Synthesis of novel pyrazole derivatives as promising DNA-binding agents and evaluation of antitumor and antitopoisomerases I/II activities

Article abstract of DOI:10.1248/cpb.c18-00546

Molecules bearing pyrazole nucleus present diverse biological properties such as antitumor and antiinflammatory activities that can be associated with DNA interactions. This study aimed to the synthesis of new pyrazol derivatives and evaluated their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized, and their structures were elucidated by ¹H-NMR and high resolution (HR)-MS (electrospray ionization positive mode (ESI⁺)). Antiproliferative inhibition assays, UV titration assays, fluorescence titration assays, circular dichroism (CD) assays, KI quenching studies, topoisomerase inhibitory activity assays and molecular docking were evaluated for these compounds. Especially, compounds 5e and 5q showed higher antitumor activity with IC₅₀ values <13 μM for the tested cell lines. However, compounds 5e and 5q did not inhibit the topoisomerase activity evaluated by relaxation assay. These results show that the pyrazole nucleus contributes to the incorporation of molecules into the DNA. Moreover, it was highlighted that positive charges are relevant for the design of promising antitumor and DNA binding compounds.

Full text of DOI:10.1248/cpb.c18-00546

Chemical and Pharmaceutical Bulletin Advance Publication by J-STAGE
DOI:10.1248/cpb.c18-00546
Advance Publication
September 7, 2018
Chem. Pharm. Bull.
Regular Article
Synthesis of novel pyrazole derivatives as promising DNA-binding agents and
evaluation of antitumor and antitopoisomerase I/II activities
a
a
a
a
c
a,
Jiajia Feng , Hui Qi , Xiaoyang Sun , Siran Feng , Zhenming Liu , Yali Song *,
a,b⇑
Xiaoqiang Qiao
a
Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei
University, Baoding, 071002, China
b
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education
c
Drug Design Center, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking
University, Beijing 100191, China
*
Corresponding author. E-mail: yalisong@hbu.edu.cn
⇑
Corresponding author. E-mail: xiaoqiao@hbu.edu.cn
Ⓒ
2018 The Pharmaceutical Society of Japan

Abstract
Molecules bearing pyrazole nucleus present diverse biological properties such as
antitumor and anti-inflammatory activities that can be associated with DNA interactions. This
study aimed to the synthesis of new pyrazol derivatives and evaluated their ability to interact
with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were
1
+
successfully synthesized, and their structures were elucidated by HNMR and HRMS (ESI ).
Antiproliferative inhibition assays, UV titration assays, fluorescence titration assays, circular
dichroism (CD) assays, KI quenching studies, topoisomerase inhibitory activity assays and
molecular docking were evaluated for these compounds. Especially, compounds 5e and 5q
showed higher antitumor activity with IC50 values <13 μM for the tested cell lines. However,
compounds 5e and 5q did not inhibit the topoisomerase activity evaluated by relaxation assay.
These results show that the pyrazole nucleus contributes to the incorporation of molecules
into the DNA. Moreover, it was highlighted that positive charges are relevant for the design
of promising antitumor and DNA binding compounds.
Keywords: pyrazole; DNA; Antitumor; Antitopoisomerase
Chemical and Pharmaceutical Bulletin Advance Publication

Cancer has always been a dreadful disease and continues to attract extensive research
investigations. An estimated 8.2 million deaths are reported in 2012 worldwide, the annual
number of new cases due to cancer is projected to rise from 14.1 million in 2012 to 21.6
[
1]
million by 2030 with an increase in the death rate by 60%. Various targets have been
identified to restrain cancer among these DNA happens to be the most explored one. DNA is
an important biological material whose base sequence controls the heredity of life and is the
[
2]
primary target for most anticancer and antiviral therapies. The DNA binders are classified
into three categories based on their mode of interaction, such as I) intercalators II) groove
[3]
binders III) and combilexins.
Topoisomerase is a vital nuclear enzyme involved in various DNA processes and also
important targets for inhibiting the cell proliferation. These are nuclear enzymes that
transiently break one or two strands of DNA allowing to solve various DNA topological
problems associated with DNA replication, transcription, recombination, and other vital
[
4-5]
cellular processes.
DNA topoisomerases are generally classified into topoisomerase I
(
topo I) and topoisomerase II (topo II) depending on their mechanism of action, making
[6]
either single- or double-stranded breaks, respectively.
To date, some topoisomerase inhibitors, such as camptothecin (CPT) and its derivatives that
target Topo I and etoposide (VP-16) , doxorubicin and mitoxantrone which target Topo
II, have been clinically used as potent anticancer drugs.
[7]
[8]
[9]
[10]
Pyrazole has shown a variety of biological and pharmacological properties. As potential
antitumor compounds, they have shown good antitumor activity, multiple targets and high
[
11-12]
selectivity in vitro.
Lansiaux A. et al. studied a correlation between DNA binding
affinity and nuclear uptake, and have found cationic drugs can be delivered selectively to the
cell nucleus. It has been postulated that they gain entry into the cell via the human organic
[
13]
cation transporter 1(hOCT1).
Based on this information, our research group had
synthesized new 1,3,5-triphenyl pyrazole derivatives which different cationic groups were
used as side chains. Therefore, these compounds may easily cross the cell membrane and
accumulate in the nucleus and enhance anticancer activity. These compounds were evaluated
for their DNA interaction ability, giving the binding mode and affinity with DNA molecule.
In addition, it was also analyzed the antiproliferative activity on tumor cells and inhibition of
the topoisomerase enzyme.
Results and discussion
Chemistry The synthetic strategy for the preparation of 1,3,5-triphenyl pyrazole is
[
14-17]
outlined in the Chart 1. Using Claisene-Schmidt condensation reaction
compound 1
were synthesized. Reactions were base catalyzed, without any protection of hydroxyl groups.
In the first step, 20% NaOH aqueous solution was added to the solution of equimolar
amounts of aryl ketone and aryl aldehyde in ethanol to obtain compound 1. Next, compound
2
was prepared by oxidation of compound 1. In the next step, compound 3 was synthesized in
quantitative yield by the treatment of phenylhydrazine and compound 2 in ethanol.
Compound 4 was synthesized by compound 3 and dibromo alkane in the presence of pure
water, KOH and TBAB. Finally, compound 4 and aliphatic amine were reacted in the
2 3
presence of KI, K CO and acetonitrile reflux for 7 h to give the crude product. The crude
Chemical and Pharmaceutical Bulletin Advance Publication

product was dissolved in acetone, and then HCl was added into the solution to adjust the pH
to 2-3, and white precipitates precipitated, then filtered to get the final product (5a-5r). All
1
+
the compounds were confirmed by HNMR and HRMS (ESI ).
Chart 1. Synthesis of compounds 5a-5r.
Chemical and Pharmaceutical Bulletin Advance Publication

Table 1
Structure of compounds 5a-5r.
Compounds
n
2
R
yield/%
melting-point/°C
163-165
18.6
64.0
64.8
5
a
211-213
236-238
248-250
226-228
224-226
185-187
224-226
195-197
5
b
2
2
2
2
2
3
3
5
c
5
4
3
2
6
4
1.5
8.2
6.3
0.8
9.2
7.2
5
d
5
e
5
f
5
g
5
h
5
i
3
5
5
3
5
6
5.4
4.0
5.4
8.2
8.1
203-205
202-204
208-210
212-214
213-215
5
j
3
3
3
4
4
5
k
5
l
5
m
5
n
Chemical and Pharmaceutical Bulletin Advance Publication

5
9.6
195-197
5
o
4
3
3
5
7.4
3.1
6.2
204-206
207-209
66-68
5
5
p
q
4
4
4
5
r
Biological activity
Antiproliferative activity The antitumor potency of target compounds against four
human cancer cell lines including MCF-7 (breast cancer), MGC-803 (gastric cancer), HeLa
(
cervical cancer), and Huh-7 (liver cancer) cells were evaluated by MTT assay. Camptothecin
and etoposide were used as positive controls. The results were shown in Table 2. By
comparing the IC50 values, compounds 5e and 5q showed higher antitumor activity with IC50
values <13 μM for all tested cell lines. Compound 5f showed good inhibitory activity
selectivity for MGC-803 as well as Huh-7, and compounds 5k selectivity for Huh-7.
Furthermore, compounds 5d had relatively weak inhibitory activity in the four cancer cell
lines. The preliminary results are promising, and some of these compounds may be potential
candidates for new anticancer agents.
Table 2
The IC50 values of compounds 5a-5r against various human cancer cells.
IC (μM)
5
0
Compounds
MCF-7
2.86±1.25
1.56±0.75
>60
MGC-803
4.35±0.47
2.61±0.74
26.48±1.13
46.14±1.32
>60
Hela
Huh-7
1.28±0.50
1.35±0.66
49.18±1.13
31.85±1.32
>60
camptothecin
etoposide
3.26±0.30
3.02±0.80
30.11±3.60
34.05±1.65
38.37±0.95
>60
5
a
5
b
30.96±1.76
52.65±5.72
>60
5
c
5
d
>60
>60
5
e
12.62±2.53
18.97±2.00
8.72±2.17
11.66±3.46
12.16±2.81
17.32±1.81
5.46±2.83
7.67±2.11
5
f
Chemical and Pharmaceutical Bulletin Advance Publication

5
g
48.35±1.68
47.89±1.70
>60
>60
32.27±1.80
>60
>60
5
h
>60
>60
5
i
29.56±4.36
30.80±1.78
16.39±2.40
46.01±2.33
50.24±1.53
28.37±1.98
17.50±1.22
36.01±0.87
6.86±0.84
23.46±2.00
>60
39.93±2.94
46.80±5.63
9.12±2.47
>60
5
j
>60
>60
5
k
43.92±1.67
>60
21.65±1.50
57.62±1.33
50.03±5.60
51.01±1.17
>60
5
l
5
m
>60
21.67±3.23
54.52±3.46
48.13±6.20
57.72±1.51
9.12±2.47
>60
5
n
>60
5
o
p
q
58.35±1.72
>60
5
53.25±1.50
9.28±2.76
20.01±2.69
5
12.97±1.36
>60
5
r
Each value represents the Mean ± S.D. from three different experiments, performed in triplicate.
Camptothecin and etoposide were used as positive controls.
DNA binding studies
To find out the nature of the interaction of active congeners 5e and 5q with DNA,
biophysical studies such as UV-visible spectroscopy, fluorescence spectroscopy and circular
dichroism spectroscopy were carried out.
UV-visible Absorption Spectroscopy To examine the binding nature of active
congeners 5e and 5q to DNA, the UV absorption spectra of these congeners in the presence
and absence of increasing concentrations of ctDNA were examined. UV-visible studies are
useful in understanding the mode of binding of these compounds with DNA. In general,
hypochromism combined with a red shift is considered as an indication of intercalation of
small molecules into DNA due to the stacking of the chromophore pairs. The hyperchromism
originates from the breaking of the DNA secondary structure with contraction in the axis of
the helix; while hypochromism results from the stabilization of the double stranded DNA
[
18]
either by intercalation or electrostatic effect and groove binding . The maxima absorption
wavelength of 5e and 5q in the absence of ctDNA was 207 and 208 nm, respectively.
Absorption spectra of 5e and 5q showed that as the concentration of ctDNA increases, the
curve presents hypochromism without any red or blue shift. Hypochromic effect without any
red or blue shift can be suggested that the groove binding is the most susceptible mode of 5e
[
19]
b
and 5q with ctDNA. .(Fig. 1) K of the compounds were determined using the following
Formula:
[DNA] / (ε
A F B F b B F
-ε ) = [DNA] / (ε -ε ) + 1 / K (ε -ε )
where [DNA] is the concentration of ctDNA. In the formula, ε
A
= the apparent absorption
Chemical and Pharmaceutical Bulletin Advance Publication

coefficient, ε
of the compound when fully bound to DNA, respectively. In plots of [DNA] / (ε
DNA], K is given by the ratio of the slope to the intercept.(table 3)
F
= the extinction coefficient of the free compound, ε
B
= the extinction coefficient
A
−ε ) versus
F
[
b
A) 5e (0.15 μΜ)
0
0
0
0
1
1
μΜ
0.5
0.4
0.3
0.2
0.1
0.0
.3 μΜ
.6 μΜ
.9 μΜ
.2 μΜ
.5 μΜ
200
205
210
215
220
Wavelength (nm)
B) 5q (0.15 μΜ)
0
0
0
0
1
1
μΜ
0.5
0.4
0.3
0.2
0.1
0.0
.3 μΜ
.6 μΜ
.9 μΜ
.2 μΜ
.5 μΜ
200
205
210
215
220
Wavelength (nm)
Chemical and Pharmaceutical Bulletin Advance Publication

Fig. 1. Absorbance changes after interaction of 5e (0.15 μΜ) and 5q (0.15 μΜ) with ctDNA.
([ctDNA]=0, 0.3, 0.6, 0.9, 1.2, 1.5 μΜ)
(
Color figure can be accessed in the online version.)
Table 3
DNA binding data for compounds.
−1
compound
λ (nm)
Change in abs.
Bathochromism
b
K (M )
(
nm)
4
4
5
e
207
208
Hypochromism
Hypochromism
0
1.98(±0.04)×10
3.88(±0.06)×10
5
q
0
Fluorescence titrations To further evaluate the ctDNA interaction, the corresponding
binding parameters were also determined by fluorescence spectroscopy. This Fluorescence
[
20]
titrations assay can provide information on the nature and affinity of binding on ctDNA.
On addition of equal increments of ctDNA solution to the solution of 5e and 5q, the
hypochromicity of fluorescence emission intensity at 396 nm was observed, which probably
indicates a non-intercalative mode of binding such as electrostatic binding mode (surface
binding or groove binding) that leads to effective protection of 5e and 5q molecules by
ctDNA. However, the less intense fluorescence peaks intensity of 5e at 480-510 nm exhibited
gradual enhancement with the addition of ctDNA. The enhancement in the fluorescence
peaks at high wavelength may be due to a partial intercalating portion of 5e with ctDNA. The
fluorescence spectra of 5e and 5r were shown in Fig. 2.
A) 5e
200
175
150
125
100
75
50
25
0
350
400
450
500
550
600
Wavelength (nm)
Chemical and Pharmaceutical Bulletin Advance Publication

B) 5q
220
200
180
160
140
120
100
80
60
40
20
0
350
400
450
500
550
600
Wavelength (nm)
Fig. 2. Fluorescence spectra depicts the interaction of compounds 5e (10 μΜ) and 5q (10 μΜ)
with increasing concentrations of ctDNA at 25°C.
([ctDNA]=0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 μΜ)
(
Color figure can be accessed in the online version.)
Circular dichroism studies Circular dichroism (CD) has been found to be a reliable
technique for detecting DNA minor groove binding by small molecules. CD monitors the
interaction of a compound to the double helix; thus, a large induced CD signal implies minor
groove binding because in this interaction, ligands would be in proximity to the chiral sugars.
Conversely, intercalators induce little or no induced CD signal, as they bind far from the
[
21]
chiral sugars. We observed CD spectra of several of the new compounds to determine if
they are binding in the DNA minor groove. Fig. 3 showed that the CD spectra for the
interaction between ctDNA and two of the compounds (5e and 5q). All of the two compounds
showed very strong induced CD signals which demonstrate the ctDNA minor groove binding
of these compounds. (Fig. 3)
Chemical and Pharmaceutical Bulletin Advance Publication

ctDNA 10 μΜ
3
2
1
0
1
2
3
ctDNA and 5e (1:1)
ctDNA and 5e (1:2)
220
240
260
280
300
320
Wavelength (nm)
-
-
-
(A)
ctDNA 10 μΜ
ctDNA and 5q (1:1)
ctDNA and 5q (1:2)
3
2
1
0
1
2
3
220
240
260
280
300
320
Wavelength (nm)
-
-
-
(B)
Fig. 3. Circular dichroism spectroscopy of 5e and 5q with ctDNA.
KI quenching studies Iodide quenching experiments were conducted on the same
fluorescence spectrophotometer described previously. Iodide ions can effectively quench the
[
22-23]
fluorescence intensity of the small molecule in an aqueous medium.
In the presence of
DNA, iodide ions are repelled by similarly charged phosphate backbone of DNA and any
small molecule that penetrates inside DNA helix is well protected from being quenched by
Chemical and Pharmaceutical Bulletin Advance Publication

these negatively charged quenchers. However, electrostatically bounded molecules, as well as
groove binders, are not well protected from anionic quenchers even in the presence of DNA
[
24]
environment and are readily quenched by KI. The quenching was investigated by gradually
adding KI to compound and compound–ctDNA complex solutions to measure the relative
accessibilities of the free and bound compound. Varying concentrations of KI (0–20 mM)
were added to the compound (10 µM) and compound–ctDNA (containing 10 µM compound
and 40 µM ctDNA) solutions, respectively. The quenching constants in the absence and
presence of ctDNA were calculated and then compared to analyze the interaction mode of the
compound with ctDNA.
Fig. 4 revealed the quenching behaviors of KI in the compound and compound–ctDNA
−1
systems. It was seen that the Ksv values of 5e were 15.48 and 16.77 L mol , and that the Ksv
−1
values of 5q were 20.57 and 24.82 L mol without and with ctDNA, which indicated that the
double helix of ctDNA could not protect the compound from the anionic quencher. Therefore,
the interaction mode of the compound with ctDNA should be groove binding.
A) 5e
B) 5q
5
q alone,Ksv=20.57
5
e alone,Ksv=15.48
5q+DNA,Ksv=24.82
1.6
1
1
1
1
1
1
1
1
1
0
.40
5e+DNA,Ksv=16.77
.35
.30
.25
.20
.15
.10
.05
.00
.95
1.5
1.4
1.3
1.2
1.1
1.0
0
5
10
15
20
0
5
10
15
20
-
3
-
3
[
I
] × 10 ( Μ
)
[ I ] × 10 ( M)
Fig. 4 KI quenching studies. Stern–Volmer plot to calculate the KI quenching constant in
absence and presence of DNA. Slight increase in KSV value is obtained in case of groove
binding.
Molecular docking studies To further substantiate the biological activity of these
compounds, molecular docking studies were performed to characterize the interaction of
1,3,5-triphenyl pyrazole with DNA. The 3D co-crystal structures of DNA (PDB: 1DNH) is
selected as the receptor for molecular docking study. The results from the molecular docking
indicated that these compounds bind to the minor groove of DNA sequences. Compounds 5e
and 5q are complementary to that of the DNA groove, and a similar binding affinity was
observed in comparison with the Niacin 33258 (the original ligands of 1DNH). The methoxy
Chemical and Pharmaceutical Bulletin Advance Publication

groups and the alkylamine groups on both ends of the ligand were involved in extensive and
dynamic H-bonds to the DNA bases. Molecular docking and fluorescence studies also
support this claim.
(A) Niacin 33258
(B) compound 5e
(C) compound 5q
Fig 5 View of Niacin 33258 (A) compound 5e (B) and 5q (C) docked in the DNA binding
domain
Antitopoisomerase activity The enzymes which control the topology of DNA are called
topoisomerases and play a crucial role in several important processes such as DNA
[
25]
replications, transcription, segregation and recombination.
The two major classes of
topoisomerase type I (topo I) and type II (topo II), are mainly classified by cleavage of
[26]
single-stranded or double-stranded DNA, respectively. Generally, in various tumor cells,
topoisomerase is expressed much more than in normal cells, so the modulating of
[
27]
topoisomerase levels could be an important treatment for cancer.
Well-known
topoisomerase I and II inhibitors, camptothecin and etoposide, were used as positive controls.
The reaction products of topoisomerase I and II relaxation assays were analyzed by
electrophoretic mobility and developed in ethidium bromide in the presence of UV light. The
inhibitory activities were evaluated at 100 µM for all compounds. Only those compounds
with moderate to significant activity were tested further at 20 µM.
Antitopoisomerase I activity All of the compounds showed no inhibitory activity on
topo I at 100 µM concentrations. Fig 6 showed that the DNA fraction of super helicoidal was
completely relaxed by the enzyme topo I.
Chemical and Pharmaceutical Bulletin Advance Publication

A) 100 µM
D
T
C 5a 5b 5c 5d 5e 5f 5g 5h
Relaxed
Supercoiled
D
T
C
5i 5j 5k 5l 5m 5n 5o 5p
Relaxed
Supercoiled
D
T
C
5q 5r
Relaxed
Supercoiled
Lane D: pBR322 only,
Lane T: pBR322 + topoisomerase I,
Lane C: pBR322 + topoisomerase I + Camptothecin,
Lane 5a-5r: pBR322 + topoisomerase I + compounds 5a-5r,
Fig 6. Topoisomerase I inhibitory activity of compounds 5a-5r
Antitopoisomerase II activity As shown in Fig 7, most of the compounds (5c, 5h, 5k, 5l,
5
m, 5n, 5q, 5r) showed topoisomerase II inhibitory activity at 100 µM. Noteworthy, the
compounds of 5r (48.2% and 13.3% at 100 and 20 µM, respectively) showed better
topoisomerase II inhibitory activity.
It was suggested that the cytotoxic activity of 5e was not due to topo II inhibition and
the cytotoxic activity of 5q showed lower topoisomerase II inhibitory activity. However,
according to research findings, pyrazole compounds have a wide range of biological
[
28-30]
targets.
In future analysis, other target molecules will be investigated for better
elucidation of the action mechanism of the new pyrazole derivatives synthesized in this work.
Chemical and Pharmaceutical Bulletin Advance Publication

A) 100 µM
D
T
C 5a 5b 5c 5d 5e 5f 5g 5h
Relaxed
Supercoiled
D
T
C 5i 5j 5k 5l 5m 5n 5o 5p
Relaxed
Supercoiled
D
T
C
5q
5r
Relaxed
Supercoiled
B) 20 µM
D
T C 5a 5b 5c 5h 5k 5l 5m 5n
Relaxed
Supercoiled
D
T C 5q 5r
Relaxed
Supercoiled
Lane D: pBR322 only,
Lane T: pBR322 + topoisomerase II,
Lane C: pBR322 + topoisomerase II + Etoposide,
Lane 5a-5g: pBR322 + topoisomerase II + compounds 5a-5r,
Fig 7. Topoisomerase II inhibitory activity of compounds 5a-5r
Conclusion
In conclusion, a novel series of 1,3,5-triphenyl pyrazole compounds were synthesized,
and their antiproliferative properties were evaluated against four human cancer cell lines.
Especially, the compounds 5e and 5q showed higher antitumor activity with IC50 values <13
μM for the tested cell lines. Compound 5e and 5q did not inhibit the topoisomerase activity
evaluated by relaxation assay. However, the DNA binding studies disclosed that they are
DNA minor groove binding and the docking studies correlated with DNA binding studies.
Chemical and Pharmaceutical Bulletin Advance Publication

The findings give us an insight into the DNA binding mechanism and the anticancer activity
of these 1,3,5-triphenyl pyrazole compounds. Overall, these studies are very important to
understand the role of 1,3,5-triphenyl pyrazole compounds for the cytotoxic activity and
DNA binding ability. And the positive charges can be used as a strategy for increasing the
DNA binding affinity and anticancer activity of these compounds. It is suggested that these
compounds may act as potential anticancer agents.
Acknowledgments
We gratefully acknowledge the funding support from National Natural Science
Foundation of China (No. 21675039); China Postdoctoral Science Foundation (No.
2
016M591401); Young Talent of Hebei Province; Natural Science Foundation of Hebei
Province (No. B2018201269); Hebei University Science Fund for Distinguished Young
Scholars (No. 2015JQ06).
Conflict of Interest
The authors declare no conflict of interest.
Supplementary Materials
The online version of this article contains supplementary materials.
General chemistry methods, synthesis procedures, spectral data, biological assays,
molecular docking are given in Supplementary materials.
Chemical and Pharmaceutical Bulletin Advance Publication

References
[
1] Torre L. A., Siegel R. L., Ward E. M., Jemal A., Cancer Epidemiol Biomarkers Prev. 25,
6-27 (2016).
1
[
[
[
[
[
[
2] Jain A. K., Bhattacharya S., Bioconjug Chem. 22, 2355-2368 (2011).
3] Dileep K. V., Vijeesh V., Remya C., Biosystems. 12, 860-867 (2016).
4] Wang J. C., Annu Rev Biochem. 65, 635-692 (1996).
5] Nitiss J. L., Biochim Biophys Acta. 1400, 63-81 (1998).
6] Forterre P., Gribaldo S., Gadelle D., Serre M. C., Biochimie. 89, 427-446 (2007).
7] Demarquay D., Huchet M., Coulomb H., Lesueur-Ginot L., Lavergne O., Kasprzyk P. G.,
Anticancer Drugs. 12, 9-19 (2001).
[
[
8] Baldwin E. L., Osheroff N., Curr Med Chem. 5, 363-372 (2005).
9] Yi L. L., Kerrigan J. E., Lin C. P., Azarova A. M., Tsai Y. C., Ban Y., Cancer Res. 67,
8
839-8846 (2007).
[
[
[
[
[
[
10] Murdock K. C., Child R. G., Fabio P. F., Angier R. D., Wallace R. E., Durr F. E., J Med
Chem. 22, 1024-1030 (1979).
11] Chavan H. V., Bandgar B. P., Adsul L. K., Dhakane V. D., Bhale P. S., Thakare V. N.,
Bioorg Med Chem Lett. 23, 1315-1321 (2013).
12] Lowe G., Droz A. S., Vilaivan T., Weaver G. W., Tweedale L., Pratt J. M., J Med Chem.
4
2, 999-1006 (1999).
13] Lansiaux A., Dassonneville L., Facompré M., Kumar A., Stephens C. E., Bajic M., J
Med Chem. 45, 1994-2002 (2002).
14] Jahng Y., Zhao L. X., Moon Y. S., Basnet A., Kim E. K., Chang H. W., Bioorg Med
Chem Lett. 14, 2559-2562 (2004).
15] Batovska D., Parushev S., Slavova A., Bankova V., Tsvetkova I., Ninova M., Eur J Med
Chem. 42, 87-92 (2007).
[16] Breslow D. S., Hauser C. R., J Am Chem Soc. 62, 2385-2388 (2002) .
[17] Narender T., Reddy K. P., Tetrahedron Lett. 48, 3177-3180 (2007).
[18] C. Y. Zhou., X. L. Xi., P. Yang., Biochem. 72 37-43 (2007) .
[19] G. Zhang., X. Hu., P. Fu., J. Photochem Photobiol B. 108, 53-61 (2012).
[20] Shah A., Nosheen E., Munir S., Badshah A., Qureshi R., Zia-ur-Rehman, J Photochem
Photobiol B. 120, 90-97 (2013).
[
[
[
21] Nagle P. S., Mckeever C., Rodriguez F., Nguyen B., Wilson W. D., Rozas I., J Med
Chem. 57, 7663-7672 (2014).
22] Rehman S. U., Sarwar T., Ishqi H. M., Husain M. A., Hasan Z., Tabish M., Arch
Biochem Biophys. 566, 7-14 (2015).
23] Sadeghi M., Bayat M., Cheraghi S., Yari K., Heydari R., Dehdashtian S., Luminescence.
3
1, 108-117 (2016).
[
[
[
[
[
[
24] Zhang G., Wang L., Zhou X., Li Y., Gong D., J Agric Food Chem. 62, 991-1000 (2014).
25] Nitiss J. L, Beck W. T., Eur J Cancer. 32, 958-966 (1996).
26] Sherer C., Snape T. J., Eur J Med Chem. 97, 552-560 (2015).
27] Pommier Y., Nat Rev Rheumatol. 6, 789-802 (2006).
28] Evstigneev M. P., Rybakova K. A., Davies D. B., Biophys Chem. 121, 84-95 (2006).
29] Croney J. C., Jameson D. M., Learmonth R. P., Biochem Mol Biol Edu. 29, 60-65 (2001).
Chemical and Pharmaceutical Bulletin Advance Publication

[
30] Beraldo H., Garniersuillerot A., Tosi L., Lavelle F., Biochemistry. 24, 284-289 (1985).
Chemical and Pharmaceutical Bulletin Advance Publication