponding 3-aryl-1-phe-
cytotoxic activity; pyrazoles.
nylpyrazol-4-carboxaldehydes 3a–i [29–33] which, in turn,
were synthesized from the heterocyclic substrates 2a–i
[30] (see Supplementary Material). The Claisen-Schmidt
condensation of compounds 3a–i with 3-acetylpyridine
in methanolic NaOH afforded the desired (E)-3-(3-(aryl)-
1-phenyl-1H-pyrazol-4-yl)-pyridin-3-yl)prop-2-en-1-ones
4a–i. Compounds 3a–i and 4a–i were characterized by
spectral methods and elemental analysis.
Although there has been considerable progress in reduc-
ing cancer incidence in the United States, the number of
cancer patients continues to increase [1]. Chemotherapy
is one of the most effective approaches used for treating
cancer patients. However, the lack of selectivity and devel-
opment of drug-resistance reduces the efficacy of cancer
chemotherapy [2]. Therefore development of effective and
safe anticancer agents with high potency and less toxic-
ity is a major focus for researchers across the world. The
heterocyclic compounds containing a pyrazole ring have
received considerable attention owing to their diverse
chemotherapeutic potential [3–5]. Important pyrazole-
based antitumor drugs available in the market include
ruxolitinib and crizotinib [6]. Celecoxib is a typical model
of pyrazole-based diaryl heterocyclic small molecule [7]
with antitumor activity against prostate tumors in experi-
mental models [8–10]. Chalcones show anti-cancer activity
In vitro cytotoxicity of compounds 4a–i was measured
by an MTT [(3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-
2H-tetrazolium bromide)] assay against a panel of three
H2N
Me
O
Me
NH
H
N
i
ii
N
R
R
1a–i
2a–i
O
R
H
N
6
O
R
N
7
4
3
iii
5
2
N
1 N
N
*Corresponding author: Rahis Uddin, Department of Chemistry,
Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi
110025, India, e-mail: rahisuddin@jmi.ac.in
4a–i
3a–i
Raquib Alam: Department of Chemistry, Jamia Millia Islamia
(A Central University), Jamia Nagar, New Delhi 110025, India
Md. Aftab Alam: Department of pharmacy, School of Medical and
Allied Science, Galgotias University, Greater Noida 201301, UP, India
Amulya K. Panda: Product Development Cell, National Institute of
Immunology, New Delhi 110067, India
a: R = H
d: R = 3-Br
e: R = 4-Br
f: R = 3-NO2
g: R = 4-NO2
h: R = 4-Me
i: R = 4-OMe
b: R = 4-F
c: R = 4-Cl
Scheme 1ꢀConditions: (i) EtOH, H2SO4, reflux; (ii) POCl3/DMF, 80°C,
then NaHCO3/H2O; (iii) 3-acetylpyridine, MeOH, NaOH, r.t.
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Table 1ꢀIn vitro cytotoxicity evaluation of the synthesized compounds against a panel of human cancer cell lines and a normal cell line in
terms of IC50 value in μm.
Compounds
R
Caco-2
MIA PaCa-2
MCF-7
NIH-3T3
4a
H
32.30 0.65
23.09 0.93
38.93 2.49
30.28 2.01
27.95 0.29
19.62 0.76
15.32 0.62
37.83 2.85
49.12 8.37
17.51 0.24
38.52 2.31
28.28 2.17
46.57 2.30
24.80 1.46
30.40 0.84
19.70 0.32
18.89 0.44
21.94 5.10
32.05 1.23
23.66 0.33
56.65 2.75
34.38 3.83
54.53 1.10
46.67 2.01
39.79 1.07
29.78 0.84
29.59 2.18
68.78 1.16
44.36 1.08
32.31 1.48
ꢂ>ꢂ100
91.46 2.99
92.58 2.52
96.56 1.55
96.13 2.09
87.58 1.96
87.39 0.44
ꢂ>ꢂ100
4b
4-F
4c
4-Cl
3-Br
4-Br
3-NO2
4-NO2
4-CH3
4-OCH3
–
4d
4e
4f
4g
4h
4i
ꢂ>ꢂ100
Etoposide
90.53 4.6
60 F254, Merck) and spots were visualized under UV light. IR spec-
tra were recorded on an Agilent Cary 630 FT-IR spectrometer. The 1H
NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a
Bruker Avance 400 spectrometer using CDCl3 or DMSO-d6 as a solvent
and TMS as an internal standard. Elemental analysis were performed
on an Elementar Vario analyzer. Mass spectra (ESI-MS) were recorded
on an AB-Sciex 2000 spectrometer.
different human cancer cell lines, namely Caco-2 (human
intestinal), MIA PaCa-2 (human pancreatic) and MCF-7
(human breast) and one normal cell line (mouse embryo
fibroblasts NIH-3T3) [34]. Etoposide was taken as the ref-
erence drug and the results are summarized in terms of
IC50 values (Table 1). Most of the compounds show moder-
ate to good cytotoxicity against intestinal, pancreatic and
breast cancer cell lines and very weak toxicity towards
NIH-3T3 normal cell line. Analogs 4f–h show significant
cytotoxicity as compared to standard drug etoposide.
Out of 9 pyrazolic chalcones synthesized, compound 4g
displays the most potent cytotoxicity against Caco-2 cell
line. SAR analysis of these pyrazolic chalcones indicate
that compounds with a para substituted NO2 group in the
benzene ring are more cytotoxic. Compounds with F, Cl,
Br, CH3 or OCH3 substituent show more moderate effects,
which is clearly seen from Table 1. The cytotoxic activity
against all tested cancer cell lines shows that the strength
order is NO2ꢀ>ꢀFꢀ>ꢀBrꢀ>ꢀCl for compounds with a para substi-
tuted electron-withdrawing group present in the benzene
ring. Among compounds with meta substituted electron-
withdrawing group, the cytotoxic activity order is NO2ꢀ>ꢀBr.
Finally, cytotoxic activity against Caco-2 and MIA PaCa-2
shows that the strength order is CH3ꢀ>ꢀOCH3 for compounds
with electron-donating substituent present in para posi-
General synthesis of compounds 4a–i
A mixture of 3-aryl-1-phenylpyrazol-4-carboxaldehyde 3a–i (10 mmol)
and 3-acetylpyridine (10 mmol) in methanolic solution of sodium
hydroxide was stirred for 24 h at room temperature. The resultant pre-
cipitate of 4a–i was filtered off, washed with water, dried, and crystal-
lized from ethanol (4a–e and 4h,i) or N,N-dimethylformamide (4f,g).
(E)-3-(1,3-Diphenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-
1-one (4a)ꢁYellow solid; yield 64%; mp 168–170°C; IR (neat, νmax):
1
3132, 1665, 1585, 1415 cm-1; H NMR (CDCl3): δ 9.13 (s, 1H), 8.73–8.75
(m, 1H), 8.37(s, 1H), 8.21 (m, 1H), 7.91 (d, J ꢀ=ꢀ 15.6 Hz, 1H), 7.26–7.78 (m,
12H); 13C NMR (CDCl3): δ 188.5, 154.0, 153.0, 149.6, 139.3, 136.5, 135.7,
133.5, 132.1, 129.6, 128.9, 128.8, 128.8, 127.3, 127.2, 123.6, 120.5, 119.3,
+
117.9. ESI-MS. Calcd for C23H17N3O, [M + H] : m/z 352.1. Found: m/z
352.2. Anal. Calcd for C23H17N3O: C, 78.61; H, 4.55; N, 11.96. Found: C,
78.33; H, 4.84; N, 11.94.
(E)-3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-
3-yl)prop-2-en-1-one (4b)ꢁYellow solid; yield: 70%; mp 170–172°C;
tion of the benzene ring. Furthermore, cytotoxic activity IR (neat, νmax): 3119, 1667, 1596, 1525, 1419 cm-1; 1H NMR (CDCl3): δ 9.20
(s, 1H), 8.80 (d, J ꢀ=ꢀ 3.6 Hz, 1H), 8.40 (s, 1H), 8.28 (d, J ꢀ=ꢀ 8 Hz, 1H), 7.91
against MCF-7 shows the strength order is OCH3ꢀ>ꢀCH3 for
compounds with para electron-donating substituent.
(d, J ꢀ=ꢀ 15.6 Hz, 1H), 7.80 (d, J ꢀ=ꢀ 8 Hz, 2H), 7.33–7.70 (m, 7H), 7.20 (t, J ꢀ=ꢀ
8.4 Hz, 2H); 13C NMR (CDCl3): δ 188.4, 164.4, 162.0, 153.1, 149.6, 139.2,
136.2, 135.8, 133.4, 130.6, 130.5, 129.6, 128.2, 127.5, 127.1, 123.7, 120.6,
+
119.4, 117.9, 116.0, 115.8. ESI-MS. Calcd for C23H16FN3O, [M + H] : m/z
370.1. Found: m/z 370.5. Anal. Calcd for C23H16FN3O: 74.78; H, 4.37; N,
Experimental
11.38. Found: C, 74.73; H, 4.39; N, 11.41.
All starting materials and solvents were purchased from commercial (E)-3-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-
sources and used without further purification. Melting points were 3-yl)prop-2-en-1-one (4c)ꢁYellow solid; yield 64%; mp 162–164°C;
1
determined in open capillaries using an electro-thermal melting IR (neat, νmax): 3134, 1665, 1583, 1501, 1404 cm-1; H NMR (CDCl3): δ
point apparatus and are uncorrected. The progress of the reactions 9.16 (s, 1H), 8.76 (d, J ꢀ=ꢀ 4.4 Hz, 1H), 8.37 (s, 1H), 8.21 (d, J ꢀ=ꢀ 8 Hz, 1H),
was monitored by TLC using precoated aluminum sheets (Silica gel 7.85 (d, J ꢀ=ꢀ 15.2 Hz, 1H), 7.76 (d, J ꢀ=ꢀ 8 Hz, 2H), 7.61 (d, J ꢀ=ꢀ 8.4 Hz, 2H),
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R. Alam et al.: (E)-3-(3-Aryl-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-ones as anticancer agentsꢃ
7.29–7.50 (m, 7H); 13C NMR (CDCl3): δ 188.8, 153.1, 152.8, 149.6, 139.2,
(E)-3-(3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-
3-yl)prop-2-en-1-one (4i)ꢁYellow solid; yield 61%; mp 158–160°C; IR
136.0, 135.7, 134.9, 133.4, 130.6, 130.0, 129.6, 129.0, 127.5, 127.1, 123.7,
1
(neat, νmax): 3119, 1665, 1596, 1525, 1503, 1419 cm-1; H NMR (CDCl3): δ
+
120.8, 119.4, 117.9. ESI-MS. Calcd for C23H16ClN3O, [M + H] : m/z 386.1.
9.15 (s, 1H), 8.74 (d, J ꢀ=ꢀ 4.8 Hz, 1H), 8.35 (s, 1H), 8.21 (d, J ꢀ=ꢀ 8Hz, 1H),
7.89 (d, J ꢀ=ꢀ 15.6 Hz, 1H), 7.76 (d, J ꢀ=ꢀ 8 Hz, 2H), 7.60 (d, J ꢀ=ꢀ 8.4 Hz, 2H),
7.26–7.47 (m, 5H), 6.99 (d, J ꢀ=ꢀ 8.8 Hz, 2H), 3.83 (s, 3H); 13C NMR (CDCl3):
δ 188.5, 160.2, 153.9, 153.0, 149.6, 139.3, 136.7, 135.7, 133.5, 130.0, 129.5,
127.2, 127.0, 124.5, 123.6, 120.2, 119.3, 117.8, 114.3, 55.3. ESI-MS. Calcd
Found: m/z 386.4. Anal. Calcd for C23H16ClN3O: C, 71.59; H, 4.18; N,
10.89. Found: C, 71.65; H, 4.16; N, 10.85.
(E)-3-(3-(3-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-
3-yl)prop-2-en-1-one (4d)ꢁYellow solid; yield 82%; mp 172–174°C;
IR (neat, νmax): 3136, 1663, 1596, 1493, 1404 cm-1; 1H NMR (CDCl3): δ 9.17
(s, 1H), 8.80 (d, J ꢀ=ꢀ 3.2 Hz, 1H), 8.39 (s, 1H), 8.26 (d, J ꢀ=ꢀ 7.6 Hz, 1H),
7.89 (d, J ꢀ=ꢀ 15.2 Hz, 2H), 7.80 (d, J ꢀ=ꢀ 8 Hz, 2H), 7.36–7.62 (m, 8H); 13C
NMR (CDCl3): δ 188.5, 153.1, 152.3, 149.6, 139.1, 135.8, 135.8, 134.2, 133.4,
131.8, 131.6, 130.3, 129.6, 127.6, 127.4, 127.3, 123.6, 122.9, 121.0, 119.4,
+
for C24H19N3O2, [M + H] : m/z 382.1. Found: m/z 382.2. Anal. Calcd for
C24H19N3O2: C, 75.57; H, 5.02; N, 11.02. Found: C, 75.54; H, 5.03; N, 11.04.
In vitro cytotoxic activity
+
118.0. ESI-MS. Calcd. for C23H16BrN3O, [M + H] : m/z 430.05. Found:
m/z 430.04. Anal. Calcd for C23H16BrN3O: C, 64.20; H, 3.75; N, 9.77.
Found: C, 64.26; H, 3.71; N, 9.75.
The MTT [(3-(4, 5-dimethyl-2-thiazolyl) 2,5-diphenyl-2H-tetrazolium
bromide)] assay is based on conversion of yellow, water soluble
tetrazolium dye to a water-insoluble purple formazan by living
cells. The amount of formazan crystals generated is directly propor-
tional to the number of viable cells. The Caco-2, MIA PaCa-2, MCF-7
and NIH-3T3 cells were grown (37°C, 5% CO2 in water jacketed incu-
bator shell) using DMEM media with 10% FBS (fotal bovine serum),
seeded on a single 96 well plate and allowed to adhere for MTT
assays. The plate was treated with increasing concentrations of 1,
12.5, 25, 50 and 100 μm of the compounds. These concentrations
were used in triplicate to the single 96 well tissue culture plate.
After 24 h of treatment, the MTT assay was performed to check cell
viability. For the MTT assay, the media were removed from all the
wells, 10 μL of MTT reagent per well from a working stock (5 mg/
mL) was added and the plates were incubated (37°C and 5% CO2)
for 2–3 h, and then the reagent was removed and the crystals were
dissolved in dimethyl sulfoxide. The absorbance was measured at a
test wavelength of 570 nm using an ELISA plate reader, LMR-340 M
with a microplate reader. The percentage inhibition was calculated
by the formulae:
(E)-3-(3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-
3-yl)prop-2-en-1-one (4e)ꢁYellow solid; yield 75%; mp 158–160°C;
1
IR (neat, νmax ): 3136, 1663, 1596, 1501, 1400 cm-1; H NMR (CDCl3): δ
9.20 (s, 1H), 8.80 (d, J ꢀ=ꢀ 4.4 Hz, 1H), 8.40 (s, 1H), 8.27 (d, J ꢀ=ꢀ 7.6 Hz,
1H), 7.90 (d, J ꢀ=ꢀ 15.6 Hz, 1H), 7.80 (d, J ꢀ=ꢀ 8 Hz, 2H), 7.64 (d, J ꢀ=ꢀ 8 Hz, 2H),
7.58 (d, J ꢀ=ꢀ 8 Hz, 2H), 7.33–7.53 (m, 5H); 13C NMR (CDCl3): δ 188.3, 153.1,
152.8, 149.6, 139.1, 136.0, 135.8, 133.4, 132.0, 131.0, 130.2, 129.6, 127.5,
127.1, 123.7, 123.2, 120.8, 119.3, 117.9. ESI-MS. Calcd for C23H16BrN3O, [M +
+
H] : m/z 430.05. Found: 430.04. Anal. Calcd for C23H16BrN3O: C, 64.20;
H, 3.75; N, 9.75. Found: C, 64.14; H, 3.77; N, 9.79.
(E)-3-(3-(3-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-
3-yl)prop-2-en-1-one (4f)ꢁYellow solid; yield 69%; mp 206–208°C;
IR (neat, νmax): 3136, 1665, 1596, 1533, 1423, 1344 cm-1; 1H NMR (DMSO-
d6): δ 9.40 (s, 1H), 9.24 (d, J ꢀ=ꢀ 1.6 Hz, 1H), 8.78–8.80 (m, 1H), 8.40 (s,
1H), 8.32 (d, J ꢀ=ꢀ 8 Hz, 1H), 8.27 (d, J ꢀ=ꢀ 8 Hz, 1H), 8.06 (d, J ꢀ=ꢀ 8 Hz, 1H),
7.77–7.89 (m, 4H), 7.65 (d, J ꢀ=ꢀ 15.2 Hz, 1H), 7.37–7.58 (m, 4H); 13C NMR
(DMSO-d6): δ 188.1, 153.7, 150.8, 149.9, 148.5, 139.1, 136.0, 134.9, 134.3,
133.8, 133.1, 131.0, 130.1, 129.9, 127.9, 124.4, 123.8, 122.9, 122.2, 119.2,
% Inhibition=100
+
118.4. ESI-MS. Calcd. for C23H16N4O3, [M + H] : m/z 397.2. Found: m/z
Mean OD of treated cells
Mean OD of the vehicle control cells (negative control)
397.2. Anal. Calcd for C23H16N4O3: C, 69.69; H, 4.07; N, 14.13. Found: C,
69.65; H, 4.08; N, 14.16.
-
×100
Each assay was repeated three times. The IC50 values were calcu-
lated from the dose effect curve (Figure S1) and expressed as concen-
tration (μm) of drug [34].
(E)-3-(3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-
3-yl)prop-2-en-1-one (4g)ꢁYellow solid; yield 76%; mp 220–222°C;
1
IR (neat, νmax): 3131, 1669, 1596, 1542, 1512, 1421, 1346 cm-1; H NMR
(DMSO-d6): δ 9.38 (s, 1H), 9.23 (s, 1H), 8.78 (d, J ꢀ=ꢀ 3.6 Hz, 1H), 7.80–8.32
(m, 8H), 7.63 (d, J ꢀ=ꢀ 15.2 Hz, 1H), 7.34–7.57 (m, 4H, 1H); 13C NMR (DMSO-
d6): δ 187.9, 153.7, 150.8, 149.9, 147.6, 139.0, 138.6, 136.0, 134.3, 133.1,
130.1, 129.9, 129.6, 127.9, 124.4, 124.4, 122.2, 119.2, 118.7. ESI-MS. Calcd
Acknowledgments: The authors thank the Head, Depart-
ment of Chemistry, JMI, New Delhi, for providing research
facilities, Prof. Vibha Tandon and Dr. Mohammad Abid for
helpful discussions, and UGC, New Delhi, for research fel-
lowship for Raquib Alam.
+
for C23H16N4O3, [M + H] : m/z 397.2. Found: m/z 397.2. Anal. Calcd for
C23H16N4O3: C, 69.69; H, 4.07; N, 14.13. Found: C, 69.67; H, 4.08; N, 14.14.
(E)-3-(1-Phenyl-3-p-tolyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-
2-en-1-one (4h)ꢁYellow Solid; yield 61%; mp 146–148°C; IR (neat,
νmax): 3119, 1667, 1596, 1538, 1499, 1419 cm-1; 1H NMR (CDCl3): δ 9.15 (s,
1H), 8.76 (d, J ꢀ=ꢀ 3.2 Hz, 1H), 8.36 (s, 1H), 8.21 (d, J ꢀ=ꢀ 8Hz, 1H), 7.91 (d,
J ꢀ=ꢀ 15.6 Hz, 1H), 7.77 (d, J ꢀ=ꢀ 7.6 Hz, 2H), 7.57 (d, J ꢀ=ꢀ 8Hz, 2H), 7.26–7.49
(m, 7H), 2.41 (s, 3H); 13C NMR (CDCl3): δ 188.5, 154.1, 152.9, 149.6, 139.3,
References
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+
120.4, 119.3, 117.9, 21.3. ESI-MS. Calcd for C24H19N3O, [M + H] : m/z 366.1.
Found: m/z 366.2. Anal. Calcd for C24H19N3O: C, 78.88; H, 5.24; N, 11.50.
Found: C, 78.85; H, 5.25; N, 11.52.
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