Design, Synthesis and Biological Activities of New Pyrazole Derivatives Possessing Both Coxib and Combretastatins Pharmacophores

Article abstract of DOI:10.1002/cbdv.201900108

In our efforts to discover novel multi-target agents having better antitumor activities than celecoxib, 21 new aryl-substituted pyrazole derivatives possessing cis-diphenylethylene scaffold were mostly synthesized by a one-pot approach to ethyl 1,4,5-tria

Full text of DOI:10.1002/cbdv.201900108

Title: Design, Synthesis and Biological Activities of New Pyrazole
Derivatives Possessing Both Coxib and Combretastatins
Pharmacophores
Authors: Quoc Anh NGO, Thi Thuy Hang Nguyen, Yen Thi Tran, Anh
Le Nguyen, and Binh Ngoc Vo
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10.1002/cbdv.201900108
Chemistry & Biodiversity
Chem. Biodiversity
Design, Synthesis and Biological Activities of New Pyrazole
Derivatives Possessing Both Coxib and Combretastatins
Pharmacophores
Thuy Hang Nguyen Thia,b, Yen Tran Thia, Le Anh Nguyena, Ngoc Binh Voa, Quoc Anh Ngo*a,b
a Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, CauGiay, Hanoi, Viet Nam;
b Graduate University of Science and technology, 18 Hoang Quoc Viet, CauGiay, Hanoi, Viet Nam;
*Corresponding authors: ngoqanh@ich.vast.vn
In our efforts to discover novel multi-target agents having better anti-tumor activities than celecoxib, twenty-one new
aryl-substituted pyrazole derivatives possessing cis-diphenylethylene scaffold were mostly synthesized by a one-pot
approach to ethyl 1,4,5-triaryl-1h-pyrazole-3-carboxylates via an improved Claisen condensation - Knorr reaction
sequence. The cytotoxic effects of these compounds against three human cancer cell lines HT-29, Hep-G2, MCF-7 as
well as their inhibition of NO production were studied. Results showed that incorporation of the important
pharmacophoric groups of two original molecules celecoxib and Combretastatin A-4 in a single molecule plays an
important role in determining a better biological activities of the new coxib-hybrided compounds.
Keywords: celecoxib • combretastatin • COX-2 • cytotoxicity • hybrid compounds• multi-target agents
Introduction
From a medicinal chemistry point of view, the cis-diphenylethylene scaffold represents a privileged
structures thoroughly investigated. Celecoxib (Celebrex®, Onsenal®), a 1,5-diphenylpyrazole derivative containing
cis-diphenylethylene scaffold, constitutes a potent and specific inhibitor of the human cyclooxygenase-2 (COX-2).
Celecoxib has been shown to be efficacious in pain and arthritis in humans without many of the potentially serious
toxicities associated with traditional NSAIDs. COX-2 is also constitutively overexpressed in many human
premalignant, malignant and metastatic epithelial tumors, e.g. colorectal, lung, breast, prostate, and head/ neck
cancer.[1-4] Preclinical investigations demonstrate promising anti-tumor activity of Celecoxib in a variety of human
tumors.[5-9] It has been approved for oral use in the prevention of colon cancer development in patients with FAP.
However, it was discovered that celecoxib and related compounds may induce cell cycle arrest, apoptotic cell death,
inhibit tumor growth, and suppress tumor neo-angiogenesis in the absence of any apparent involvement of COX-2.[10-
12]
The two pharmacologic effects, inhibition of COX-2 and suppression of tumor growth, were found to reside in
different structural aspects of the celecoxib molecule. These findings make Celecoxib an attractive leading compound
for developing new anticancer agents.[13-16]
Figure 1
Combretastatins, a family of stilbenoids from the South African willow tree Combretum caffrum Kuntze
(Combretaceae), are also characterized by the presence of 1,2-diphenylethylene nucleus and have become of particular
1
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10.1002/cbdv.201900108
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interest to chemists and biologists because of their wide range of biological activities including antiinflammatory,
anticancer, antiviral, antioxidant and more recently neuroprotective effects.[17] Combretastatin A-4 (CA-4) exhibits
strong antitubulin activity by binding to the colchicine binding site of tubulin.[18] It exhibits potent cytotoxicity against
a broad spectrum of human cancer lines. The multiple biological activities and the structural simplicity of
combretastatin derivatives make them suitable for the design of hybrid drugs and many example of stilbene based
hybrid compounds as potential agents in the fields of cancer, antiinflammation and other relevant diseases have been
reported in the last decade.[17]
We now report the synthesis and biological activities of novel aryl-substituted pyrazole derivatives
mimicking cis-diphenylethylene scaffold of celecoxib as well as CA-4. The cytotoxic effects of these compounds
against three human cancer cell lines HT-29, Hep-G2, MCF-7 as well as the inhibition of NO production using
lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells were studied. The role of NO in tumour
biology is complex, because it has both facilitatory and inhibitory roles in cellular processes depending on the
conditions, so NO inhibition is directly unrelated to the cytotoxicity.[19] But NO displays a variety of the same useful
pharmacological properties as prostaglandins in the cardiovascular system including vasodilation, inhibition of platelet
aggregation, modulation of platelet and leukocytes adherence to vessels.[20] The use of selective COX-2 inhibitor
celecoxib in chemoprevention of breast cancer and other malignancies has been limited by its adverse effects, in
particular the risk of cardiovascular events principally connected to their ability to reduce the production of
prostacyclin PGI2.[21] Based on the observation that maintaining of NO production together with coxib-induced
activities thus might help avoiding risk of cardiovascular toxicity, a strategy to design a multi-target drug by
combining COX-2-selective inhibition with nitric oxide (NO)-dependent activities has been initiated.[9, 22-23]
Results and Discussion
In this study, we adopted the hybridization strategy to incorporate the important pharmacophoric groups of
two original compounds celecoxib and CA-4 in a single molecule. We utilized 1,2-diphenyl substituted pyrazole ring
of celecoxib as a scaffold to mimic the cis-1,2-diphenylethylene motif in CA-4. Replacement of the double bond with
heterocyclic five membered rings was demonstrated to retain both cytotoxic and antitubulin activities of the
compounds.[24] Indeed, these cis-locked analogues provide several advantages: preventing of isomerization from cis to
trans; increasing specificity of these drugs to cellular targets; and improving the therapeutic potential of these drugs.
The presence of the trimethoxybenzene moiety of CA-4 is also crucial to obtain relevant cytotoxic and antitubulin
responses.[25] We were particularly interested in maintaining the sulfonamid group or related bioisosteres of celecoxib
which seems to result in its COX-2 selectivity.[26] The COX-2 inhibitory effect, if any, will contribute to the overall
anti-tumor activity of new molecules.
An one-pot approach has been applied to prepare a variety of ethyl 1,4,5-triaryl-1H pyrazole-3-carboxylates
in moderate to high yields from ethyl oxalyl chloride, 1,2-diarylethanones and arylhydrazine hydrochlorides.[27] The
tert-BuOLi mediated Claisen condensation of 1,2-diarylethanones and ethyl oxalyl chloride efficiently provided the
enolized lithium salts of ethyl 2,4-dioxo-3,4-diarylbutanoates, which in situ reacted with arylhydrazine hydrochlorides
via a hydrochloric acid-promoted Knorr reaction to produce the exquisite triarylpyrazole-3-carboxylates. A process for
the preparation of celecoxib was also applied (Scheme 2). 3,4,5-trimethoxyphenyl - 1,1,1-trifluoro-2,4-butanedione
obtained from a Claisen condensation between acetophenone derivatives and ethyl trifluoroacetate thereby react with
4-sulfamidophenyl hydrazine halide salt to form the 3,4,5-trimethoxyphenyl analog of celecoxib.
Scheme 1. Synthesis of ethyl 1,4,5-triaryl-1H-pyrazole-3-carboxylates 6
2
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(i) Ethyl oxalyl chloride 4 (1 equiv.), 3 (1.0 mmol), tert-BuOLi (2,5 equiv.) in anhydrous THF (5 mL), for 6 h under
reflux then remove THF. (ii) EtOH (5 mL), concentrated HCl (1.0 equiv), arylhydrazine hydrochlorides 5 (1.0 mmol)
for 6 h under reflux. 6 Isolated via column chromatography.
Scheme 2. Synthesis of 3,4,5-trimethoxyphenyl analog of celecoxib.
(i) 7 (0.21 g, 1.0 m mole), Ethyl trifluoroacetate (0.18 g, 1.3 mmoles), NaH (0.03 g, 1.2 mmoles) in THF (5 mL),
50 °C for 2 hours. (ii) Trifluoroacetic acid (0.18 g, 1.6 mmoles), 4-Sulfonamidophenylhydrazine hydrochloride (4-
SAPH.HCl) (23.0 g, 1.0 mmoles) 55 °C for one hour.
Cytotoxicity of 21 compounds and celecoxib were evaluated for their inhibition rate of cell growth against
three human tumor cell lines (HT-29, Hep-G2 and MCF-7) by a method developed by Monks et al and the results
were summarized in Table 1.[28] The antiproliferative activity of celecoxib on human breast cancer cells (MCF-7),
human hepatocellular carcinoma cell (HepG2) and human colorectal cancer cells (HT-29) were similar to those
previously published.[5, 29-30] Here, 12 new coxib-hybrided compounds (entries 1 – 12) exhibit a higher range of
cytotoxicity on MCF-7 cells than celecoxib (entry 13) and five compounds (entries 1-5) have their IC50 < 10µM. Some
compounds in this group (entries 1,2,5,6 and 11) also have a comparable cytotoxicity on Hep-G2 cells to celecoxib.
Morever, five new coxib-hybrided compounds (entries 2, 5, 10, 11, 20) show their inhibition rate of cell growth
against HT-29 cells from three to six folds stronger than celecoxib and compound 6cb (entry 10) possesses IC50 around
10µM. Generally, the presence of a nitrogen-bearing group together with a halogen-bearing group at position para- of
both adjacent phenyl rings (entries 2, 6. 7, 8, 11) contribute to the increase of cytotoxicity while para-halogen-bearing
group, para-hydroxyl group or even no substituted group at para- (entries 2-11) may play a better role in cytotoxic
activity than para-methyl group in case of celecoxib or para-methoxyl group (entries 17, 18, 19, 21). Adding one more
non substituted phenyl ring to coxib pharmacophore may play an important role in determining a better cytotoxicity
against MCF-7 and HT-29 cells (entries 2-11). Compound 9 (entry 1) in which both the coxib and CA-4
pharmacophore were superimposed showed the most cytotoxic activity against MCF-7 even it does not need more
additional phenyl ring. 21 compounds and celecoxib were also examined their effects on nitric oxide (NO) production
in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells.[31] Except compound 9 and 6he (entry
14) have unexpected strong activities on inhibition of NO production, most of compounds in this new series exhibit
comparable or weaker inhibitory activity on NO production than celecoxib, underlining that they may possess a better
safety profiles on cardiovascular systems.
3
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Table 1. The cytotoxic effects of these compounds against three human cancer cell lines HT-29, Hep-G2, MCF-7 and
inhibition of NO production
Entry
Comp.
R
R’
R’’
IC50 (µM)
inhibition of
HT-29
Hep-G2
MCF-7
NO production
1
9
3,4,5-
4-NH2SO2
1.95±0.11
43.0 ± 6.0
39.96± 3.36
4.63± 0.59
triOMe
2
6fe
H
H
H
H
H
H
H
H
H
H
4-F
4-NH2SO2
4-CN
81.6 ± 10.6
116.83±7.7
129.88±15.7
18.7 ± 1.7
37.6±3.5
21.2±2.1
18.8 ± 1.5
23.5 ± 1.8
32.6± 3.0
153.2± 10
39.6±2.9
10.0±0.7
14.1 ± 1
29.37± 1.90
>254
7.97±0.51
3
6ac
H
8.20± 0.93
9.67± 0.92
8.90± 0.79
19.27±0.27
20.16± 1.83
21.30± 1.40
21.51± 1.48
21.65± 1.86
23.79± 3.11
29.80± 2.71
30.67±3.79
39.93± 2.64
4
6ad
H
4-NO2
>242
5
6de
4-OH
4-Br
4-Br
4-Br
4-Br
4-Br
4-Cl
4-NH2SO2
4-NH2SO2
4-CN
92.3 ± 7.2
73.7 ± 2.6
14.51±1.36
35.48±2.85
>211
6
6ce
7
6cc
116.01±13.6
91.58±7.8
21.01±4.3
> 233
8
6cd
4-NO2
>203
9
6ca
4-OMe
4-CF3
>209
10
11
12
13
14
6cb
75.87±4.41
37.04±4.95
>201
6ge
4-NH2SO2
4-CF3
122.2 ± 9.7
134.10±15.7
6bb
Celecoxib
6he
4-OMe 4-OMe
107± 10
4-Me
4-NH2SO2 83.59 ± 5.0
58.4 ± 3.4
136.0 ± 12
37.11±2.14
>197
H
4,6-
4-NH2SO2
4.41±0.17
diOMe
15
16
17
18
19
20
21
6ae
6aa
6bd
6bc
6ba
6ab
6be
H
H
H
H
4-NH2SO2
4-OMe
4-NO2
> 233
100 ± 10
>251
54.35±4.57
21.43±1.93
>211
40.54±2.56
43.19±4.86
48.81± 2.62
48.86± 3.13
49.32± 1.72
50.66± 4.46
68.43± 7.05
30.0±13.4
148.85±8.4
76.42±9.4
67.06±3.7
59.52±5.5
103.4 ±10.5
4-OMe 4-OMe
4-OMe 4-OMe
4-OMe 4-OMe
>211
4-CN
110.3±7.0
160±15
17.3±2.0
99.0±6.3
>220
4-OMe
4-CF3
>218
H
H
63.17± 3.01
58.57± 4.70
4-OMe 4-OMe
4-NH2SO2
4
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22
6ee
H
4,6-diOH
4-NH2SO2
> 208.5
173.9 ± 12
0.18± 0.04
64.03± 5.75
83.60± 3.44
0.36± 0.04
L-NMMA
Ellipticine
8.39±0.31
0.44± 0.05
Conclusions
In this report, we have described the concise elaboration of 21 novel aryl-substituted pyrazole derivatives
mimicking cis-diphenylethylene scaffold of celecoxib as well as CA-4 and their biological activities against three
human cancer cell lines HT-29, Hep-G2, MCF-7 and inhibition of NO production. Some new coxib-hybrided
compounds show their stronger inhibition rate of cell growth against MCF-7, HT-29 cells than celecoxib and possesses
IC50 under 10µM. Some compounds in this new series also exhibit weaker inhibitory activity on NO production than
celecoxib, opening further optimised studies of their safety profiles on cardiovascular systems. Therefore,
incorporation of the important pharmacophoric groups of two original compounds celecoxib and CA-4 in a single
molecule plays an important role in determining a better biological activities of the new coxib-hybrided compounds.
Experimental Section
General. Compounds 6 were synthesized according to methods described in the literature. The NMR spectra were
recorded using a Bruker DRX 500 spectrometer or 400-MR spectrometer. All J coupling values expressed in Hz. The
chemical shifts (δ) expressed in ppm relative to tetramethylsilane, using CDCl3, DMSO as the solvent. The HR-ESI-
MS were obtained using SCIEX-X500R QTOF LC/MS system. Column chromatography was performed using silica-
gel (Kieselgel 60, 70-230 mesh and 230-400 mesh, Merck) and thin layer chromatography (TLC) was performed using
a precoated silica gel 60 F254 (0.25 mm, Merck). Cytotoxic assays were performed according to a method developed
by Monks et al, which is being used at the National Institute of Health (USA) as a standard method for the evaluation
of the cytotoxic potential of compounds or extracts using a panel of human cancer cell lines.[28] The cancer cell lines
HT-29 (human colon cancer), MCF7 (human breast cancer), HepG2 (Hepatocellular carcinoma) were used for the
assays. The inhibitory effects of samples on NO production were evaluated in LPS-activated murine macrophage
RAW 264.7 cells.
General Procedure for the Preparation of Ethyl-1,4,5-triphenyl-1H-pyrazole-3-carboxylate 6
Ethyl oxalyl chloride 4 (1 equiv.) was added to a solution of 3 (1.0 mmol) and tert-BuOLi (2,5 equiv.) in anhydrous
THF (5 mL). The resulting mixture was stirred under reflux for 6 h. Then, the mixture was concentrated in vacuo to
remove THF giving a residual. Afterwards, EtOH (5 mL), concentrated hydrochloric acid (1.0 equiv) and
arylhydrazine hydrochlorides 5 (1.0 mmol) were added to the residual at room temperature, and then the mixtures were
refluxed for another 6 h. Reaction progress was monitored by TLC until no starting material remained. After reaction
was complete, 25 mL of water added to quench reaction and the aqueous layer was extracted with CH2Cl2 (20 mL× 3).
Finally, the combined organic phase was washed with brine (25 mL× 2), dried over anhydrous sodium sulfate, and
concentrated to provide a crude product, which was purified by column chromatography (10 – 30% EtOAc in hexane)
to give the corresponding 6.
Ethyl 1-(4-methoxyphenyl)-4,5-diphenyl-1H-pyrazole-3-carboxylate (6aa, yield 83%)
5
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1H NMR (500 MHz, CDCl3) δ1.26 (t, J＝7.2, 3H, Me); 3.77 (s, 3H, OMe); 4.33 (q, J＝7.1, 2H, CH2); 6.81 (d, J＝7.0,
2H, Ph); 6.98 (d, J＝7.0, 2H, Ph); 7.18－7.25 (m, 10H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.5; 55.5; 60.8; 113.9
(2C); 124.5; 127.0 (2C); 127.1; 127.6 (2C); 128.3 (2C); 128.4; 129.1; 130.4 (2C); 130.7 (2C); 131.9; 132.6; 141.2;
+
142.2; 159.2; 162.5. ESI-MS, m/z = 399.1710 ([M+H]+, C25H23N2O3 , calc. 399.1703).
Ethyl 4,5-diphenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate (6ab, yield 76%)
1H NMR (500 MHz, CDCl3) δ1.26 (t, J＝7.2, 3H, Me); 4.33 (q, J＝7.1, 2H, CH2); 7.01 (d, J＝7.0, 2H, Ph); 7.20－
7.27 (m, 8H, Ph); 7.45 (d, J＝8.3,2H, Ph); 7.58 (d, J＝8.3, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.1; 61.1; 125.4;
125.5 (2C); 126.1; 127.0 (2C); 127.3 (2C); 127.7 (2C); 128.6 (3C); 128.9; 130.3 (2C); 130.6 (2C); 131.4; 142.1; 142.3;
+
142.5; 162.2. ESI-MS, m/z = 437.1476 ([M+H]+, C25H20F3N2O2 , calc. 437.1471).
Ethyl 1-(4-cyanophenyl)-4,5-diphenyl-1H-pyrazole-3-carboxylate (6ac, yield 69%)
1H NMR (500 MHz, CDCl3) δ1.26 (t, J＝7.2, 3H, Me); 4.33 (q, J＝7.1, 2H, CH2); 7.01 (d, J＝7.0, 2H, Ph); 7.18－
7.30 (m, 8H, Ph); 7.45 (d, J＝8.3, 2H, Ph); 7.61 (d, J＝8.3, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.1; 61.2; 111.6;
117.9; 125.6 (2C); 125.7; 127.4; 127.7 (2C); 128.4;128.7 (2C); 129.1; 130.2 (2C); 130.5 (2C); 131.1; 132.8 (2C);
+
142.3; 142.7; 142.9; 162.1. ESI-MS, m/z = 394.1551 ([M+H]+,C25H20N3O2 , calc. 394.1550).
Ethyl 1-(4-nitrophenyl)-4,5-diphenyl-1H-pyrazole-3-carboxylate (6ad, yield 65%)
1H NMR (500 MHz, CDCl3) δ1.26 (t, J＝7.2, 3H, Me); 4.33 (q, J＝7.1, 2H, CH2), 7.01 (d, J＝7.0, 2H, Ph); 7.19－
7.33 (m, 8H, Ph); 7.50 (d, J＝8.3, 2H, Ph); 8.18 (d, J＝8.3, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.5; 61.2; 121.3
(2C); 125.5 (2C); 125.8; 127.4; 127.7 (2C); 128.4; 128.8 (2C); 129.2; 130.2 (2C); 130.5 (2C); 131.0; 142.5; 143.1;
144.2; 146.6; 162.0. ESI-MS, m/z = 414.1449 ([M+H]+,C24H20N3O+, calc. 414.1448).
Ethyl 4,5-diphenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (6ae, yield 85%)
1H NMR (500 MHz, CDCl3) δ1.25 (t, J＝7.2, 3H, Me); 4.33 (q, J＝7.1, 2H, CH2); 4.96 (s, 2H, NH2); 7.00 (d, J＝7.0,
2H, Ph); 7.18－7.29 (m, 8H, Ph); 7.46 (d, J＝8.3, 2H, Ph); 7.85 (d, J＝8.3, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ
14.1; 61.2; 125.6 (2C); 127.3 (3C); 127.7 (3C); 128.4; 128.7 (2C); 129.0; 130.2 (2C); 130.5 (2C); 131.2; 141.1; 142.4;
142.6; 142.7; 162.3. ESI-MS, m/z = 448.1327 ([M+H]+,C24H22N3O4S+, calc. 448.1326).
Ethyl 1,4,5-tris(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (6ba, yield 83%)
1H NMR (500 MHz, CDCl3) δ 1.27 (t, J＝7.2, 3H, Me); 3.73 (s, 3H, OMe); 3.79 (s, 6H, 2OMe); 4.31 (q, J＝7.2, 2H,
CH2); 6.68 (d, J＝8.7, 2H, Ph); 6.81- 6.83 (m, 4H, Ph); 6.87 (d, J＝8.7, 2H, Ph); 7.13 (d, J＝8.8, 2H, Ph); 7.20 (d, J＝
8.8, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.2; 55.1 (2C); 55.47; 60.78; 113.2; 113.7 (2C); 113.9 (2C); 121.3;
123.9 (2C); 124.3; 127.0 (2C); 131.6 (2C); 131.8 (2C); 132.8; 141.1; 142.0; 158.6; 159.1; 159.4; 162.6. HRMS, m/z =
+
459.1914 ([M+H]+, C27H27N2O5 , calc. 459.1914).
Ethyl 4,5-bis(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate (6bb, yield 78%)
1H NMR (500 MHz, CDCl3) δ 1.27 (t, J＝7.2, 3H, Me); 3.76 (s, 3H, OMe); 3.79 (s, 3H, OMe); 4.32 (q, J＝7.2, 2H,
CH2); 6.73 (d, J＝8, 2H, Ph); 6.82 (d, J＝8.7, 2H, Ph); 6.90 (d, J＝8.9, 2H, Ph); 7.13 (d, J＝8.7, 2H, Ph); 7.40 (d, J＝
8.2, 2H, Ph); 7.57 (d, J＝8.2, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.2; 55.1 (2C); 61.0;113.2 (2C); 114.1
(2C);120.8; 123.7 (2C); 124.8 (2C); 125.5 (2C); 126.0 (4C); 131.6; 131.7; 142.1; 142.3; 142.4; 158.8; 159.8; 162.4.
+
HRMS, m/z = 497.1683 ([M+H]+, C27H24F3N2O4 , calc. 497.1683)
Ethyl 1-(4-cyanophenyl)-4,5-bis(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (6bc, yield 70%)
1H NMR (500 MHz, CDCl3) δ 1,29 (t, J＝7.2, 3H, Me); 3.77 (s, 3H, OMe); 3.79 (s, 3H, OMe); 4.33 (q, J＝7.2, 2H,
CH2); 6.75 (d, J＝8.9, 2H, Ph); 6.81 (d, J＝8.3, 2H, Ph); 6.90 (d, J＝8.7, 2H, Ph); 7.11 (d, J＝8.4, 2H, Ph); 7.40 (d, J
＝8.00, 2H, Ph); 7.60 (d, J＝9.0, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.2; 55.1; 55.2; 61.1; 111.4; 113.3 (2C);
114.2; 118.2 (2C); 120.6; 123.4 (2C); 125.1; 125.6 (2C); 131.5 (2C); 131.7 (2C); 132.8; 142.1; 142.8; 142.9; 158.8;
+
160.0; 162.2. HRMS, m/z = 454.1765 ([M+H]+, C27H24N3O4 , calc. 454.1761).
Ethyl 4,5-bis(4-methoxyphenyl)-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (6bd, yield 60%)
1H NMR (500 MHz, CDCl3) δ 1.29 (t, J＝7.2, 3H, Me); 3.77 (s, 3H, OMe); 3.79 (s, 3H, OMe); 4.33 (q, J＝7.2, 2H,
CH2); 6.76 (d, J＝8.9, 2H, Ph); 6,81 (d, J＝8.3, 2H, Ph); 6.92 (d, J＝8.7, 2H, Ph); 7.12 (d, J＝8.4, 2H, Ph); 7.49 (d, J
6
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＝8.00, 2H, Ph); 8.17 (d, J＝9.0, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.2; 55.1; 55.2; 61.1; 113.4 (2C); 114.3
(2C); 120.5; 123.3 (2C); 124.3 (2C); 125.3 (2C); 131.1 (2C); 131.6 (2C); 142.3; 143.0; 144.4; 146.5; 158.8; 160.0;
+
162.2. HRMS, m/z = 474.1659 ([M+H]+, C26H24N3O6 , calc. 474.1660).
Ethyl 4,5-bis(4-methoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (6be, yield 78%)
1H NMR (500 MHz, CDCl3) δ 1.25 (t, J＝7.0, 3H, Me); 3.76 (s, 3H, OMe); 3.79 (s, 3H, OMe); 4.30 (q, J＝7.2, 2H,
CH2); 6.73 (d, J＝8.9, 2H, Ph); 6.80 (d, J＝8.3, 2H, Ph); 6.89 (d, J＝8.7, 2H, Ph); 7.11 (d, J＝8.4, 2H, Ph); 7.42 (d, J
＝8.00, 2H, Ph); 7.82 (d, J＝9.0, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.1; 55.1; 55.2; 61.1; 113.2 (2C); 114.3
(2C); 120.5; 123.5 (2C); 125.6 (2C); 127.2(2C); 131.6 (2C); 131.7 (2C); 141.1; 142.2; 142.6; 142.7; 158.8; 159.9;
162.3. HRMS, m/z = 508.1540 ([M+H]+, C26H26N3O6S+, calc. 408.1537).
Ethyl 5-(4-bromophenyl)-1-(4-methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylate (6ca, yield 77%)
1H NMR (500 MHz, CDCl3) δ1.25 (t, J＝7.2, 3H, Me); 3.80 (s, 3H, OMe); 4.32 (q, J＝7.1, 2H, CH2); 6.82-6.85 (m,
4H, Ph); 7.19－7.21 (m, 4H, Ph); 7.25－7.30 (m, 5H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.1; 55.6; 60.8; 113.9
(2C); 124.5; 127.0 (2C); 127.1; 127.6 (2C); 128.3 (2C); 128.4; 129.1; 130.4 (2C); 130.7 (2C); 131.9; 132.6; 141.2;
+
142.2; 159.2; 162.5. ESI - MS, m/z = 477.0813 ([M+H]+, C25H22BrN2O3 , calc. 477.0808).
Ethyl 5-(4-bromophenyl)-4-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate (6cb, yield 75%)
1H NMR (500 MHz, CDCl3) δ1.26 (t, J＝7.2, 3H, Me); 4.32 (q, J＝7.1, 2H, CH2); 6.85 (m, 2H, Ph); 7.10－7.20 (m,
2H, Ph); 7.29－7.30 (m, 3H, Ph); 7.35－7.36 (m, 2H, Ph); 7.45 (d, J＝7.4, 2H, Ph); 7.3 (d, J＝7.6, 2H, Ph). 13C NMR
(125 MHz, CDCl3): δ 14.0; 61.1; 125.5 (2C); 125.6; 126.2 (3C); 127.5 (3C); 127.9 (3C); 130.5 (2C); 131.0 (2C);
+
131.7 (2C); 132.0; 141.9; 142.0; 142.6; 162.0. ESI - MS, m/z = 515.0576 ([M+H]+, C25H19BrF3N2O2 , calc. 515.0577).
Ethyl 5-(4-bromophenyl)-1-(4-cyanophenyl)-4-phenyl-1H-pyrazole-3-carboxylate (6cc, yield 65%)
1H NMR (500 MHz, CDCl3) δ1.23 (t, J＝7.2, 3H, Me); 4.33 (q, J＝7.1, 2H, CH2); 6.87 (d, J＝6.86, 2H, Ph); 7.17－
7.18 (m, 2H, Ph); 7.26-7.29 (m, 3H, Ph); 7.38 (d, J＝7.3, 2H, Ph) ); 7.45 (d, J＝7.4, 2H, Ph); 7.65 (d, J＝7.6, 2H, Ph).
13C NMR (125 MHz, CDCl3): δ 14.1; 61.2; 111.9; 117.8; 123.7; 125.7 (2C); 125.9; 127.3; 127.6; 127.9 (2C); 130.4
(2C); 130.8; 131.6 (2C); 132.1 (2C); 133.0 (2C); 141.1; 142.4; 143.0; 161.9. ESI-MS, m/z = 472.0661 ([M+H]+,
+
C25H19BrN3O2 , calc. 472.0655).
Ethyl 5-(4-bromophenyl)-1-(4-nitrophenyl)-4-phenyl-1H-pyrazole-3-carboxylate (6cd, yield 67%)
1H NMR (500 MHz, CDCl3) δ1.25 (t, J＝7.2, 3H, Me); 4.34 (q, J＝7.1, 2H, CH2), 6.88 (d, J＝8.2, 2H, Ph); 7.17－
7.19 (m, 2H, Ph); 7.29－7.30 (m, 3H, Ph); 7.39 (d, J＝8.2, 2H, Ph); 7.5 (d, J＝8.6, 2H, Ph); 8.2 (d, J＝9.3, 2H, Ph);
13C NMR (125 MHz, CDCl3): δ 14.2; 61.2; 111.8; 117.8; 123.7; 125.6 (2C); 125.9; 127.5; 127.6; 127.9 (2C); 130.9
(2C); 130.8; 131.1 (2C); 132.4 (2C); 133.0 (2C); 141.2; 142.2; 143.1; 161.9. ESI-MS, m/z = 492.0555 ([M+H]+,
+
C24H19BrN3O2 , calc. 492.0553).
Ethyl 5-(4-bromophenyl)-4-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (6ce, yield 75%)
1H NMR (500 MHz, CDCl3): δ 1.25 (t, J＝7.2, 3H, Me); 4.33 (q, J＝7.1, 2H, CH2); 4.91 (s, 2H, NH2); 6.87 (d, J＝
7.0, 2H, Ph); 7.17－7.29 (m, 2H, Ph); 7.28－7.30 (m, 3H, Ph); 7.36 (d, J＝8.3, 2H, Ph); 7.47 (d, J＝8.3, 2H, Ph); 7,91
(d, J＝9.1, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.1; 61.4; 123.7; 125.6 (2C); 125.8; 127.3 ; 127.5(2C); 127.6
(2C); 127.9; 130.4 (2C); 130.9; 131.7 (2C); 132.1 (2C); 141.4; 142.4; 142.6; 142.8; 162.0. ESI-MS, m/z =
526.0429([M+H]+, C24H21BrN3O4S+, calc. 526.0431).
Ethyl 5-(4-hydroxyphenyl)-4-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (6de, yield 73%)
1H NMR (500 MHz, DMSO) δ 1.14 (t, J＝7.0, 3H, Me); 4.22 (q, J＝7.0, 2H, CH2); 6.64 (d, J＝8.3, 2H, Ph); 6.93 (d, J
＝8.4, 2H, Ph); 7.20 (m, 2H, Ph); 7,27 (m, 3H, Ph); 7,45 (s, 2H, NH2); 7.49 (d, J＝8.5, 2H, Ph); 7.83 (d, J＝8.6, 2H,
Ph); 9.72 (s, 1H, OH); 13C NMR (125 MHz, CDCl3): δ 14.3; 60.8; 115.9 (2C); 111.9; 124.5 (2C); 126.0 (2C); 127.4 ;
128.0(2C); 130.8 (2C); 132.0 (2C); 132.2 (2C); 141.9; 142.0; 143.1; 143.8; 158.3; 162.2. ESI-MS, m/z = 464.1276
([M+H]+, C24H22N3O5S+, calc. 464.1275).
Ethyl 5-(2,4-dihydroxyphenyl)-4-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (6ee, yield 66%)
7
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1H NMR (500 MHz, DMSO) δ 1.22 (t, J＝7.0, 3H, Me); 4.08 (q, J＝7.0, 2H, CH2); 6.93 (d, J＝8.3, 2H); 6,98-7.11
(dd, J＝8.4, 2H, Ph); 7.23 – 7.25 (m, 4H, Ph); 7.40 – 7.41 (m, 6H, Ph, NH2); 7.95 (d, J＝7.0, 2H, Ph). 13C NMR (125
MHz, CDCl3): δ 14.5; 62.5; 102.6; 116.3; 116.4; 125.5; 127.8 (2C); 128.2 (3C); 128.3 (2C); 128.8; 129.9; 130.2 (3C);
132.1; 150.3; 157.3; 161.4; 164.1; 175.7; ESI-MS, m/z = 480.1200 ([M+H]+, C24H22N3O6S+, calc. 480.1224).
Ethyl 5-(4-fluorophenyl)-4-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (6fe, yield 67%)
1H NMR (500 MHz, DMSO) δ 1.13 (t, J＝7.0, 3H, Me); 4.18 (q, J＝7.0, 2H, CH2); 6.93 (d, J＝8.3, 2H, Ph); 7.11-
7.17 (dd, J＝8.4, 3H, Ph); 7.48 – 7.51 (m, 2H, Ph); 7.52 – 7.53 (m, 2H, Ph); 7.84 (d, J＝7.0, 2H, Ph).13C NMR (125
MHz, CDCl3): δ 14.1; 61.4; 102.6; 116.3; 116.4; 125.5; 127.8 (2C); 128.2 (3C); 128.3 (2C); 128.8; 129.9; 130.2 (3C);
132.1; 141.3; 142.3; 162.0; ESI-MS, m/z = 466.1230 ([M+H]+, C24H21FN3O4S+, calc. 466.1231).
Ethyl 5-(4-chlorophenyl)-4-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (6ge, yield 75%)
1H NMR (500 MHz, CDCl3): δ 1.25 (t, J＝7.2, 3H, Me); 4.27 (q, J＝7.1, 2H, CH2); 5.2 (s, 2H, NH2); 6.9 (d, J＝7.0,
2H, Ph); 7.19－7.20 (m, 2H, Ph); 7.26－7.29 (m, 3H, Ph); 7.41 (d, J＝8.3, 2H, Ph); 7.43 (d, J＝8.3, 2H, Ph); 7.85 (d,
J＝9.1, 2H, Ph). 13C NMR (125 MHz, CDCl3): δ 14.1; 61.2; 126.6; 125.6 (2C); 125.8; 127.3 ; 127.5(2C); 127.6 (2C);
127.9; 130.4 (2C); 130.9; 131.7 (2C); 132.1 (2C); 141.4; 142.4; 141.6; 142.7; 162.0. ESI-MS, m/z = 482.0935
([M+H]+, C24H21ClN3O4S+, calc. 482.0936).
Ethyl 5-(2,4-dimethoxyphenyl)-4-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (6he, yield 64%)
1H NMR (500 MHz, DMSO) δ 1.25 (m, 3H, Me); 3.84 (s, 3H, OMe); 3.88 (s, 3H, OMe); 4.27 (s, 2H, CH2); 6.44 (d, J
＝3.1, 1H, Ph); 6,50 (dd, J＝8.3, 1H, Ph); 7.20 – 7.22 (m, 4H, Ph); 7.25 – 7.28 (m, 5H, Ph); 7.78(d, J = 8.0, 1H, Ph).
13C NMR (125 MHz, CDCl3): δ 14.4;55.6 (C); 61.2 (2C); 102.6; 116.3; 116.4; 125.5; 127.8 (2C); 128.2 (3C); 128.3
(2C); 128.8; 129.9; 130.2 (3C); 132.1; 150.3; 157.3; 161.4; 164.1; 175.7; ESI-MS, m/z = 508.1570 ([M+H]+,
C26H26N3O6S+, calc. 508.1537).
4-(3-(trifluoromethyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide (9)
To a reaction maintained under a nitrogen atmosphere, was added THF (5 mL), ethyl trifluoroacetate (0.18 g, 1.3
mmoles), NaH (0.03 g, 1.2 mmoles), and then 3,4,5-trimethoxyacetophenone (0.21 g, 1.0 m mole). The reaction
mixture was heated to 50 °C and maintained for 2 hours. Trifluoroacetic acid (0.18 g, 1.6 mmoles) was added to the
reaction mixture over a period of five minutes. 4-Sulfonamidophenylhydrazine hydrochloride (4-SAPH-HCl) (23.0 g,
1.0 mmoles) was added through a power addition funnel over a period of 5 minutes. The reaction mixture was brought
to 55 °C. and maintained for two hours. Water (0.045 g 2.5 mmoles) was added over 5 minutes. The reaction mixture
was cooled to 20 °C. over an hours. The slurry was filtered and washed twice with 50% (weight) aqueous ethyl alcohol
(10 g). The solid was dried in a vacuum oven for 6 hours to yield 9 (yield 78%).
1H NMR (500 MHz, DMSO) δ 3.69 (s, 6H, 2OMe, Ph); 3.87 (s, 3H, OMe, Ph); 4.99 (s, 2H, NH2); 6.44 (s, 2H, Ph);
6,76 (s, 1H, Ph); 7.50 (d,J = 8.0, 2H, Ph); 7.92 (d, J = 8.0, 2H, Ph).13C NMR (125 MHz, CDCl3): δ 56.2 (2C); 61.3;
102.4 (3C); 123.8; 125.5 (3C); 127.4 (3C); 141.5; 145.0; 153.5 (3C). ESI-MS, m/z = 458.0962 ([M+H]+,
C19H18F3N3O5S+, calc. 458.0992).
Cytotoxic assay. The cells were cultured as monolayer in Dulbeco’s Modified Eagle Medium (DMEM) or RPMI-1640
(depend on the cell lines) with contents including 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10
mM HEPES, 1.0 mM sodium pyruvate and supplement with Fetal Bovine Serum (FBS) 10%. The MCF7 medium was
further added with 0.01 mg/ml bovine insulin. The cells were subcultured after 3-5 days with the ratio of 1:3 and
o
incubated at 37 C, 5% CO2 and 100% humidified. The inhibitory rate of cell growth (IR) of cells was calculated by
the following equation IR = 100%-[(ODt – OD0) / (ODc - OD0)] x 100, where: ODt : average OD value at day 3;
OD0: average OD value at time-zero; ODc: average OD value of the blank DMSO control sample. The cytotoxicities
were calculated and expressed as iInhibition concentration at 50 % (IC50 values). Ellipticine was served as a positive
control. In our experiments, the isolated compounds were dissolved in DMSO 100 % at 4 mg/ml as stock solution. The
final concentration of testing compound for screening assay is 20 g/ml. The IC50 values of promising agents will be
8
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10.1002/cbdv.201900108
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Chem. Biodiversity
determined by testing a series of sample concentrations at 100, 20, 4 and 0.8 g/ml. Experiments were carried out in
triplicate for accuracy of data. The TableCurve 2Dv4 software was used for data analysis and for IC50 calculation. The
IC50 values should be in small deviation throughout the experiments.
Assay for NO inhibitory effect using RAW 264.7 cells. RAW 264.7 cells were cultured in Dulbecco's modified Eagle’s
medium (DMEM) supplemented with penicillin G sodium (100 units/mL), streptomycin sulfate (100 µg/mL),
amphotericin B (0.25 µg/mL), and 10% fetal bovine serum (FBS). The cells were seeded in 96-well culture plates with
1 × 105 cells/well and incubated for 24 h at 37 °C in a humidified atmosphere containing 5% CO2. The cells were
treated with samples dissolved in phenol red-free DMEM for 30 min followed by 1 µg/mL of LPS treatment for 20 h.
The amount of NO in the cultured medium was measured by the Griess reagent. The standard curve was created by
using known concentrations of sodium nitrite, and the absorbance was measured at 540 nm. To evaluate the cytotoxic
effect of samples in RAW 264.7 cells in the assay condition, SRB assay was performed. Briefly, after the fixation with
10% trichloroacetic acid (TCA), cells were stained with 0.4% SRB solution in 1% acetic acid followed by dissolving
bound SRB in 10 mM Tris-buffer. The optical density was determined at 515 nm.
Acknowledgements
The authors are indebted to the Vietnamese National Foundation for Science and Technology Development
(NAFOSTED, code: 104.01-2015.90) for financial support.
Author Contribution Statement
Synthesis: Thuy Hang Nguyen Thi, Ngoc Binh Vo. Design the synthesis: Quoc Anh Ngo. Wrote the paper: Quoc Anh
Ngo, Thuy Hang Nguyen Thi. Biological assay: Yen Tran Thi, Le Anh Nguyen.
References
[1] J. R. Brown and R. N. DuBois, 'COX-2: A Molecular Target for Colorectal Cancer Prevention', J. Clin. Oncol. 2005, 23, 2840-2855.
[2] S. Gupta, M. Srivastava, N. Ahmad, D. G. Bostwick and H. Mukhtar, 'Over-expression of cyclooxygenase-2 in human prostate
adenocarcinoma', The Prostate 2000, 42, 73-78.
[3] R. A. Soslow, A. J. Dannenberg, D. Rush, B. M. Woerner, K. N. Khan, J. Masferrer and A. T. Koki, 'COX-2 is expressed in human
pulmonary, colonic, and mammary tumors', Cancer 2000, 89, 2637 -2645.
[4] C. S. Williams, M. Mann and R. N. DuBois, 'The role of cyclooxygenases in inflammation, cancer, and development', Oncogene 1999,
18, 7908 -7916.
[5] C. Waskewich, R. D. Blumenthal, H. Li, R. Stein, D. M. Goldenberg and J. Burton, 'Celecoxib Exhibits the Greatest Potency amongst
Cyclooxygenase (COX) Inhibitors for Growth Inhibition of COX-2-negative Hematopoietic and Epithelial Cell Lines', Cancer Research
2002, 62, 2029 -2033.
[6] B. F. El-Rayes, S. Ali, F. H. Sarkar and P. A. Philip, 'Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic
cancer cell lines', Mol. Canc. Therapeut. 2004, 3, 1421 -1426.
[7] J. I. Johnsen, M. Lindskog, F. Ponthan, I. Pettersen, L. Elfman, A. Orrego, B. Sveinbjörnsson and P. Kogner, 'Cyclooxygenase-2 Is
Expressed in Neuroblastoma, and Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis and Inhibit Tumor GrowthIn vivo', Cancer
Research 2004, 64, 7210 -7215.
[8] Y.-Y. Kim, E.-J. Lee, Y.-K. Kim, S.-M. Kim, J.-Y. Park, H. Myoung and M.-J. Kim, 'Anti-cancer effects of celecoxib in head and
neck carcinoma', Molecules and Cells 2010, 29, 185 -194.
[9] C. Bocca, F. Bozzo, A. Bassignana and A. Miglietta, 'Antiproliferative effects of COX-2 inhibitor celecoxib on human breast cancer
cell lines', Mol. Cell. Biochem. 2011, 350, 59 -70.
[10] G. Geisslinger, S. Grösch, S. Schiffmann and T. J. Maier, 'Cyclooxygenase-2 (COX-2)–Independent Anticarcinogenic Effects of
Selective COX-2 Inhibitors', J. Natl. Cancer Inst. 2006, 98, 736-747.
[11] S. Grösch, I. Tegeder, E. Niederberger, L. Bräutigam and G. Geisslinger, 'COX-2 independent induction of cell cycle arrest and
apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib', The FASEB Journal 2001, 15, 2742-2744.
[12] K. M. Leahy, R. L. Ornberg, Y. Wang, B. S. Zweifel, A. T. Koki and J. L. Masferrer, 'Cyclooxygenase-2 Inhibition by Celecoxib
Reduces Proliferation and Induces Apoptosis in Angiogenic Endothelial Cells in Vivo', Cancer Research 2002, 62, 625 -631.
[13] A. H. Abadi, A. A. H. Eissa and G. S. Hassan,'Synthesis of Novel 1,3,4-Trisubstituted Pyrazole Derivatives and Their Evaluation as
Antitumor and Antiangiogenic Agents', Chem. Pharm. Bull. 2003, 51, 838-844.
[14] T. C. Chen, F. M. Hofman, S. G. Louie and N. A. Petasis, 'Celecoxib analogs that lack COX-2 inhibitory function: preclinical
development of novel anticancer drugs AU - Schönthal, Axel H', Expert Opin. Investig. Drugs 2008, 17, 197-208.
[15] N. Hura, A. Naaz, S. S. Prassanawar, S. K. Guchhait and D. Panda, 'Drug-Clinical Agent Molecular Hybrid: Synthesis of
Diaryl(trifluoromethyl)pyrazoles as Tubulin Targeting Anticancer Agents', ACS Omega 2018, 3, 1955-1969.
9
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900108
Chemistry & Biodiversity
Chem. Biodiversity
[16] H.-Y. Qiu, P.-F. Wang, Z. Li, J.-T. Ma, X.-M. Wang, Y.-H. Yang and H.-L. Zhu, 'Synthesis of dihydropyrazole sulphonamide
derivatives that act as anti-cancer agents through COX-2 inhibition', Pharmacological Research 2016, 104, 86-96.
[17] E. Giacomini, S. Rupiani, L. Guidotti, M. Recanatini and M. Roberti, 'The Use of Stilbene Scaffold in Medicinal Chemistry and
Multi- Target Drug Design', Curr. Med. Chem. 2016, 23, 2439-2489.
[18] C. M. Lin, H. H. Ho, G. R. Pettit and E. Hamel, 'Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on
the mechanism of their inhibition of the binding of colchicine to tubulin', Biochemistry 1989, 28, 6984-6991.
[19] P. K. Lala and C. Chakraborty, 'Role of nitric oxide in carcinogenesis and tumour progression', The Lancet Oncology 2001, 2, 149-156.
[20] S. Moncada and E. A. Higgs, 'The discovery of nitric oxide and its role in vascular biology', Br. J. Pharmacol. 2006, 147, S193-S201.
[21] E. Del Grosso, D. Boschi, L. Lazzarato, C. Cena, A. Di Stilo, R. Fruttero, S. Moro and A. Gasco, 'The Furoxan System: Design of
Selective Nitric Oxide (NO) Donor Inhibitors of COX-2 Endowed with Anti-Aggregatory and Vasodilating Activities', Chemistry &
Biodiversity 2005, 2, 886-900.
[22] D. Boschi, L. Lazzarato, B. Rolando, A. Filieri, C. Cena, A. Di Stilo, R. Fruttero and A. Gasco, 'Nitrooxymethyl-Substituted
Analogues of Celecoxib: Synthesis and Pharmacological Characterization', Chemistry & Biodiversity 2009, 6, 369-379.
[23] F. Bozzo, A. Bassignana, L. Lazzarato, D. Boschi, A. Gasco, C. Bocca and A. Miglietta, 'Novel nitro-oxy derivatives of celecoxib for
the regulation of colon cancer cell growth',Chem.-Biol. Interact. 2009, 182, 183 -190.
[24] K. Ohsumi, T. Hatanaka, K. Fujita, R. Nakagawa, Y. Fukuda, Y. Nihei, Y. Suga, Y. Morinaga, Y. Akiyama and T. Tsuji, 'Syntheses
and antitumor activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues', Bioorg. Med. Chem. Lett. 1998, 8, 3153-3158.
[25] K. Gaukroger, J. Hadfield, N. Lawrence, S. Nolan and A. T McGown, 'Structural requirements for the interaction of combretastatins
with tubulin: How important is the trimethoxy unit', Org. Biomol. Chem. 2003, 17, 3033 -3037 .
[26] R. G. Kurumbail, A. M. Stevens, J. K. Gierse, J. J. McDonald, R. A. Stegeman, J. Y. Pak, D. Gildehaus, J. M. iyashiro, T. D. Penning,
K. Seibert, P. C. Isakson and W. C. Stallings, 'Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents',
Nature 1996, 384, 644-648.
[27] J. Zhai, C. Gu, J. Jiang, S. Zhang, D. Liao, L. Wang, D. Zhu and Y. Ji, 'A One-pot Approach to Ethyl 1,4,5-Triaryl-1H-pyrazole-3-
carboxylates via an Improved Claisen Condensation-Knorr Reaction Sequence', Chin. J. Chem. 2013, 31, 1526-1538.
[28] A. D. Monks, D. A. Scudiero, P. Skehan, S. Rh, P. Kd, D. T. Vistica, C. X. Hose, J. Langley, P. Cronise and A. Vaigro-Wolff,
'Feasibility of a High-Flux Anticancer Drug Screen Using a Diverse Panel of Cultured Human Tumor Cell Lines', J. Natl. Cancer Inst. 1991,
83, 757 -766.
[29] Y. Li, Y. Niu, H. Wu, B. Zhang, Y. Sun, H. Huang, Q. Li, L. Fan, L. Liu and Q. Mei, 'PC-407, a celecoxib derivative, inhibited the
growth of colorectal tumor in vitro and in vivo', Cancer Science 2009, 100, 2451-2458.
[30] K. R Roy, G. Reddy, L. Maitreyi, S. Agarwal, C. Achari, S. Vali and R. Pallu, 'Celecoxib Inhibits MDR1 Expression through COX-2-
Dependent Mechanism in Human Hepatocellular Carcinoma (HepG2) Cell Line', Cancer Chemother. Pharmacol. 2009, 65, 903 -911.
[31] S. Cheenpracha, E.-J. Park, B. Rostama, J. M. Pezzuto and L. C. Chang, 'Inhibition of nitric oxide (NO) production in
lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells by the norsesterterpene peroxide, epimuqubilin A', Marine drugs
2010, 8, 429-437.
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