Rational design and synthesis of novel phenylsulfonyl-benzamides as anti-prostate cancer agents

Article abstract of DOI:10.1039/c7md00164a

Prostate cancer is a major cause of male death worldwide and the identification of new efficient treatments is constantly needed. Different non-steroidal androgen receptor antagonists are approved also in the case of castration-resistant cancer forms. Using a rational approach and molecular modelling studies to modify the structure of antiandrogen drug bicalutamide, a new series of phenylsulfonyl-benzamide derivatives was designed and synthesised. Their antiproliferative activities were evaluated in four different human prostate cancer cell lines and several new compounds showed significantly improved IC₅₀ values in the low μM range. The cytotoxicity profile was also evaluated for the novel structures in the HEK293 cell line.

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RESEARCH ARTICLE
Rational design and synthesis of novel
phenylsulfonyl-benzamides as anti-prostate
Cite this: DOI: 10.1039/c7md00164a
cancer agents†‡§
Marcella Bassetto, ¶* Salvatore Ferla, ¶ Gilda Giancotti,
Fabrizio Pertusati,
Andrew D. Westwell, Andrea Brancale and Christopher McGuigan
Prostate cancer is a major cause of male death worldwide and the identification of new efficient treatments
is constantly needed. Different non-steroidal androgen receptor antagonists are approved also in the case
of castration-resistant cancer forms. Using a rational approach and molecular modelling studies to modify
the structure of antiandrogen drug bicalutamide, a new series of phenylsulfonyl-benzamide derivatives was
designed and synthesised. Their antiproliferative activities were evaluated in four different human prostate
cancer cell lines and several new compounds showed significantly improved IC50 values in the low μM
range. The cytotoxicity profile was also evaluated for the novel structures in the HEK293 cell line.
Received 5th April 2017,
Accepted 3rd May 2017
DOI: 10.1039/c7md00164a
rsc.li/medchemcomm
5
Phase III clinical trials, is also associated with the insur-
gence of resistance through the F876L mutation, while new-
Introduction
6
Prostate cancer (PC) is one of the major causes of male death
worldwide, representing the second most common cancer in
generation AR inhibitor ODM-201 (Fig. 1), now in Phase III
trials, has shown retained activity in the F876L AR mutant.
Most non-steroidal antiandrogens are structurally
characterised by two differently substituted aromatic rings,
named ring A and ring B, connected by a linker, either linear
7
1
males. One of the main treatment strategies against this dis-
2
ease is currently represented by androgen deprivation:
bicalutamide (1) and enzalutamide (2) are two non-steroidal
androgen receptor (AR) antagonist drugs approved to treat PC
(bicalutamide-like compounds) or cyclic (enzalutamide-like
8
(Fig. 1). Unfortunately, these anti-androgens tend to become
compounds) (Fig. 1).
Recently,
a
novel 4-(4-benzo-
ineffective in a few years' time due to adaptive mutations on
the structure of the androgen receptor, which switch the func-
tion of these drugs from antagonist to agonist.
ylaminophenoxy) phenol antiandrogen scaffold (4), derived
from the natural pigment curcumin, has been reported, in
which a central phenyl group is acting as linker connecting
2
9
One of the most common mutations found for
two different aromatic rings.
3
bicalutamide is W741L in helix 12 of the receptor, which al-
With the aim to rigidify the structure of bicalutamide and
obtain new anticancer agents, we designed a novel molecular
scaffold in which we replaced the flexible bicalutamide
methyl-hydroxy-methylene linker with a rigid phenyl group,
maintaining the two lateral aromatic rings commonly found
in antiandrogen compounds (Fig. 2). Moreover, following an
approach previously proven successful in our research group
lows the protein to adopt its closed agonist conformation
even in the presence of the antagonist: with this mutation,
due to some residual structural flexibility in 1, ring B can
bend to occupy an inner portion of the ligand-binding do-
main, thus allowing the closure of the receptor into its ago-
nist conformation. Treatment with enzalutamide induces in-
stead a F876L mutation in the AR, which also confers an
for increasing bicalutamide and enzalutamide anti-prostate
4
10,11
antagonist to agonist switch in activity for the drug. Second-
cancer activity,
different perfluoro groups were systemati-
generation antiandrogen ARN-509 (Fig. 1), which is now in
cally inserted in aromatic ring B (R2 substituent), replacing
the classical 4-cyano substituent. The phenolic 4-hydroxy
group of 4, previously reported as essential for AR antagonis-
tic activity, was either maintained, in order to evaluate its
importance for anti-prostate cancer effect, or replaced with a
School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King
Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
E-mail: BassettoM@cardiff.ac.uk
9
†
‡
The authors declare no competing interests.
3-trifluoromethyl group, as a means to incorporate and evalu-
Electronic supplementary information (ESI) available. See DOI: 10.1039/
ate one of the most successful modifications we have previ-
c7md00164a
This work is dedicated to the memory of Prof. Chris McGuigan, a great col-
league and scientist, invaluable source of inspiration and love for research.
These authors contributed equally to this work.
1
0,11
ously found in other series of related compounds.
§
Following this approach, a novel family of phenylsulfonyl-
benzamides was developed (Fig. 2), and their potential anti
¶
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Fig. 1 Structure of anti-androgen small molecules approved by FDA (1 and 2a), in clinical development for the treatment of PC (2b and 3) or in
early-stage development (4). Two differently substituted aromatic rings, A and B, are connected by a linker.
Fig. 2 Rational design of novel phenylsulfonyl-benzamide scaffold.
prostate cancer activity was evaluated in four different hu-
man prostate cancer cell lines, together with their cytotoxicity
in the HEK293 cell line.
to evaluate its potential structural overlapping with the two
active conformations. 13a aligns well with the binding pose
of the parent compounds, with the newly introduced phenyl
ring conferring the desired structural rigidity to lock the mol-
ecule in the active conformation (Fig. 3). Moreover, as
reported in the ESI‡ (Table S1), the two conformations
obtained for 13a show a large negative similarity score F,
meaning that 13a shows a high shape and functional similar-
ity to the two parent compounds. Finally, the dU value found
Results and discussion
Molecular modelling
A series of flexible alignment and molecular docking studies
was performed to evaluate the proposed structural modifica-
tions. For these analyses, compound 13a, which maintains
bicalutamide and enzalutamide aromatic substituents in ring
A and is characterised by the fully oxidised sulfonyl linker,
was chosen as representative for the novel series of com-
−
1
for both alignments is lower than 1 kcal mol , meaning that
the obtained conformations are energetically favoured. The
better (more negative) similarity score obtained for the align-
ment with enzalutamide is a further confirmation that the in-
troduction of the phenyl linker rigidifies the novel structure,
potentially locking the molecule in an active conformation.
Fig. 4A shows the docking results found for 13a in the li-
gand binding domain (LBD) of the open AR homology model,
1
0
pounds. In a previous work, we have extensively discussed
and described the most likely binding mode of bicalutamide
and enzalutamide in the homology model of the androgen re-
ceptor (AR) open antagonist conformation. In the present
study, the predicted active conformation for the two drugs
was kept rigid and a flexible alignment with newly designed
1
3
obtained using Plants docking software. The extra phenyl
ring, as observed in the flexible alignment results, maintains
the molecule in a rigid extended conformation that entirely
1
2
compound 13a was performed using MOE2015.10, in order
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Fig. 3 Flexible alignment between 13a (carbon atoms in light blue) with the predicted active binding conformations of bicalutamide (A-carbon
atoms in purple) and enzalutamide (B-carbon atoms in dark green).
occupies the binding site, similarly to bicalutamide and
enzalutamide. The phenolic hydroxyl group is facing outside
the binding groove, therefore its replacement with other
functions is predicted to be tolerated. Docking results for 13a
in the bicalutamide-resistant AR mutant W741L crystal struc-
ing anilines 10a–i with 8 and 9 in the presence of thionyl
1
5
chloride in DMA, modifying a literature procedure. In the
last step, sulphur derivatives 11a–i and 12a, h were oxidized
to the corresponding sulfones 13a–i and 15a, h using mCPBA
1
0
at 25 °C. In two cases, the corresponding product of sul-
phur partial oxidation was also isolated (14e and 14i). These
two sulfoxides were characterised by low solubility in the re-
action solvent, therefore complete oxidation to the corre-
sponding sulfone was much slower and did not go to comple-
tion within the reaction time. Using this synthetic approach,
24 novel phenylsulfonyl-benzamides derivatives were pre-
pared, purified and fully characterised.
3
ture (PDB ID 1Z95), which corresponds to the closed active
conformation of the receptor, indicate that, due to its in-
creased rigidity, the novel molecule cannot fit the AR antago-
nist conformation, as highlighted by the steric clashes be-
tween 13a and helix 12 (Fig. 4B). These results suggest that
the novel scaffold could maintain its antagonist activity also
in the presence of the W741L mutation.
Standard bicalutamide and enzalutamide were also pre-
1
0
pared following reported procedures.
Chemistry
Scheme 1 reports the three-step synthetic pathway developed
and optimised for the preparation of the newly designed
compounds.
In vitro 2D monolayer antiproliferative assay
All new compounds along with the two standards were tested
for their ability to inhibit survival and/or cell proliferation in
four human prostate cancer cell lines: LNCaP, 22Rv1, VCaP,
androgen-sensitive cell lines, and DU145, a non hormone-
sensitive cell line. Table 1 shows the antiproliferative results
for each single cell line (absolute IC50 in μM), along with the
overall effect in the four cell lines reported as geometric
mean. Activity found for bicalutamide and enzalutamide is
consistent with previously published data for some of these
In the first step a copper catalysed C–S coupling reaction
was used for the preparation of intermediates 8–9. The condi-
tions for this step were optimised from a reported proce-
1
4
dure. After 12 hours reflux as in the published protocol,
-iodobenzoic acid 7 was still present in the reaction mixture.
4
No difference could be observed with a prolonged reaction
time, while total consumption of starting material 7 was fi-
nally achieved by doubling the equivalents of thiophenol and
base. The new conditions were applied to react differently
substituted thiophenols 5–6 with 4-iodobenzoic acid 7 for 24
hours in water, giving the desired different substituted
phenylthio-benzoic acids in an almost quantitative yield. Am-
ides 11a–i and 12a, h were obtained reacting the correspond-
1
6–18
specific cell lines,
confirming the reliability of the assay.
Considering their overall profile in the four cell lines (geo-
metric mean), almost all the new derivatives performed sig-
nificantly better than bicalutamide, improving its effect up to
16-fold. The new inhibitors showed concentration-dependent
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10
Fig. 4 A) Predicted binding mode of 13a (carbon atoms in light blue) in the AR homology model. The compound occupies the LBD in a similar
3
way to bicalutamide (carbon atoms in purple). B) 13a in the bicalutamide-W741I AR closed conformation crystal structure 1Z95 (B). The compound
shows major clashes (purple surface), highlighted by red circles, with the protein surface (in grey) of the closed AR structure, especially with helix
1
2, indicating that it might impede the AR closure even in the presence of adaptive mutations.
1
0,16
activity with mean IC50 values ranging from 3.2 μM to >100
μM. Compared with standard enzalutamide, antiproliferative
effect was improved up to 8-fold.
androgen receptor modulators),
= S) are associated with better antiproliferative activities than
the corresponding sulfones (X = SO ), with a decrease of effect
thioether compounds (X
2
Substituent R in ring B does not seem to influence the
anticancer profile of the scaffold, as no substantial differ-
ences were found between the OH group in the para position
in the sulfones up to 8-fold. In the new scaffold presented in
this work, no particular differences can be observed between
thioether and sulfone compounds, with retained activity in
most sulfones (i.e. 11a vs. 13a) and only a small increase of
IC50 values up to 2-fold in few cases (i.e. 11c vs. 13c). The par-
tially oxidized derivatives (X = SO) retain the effect of the cor-
responding thioethers and sulfones (i.e. 11e and 13e vs. 14e).
1
or the CF in meta (i.e. 11a vs. 12a). This finding is in accor-
3
dance with the proposed binding mode for 13a, in which the
R substituent is facing outside the AR binding domain with-
1
out making specific interactions.
In both our previous work on bicalutamide derivatives and
in another published work on analogues of SARMs (selective
2
Removal of the CN or the NO group in the para position
of ring B is associated with retained activity, as found for
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Scheme 1 Synthetic pathway for the synthesis of phenylsulfonyl-benzamides analogues. Reagents and conditions: (a) KOH, Cu, H
2
O, reflux, 24 h;
(1.2 equiv.), DMA, −15 to −10 °C to rt. After 1 h 10a–i (1 equiv.) dissolved in DMA is added, rt, on; (c) mCPBA (1.4 equiv.),
(
b) 8–9 (1 equiv.), SOCl
2
DCM, rt, on.
mono 3-CF
3
derivative 11h. Moving the trifluoromethyl group
5
group with a bigger –SF moiety in para or meta position is
from meta to para position does not have a significant effect
on activity (i.e. 11h vs. 14g), whereas the ortho substitution is
characterized by a 3-fold reduction of overall effect in the
four cell lines (i.e. 11h vs. 11i). Replacing the trifluoromethyl
associated with a mildly improved activity profile (i.e. 11g vs.
14e).
Addition of an extra CF
3 2 3
in meta (R = 3,5-CF ), gives the
best results in terms of overall activity in the four cell lines
Table 1 Antiproliferative activity for the novel phenylsulfonyl-benzamide derivatives. All data are mean values from triplicate experiments, with standard
deviations of ±10% of the value quoted unless otherwise stated. Compound 15h showed solubility issues
Compound
R
1
X
R
2
Absolute IC50 (μM)
2
2Rv1
DU-145
49.20
44.55
7.77
LNCaP
45.27
20.90
5.43
VCaP
68.37
24.47
9.55
Geo. mean
52.42
27.41
7.08
Bicalutamide
Enzalutamide
—
—
—
—
S
S
S
S
S
S
S
S
S
S
S
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
—
—
49.58
24.77
6.24
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2h
3a
3b
3c
3d
3e
4e
3f
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-CN, 3-CF
4-NO , 3-CF
3,5-CF
2,5-CF
4-SF
3-SF
4-CF
3-CF
2-CF
4-CN, 3-CF
3-CF
4-CN, 3-CF
4-NO , 3-CF
3,5-CF
2,5-CF
4-SF
4-SF
3-SF
3
2
3
4.50
5.74
3.58
5.19
4.68
3
3.35
5.60
2.39
2.59
3.28
3
10.34
3.71
16.63
6.76
11.42
4.86
10.88
7.15
12.09
5.43
5
5
2.94
4.35
3.32
6.10
4.01
3
6.23
8.55
8.30
9.68
8.09
3
5.73
30.92
3.57
5.95
35.68
5.12
9.66
11.43
8.87
10.58
32.27
5.66
7.69
25.25
5.50
3
3-CF
3-CF
3
3
3
3
6.96
12.08
7.30
9.89
12.62
8.85
12.47
4.68
4.96
28.22
8.56
8.57
12.47
8.84
7.24
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
4-OH
2
2
2
2
2
3
2
3
3
6.44
9.92
8.41
9.72
8.50
3
20.66
5.78
5.60
27.79
10.85
11.02
6.01
30.69
17.73
45.88
100.00
4.70
23.18
2.49
0.90
30.48
5.35
3.53
10.81
27.16
30.08
65.20
97.60
7.87
25.24
5.37
3.75
5
5
5
2
2
2
2
5.66
3.98
6.18
3g
3h
3i
4i
5a
5h
4-CF
3-CF
2-CF
2-CF
4-CN, 3-CF
3-CF
3
16.79
15.06
49.31
100.00
3.57
10.75
10.19
39.31
61.98
3.73
19.69
16.84
49.07
88.19
4.71
3
3
3
3-CF
3-CF
3
2
2
3
3
3
n.d
n.d
n.d
n.d
n.d
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Fig. 5 HEK293 human embryonic kidney cells were treated at 70% confluence with negative controls (0.1% DMSO, BICAL at 10 μM), positive
control (10% DMSO) and compounds at 10 μM concentration for 24 hours. 20 μl of Cell Titer Blue reagent (Promega) was added to each well
2
containing 100 μl media and cell were incubated for 2 h at 37 °C 5% CO . Fluorescence was measured at 560/590 nm using a CLARIOstar
luminescence plate reader (BMG Labtech). N = 4, n = 6 for controls, n = 3 for drugs. Errors are calculated as standard error of the mean. * =
p-value < 0.05, ** = p-value < 0.01, *** = p-value < 0.001 **** = p-value < 0.0001 between bicalutamide and compounds.
(
i.e. 11a and 13h vs. 14c), as we had similarly observed in our
cytotoxicity profile of the newly prepared compounds. Fig. 5
shows the reduction of cell viability caused by the novel ana-
logues and standard bicalutamide at a fixed concentration of
10 μM. Interestingly, as reported in the graph, only three com-
pounds (11d, 11e and 13e) significantly reduced cell viability
if compared to bicalutamide (statistical significance), and only
one of them (13e) killed more than 50% of cells. Due to their
higher cytotoxicity in comparison with bicalutamide, the anti-
proliferative effect of these three compounds in the prostate
cancer cell lines could also be a consequence of their intrinsic
toxicity, besides the canonical AR antagonist activity. Compar-
ing the rest of the compounds with bicalutamide, even if
some of them are characterized by an increased cytotoxicity,
cell viability reduction is not statistically significant and less
than 40% in most cases, therefore the observed cytotoxicity is
comparable to the one found for bicalutamide. Moreover, it is
worth to note that bicalutamide reaches its antiproliferative
IC50 at 50 μM, therefore it would not show reduction of cell vi-
ability at 10 μM. On the contrary, most of our new compounds
showed antiproliferative activity in the four prostate cancer
cell lines at a low μM concentration (<10 μM), and even if
some of them show a reduction of cell viability by 35–40%,
their anticancer therapeutic window is still wide enough for
consideration as a potential treatment for prostate cancer. In
particular, compounds 11h, 12h, 13b and 13h are associated
with a promising antiproliferative/cytotoxicity profile, with an
antiproliferative effect much better than bicalutamide (<16
μM), and with the same cytotoxicity of bicalutamide at 10 μM
(none or minimal reduction of cell viability).
1
0
previous research efforts. Also in this case, moving one
trifluoromethyl group from meta to ortho position is associ-
ated with activity reduction (i.e. 11c vs. 11d).
Examining each individual cell line, most of the new com-
pounds showed the best results in the cell lines that highly
express the androgen receptor. Among them, LNCaP cells
were found to be the most sensitive to the new derivatives,
with different compounds active at low μM concentrations
and one reaching a sub μM IC50 value (14e). These data sug-
gest that the newly prepared compounds are likely to retain
an antagonistic effect on the androgen receptor. An interest-
ing activity profile was also found in the DU-145 cell line (the
least sensitive to our new molecules), which expresses low
levels of the androgen receptor and is insensitive to andro-
gen activity. The same effect can be observed also for parent
bicalutamide (similar IC50 values across the four cell lines),
suggesting that besides its canonical anti-androgen receptor
action, a different antiproliferative mechanism could also be
involved. The new phenylsulfonyl-benzamides, in addition to
potentially increase the antagonistic activity on the AR, might
also enhance the potential off target effect, even though in
some cases they seem more selective for androgen-sensitive
cell lines than bicalutamide (i.e. 13e, 14e, 13g). As a general
observation, the improved antiproliferative activity of the
novel compounds should be regarded as the result of the
whole structure of each single derivative, since the data
found appear to be a combination of the simultaneous ef-
fects of the substituent in ring B and linker X.
1
9
Conclusions
Cytotoxicity assay
A Cell Titer Blue viability assay was performed in the human
embryonic kidney cell line HEK293, in order to evaluate the
A novel family of phenylsulfonyl-benzamides was designed
and synthesised after rational modification of the structure
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of antiandrogen drug bicalutamide, and many of the novel
derivatives prepared show improved anti-prostate cancer
properties. In particular, most of the new compounds display
significantly improved anticancer activities in four different
prostate cancer cell lines, with a cell viability reduction effect
comparable to the one found for bicalutamide. Differently from
previously reported SARMs, no significant difference in anti-
proliferative activity has been observed between our novel thio-
ether and sulfone derivatives, representing a promising feature
for future metabolic stability considerations. Within the 24
novel analogues evaluated, 11h, 12h, 13b and 13h have been se-
lected as candidates for further investigations, due to their im-
proved anticancer properties and their cytotoxicity profiles.
With the aim to identify a pre-clinical candidate, these com-
pounds will be studied for their binding to the AR, their po-
tential off target effect and their pharmacokinetic properties.
S. Dorow, V. Arora, G. Shao, J. Qian, H. Zhao, G. Yang, C.
Cao, J. Sensintaffar, T. Wasielewska, M. R. Herbert, C.
Bonnefous, B. Darimont, H. I. Scher, P. Smith-Jones, M.
Klang, N. D. Smith, E. De Stanchina, N. Wu, O. Ouerfelli,
P. J. Rix, R. A. Heyman, M. E. Jung, C. L. Sawyers and J. H.
Hager, Cancer Res., 2012, 72, 1494–1503.
6 J. D. Joseph, N. Lu, J. Qian, J. Sensintaffar, G. Shao, D.
Brigham, M. Moon, E. C. Maneval, I. Chen, B. Darimont and
J. H. Hager, Cancer Discovery, 2013, 3, 1020–1029.
7 K. Fizazi, L. Albiges, Y. Loirot and C. Massard, Expert Rev.
Anticancer Ther., 2015, 15, 1007–1017.
8 C. Ferroni, A. Pepe, Y. Sang Kim, S. Lee, A. Guerrini, M. D.
Parenti, A. Tesei, A. Zamagni, M. Cortesi, N. Zaffaroni, M. De
Cesare, G. L. Beretta, J. B. Trepel, S. V. Malhotra and G.
Varchi, J. Med. Chem., 2017, 60, 3082–3093.
9 A. Yamada, S. Fujii, S. Mori and H. Kagechika, ACS Med.
Chem. Lett., 2013, 4, 937–941.
Experimental
10 M. Bassetto, S. Ferla, F. Pertusati, S. Kandil, A. D. Westwell,
A. Brancale and C. McGuigan, Eur. J. Med. Chem., 2016, 118,
All chemistry, biology and molecular modelling experimental
procedures, along with compound characterisation, are fully
described in the ESI.‡ All final compounds were purified by
column chromatography or recrystallization and fully
characterised by NMR ( H, C, F) and LRMS. All final com-
pounds were found to be >95% pure by HPLC.
2
30–243.
1
1 S. Ferla, M. Bassetto, F. Pertusati, S. Kandil, A. D. Westwell,
A. Brancale and C. McGuigan, Bioorg. Med. Chem. Lett.,
2
016, 26, 3636–3640.
1
13
19
1
2 Molecular Operating Environment (MOE 2015.10); Chemical
Computing Group, Inc.: Montreal, Quebec, Canada; URL
http://www.chemcomp.com.
Acknowledgements
1
1
1
3 O. Korb, T. Stützle and T. E. Exner, Swarm Intell., 2007, 1,
1
15–134.
The authors would like to thank Oncotest (Freiburg, Germany)
for provision of human prostate cancer cell line testing as an
outsourced service. The Welsh Government is acknowledged
for funding (A4B-Academic Expertise for Business grant).
4 L. Costantino, A. M. Ferrari, M. C. Gamberini and G.
Rastelli, Bioorg. Med. Chem., 2002, 10, 3923–3931.
5 Y. He, D. Yin, M. Perera, L. Kirkovsky, N. Stourman, W. Li,
J. T. Dalton and D. D. Miller, Eur. J. Med. Chem., 2002, 37,
6
19–634.
References
1
6 D. J. Hwang, J. Yang, H. Xu, I. M. Rakov, M. L. Mohler, J. T.
Dalton and D. D. Miller, Bioorg. Med. Chem., 2006, 14,
6525–6538.
17 A. Colabufo, V. Pagliarulo, F. Berardi, M. Contino, C.
Inglese, M. Niso, P. Ancona, G. Albo, A. Pagliarulo and R.
Perrone, Eur. J. Pharmacol., 2008, 601, 38–42.
18 H. Kuruma, H. Matsumoto, M. Shiota, J. Bishpo, F.
Lamoureux, C. Thomas, D. Briere, G. Los, M. Gleave, A.
Fanjui and A. Zoubeidi, Mol. Cancer Ther., 2013, 12,
567–576.
19 F. Alimirah, J. Chen, Z. Basrawala, H. Xin and D. Choubey,
FEBS Lett., 2006, 580, 2294–2300.
1
2
www.cancerresearchuk.gov (accessed April 3, 2017).
J. Ferlay, H.-R. Shin, F. Bray, D. Forman, C. Mathers and
D. M. Parkin, Int. J. Cancer, 2010, 127, 2893–2917.
3
4
C. E. Bohl, W. Gao, D. D. Miller, C. E. Bell and J. T. Dalton,
Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 6201–6206.
M. Korpal, J. M. Korn, X. Gao, D. P. Rakiec, D. A. Ruddy, S.
Doshi, J. Yuan, S. G. Kovats, S. Kim, V. G. Cooke, J. E.
Monahan, F. Stegmeier, T. M. Roberts, W. R. Sellers, W.
Zhou and P. Zhu, Cancer Discovery, 2013, 3, 1030–1043.
N. J. Clegg, J. Wongvipat, J. D. Joseph, C. Tran, S. Ouk, A.
Dilhas, Y. Chen, K. Grillot, E. D. Bischoff, L. Cai, A. Aparicio,
5
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