Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation

Article abstract of DOI:10.1016/j.bmcl.2015.08.060

A series of AG014699 derivatives containing a novel scaffold of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4(6H)-dione were synthesized and evaluated for their inhibitory activities toward PARP-1 enzyme and two cell lines, MCF-7 cells and the BRCA1-deficient MDA-MB-436 cells. Our results demonstrated that of all AG014699 derivatives synthesized in this work, compounds 6 and 7 showed strong PARP-1 inhibitory activity (IC₅₀ = 3.5 nM and 2.4 nM, respectively), only four and three times less potent than AG014699. Compound 6 also had significantly cell inhibitory activity against both MCF-7 cells (CC₅₀ = 25.8 μM) and the BRCA1-deficient MDA-MB-436 cells (CC₅₀ = 5.4 μM), nearly as good as AG014699, indicating that it can be a promising compound for further evaluation.

Full text of DOI:10.1016/j.bmcl.2015.08.060

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of novel PARP-1 inhibitors: Drug design, synthesis and
biological evaluation
a,
Zhouling Xie a, Youli Zhou a, Wei Zhao b, He Jiao a, Yu Chen a, Yong Yang b, , Zhiyu Li
⇑
⇑
a Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China
b State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research,
China Pharmaceutical University, Nanjing 21009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of AG014699 derivatives containing a novel scaffold of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]
indole-1,4(6H)-dione were synthesized and evaluated for their inhibitory activities toward PARP-1
enzyme and two cell lines, MCF-7 cells and the BRCA1-deficient MDA-MB-436 cells. Our results demon-
strated that of all AG014699 derivatives synthesized in this work, compounds 6 and 7 showed strong
PARP-1 inhibitory activity (IC50 = 3.5 nM and 2.4 nM, respectively), only four and three times less potent
than AG014699. Compound 6 also had significantly cell inhibitory activity against both MCF-7 cells
Received 28 May 2015
Revised 26 July 2015
Accepted 22 August 2015
Available online xxxx
Keywords:
(CC50 = 25.8
AG014699, indicating that it can be a promising compound for further evaluation.
Ó 2015 Elsevier Ltd. All rights reserved.
lM) and the BRCA1-deficient MDA-MB-436 cells (CC50 = 5.4 lM), nearly as good as
Poly ADP-ribose polymerase-1 (PARP-1)
Inhibitor
Molecular docking
DNA damage
BRCA1/2-deficient
Poly ADP-ribose polymerases (PARPs),
a
family of 18
glycohydrolase (PARG).5–8 According to the key function of PARP-
1 in DNA damage repair, many small molecules targeting PARP-1
catalytic domain have been developed either as chemo-sensitizers
in combination with ionizing radiation or DNA-damaging
chemotherapeutic agents or as stand-alone therapies (synthetic
lethal) to kill cancers cells that are defective in DNA repair
mechanisms.9
parp-enzymes, participates in ADP-ribose glycosylation in cell
nucleus/cytoplasm exerting important cellular functions.1 PARP-
1, a 113 kDa protein, is the most widely studied in PARPs that
possesses three main functional regions: DNA-binding domain
(DBD), auto-modification domain (AMD), and catalytic domain
(CD).2
PARP-1 displays a key role in single-stranded and double-
stranded DNA damage repair (SSBs and DSBs), especially in tumor
cells with BRCA1/2-deficient and lack of homologous recombina-
tion (HR) repair.3 Once DNA was damaged by radiation, oxidation
or alkylation, PARP-1 will be activated to bind the damaged DNA
to form homodimers, catalyzing the conversion of nicotinamide
adenine dinucleotide (NAD+) into niacinamide and ADP ribose
within its catalytic domain.4 The ADP ribose can subsequently form
ADP-ribose polymer and the poly ADP-ribose complex combining
with PARP-1 auto-modification domain, histone, and other nuclear
receptor proteins, to facilitate the recruitment of a variety of DNA
repairing enzymes, such as X-ray repair cross complementary
Nicotinamide
(IC50 = 210
l
M)
and
3-aminobenzamide
(IC50 = 30 M) were the earliest PARP-1 inhibitors, which were
l
designed to mimic the substrate–protein interactions of NAD+ with
PARP-1.10 However, their low potency and poor specificity
prompted researchers to find new PARP-1 inhibitors with
improved potency. To date, a number of PARP-1 inhibitors have
been developed into preclinical or clinical trials, including
AG014699, E-7016, BMN-673, AZD2281 and ABT-888 et al.
(Fig. 1).11,12 However, only AZD2281 became commercially avail-
able as an approved drug with high efficacy, proven safety, and
excellent pharmacokinetic profiles in 2014.13 Among all clinically
used PARP-1 inhibitors, the tricyclic ones containing a lactam ring
with S-trans conformation, have a more favorable binding confor-
mation for PARP-1 inhibition. In addition, the aromatic ring in
enzymes 1 (XRCC1), DNA polymerase III-ab, and DNA ligase
(LIG-III ). These DNA repairing enzymes will be stimulated to rec-
a
ognize and repair DNA damage. After the base excision repair, the
the tricyclic scaffolds exerts critical function for forming p–p
poly ADP-ribose will be cleaved from PARP-1 by poly ADP-ribose
stacking between the aryl ring and Tyr907 in PARP-1. The
structural rigidity of the tricyclic scaffold is beneficial for PARP-1
inhibitors to bind to the catalytic site of PARP-1. To modulate
the pharmacokinetic profiles and physical properties of PARP-1
⇑
Corresponding authors. Tel.: +86 13951678592 (Z. Li).
E-mail address: zhiyuli@cpu.edu.cn (Z. Li).
http://dx.doi.org/10.1016/j.bmcl.2015.08.060
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Xie, Z.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.060

2
Z. Xie et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
H
N
H
N
O
O
O
N
N
NH
N
OH
N
N
F
H
N
N
F
N
H
N
O
H
F
AG014699
BMN-673
E-7016
O
O
NH
NH
2
N
O
F
N
HN
N
N
HN
ABT-888
O
AZD2281
Figure 1. The structures of representative PARP-1 inhibitors in the clinic (AG014699, E-7016, BMN-673, ABT-888) and on the market (AZD2281).
carboxamide hydrogen exhibit hydrogen bonding interaction with
the backbone carbonyl oxygen of Gly863. The aromatic ring of the
core can be stabilized through stacking interaction with the
nearly coplanar electron-rich phenyl rings of Tyr907 and Tyr 896.
The N–H of indole can form Hydrogen bonding with Glu988 via a
water molecule. The docking results indicated that novel antitu-
mor agents could be developed based on this novel tricyclic scaf-
Gly863
O
p–p
Tyr896
H
904Ser
Tyr907
O
H
H
O
H
N
3
0
N
9
s
y
L
OH
O
6
fold. Thus,
a series of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]
7
2
indole-1,4(6H)-diones were synthesized by introducing a fluorine
atom to the 6-position of indole and an aryl chain with different
basic groups to the 2 or 6-position of indole. The PARP-1 inhibitory
activities were determined to identify potential novel PARP-1
inhibitors.
N
H
1
OH
HO
H
O
H
O
Glu988
The two critical intermediates, compounds 28 and 29 were pre-
pared according to Scheme 1. Briefly, methyl esterification of mate-
rials 12 and 13 afforded 14 and 15 which were treated with NBS to
give 16 and 17. Cyanogenation of 16 and 17 using NaCN afforded
18 and 19 which were hydrolyzed with concentrated HCl under
refluxing to give 20 and 21. Methyl esterification of 20 and 21
leaded to the formation of 22 and 23, which cyclized to give 24
and 25 via catalytic hydrogenation over Palladium/charcoal.
Bromination of 24 and 25 with POBr3 afforded 26 and 27, which
reacted with (4-formylphenyl)boronic acid to give 28 and 29 via
Suzuki reaction.
Sequentially, as shown in Scheme 2, the intermediates 28 and
29 were reacted with secondary amines to afford schiff bases
which were reduced to give 57–63 using NaBH4. Protection of
57–63 with Boc afforded 64–70. The formyl group was introduced
to the 3-position of 64–70 by Vilsmeier reaction and the resulting
compounds 71–77 were oxidized using NaClO2 to give 78–84.
Figure 2. The docking model of novel core binding to PARP-1 by discovery studio
3.0.
inhibitors: a region, a short chain with basic group needs to be
introduced to the tricyclic scaffolds.
To obtain more potent and novel PARP-1 inhibitors possessing
favorable PK properties and improved efficacy against tumor, on
the basis of reported structure–activity relationship of clinically
effective tricyclic PARP-1 inhibitors, we proposed that a novel tri-
cyclic scaffold, 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4
(6H)-dione derived from AG014699 would restrict the carboxam-
ido rotation and offer a favorable binding conformation to the cat-
alytic site of PARP-1 enzyme. The docking model (PDB code: 4OQA,
Fig. 2) reveals that the carbonyl oxygen in 2,3-dihydro-1H-[1,2]di-
azepino[4,5,6-cd]indole-1,4(6H)-dione can form a hydrogen bond
with the side chain hydroxyl group of Ser904, while the double
COOCH3
COOCH3
NO2
X=H 22
COOH
COOCH3
COOH
CH3
COOCH3
CH2Br
COOCH3
CH3
COOCH3
NO2
c
d
f
a
b
e
COOH
NO2
CN
O
N
H
X
X
X
X
NO2
X
NO2
X=H 16
X
NO2
X
X=H 24
X=F 25
X=H 20
X=F 21
X=H 14
X=F 15
X=H 18
X=F 19
X=H 12
X=F 13
X=F 23
X=F 17
COOCH3
COOCH3
g
h
Br
CHO
N
H
X
N
H
X
X=H 26
X=F 27
X=H 28
X=F 29
Scheme 1. Synthesis route of intermediates 28 and 29. Reagents and conditions: (a) MeOH, 0 °C, SOCl2 (2 equiv); reflux, 5 h, 96.1%; (b) benzoylperoxide (0.1 equiv), NBS
(1.4 equiv), CCl4, reflux, overnight, 84.6%; (c) NaCN (1.2 equiv), MeOH, room temperature, 5 h, 65.5%; (d) concd HCl, reflux, 10 h, 70.6%; (e) SOCl2 (8 equiv), 0 °C, MeOH; reflux
5 h, 92.3%; (f) MeOH, 10% Pd–C/H2, room temperature, 5 h, 49.7%; (g) DCE, POBr3 (1.8 equiv), 1 h, room temperature; imidazole (0.15 equiv), 4 h, reflux, 39.1%; (h) toluene,
MeOH, water, Na2CO3 (2.5 equiv), ZnCl2 (3 equiv), (4-formylphenyl)boronicacid (1.5 equiv), Pd(PPh3)4 (0.05 equiv), reflux, overnight, 75%.
Please cite this article in press as: Xie, Z.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.060

Z. Xie et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
COOCH3
COOCH3
COOCH3
CHO
COOCH3
Boc
Boc
a
b
d
c
N
N
CHO
R
R
N
H
N
H
N
H
N
H
HN
R
X
X
X
X
X=H 71~74
X=F 75~77
X=H 64~67
X=F 68~70
X=H 28
X=F 29
X=H 57~60
X=F 61~63
H
H
N
NH
N
NH
O
O
COOCH3
COOH
O
O
Boc
Boc
e
H
N
g
f
N
N
R
R
R
N
H
N
H
X
N
H
X
X
X=H 78~81
X=F 82~84
X=H 1~4
X=F 5~7
X=H 85~88
X=F 89~91
Scheme 2. Synthesis route of targeted compounds 1–7. Reagents and conditions: (a) 10a/MeOH, RNH2 (Methylamine, Propylamine, Isopropylamine or N-butyl amine)
(5 equiv), AcOH, reflux, 1 h; (b) NaBH4 (5 equiv), MeOH, room temperature, 5–8 h, 40–65%; (c) DCM, Boc2O (1.1 equiv), room temperature, overnight, 45–62%; (d) POCl3
(2 equiv), DMF, 35 °C, 2–3 h, 42–55%; (e) NaClO2 (5 equiv), 3-methyl-1-butene (1.8 equiv), 1 M NaH2PO3 (1.5 equiv), THF, 0 °C, 6 h, 36–48%; (f) DMF, Et3N (2 equiv), HBTU
(1.1 equiv), N2H4 (5 equiv), 2 h, 70 °C, 44–62%; (g) DCM, TFA, room temperature, 15–17 h, 50–71%.
CO2Me
CO2Me
CO2Me
CO2Me
CH3
CO2Me
a
b
c
d
e
f
N
H
N
H
N
H
H
N
Br
NO2
N
H
Br
N
R
OHC
R
37~40
30
33~36
32
31
H
H
N
N
NH
CO2Me
O
NH
CO2Me
O
CO2Me
O
O
CHO
COOH
g
h
i
j
N
H
Boc
N
N
H
Boc
N
N
H
N
H
Boc
N
Boc
N
N
H
H
N
R
R
R
R
R
8~11
49~52
41~44
45~48
53~56
Scheme 3. Synthesis route of targeted compounds 8–11. Reagents and conditions: (a) DMFDMA (3 equiv), DMF, 120 °C, 9–10 h; (b) MeOH, AcOH, Fe, reflux, 15 h, 63.0%;
(c) 4-formylphenylboronicacid (1.5 equiv), H2O, MeOH, toluene, LiCl (3 equiv), Na2CO3 (2.5 equiv), Pd(PPh3)4, reflux, 9–10 h, 66.6%; (d) RNH2 (Methylamine, Propylamine,
Isopropylamine or N-butyl amine) (10 equiv), MeOH, AcOH, reflux, 1–2 h, 50.6–82.8%; (e) MeOH, <10 °C, NaBH4 (3 equiv), room temperature, 2–3 h, 70.3–86.1%; (f) Boc2O
(1.1 equiv), CH2Cl2, 0 °C ? room temperature, 1–2 h, 45.4–89.2%; (g) POCl3, DMF, NaOH, H2O, <10 ? 35 °C, 2–3 h, 40.7–71.4%; (h) KMnO4 (3 equiv), acetone, <35 °C, 3–4 h,
17.1–27.4%; (i) Et3N (2 equiv), HBTU (1.1 equiv), NH2NH2, DMF, 70 °C, 0.5 h, 11.1–19.0%; (j) TFA, CH2Cl2, room temperature, 15–17 h, 57.9–81.2%.
Cyclization of 78–84 using HBTU afforded 85–91 which were
deprotected of Boc to give products 1–7.
AG014699. In addition, we found that compound 7 containing
N-butyl amine was more potent than compound 5 containing
methylamine and compound 6 containing propylamine, indicating
that the size of N-butyl amine group was more optimal for com-
pounds occupying the hydrophobic cavity of PARP-1 enzyme.
Compounds 8–11, containing the aromatic side chain at 6-posi-
tion of indole were designed and synthesized to probe the possibil-
ity of bisamides flip-binding (Fig. 3). The results have shown that
these compounds exhibited low to moderate activities toward
PARP-1, but were more potent than their counterparts (compounds
1–4). Among them, contained N-butyl amine compound 11 had the
most potency with an IC50 value of 35.4 nM. All results indicated
that the flipped structure could form more effective binding with
PARP-1 and N-butyl amine remained the more optimal basic group
in compounds.
Finally, all compounds were evaluated for their anticancer
activity using wild type breast cancer MCF-7 cells and human
breast cancer MDA-MB-436 cells carrying natural BRCA1 mutations
in comparison with AG014699. As summarized in Table 1, the
BRCA1-deficient MDA-MB-436 cells were hypersensitive to the
PARP-1 inhibition, therefore, higher potencies were observed for
most tested compounds in this cell line in comparison with those
in wild type cells. Similar to the tendency of PARP-1 inhibitory
activity in our compounds, almost compounds with big size basic
groups (Isopropylamine, N-butyl amine) had higher potencies in
both cells compared to those with small size basic groups (Methy-
lamine, Propylamine). Surprisingly, though compound 7 was the
The preparation of compounds 8–11 is shown in Scheme 3.
Obtained by Leimgruber–Batcho indole synthesis from 30, 31
was reacted with 4-formylphenylboronic acid by Suzuki reaction
to afford 32 which was condensed with secondary amines to give
33–36. 33–36 were reduced and the resulting 37–40 were then
protected with Boc to give 41–44. The formyl group was intro-
duced to the 3-position of 41–44 by Vilsmeier reaction to give
45–48 which were oxidized using KMnO4 to afford 49–52. Finally,
the products were obtained by cyclization reaction and removal of
Boc.
The PARP-1 enzyme inhibitory activities of all compounds are
shown in Table 1, compounds 1–4 containing different size basic
groups (Methylamine, Propylamine, Isopropylamine, N-butyl
amine) attached to the aromatic side chains at 2-position of indole
displayed weak activity against PARP-1 in comparison with refer-
ence compound AG014699. Among them, compound 4 was the
most potent with an IC50 value of 249.7 nM, indicating that N-butyl
amine is a more effective substituent group for PARP-1 enzyme
inhibitory activity. Further research, considering that fluorine
played a critical role in improving activity in several clinically pro-
ven PARP-1 inhibitors including AG014699, BMN-673 et al.,14 it
was introduced to 6-position of indole of compounds 1, 2 and 4.
The potency of compounds with fluorine substituent 5–7 were
increased markedly and compound 7 showed an IC50 value of
2.4 nM, which was only about three times less potent than
Please cite this article in press as: Xie, Z.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.060

4
Z. Xie et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 1
The IC50 value of compounds against PARP-1 enzyme and the CC50 value of potent compounds in MCF-7 cells and MDA-MB-436, BRCA-1 deficient cellsa
Compd
20-Substitution
60-Substitution
IC50 (nM)
2697
CC50 (MCF-7,
83.11
l
M)
CC50 (MDA-MB-436, BRCA-1, lM)
N
H
1
H
11.29
N
H
2
3
H
H
6.076E+013
11292
100.8
40.71
8.64E+07
55.67
N
H
N
H
4
5
6
7
8
9
H
F
F
F
249.7
17.96
65.29
25.87
2.84E+10
1244
18.94
56.2
N
H
6.643
N
H
3.501
5.454
114.5
ND
N
H
2.416
N
H
H
H
2.952E+008
137.6
N
H
5556
111.7
N
H
10
H
H
465.4
1921
105
N
H
11
35.44
236.7
19.47
68.81
3.0
AG014699
0.8044
ND, not determined.
a
Values are means from two to three independent dose–response curves.
Gly863
Tyr896
Acknowledgment
Gly863
Tyr896
H
N
H
N
This work was supported by the National Natural Science Foun-
dation of China (Nos. 81273375 and 21372260).
NH
O
6
NH
O
O
O
2
N
H
Supplementary data
N
H
a short chain
a short chain
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.08.
060. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Figure 3. Bisamides flip-binding of compounds 8–11 containing the aromatic side
chain at 6-position of indole.
References and notes
most potent toward PARP-1 enzyme, the activities of both the
BRCA1-deficient MDA-MB-436 cells and wild type MCF-7 cells
were weak with CC50 values of 2.84E+10 lM and 114.5 lM respec-
1. Sandhu, S. K.; Yap, T. A.; de Bono, J. S. Eur. J. Cancer 2010, 46, 9.
2. Curtin, N. Biochem. Soc. Trans. 2014, 42, 82.
3. Yunsong, T.; Jennifer, J. B.; Paul, A. E.; Eric, F. J.; Joel, L.; Xuesong, L.; Patrick, A.
M.; Amanda, M. O.; Donald, J. O.; Magdalena, P.; Luis, E. R.; Yan, S.; Nirupama,
S.; Jason, S.; Sheela, T.; Cherrie, K. D.; David, J. F.; Yan, L.; Vincent, L. G.; Thomas,
D. P. J. Med. Chem. 2009, 52, 6803.
4. Liu, J. F.; Konstantinopoulos, P. A.; Matulonis, U. A. Gynecol. Oncol. 2014, 133,
362.
5. Curtin, N. J.; Szabo, C. Mol. Aspects Med. 2013, 34, 1217.
6. Rachel, A. D.; Agata, L. R.; Huw, D. T.; Evan, A. M.; Yvette, D.; Deborah, J. C.;
Zdenek, H.; E. Ruth, P.; Alan, V. B.; Deborah, A. T.; Nicola, J. C.; Steven, C. C. Clin.
Cancer Res. 2009, 15, 1241.
7. Andrea, L. R.; Hyuk-Chan, K.; William, E. B.; Donna, C.; Katie, B.; Xu, W.; Jie, Z.;
Barbara, S. S.; Arnab, C.; Philip, J. T.; Kevin, C. Clin. Cancer Res. 2009, 15, 607.
8. Sven, R.; Janneke, E. J.; Ariena, K.; Eline van der, B.; Anders, O. H. N.; Serge, A. L.
Z.; Patrick, W. B. D.; Michiel de, B.; John, Z.; Alan, L.; Robert, B.; Aaron, C.; Mark,
J. O.; Niall, M. B. M.; Piet, B.; Jos, J. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17079.
9. Foulkes, W. D.; Shuen, A. Y. J. Pathol. 2013, 230, 347.
tively. This result might due to its non-optimal PK properties.
Thankfully, compound 6 showed almost similar activity to positive
control AG014699 in both the BRCA1-deficient MDA-MB-436 cells
and wild type MCF-7 cells, representing an effective agent to treat
BRCA1-deficient human breast cancer.
In summary, we reported the synthesis and biological evalua-
tion of novel 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4
(6H)-dione derivatives as potent PARP-1 inhibitors. Among all
compounds synthesized in this work, contained fluoro compounds
5–7 had strong potencies toward PARP-1 with IC50 values of
6.6 nM, 3.5 nM and 2.4 nM, respectively, which were only three
to six times less potent than AG014699. More importantly, com-
pound 6 exhibited excellent cell inhibitory activities in both wild
10. Rigakos, G.; Razis, E. Oncologist 2012, 17, 956.
11. Muggia, F.; Safra, T. Anticancer Res. 2014, 34, 551.
12. Tinker, A. V.; Gelmon, K. Curr. Pharm. Des. 2012, 18, 3770.
13. Hannah, F.; Nuala, M.; Christopher, J. L.; Andrew, N. J. T.; Damian, A. J.; Tobias,
B. R.; Manuela, S.; Krystyna, J. D.; Ian, H.; Charlotte, K.; Niall, M. B. M.; Stephen,
P. J.; Graeme, C. M. S.; Alan, A. Nature 2005, 434, 917.
type MCF-7 cells (CC50 = 25.8
lM) and BRCA1-deficient MDA-MB-
436 cells (CC50 = 5.4 M), which were almost similar with
l
AG014699. Further biological evaluation of this class of derivatives
is ongoing in our laboratory and will be reported in the near future.
Please cite this article in press as: Xie, Z.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.060

Z. Xie et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
14. Bryant, H. E.; Schultz, N.; Thomas, H. D.; Parker, K. M.; Flower, D.; Lopez, E.;
7. Andrea, L. R.; Hyuk-Chan, K.; William, E. B.; Donna, C.; Katie, B.; Xu, W.; Jie, Z.;
Barbara, S. S.; Arnab, C.; Philip, J. T.; Kevin, C. Clin. Cancer Res. 2009, 15, 607.
http://dx.doi.org/10.1158/1078-0432.CCR-08-2079.
Kyle, S.; Meuth, M.; Curtin, N. J.; Helleday, T. Nature 2005, 434, 913.
8. Sven, R.; Janneke, E. J.; Ariena, K.; Eline van der, B.; Anders, O. H. N.; Serge, A. L.
Z.; Patrick, W. B. D.; Michiel de, B.; John, Z.; Alan, L.; Robert, B.; Aaron, C.; Mark,
J. O.; Niall, M. B. M.; Piet, B.; Jos, J. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17079.
http://dx.doi.org/10.1073/pnas.0806092105.
9. Foulkes, W. D.; Shuen, A. Y. J. Pathol. 2013, 230, 347. http://dx.doi.org/
10.1002/path.4205.
10. Rigakos, G.; Razis, E. Oncologist 2012, 17, 956. http://dx.doi.org/10.1634/
theoncologist.2012-0028. Epub 2012 Jun 6.
11. Muggia, F.; Safra, T. Anticancer Res. 2014, 34, 551. http://ar.iiarjournals.
org/content/34/2/551.long.
12. Tinker, A. V.; Gelmon, K. Curr. Pharm. Des. 2012, 18, 3770. http://dx.doi.org/
10.2174/138161212802002823.
13. Hannah, F.; Nuala, M.; Christopher, J. L.; Andrew, N. J. T.; Damian, A. J.; Tobias,
B. R.; Manuela, S.; Krystyna, J. D.; Ian, H.; Charlotte, K.; Niall, M. B. M.; Stephen,
P. J.; Graeme, C. M. S.; Alan, A. Nature 2005, 434, 917. http://dx.doi.org/
10.1038/nature03445.
14. Bryant, H. E.; Schultz, N.; Thomas, H. D.; Parker, K. M.; Flower, D.; Lopez, E.;
Kyle, S.; Meuth, M.; Curtin, N. J.; Helleday, T. Nature 2005, 434, 913. http://dx.
doi.org/10.1038/nature03443.
Web references
1. Sandhu, S. K.; Yap, T. A.; de Bono, J. S. Eur. J. Cancer 2010, 46, 9. http://
www.sciencedirect.com/science/article/pii/S0959804909007795.
2. Curtin, N. Biochem. Soc. Trans. 2014, 42, 82. http://www.biochemsoctrans.org/
bst/042/bst0420082.htm.
3. Yunsong, T.; Jennifer, J. B.; Paul, A. E.; Eric, F. J.; Joel, L.; Xuesong, L.; Patrick, A.
M.; Amanda, M. O.; Donald, J. O.; Magdalena, P.; Luis, E. R.; Yan, S.; Nirupama,
S.; Jason, S.; Sheela, T.; Cherrie, K. D.; David, J. F.; Yan, L.; Vincent, L. G.; Thomas,
D. P. J. Med. Chem. 2009, 52, 6803. http://dx.doi.org/10.1021/jm900697r.
4. Liu, J. F.; Konstantinopoulos, P. A.; Matulonis, U. A. Gynecol. Oncol. 2014, 133,
362. http://www.sciencedirect.com/science/article/pii/S0090825814002030.
5. Curtin, N. J.; Szabo, C. Mol. Aspects Med. 2013, 34, 1217. http://
www.sciencedirect.com/science/article/pii/S0098299713000071.
6. Rachel, A. D.; Agata, L. R.; Huw, D. T.; Evan, A. M.; Yvette, D.; Deborah, J. C.;
Zdenek, H.; E. Ruth, P.; Alan, V. B.; Deborah, A. T.; Nicola, J. C.; Steven, C. C.
Clin. Cancer Res. 2009, 15, 1241. http://dx.doi.org/10.1158/1078-0432.CCR-08-
1095.
Please cite this article in press as: Xie, Z.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.08.060