Synthesis of novel ethyl 2,4-disubstituted 8-(trifluoromethyl)pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-9-carboxylate derivatives as promising anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2016.09.062

A series of novel pyrido[2',3':3,4] pyrazolo[1,5-a]pyrimidine derivatives 6–9 were prepared in single step starting from 3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 5 on reaction with symmetrical and unsymmetrical aliphatic and ar

Full text of DOI:10.1016/j.bmcl.2016.09.062

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel ethyl 2,4-disubstituted 8-(trifluoromethyl)pyrido
0
0
[
2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine-9-carboxylate derivatives as
promising anticancer agents
a
b
a
a
b
N. Ravi Kumar , Y. Poornachandra , D. Krishna Swaroop , G. Jitender Dev , C. Ganesh Kumar ,
B. Narsaiah
a
a,
⇑
Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
b
a r t i c l e i n f o
a b s t r a c t
0
0
Article history:
A series of novel pyrido[2 ,3 :3,4] pyrazolo[1,5-a]pyrimidine derivatives 6–9 were prepared in single step
starting from 3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 5 on reaction with
Received 2 May 2016
Revised 5 September 2016
Accepted 26 September 2016
Available online xxxx
symmetrical and unsymmetrical aliphatic and aromatic 1,3-diketones/a,b unsaturated ketones/a,b
unsaturated keto ethers under conventional method. All the final compounds 6a–c, 8a–b and 9a–l were
screened for anticancer activity against five human cancer cell lines such as PC-3 (CRL-1435), MDA-MB-
2
31 (HTB-26), Hep G2 (HB-8065), HeLa (CCL-2) and normal HUVEC (CRL-1730). Compounds 8a, 9f and 9k
Keywords:
Pyrazolo[3,4-b]pyridine
Pyrimidine
which showed promising anticancer activity have been identified. Further, the promising compounds (8a
and 9f) were able to inhibit the human topoisomerase I (TopI) activity similar to that of camptothecin.
Ó 2016 Elsevier Ltd. All rights reserved.
a
,b unsaturated ketones
,3 diketones
Anticancer activity
1
Cancer is considered as one of the most debilitating disease
causes health problem in human beings all over the world.
observed that the presence of fluorine20 or trifluoromethyl21,22
group at a strategic position in heterocycles can modulate the
physical, chemical and biological properties. Further, it is also doc-
umented that the trifluoromethyl group in a molecule can influ-
ence the increased lipophilicity, greater cell permeability and
1
,2
Although many classes of drugs were used for the treatment, still
there is a challenge to identify safe and effective anticancer
compounds as drugs. The high proliferative nature is an important
feature of cancer cells. In this regard, topoisomerase I (TopI), whose
activity is higher in cancer cells as compared to healthy cells, is one
of the most important molecular target for the design of various
2
3
resistance to enzyme degradation.
Based on the broad range of pharmacological activity of this
class of compounds and in continuation of our efforts,2
prompted us to synthesize the novel trifluoromethyl substituted
4–26
3
,4
anticancer drugs.
Several heterocyclic compounds were
intensively studied to discover new anticancer agents.5
Pyrazolo[3,4-b]pyridine frame work is identified as one of the most
important classes of heterocyclic compounds because of their
significant and versatile biological and pharmacological
–7
pyrido[2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine derivatives and to eval-
uate their anticancer activity against five human cancer cell lines.
The compounds which showed promising activity have been
identified.
0
0
8
–10
properties.
have exhibited antiviral,1
and antimicrobial properties.15
Pyrazolo[3,4-b]pyridine nucleus also present in diaryl pyra-
In the last decade, some heterocycles of this class
Ethyl 5-cyano-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-
1,12
13
14
30
antileishmanial, GSK-3 inhibitor
3-carboxylate 3 was prepared starting from b-ketoester, on
reaction with triethylorthoformate in acetic anhydride at 120 °C
followed by reaction with cyanoacetamide in presence of sodium
ethoxide in ethanol under reflux conditions. Compound 3 was
16
1
7
18
zolopyridine, isoxazolopyrazolopyridine displayed anxiolytic
and hypotensive activities. In addition, pyrazolo[3,4-b]pyridine
derivatives with a trifluoromethyl group were known to possess
multidrug action with antimalarial activity.19 Recently, it was
selectively O-alkylated with a-bromoethylacetate in acetone using
potassium carbonate as a base under reflux conditions and then
reacted with hydrazine hydrate to obtain ethyl 3-amino-6-(trifluo-
romethyl)-1H-pyrazolo[3,4-b] pyridine-5-carboxylate 5. The pyra-
zolo[3,4-b]pyridine 5 is a key intermediate in the synthesis of the
0
0
⇑
Corresponding author. Tel.: +91 40 27193185; fax: +91 40 27160387.
E-mail address: narsaiah@iict.res.in (B. Narsaiah).
final pyrido[2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine derivatives. Thus,
http://dx.doi.org/10.1016/j.bmcl.2016.09.062
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Ravi Kumar, N.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.09.062

2
N. Ravi Kumar et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
the compound 5 was reacted with symmetrical, unsymmetrical
,3-diketones (aliphatic and aromatic), ,b-unsaturated ketones
and ,b-unsaturated keto ethyl ethers under different set of condi-
R
O
O
O
N
N
1
a
EtO
R
R
O
1
a
0
0
F3C
N
R
1
tions afforded the final pyrido[2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine
derivatives 6a–c, 8a–b and 9a–l. Initially, compound 5 on reaction
with aliphatic symmetrical 1,3-diketones in presence of acetic acid
at 120 °C, reaction proceeded smoothly and the anticipated pyrido
N
6a-6c
O
NH
N
2
O
O
0
0
HN
[
2 ,3 :3,4]pyrazolo[1,5-a] pyrimidine derivatives, 6a and 6c, were
O
EtO
F
Aceticacid Ar/R
120 o
0-12 h
Ar
EtO
obtained. While compound 5 on reaction with trifluoroacetyl ace-
tone (unsymmetrical 1,3-diketone) resulted exclusively in the for-
mation of compound 6b. It is attributed to the enolization of
N
N
C
3
C
N
F
C
N
N
H
H
3
1
7
5
carbonyl carbon attached to CF
attached to CH is available for initial nucleophilic attack thereby
exclusive formation of compound 6b is observed. This corroborates
3
function as a result other carbonyl
R
3
O
O
N
R
OEt
EtO
F
with the observations made in the earlier reports.2
7,28
However, in
N
N
3
C
N
case of aromatic 1,3-diketones, an unexpected acylated product 7
was formed which was confirmed by NMR and mass spectra. This
may be attributed to the low reactivity of aromatic 1,3-diketones
and solvent only reacted to give product 7. In order to get the
desired product, the reaction of compound 5 was repeated with
aromatic 1,3-diketone under different set of conditions, showed
no reaction.
8
a, 8b
Ar/R
Ar
O
O
NH
2
O
N
O
R/Ar
Ar
EtO
N
N
N
K
2
CO
3
, DMF
C
F3C
N
F3C
N
N
H
o
110
Alternately, compound 5 was treated with aromatic 1,3-
diketone in absence of acetic acid in DMF solvent at 110 °C and
potassium carbonate as base also could not give the expected
product except the recovery of the starting material. To synthesize
8-10 hrs
9a-9l
0
0
Scheme 2. Synthesis of pyrido[2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine derivatives
6a–c, 8a–b, 9a–l.
0
0
the aryl substituted pyrido[2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine
derivatives 9a–l, we adopted a different strategy that, the aromatic
a,b-unsaturated ketones on treating with compound 5 in presence
cancer cell lines with concentrations ranging between 10.3 and
17.2 lM. Compound 8a showed significant activity against PC3,
HeLa and HepG2 cell lines, whereas the compound 9f showed good
of potassium carbonate in DMF at 110 °C resulted aromatic substi-
0
0
tuted pyrido[2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine derivatives 9a–l.
The synthetic sequence involved in the synthesis of target com-
pounds is outlined in Scheme 1 and 2 and the product formed
are presented in Table 1.
cytotoxicity against MDA-MB-231 cell line.
The structure–activity relationship (SAR) studies revealed that
the compound 8a which has CH group on pyrimidine ring showed
3
The compounds 6a–c, 8a–b and 9a–l were screened for
promising cytotoxicity; however, in presence of two methyl groups
on the pyrimidine ring showed moderate cytotoxicity in case of
compound 6a. Similarly, when one methyl group is replaced with
3
1
cytotoxicity against five human cancer cell lines, namely, PC3:
Human prostate cancer (CRL-1435), MDA-MB-231: human breast
adenocarcinoma cancer (HTB-26), HepG2: human liver cancer
3
CF group, the cytotoxicity was further lower in case of compound
(
HB-8065), HeLa: human cervical cancer (CCL-2), and HUVEC:
normal human umbilical vein endothelial cells (CRL-1730) using
-fluorouracil (5-FU) as positive and DMSO as negative controls,
6b. Compound 6c which has two ethyl groups on pyrimidine ring
did not show any cytotoxicity against all the five tested human
cancer cell lines upto the maximum tested concentration of
5
respectively. All the test compounds showed above 60% inhibition
and subsequently, their IC50 values were calculated from the
dose–response curves (Table 2). From the data reported in Table 2,
most of the prepared compounds exhibited significant anticancer
activity on all the tested cell lines.
Compounds 6a, 8a, 9e–g and 9j–l showed promising activity
against all the five human cancer cell lines. Compounds 6b and
9
100 lM. Thus, it is concluded that the presence of electron releas-
ing groups with increase in the alkyl chain length on the pyrim-
idine ring showed no cytotoxicity. Among the compounds (9a–l)
having aryl substituent on pyrimidine ring, it was observed that
the compounds having electron donating groups on the aromatic
ring (9c, 9d, 9h and 9i) showed no cytotoxicity, whereas electron
withdrawing groups on the compounds (9e–g, 9j–l) having aryl
substituent on the pyrimidine ring showed very good cytotoxicity;
a showed moderate cytotoxicity against HeLa and MDA-MB-231
cancer cell lines. Among all the compounds, compound 8a, 9f
and 9k exhibited very good cytotoxicity against all the tested
3
in particular, the compound having OCF group showed promising
cytotoxicity. In general, compounds having thiophene and pyrrole
O
O
O
O
O
O
CN
CH(OEt)
3
2
H N
CN
O
O
F
F
3
C
O
F
3
C
O
AC
0
2
O
NaOEt
EtOH, RT
16 hr
3
C
N
H
1
20 2hr
OEt
0
1
140 4hr
2
3
O
O
C
O
O
NH
2
Br
CN
O
EtO
F
NH
EtOH, reflux
hr
2 2 2
-NH H O
N
K
2
CO
Acetone
reflux,3-5 hr
3
OEt
N
H
3
N
O
F3C
N
3
O
4
5
Scheme 1. Synthesis of 3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-5 carboxylate 5.
Please cite this article in press as: Ravi Kumar, N.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.09.062

N. Ravi Kumar et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Table 1
Synthesis of pyrido[2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine derivatives 6a–c, 8a–8b, 9a–l
0
0
S. No.
Compd
R
R1
Yield (%)
mp (°C)
1
2
3
4
5
6
7
8
9
6a
6b
6c
8a
8b
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
CH
CH
3
3
CH
3
85
87
88
72
68
76
73
67
69
86
77
74
76
82
83
88
86
158–160
150–153
169–172
134–136
168–171
216–217
188–190
153–155
201–203
215–217
228–230
140–142
141–143
213–215
219–221
217–219
239–241
CF
3
C
2
H
5
C
2
H
5
CH
3
—
—
CF
3
CH
3
C
C
6
H
H
5
5
C
C
C
C
C
6
H
6
H
6
H
6
H
6
H
5
5
5
5
5
6
4-OCH
4-Cl C
4-NO
3
C
H
5
6
H
5
6
10
11
12
13
14
15
16
17
2
C
6
H
5
4 4
C H N
4-OCH
4-OCH
3
3
C
C
6
H
H
5
5
4-F C
4-OCH
2-CH
4-F C
4-OCF
4-OCH
6 5
H
6
3
C
6
H
5
-C
-C
-C
-C
4
4
4
4
H
H
H
H
3
3
3
3
S
3
C
6
H
5
S
S
S
6 5
H
C H
3 6 5
2,6-di F-C H
6 2
3
Table 2
0
0
In vitro cytotoxicity evaluation of pyrido[2 ,3 :3,4]pyrazolo[1,5-a]pyrimidine derivatives
Test compound
IC50 values (lM)
PC3a
SIf
HeLab
SIf
MDA-MB231c
SIf
Hep G2d
SIf
HUVECe
6
6
6
8
8
9
9
9
9
9
9
9
9
9
9
9
9
5
a
b
c
a
b
a
b
c
d
e
f
g
h
i
j
k
22.1 ± 0.36
—
—
11.4 ± 0.12
—
—
—
4.48
—
—
8.17
—
—
—
—
—
5.57
7.86
5.43
—
18.2 ± 0.28
25.6 ± 0.32
—
10.6 ± 0.15
—
29.8 ± 0.36
—
——
5.45
3.44
—
8.79
—
3.05
—
—
20.1 ± 0.42
24.3 ± 0.26
—
12.1 ± 0.18
—
28.6 ± 0.28
—
—
4.93
3.62
—
7.70
—
3.18
—
—
21.2 ± 0.32
—
—
11.8 ± 0.24
—
—
—
4.67
—
—
7.89
—
—
—
—
—
6.39
6.43
5.36
—
99.2 ± 0.24
88.2 ± 0.26
—
93.2 ± 0.14
——
91.1 ± 0.18
—
—
—
—
—
—
—
—
—
—
—
16.3 ± 0.24
12.1 ± 0.26
15.9 ± 0.12
—
18.2 ± 0.18
13.1 ± 0.22
15.8 ± 0.16
—
4.98
7.26
5.46
—
12.2 ± 0.19
10.3 ± 0.14
17.2 ± 0.21
—
7.44
9.24
5.02
—
14.2 ± 0.24
14.8 ± 0.32
16.1 ± 0.12
—
90.8 ± 0.25
95.2 ± 0.26
86.4 ± 0.34
—
—
—
—
—
——
—
—
—
—
15.1 ± 0.18
11.9 ± 0.24
22.8 ± 0.12
1.8 ± 0.11
5.68
7.55
4.07
44.22
15.3 ± 0.18
16.1 ± 0.42
20.4 ± 0.24
1.6 ± 0.12
5.61
5.58
4.54
49.75
17.1 ± 0.14
17.2 ± 0.16
21.1 ± 0.28
1.9 ± 0.09
5.02
5.22
4.39
41.89
16.8 ± 0.12
12.6 ± 0.24
23.5 ± 0.42
1.8 ± 0.11
5.11
7.13
3.94
44.22
85.9 ± 0.32
89.9 ± 0.26
92.8 ± 0.42
79.6 ± 0.24
l
-Fluorouracil (Control)
a
b
c
d
e
f
PC3: Human prostate cancer (ATCC No. CRL-1435).
HeLa: Human cervical cancer (ATCC No. CCL-2).
MDA-MB-231: Human breast adenocarcinoma cancer (ATCC No. HTB-26).
HepG2: Human Liver cancer (ATCC No. HB-8065).
HUVEC: Human umbilical vein endothelial cells (ATCC No. CRL-1730).
Selectivity index (SI) = IC50 of pure compound in a normal cell line/IC50 of the same pure com -pound in cancer cell line, where IC50 is the concentration required to inhibit
0% of the cell population.
5
substituent on pyrimidine ring also exhibited good cytotoxicity.
Pyrrole derivative (9f) also showed promising cytotoxicity as com-
pared to thiophene derivatives. From the cytotoxicity results, it
was observed that the compounds 8a, 9f and 9k exhibited promis-
ing cytotoxicity among all the tested compounds. All the
compounds when tested on HUVEC (normal cell line), showed
IC50 values of >80 lM and were thus considered as less or
non-cytotoxic. Further, the selectivity index (SI) values were also
determined and the values to this regard are represented in
Table 2.
Based on the cytotoxicity results of the synthesized compounds,
we examined two promising compounds (8a and 9f) for in vitro
human DNA Topoisomerase I inhibitory activity using camp-
tothecin (CPT) as positive control (Fig. 1). Based on the results pre-
sented in Figure 1, it was observed that the supercoiled (sc) DNA
Figure 1. Effect of test compounds (8a and 9f) on human topoisomerase I activity.
The supercoiled DNA (pHOT1) substrate was incubated with topoisomerase I; and
test compounds (8a and 9f) and camptothecin (CPT) at a concentration of 10 and
20 lM. Relaxation of the DNA was evaluated by 1% ag- -arose gel electrophoresis in
the presence of ethidium bromide. R, relaxed DNA and S, supercoiled pHOT1.
(
lane S) was fully relaxed by the enzyme (lane R). Relaxation of
sc plasmid substrate, pHOT1, was inhibited upon incubation with
the test compounds at two different concentrations (10 and
20 lM) similar to that of camptothecin. The results clearly suggest
that the synthesized compounds (8a and 9f) successfully inhibited
the enzymatic activity of topoisomerase I. The human solid
tumors generally shows high levels of intracellular accumulation
2
9
Please cite this article in press as: Ravi Kumar, N.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.09.062

4
N. Ravi Kumar et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
of topoisomerase I as compared to that of normal tissues, which
signifies that controlling the topoisomerase I level is essential for
treating cancers.
6. Al-Suwaidan, I. A.; Abdel-Aziz, N. I.; El-Azab, A. S.; El-Sayed, M. A.-A.; Alanazi, A.
M.; El-Ashmawy, M. B.; Abdel-Aziz, A. A.-M. J. Med. Chem. 2014, 1.
7.
Abdel-Aziz, A. A.-M.; El-Azab, A. S.; Alanazi, A. M.; Asiri, Y. A.; Al-Suwaidan, I.
A.; Maarouf, A. R.; Ayyad, R. R.; Shawer, T. Z. J. Med. Chem. 2015, 1.
8. Nagender, P.; Malla Reddy, G.; Naresh Kumar, R.; Poornachandra, Y.; Ganesh
0
0
In conclusion, substituted pyrido[2 ,3 :3,4]pyrazolo[1,5-a]
pyrimidine derivatives were prepared from the key intermediate
pyrazolo[3,4-b]pyridine 5 and all the final compounds were
screened for cytotoxicity against different cancer cell lines. Among
all the tested compounds, the compounds 8a, 9f and 9k showed
promising cytotoxicity. Further, the promising compounds (8a
and 9f) were able to inhibit the Topoisomerase I (TopI) activity
similar to that of camptothecin and would thus be an effective tar-
get in cancer therapy. Based on the results of the present study,
further modification on the pyrazolo [3,4-b] pyridine ring may
yield a prospective anticancer agent.
Kumar, C. Bioorg. Med. Chem. Lett. 2014, 24, 2905.
9.
Hao, Y.; Xiao-Ping, X.; Chen, T.; LiZhao, L.; JunJi, S. Org. Biomol. Chem. 2012, 10,
24.
7
10. Golubev, A. S.; Starostin, G. S.; Ghunikhin, K. S.; Peregudov, A. S.; Rodygin, K. C.;
Rubtsova, S. A.; Slepukhin, P. A.; Kuchin, A. V.; Chkamokov, N. D. Russ. Chem.
Bull. 2011, 60, 733. Molecules, 2011, 17, 10915.
11. De Clercq, E. Curr. Opin. Microbiol. 2005, 8, 552.
12. Eizuru, Y. Antivir. Chem. Chemother. 2003, 14, 299.
1
3. Witherington, J.; Bordas, V.; Garland, S. L.; Hickey, M. B.; Ife, R. J.; John, L.;
Saunders, M.; Smith, D. G.; Ward, R. W. Bioorg. Med. Chem. Lett. 2003, 13, 1577.
4. Mellol, H.; Echevarria, A.; Bernardino, A. M. R.; Canto-Cavalheiro, M.; Leon, L. L.
J. Med. Chem. 2004, 47, 5427.
1
1
1
5. Tarik, E. S. A. Eur. J. Med. Chem. 2009, 44, 4385.
6. (a) Shi, D.; Padgett, W. L.; Hutchinson, K. D.; Moore, G. P.; Daly, J. W. Drug Dev.
Res. 1997, 42, 41; (b) Kusuhara, H.; Komatsu, H.; Hisadome, M.; Ikeda, Y. Int. J.
Immunopharmac. 1996, 18, 719.
Acknowledgement
1
7. Khan, M. A.; Pedrotti, F. Monatsh. Chem. 1982, 113, 123. Baer, T.M.; Campbell, J.
B.; Heald, A.F. Eur. Pat. Appl. EP 94175. 1982. Chem. Abstr. 1984, 100, 121059t.
8. Shutske, G. M.; Huger, F. P. J. Heterocycl. Chem. 1988, 25, 703.
9. Dias, R. S.; Freitas, A. C.; Barreiro, E. J.; Goins, D. K.; Nanayakkara, D.;
Mcchesney, J. D. Bull. Chim. Farm 2000, 139, 14.
Authors are thankful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, India for providing funding through
1
1
th
XII five year plan project, DITSF, code: CSC-0204. Authors (N. Ravi
2
2
0. Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988, 53, 2406.
1. Filler, R. et al. (Eds.), Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications Stud. Org. Chem. 1993, 48, 362.
Kumar, Y. Poornachandra, D. Krishna Swaroop, G. Jitender Dev) are
also thankful to CSIR, New Delhi, India for financial assistance in
the form of senior research fellowship and contingency grant.
22. Chae, J.; Konno, T.; Ishihara, T.; Yamanaka, H. Chem. Lett. 2004, 33, 314.
23. Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
2
4. Kurumurthy, C.; Veeraswamy, B.; Sambasiva Rao, P.; Santhosh Kumar, G.;
Shanthan Rao, P.; Loka Reddy, V.; Venkateswara Rao, J.; Narsaiah, B. Bioorg.
Med. Chem. Lett. 2014, 24, 746.
Supplementary data
2
5. Naresh Kumar, R.; Poornachandra, Y.; Nagender, P.; Mallareddy, P.; Ravi
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.09.
Kumar, N.; Ranjithreddy, P.; Ganesh Kumar, C.; Narsaiah, B. Eur. J. Med. Chem.
2016, 108, 68.
0
62.
26. Chavva, K.; Pillalamarri, S.; Banda, V.; Gautham, S.; Gaddamedi, J.; Yedla, P.;
Kumar, C. G.; Banda, N. Bioorg. Med. Chem. Lett. 2013, 23, 5893.
2
7. Singh, S. P.; Kapoor, J. K.; Kumar, D.; Threadgil, M. D. J. Fluorine Chem. 1997, 83,
3.
8. Krishniah, A.; Narsaiah, J. Fluorine Chem. 2001, 109, 183.
References and notes
7
2
1
2
.
.
Eckhardt, S. Curr. Med. Chem. Anticancer Agents 2002, 2, 419.
Lee, C. W.; Hong, D. H.; Han, S. B.; Jung, S. H.; Kim, H. C.; Fine, R. L.; Lee, S. H.;
Kim, H. M. Biochem. Pharmacol. 2002, 64, 473.
Holden, J. A. Curr. Med. Chem. Anticancer Agents 2001, 1, 1.
Pommier, Y. DNA Topoisomerases and Cancer; Springer: New York, 2012.
Kim, M. H.; Kim, M.; Yu, H.; Kim, H.; Yoo, K. H.; Sim, T.; Hah, J. M. Bioorg. Med.
Chem. 2011, 19, 1915.
29. Kang, K.; Oh, S. H.; Yun, J. H.; Jho, E. H.; Kang, J. H.; Batsuren, D.; Tunsag, J.; Park,
K. H.; Kim, M.; Nho, C. W. Neoplasia 2011, 13, 1043.
30. Peter, B.; Boström, J.; Brickmann, K.; van Giezen, J. J. J.; Ragnar, H.; Petersson,
Annika U.; Asim, R.; Zetterberg, F. Bioorg. Med. Chem. Lett. 2011, 21, 2877.
31. Mosmann, T. J. Immunol. Methods 1983, 65, 55.
3.
4.
5.
Please cite this article in press as: Ravi Kumar, N.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.09.062