Anticancer activity of 4-aminoquinoline-triazine based molecular hybrids

Article abstract of DOI:10.1039/c3ra45333b

In this study the potential for anticancer activity of 4-aminoquinoline- triazine based hybrids has been investigated on 60 human cancer cell lines (NCI 60). The representative compounds show activity on a range of cell lines and apoptosis as the mode of growth inhibition. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ra45333b

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Anticancer activity of 4-aminoquinoline-triazine
based molecular hybrids†
Cite this: RSC Adv., 2014, 4, 7062
Sunny Manohar,a Antonella Pepe,b Christian E. Velez Gerena,c Beatriz Zayas,c
´
b
a
*
*
Sanjay V. Malhotra and Diwan S. Rawat
Received 25th September 2013
Accepted 21st November 2013
In this study the potential for anticancer activity of 4-aminoquinoline-triazine based hybrids has been
investigated on 60 human cancer cell lines (NCI 60). The representative compounds show activity on a
range of cell lines and apoptosis as the mode of growth inhibition.
DOI: 10.1039/c3ra45333b
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displayed inhibitory activity against colon (Caco-2, HTB-37) and
breast (HTB-129) cancer cells.11
Introduction
Previous reports from our lab showed that hybrids of 4-
aminoquinoline and triazine moieties when covalently con-
nected via different alkyl chain linkers (Fig. 1d), showed
improved antimalarial activity against both CQ-sensitive (D6)
and CQ-resistant (W2) strains of P. falciparum.12,13 A few of these
hybrids were found to be 3–4 times more potent than the
reference molecule CQ (IC50 ¼ 0.04 mM for D6 clone and 0.4 mM
for W2 clone) used in this study. Encouraged by these results,
and as a part of our on-going work towards the synthesis of
biologically relevant molecules,14 we were interested to explore
the anticancer activity of these hybrids against a panel of
different cancer cell lines. Therefore, a series of 4-amino-
quinoline-triazine based hybrids (4–15) were initially screened
against 60 human cancer cell lines (NCI 60) and two represen-
tative hybrid molecules (11 and 14; Fig. 2) were selected for a
dose–response study, followed by investigation of the mecha-
nism-of-action of their anticancer activity. These two hybrids
(11 and 14) were also tested against VERO, LLC-PK11 and
HepG2 mammalian cells and found to be noncytotoxic up to a
concentration of 25 mM, proving their safe toxicity prole.13
To combat an array of diseases and counter drug resistance
problems, the development of newer, cheaper and safer drugs
will always remain a current need. In this perspective, the
strategy of synthesizing hybrid molecules by covalently con-
necting two (or more) pharmacophores to generate a new ‘dual-
drug’ species is fast becoming an alternative to other strategies.1
These dual-drugs are believed to act by inhibiting two biological
targets simultaneously. This concept, of hybrids as a dual-sword
molecule to create efficient drugs, was rst suggested by Meu-
nier et al.2 In the past few years some of these hybrid molecules
have shown excellent biological activity.3
Chloroquine (CQ, Fig. 1a) and other 4-aminoquinoline based
molecules are well known for their antimalarial activity.4
4-Aminoquinoline based compounds are also known for their
antimicrobial,5 anti-prion,6 anti-trypanosomal7 and anticancer
activities.8 The mechanism of action for their anticancer activity
is not clearly understood, however, reports suggest their radi-
osensitizing effects through lysosome permeabilization as the
cause of their activity. The accumulation of CQ in the lysosomes
hampers signicantly the proteolytic processes and metabolism
of neoglycolipids, resulting in an alterations of various cellular
signal pathways.8 Similarly, several other 4-aminoquinoline
based derivatives were also reported for their activity against
different cancer cell lines.9 Earlier studies have shown ruth-
enium(II) complexes of CQ (Fig. 1b) to inhibit the growth of
colon cancer cells (HCT-116),10 and ferrocenyl-aminoquinoline-
carboxamide based hybrid bioorganometallics (Fig. 1c)
aDepartment of Chemistry, University of Delhi, Delhi-110007, India. E-mail: dsrawat@
chemistry.du.ac.in; Fax: +91-11-27667501; Tel: +91-11-27662683
bLaboratory of Synthetic Chemistry, SAIC-Frederick Inc., Frederick National
Laboratory for Cancer Research, Frederick, MD 21702, USA. E-mail: malhotrasa@
mail.nih.gov; Tel: +1-301-846-5141
cSchool of Environmental Affairs, Universidad Metropolitana, San Juan, Puerto Rico,
00928, USA
† Electronic supplementary information (ESI) available: One dose mean graphs,
drug response curves, ve dose mean graphs and GI50 and LC50 values of
compound 11 and 14. See DOI: 10.1039/c3ra45333b
Fig. 1 (a) Chloroquine (CQ); (b) ruthenium(II) complex of CQ; (c) fer-
rocenyl-aminoquinoline-carboxamide based bio-organometallics; (d)
general structure of 4-aminoquinoline-triazine based hybrids.
7062 | RSC Adv., 2014, 4, 7062–7067
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assay is terminated by addition of cold trichloroacetic acid, and
the cells are xed and stained with sulforhodamine B. The
bound stain is solubilized, and the absorbance is read on an
automated plate reader. The cytostatic parameter, that is 50%
growth inhibition (GI50), was calculated from the absorbance at
time zero, in the control growth, and at the ve concentration
levels. The cytotoxic parameter, that is the inhibitory concen-
tration (LC50), represents the average of two independent
experiments. The in vitro screening is a two-stage process that
started with the evaluation of the compound against the 60
human tumor cell lines with a single dose of 10.0 mM, which is
done by following same protocol as for the ve-dose screening.
Only the compounds which show more than 60% growth inhi-
bition in at least 8 tumor cell lines are selected for further
testing, and the others were assumed to be inactive. The
compounds (11) and (14) were initially evaluated at a single
dose of 10 mM and found to be active against various cell types.
The results of the single-dose screening are given in the ESI† of
this manuscript. Subsequently, both compounds were evalu-
ated at ve concentration levels (100, 10, 1.0, 0.1 and 0.01 mM).
The mean values for GI50 and LC50 on all 60 cell lines are given
in Table 1. The additional data for both compounds i.e. one-
dose mean graphs, drug–response curves, ve-dose mean
graphs and GI50 and LC50 values are given the ESI.† As the data
show, the 4-aminoquinoline-triazine based hybrids have activity
against various cancer panels. Both compounds (11 and 14)
show inhibitory activity at single digit micromolar concentra-
tion against most of the cell lines. The GI50 values suggest that
these compounds have inhibitory activity against a vast range of
cancer cell lines (a low micromolar effect). Also, comparison of
the LC50 values from this study, show that these compounds are
least cytotoxic to most of the cell lines in leukemia, non-small
cell lung cancer, colon, ovarian and prostate cancer panels. The
high LC50 values compared to GI50 give a high therapeutic
window for both of these compounds (Table 1). The dose–
response curves of 1 for all 60 cell lines are illustrated as Fig. 3.
(b) Mechanism of action studies
Fig. 2 4-Aminoquinoline-triazine based hybrids selected by the US
National Cancer Institute.
Results and discussion
Chemistry
The synthesis of the compounds has been reported earlier.12,13
In brief, the synthesis was accomplished by sequential nucleo-
philic substitution on commercially available cyanuric chloride
(1) (Scheme 1).12,13 First, the chlorine of cyanuric chloride (1)
was substituted with morpholine to yield a monosubstituted
triazine (2), which upon subsequent reaction with different
anilines provided disubstituted triazines (3). Thereaer, the
remaining chlorine on the triazines (3) were substituted by
4-aminoquinoline with different carbon alkyl chain lengths and
the targeted 4-aminoquinoline-traizine hybrids (4–15) were
obtained. All the compounds (4–15) were puried by column
chromatography and the products were characterized by
various spectroscopic techniques and elemental analysis.
Biological studies
(a) Anticancer activity. Details of the methodology for NCI
60 cell-line screening are described at http://dtp.nci.nih.gov/
branches/btb/ivclsp.html. Briey, the panel is organized into
nine subpanels representing diverse histologies: leukemia,
melanoma, and cancers of the lung, colon, kidney, ovary,
breast, prostate, and central nervous system. The cells are
grown in a supplemented RPM1 1640 medium for 24 h. The test
compounds were dissolved in DMSO and incubated with cells at
ve concentrations with 10-fold dilution, the highest being
10ꢀ4 M and the others being 10ꢀ5, 10ꢀ6, 10ꢀ7, and 10ꢀ8 M. The
Materials and methods. Experimental compound stock solu-
tions: 3 mM stock solutions were prepared in culture grade
DMSO under sterile conditions. All experiments were done at
the 10 mM dose, as used in the NCI 60 cell-line screening
protocol which was previously performed for these compounds.
Cell culture: The cell line used in this study was the COLO
205 human colorectal adenocarcinoma (ATCC CCL-222). These
cultures were maintained in RPMI 1640 media (ATCC, Mana-
ssas VA) supplemented with 10% fetal clone serum (ATCC).
Cultures were maintained at 37 ꢁC in a humidied atmosphere
of 95% air and 5% CO2. For all experiments, approximately 3 ꢂ
106 cells were treated with the test compound and controls
(DMSO and camptothecin).
Annexin V: Annexin V staining is a useful tool to determe the
type of cell death. It has been used to detect apoptotic cells aer
exposure to various substances;15 the expression of phosphati-
dylserine (PS) on the surface of cells can be used to determine if
cells are undergoing apoptosis. Cells were exposed to the test
compounds for 24 hours then stained with annexin V conjugate,
and propidium iodide (Biotium, Hayward, CA). Aer staining,
Scheme 1 Reagents and conditions: (a) morpholine, K2CO3, THF, 0–
5
ꢁC, 3 h, 80%; (b) different anilines, K2CO3, THF, rt, 3 h, 70–85%; (c)
substituted 4-aminoquinolines, K2CO3, DMF, 100–110 ꢁC, 10–12 h,
65–75%.
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Table 1 Antitumor activity (GI50/mM) and toxicity (LC50/mM) data of Table 1 (Contd.)
compounds selected for 5 dose studies for the NCI 60-cell lines
screena
GI50/mM
(11)
LC50/mM
(11)
GI50/mM
(14)
LC50/mM
(14)
GI50/mM
(11)
LC50/mM
(11)
GI50/mM
(14)
LC50/mM
(14)
CAK-1
RXF 393
SN12C
TK-10
4.170
1.890
8.730
7.640
1.330
45.40
35.90
57.10
46.60
39.60
5.590
1.890
11.60
10.30
3.520
48.80
28.00
54.00
50.10
41.80
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
2.950
1.130
2.090
2.010
2.750
2.010
>100
>100
>100
59.60
>100
>100
0.457
1.800
2.910
4.170
3.150
2.440
75.20
>100
79.50
65.30
74.20
>100
UO-31
Prostate cancer
PC-3
DU-145
3.940
9.800
60.30
48.40
4.870
8.680
44.90
47.20
Non-small cell lung cancer
Breast cancer
MCF7
MDA-MB-231ATCC
HS 578T
BT-549
T-47D
A549/ATCC
EKVX
4.870
>100
10.50
ND
59.90
ND
2.860
2.730
3.910
9.920
11.60
1.620
4.870
4.280
>100
48.90
68.00
9.990
3.430
3.050
7.320
8.670
10.60
1.960
49.60
39.80
97.80
51.20
69.30
15.90
8.090
1.160
3.890
1.370
13.70
10.30
4.580
3.850
60.40
50.60
51.00
5.510
64.40
49.60
79.40
39.30
HOP-62
13.40
10.30
14.40
14.60
11.80
3.440
4.250
52.40
29.40
77.00
62.10
51.20
50.90
47.00
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
MDA-MB-468
a
ND: not determined.
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
the cells were analyzed using the NucleoCounter NC3000
instrument (Chemometec, Allerød, Denmark). This instrument
utilizes differential microscopy to detect uorophores. A one-
way ANOVA was performed. If signicant results were found in
the ANOVA, a post hoc Tukey test was also performed.
DNA fragmentation: DNA fragmentation as an apoptosis
marker is a widely used assay in apoptosis studies.16 We utilized
the NC3000 system for this experiment. DNA fragmentation can
be quantied using DNA content and measuring cells contain-
ing less than 1 DNA equivalent (known as Sub-G1). The NC3000
fragmentation assay is based on removal of small DNA frag-
ments and retention of 40,6-diamidino-2-phenylindole (DAPI)-
stained higher weight fragments.
1.530
2.080
3.010
2.630
1.070
5.180
3.470
7.250
7.240
43.10
71.40
16.90
47.40
59.90
1.710
2.000
4.820
2.460
2.270
5.440
4.210
6.230
7.790
43.90
31.30
24.00
48.10
51.60
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
5.030
2.050
2.180
10.60
2.090
3.100
48.10
7.470
31.20
52.90
30.30
42.70
6.850
4.190
3.790
12.40
3.130
4.72
48.90
45.00
40.00
54.20
40.50
43.90
Caspase activity: Activation of effector caspases is key event
in apoptosis. These enzymes are responsible for many of the
typical hallmarks of apoptotic cell death.17 Caspase activation
was measured using the Fluorescent Labeled Inhibitors of
Caspases (FLICA). These probes bind covalently with active
caspase effector enzymes. Aer treatment as described above,
cells were harvested and stained using the green FAM FLICA kit
(Immunochemistry Technologies, Bloomington Min.) then
analyzed using the NucleoCounter NC3000 instrument.
Results
Melenoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
3.010
1.940
1.860
1.820
2.190
1.810
1.590
1.870
1.850
42.40
6.190
6.450
6.690
8.360
5.940
5.780
6.950
6.990
2.950
2.760
1.940
2.220
1.830
2.150
2.150
1.900
2.650
42.10
7.430
6.930
19.20
9.250
5.800
9.940
7.000
26.30
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
Annexin V. Our results indicate that only SM334 (14) pre-
sented apoptotic activity in a statistically signicant (P < 0.05)
manner. Compound (14) presented a barely signicant average
of 39.0% of apoptotic cells (Fig. 4) whereas SM332 (11) did not
present statistically signicant activation with 34.5% of
apoptotic cells. Both compounds where signicantly lower than
the positive camptothecin control (53%).
8.430
11.50
9.000
15.70
6.460
6.380
1.170
58.00
51.00
62.60
62.90
91.60
79.70
51.80
6.300
11.90
10.70
17.50
11.60
9.360
11.90
56.10
50.60
50.00
58.70
>100
72.10
50.90
Caspase activation. Caspase 8: Caspase 8 activation is
measured as a marker for an extrinsic apoptotic mechanism.
Our data (Fig. 5) shows that compound (11) presented the
highest average activation at 50.5% (Fig. 5). Compound (14)
presented an average activation of 26%. Only compound (11)
Renal cancer
786-0
A498
2.110
0.272
4.770
38.20
21.90
48.60
3.350
1.480
7.060
46.40
31.30
46.50
ACHN
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Fig. 3 Drug response curve from the five-dose study of compound 11.
Caspase 3 and 7: Effector caspase activation was measured
yielding negative results. None of the compounds caused
statistically signicant (P < 0.05) activation. Compound (11)
presented an average of 39% of cells with activated caspase 3
(Fig. 7) whereas compound (14) presented 33.5% activation.
In order to verify these results DNA fragmentation was
performed.
Fig. 4 Annexin V staining. Only compound (14) presented significant
apoptotic activity which was comparable to the positive control.
presented signicant activation when compared to the negative
control (P < 0.05) and higher than the camptothecin control.
Caspase 9: Caspase 9 activation is an important hallmark of
the intrinsic apoptotic pathway. Our results show both
compounds present high activation of caspase 9 (Fig. 6).
Compound (11) presented a 45.5% of cells with active caspase 9
while compound (14) presented 43%. Both of these compounds
presented higher activation than the camptothecin control
(21%).
Fig. 5 Caspase 8 activation. Compound (11) caused significant (P <
0.05) activation of caspase 8. Compound (11) caused 50.5% activation
whereas (14) caused 26%.
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Fig. 8 DNA fragmentation: none of the experimental compounds
caused significant DNA fragmentation.
Fig. 6 Caspase 9 activation. Both experimental compounds presented
significant activation of caspase 9. Compound (11) presented 45.5% of
cells with active caspase while compound SM334 (14) presented 43%.
Additionally this compound activated caspase 9, but not cas-
pase 8, in a signicant manner. This compound presented no
activation of effector caspases or DNA fragmentation. Although
activation of caspase 9 and phosphatidylserine migration
suggest an intrinsic apoptotic pathway, the lack of effector
caspase activation and DNA fragmentation remains unex-
plained. Further experiments should include protein expression
pathways, especially the apoptosis related proteins.
DNA fragmentation: As Fig. 8 shows, none of the hybrid
compounds presented statistically signicant DNA fragmenta-
tion. Compound (11) presented an average of 8.5% and
compound (14) presented an average of 9%. These denotes a
clear absence of cells with fragmented DNA, especially when
compared to the negative control which had an average of 8.5%
and positive camptothecin control with 80.5%. These results
conrm the absence of effector caspase activation.
Conclusion
Discussion
The potential for the anticancer activity of 4-aminoquinoline-
triazine based molecular hybrids has been explored. Our study
of two representative compounds (11) and (14) showed signi-
cant inhibition against NCI 60 human tumor cell lines.
Compound (11) presented activation of caspase 8 and 9 but
not the typical hallmarks of this event, such as migration of
phosphatidylserine, DNA fragmentation and effector caspase
activation. Compound (14) presented signicant migration of
phosphatidylserine, indicating apoptotic cells. It also activated
caspase 9 but not caspase 8. Also, no activation of effector
caspases or DNA fragmentation was seen. Activation of caspase
9 and phosphatidylserine migration suggest an intrinsic
apoptotic pathway as the mode of action for these compounds.
The results obtained varied between our test compounds SM332
(11) and SM334 (14). Compound SM332 (11) presented activa-
tion of caspase 8 and 9, but not the typical hallmarks of this
event such as the migration of phosphatidylserine, DNA frag-
mentation and effector caspase activation. It is known that
caspase 8 mediates apoptotic cell death in various ways, such as
direct activation of effector caspase 3 or through the Bid mito-
chondrial mediated pathway.18 Activation of messenger cas-
pases but not effectors is a phenomenon that has been
described in other apoptotic cell death settings, however it has
been suggested by other researchers that other caspases might
be involved.19 Compound SM334 (14) presented signicant
migration of phosphatidylserine, indicating apoptotic cells.
Acknowledgements
D. S. R. thanks the University Grants Commission (41-
20282012(SR), 2012), New Delhi, India and DU-PURSE, Univer-
sity of Delhi, Delhi, India for nancial support. S. M. is thankful
to CSIR for the award of a junior and senior research fellowship.
We thank USIC-CIF, University of Delhi, for analytical data. A. P.
and S. V. M. would like to acknowledge support from the
National Cancer Institute, National Institutes of Health, under
Contract no. HHSN261200800001E.
Notes and references
1 (a) B. Meunier, Acc. Chem. Res., 2008, 41, 69; (b)
V. Pokrovskaya and T. Baasov, Expert Opin. Drug Discovery,
Fig. 7 Effector caspase activation. None of the compounds caused
statistically significant activation of effector caspases.
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2010, 5, 883; (c) F. W. Muregi and A. Ishih, Drug Dev. Res.,
2010, 71, 20.
G. Ambrosini, G. K. Schwartz and R. A. Sanchez-Delgado,
Inorg. Chem., 2009, 48, 1122.
2 (a) O. Dechy-Cabaret, F. Benoit-Vical, A. Robert and 11 A. Esparza-Ruiz, C. Herrmann, J. Chen, B. O. Patrick,
B. Meunier, ChemBioChem, 2000, 1, 281; (b) A. Robert, E. Polishchuk and C. Orvig, Inorg. Chim. Acta, 2012, 393, 276.
O. Dechy-Cabaret, J. Cazelles and B. Meunier, Acc. Chem. 12 S. Manohar, S. I. Khan and D. S. Rawat, Bioorg. Med. Chem.
Res., 2002, 35, 167; (c) O. Dechy-Cabaret, F. Benoit-Vical, Lett., 2010, 20, 322.
C. Loup, A. Robert, H. Vial, H. Gomitzka, A. Bonhoure, 13 S. Manohar, S. I. Khan and D. S. Rawat, Chem. Biol. Drug Des.,
J. F. Magnaval, J. P. Seguela and B. Meunier, Chem.–Eur. J.,
2004, 10, 1625.
2013, 81, 625.
14 (a) Beena and D. S. Rawat, Med. Res. Rev., 2013, 33, 693; (b)
D. Kumar, K. K. Raj, M. A. Bailey, T. Alling, T. Parish and
D. S. Rawat, Bioorg. Med. Chem. Lett., 2013, 23, 1365; (c)
S. Manohar, S. I. Khan, S. K. Kandi, K. Raj, G. Sun,
X. Yang, A. D. C. Molina, N. Ni, B. Wang and D. S. Rawat,
Bioorg. Med. Chem. Lett., 2013, 23, 112; (d) N. Kumar,
S. I. Khan and D. S. Rawat, Helv. Chim. Acta, 2012, 95,
1181; (e) N. Kumar, S. I. Khan, H. Atheaya, R. Mamgain
and D. S. Rawat, Eur. J. Med. Chem., 2011, 46, 2816; (f)
S. Joshi, G. S. Bisht, D. S. Rawat, A. Kumar, R. Kumar,
S. Maiti and S. Pasha, Biochim. Biophys. Acta, Biomembr.,
2010, 1798, 1864; (g) N. Kumar, S. I. Khan, Beena,
G. Rajalakshmi, P. Kumaradhas and D. S. Rawat, Bioorg.
Med. Chem., 2009, 17, 5632; (h) N. Kumar, S. I. Khan,
M. Sharma, H. Atheaya and D. S. Rawat, Bioorg. Med.
Chem. Lett., 2009, 19, 1675; (i) Beena, N. Kumar,
R. K. Rohilla, N. Roy and D. S. Rawat, Bioorg. Med. Chem.
Lett., 2009, 19, 1396; (j) R. Mamgain, R. Singh and
D. S. Rawat, J. Heterocycl. Chem., 2009, 46, 69; (k)
H. Atheaya, S. I. Khan, R. Mamgain and D. S. Rawat,
Bioorg. Med. Chem. Lett., 2008, 18, 1446; (l) G. S. Bisht,
D. S. Rawat, A. Kumar, R. Kumar and S. Pasha, Bioorg.
Med. Chem. Lett., 2007, 17, 4343; (m) A. J. Krzysiak,
D. S. Rawat, S. A. Scott, J. E. Pais, M. Handley,
M. L. Harrison, C. A. Fierke and R. A. Gibbs, ACS Chem.
Biol., 2007, 2, 385; (n) M. C. Joshi, G. S. Bisht and
D. S. Rawat, Bioorg. Med. Chem. Lett., 2007, 17, 3226; (o)
D. S. Rawat and R. A. Gibbs, Org. Lett., 2002, 4, 3027; (p)
D. S. Rawat and J. M. Zaleski, Chem. Commun., 2000, 2493.
15 C. Y. Xie, W. Yang, J. Ying, Q. C. Ni, X. D. Pan, J. H. Dong,
K. Li and X. S. Wang, Biol. Pharm. Bull., 2011, 34, 1279.
3 (a) S. Manohar, U. C. Rajesh, S. I. Khan, B. L. Tekwani and
D. S. Rawat, ACS Med. Chem. Lett., 2012, 3, 555; (b)
S. Manohar, S. I. Khan and D. S. Rawat, Chem. Biol. Drug
Des., 2011, 78, 124; (c) I. Chiyanzu, C. Clarkson, P. J. Smith,
J. Lehman, J. Gut, P. J. Rosenthal and K. Chibale, Bioorg.
Med. Chem., 2005, 13, 3249; (d) S. J. Burgess, A. Selzer,
J. X. Kelly, M. J. Smilkstein, M. K. Riscoe and D. H. Peyton,
J. Med. Chem., 2006, 49, 5623; (e) V. R. Solomon, W. Haq,
K. Srivastava, S. K. Puri and S. B. Katti, J. Med. Chem., 2007,
50, 394; (f) C. C. Musonda, J. Gut, P. J. Rosenthal,
V. Yardley, S. deCarvalho, C. Renata and K. Chibale, Bioorg.
Med. Chem., 2006, 14, 5605; (g) N. I. Wenzel, N. Chavain,
Y. Wang, W. Friebolin, L. Maes, B. Pradines, M. Lanzer,
V. Yardley, R. Brun, C. Herold-Mende, C. Biot, K. Tothand
and E. Davioud-Charvet, J. Med. Chem., 2010, 53, 3214; (h)
V. R. Solomon, C. Hu and H. Lee, Bioorg. Med. Chem.,
2009, 17, 7585.
4 (a) F. Loeb, W. M. Clark, G. R. Coateny, L. T. Coggeshall,
F. R. Dieuaide, A. R. Dochez, E. G. Hankansson,
E. K. Marshall Jr, C. S. Marvel, O. R. McCoy, J. J. Sapero,
W. H. Sebrell, J. A. Shannon and G. A. Carden Jr, J. Am.
Med. Assoc., 1946, 130, 1069; (b) V. V. Kouznetsov and
A. Gomez-Barrio, Eur. J. Med. Chem., 2009, 44, 3091.
5 K. Kaur, M. Jain, S. I. Khan, M. R. Jacob, B. L. Tekwani,
S. Singh, P. P. Singh and R. Jain, Bioorg. Med. Chem., 2011,
19, 197.
6 B. Macedo, C. H. Kaschula, R. Hunter, J. A. P. Chaves,
J. D. van der Merwe, J. L. Silva, T. J. Egan and Y. Cordeiro,
Eur. J. Med. Chem., 2010, 45, 5468.
7 S. S. Gehrke, E. G. Pinto, D. Steverding, K. Pleban,
A. G. Tempone, R. C. Hider and G. K. Wagner, Bioorg. Med. 16 T. Li, L. Wang, X.-X. Ke, X.-Y. Gong, J.-H. Wan, X.-W. Hao,
Chem., 2013, 21, 805.
8 V. R. Solomon and H. Lee, Eur. J. Pharmacol., 2009, 625, 220.
M. Xu, Z. Xiang, Z.-B. Cui and H. Cui, Cell Biol. Int., 2012,
36, 331.
9 (a) H. Zhang, V. R. Solomon, C. Hu, G. Ulibarri and H. Lee, 17 (a) D. McIlroy, H. Sakahira, R. V. Talanian and S. Nagata,
Biomed. Pharmacother., 2008, 62, 65; (b) C. Hu,
V. R. Solomon, P. Cano and H. Lee, Eur. J. Med. Chem.,
2010, 45, 705.
Oncogene, 1999, 18, 4401; (b) M. Olsson and B. Zhivotovsky,
Cell Death Differ., 2011, 18, 1441.
18 R. M. Siegel, Nat. Rev. Immunol., 2006, 6, 308.
10 C. S. K. Rajapakse, A. Martinez, B. Naoulou, A. A. Jarzecki, 19 S. Alvarez, A. Blanco, M. Fresno and M. A. Munoz-Fernandez,
L. Suarez, C. Deregnaucourt, V. Sinou, J. Schrevel, E. Musi,
PLoS One, 2011, 6, e16100.
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