Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

Article abstract of DOI:10.1016/j.bmcl.2009.12.026

Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit

Full text of DOI:10.1016/j.bmcl.2009.12.026

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1094–1099
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as
inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)
*
Giovanna Pescatore , Danila Branca, Fabrizio Fiore, Olaf Kinzel, Laura Llauger Bufi, Ester Muraglia,
Federica Orvieto, Michael Rowley, Carlo Toniatti, Caterina Torrisi, Philip Jones
IRBM/Merck Research Laboratories, Via Pontina km 30,600, 00040 Pomezia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors.
Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the prolifer-
ation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over
BRCA proficient cancer cells.
Received 27 October 2009
Revised 2 December 2009
Accepted 4 December 2009
Available online 6 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolo[1,2-a]pyrazin-1(2H)-one
Poly(ADP-ribose) polymerase
PARP-1
Oncology
Selectivity
BRCA1
Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme in-
volved in the detection and repair of DNA damage. It utilizes
NAD+ to synthesize poly(ADP-ribose) chains either on itself or on
a variety of nuclear target proteins: histones, topoisomerases,
DNA polymerases, and DNA ligases, in a process called poly-
(ADP)ribosylation. The addition of these poly(ADP-ribose) units re-
sults in a highly negatively charged chromatin, thereby opening up
the chromatin and facilitating recruitment of the base excision re-
pair machinery to the site of the DNA damage, resulting in repair.1
PARP-1 is the principal member of the PARP enzyme family con-
sisting of some 17 proteins,2 consequently, inhibition of PARP-1
may retard intracellular DNA repair. PARP inhibitors (PARPi) have
been demonstrated to function as chemosensitizers, and to en-
hance and prolong the antitumor effects of certain anticancer ther-
apies.3 Excessive DNA damage results in PARP-1 overactivation,
consumption of the NAD+ pool that ultimately leads to excessive
ATP depletion and necrotic cell death. As a result PARPi have also
been demonstrated to work in preclinical models of reperfusion in-
jury (stroke, myocardial infarction), but also in arthritis and other
forms of inflammation as well as diabetes.4 Thus PARP-1 inhibitors
may prove useful for the treatment of these diseases. Moreover, re-
cent studies have shown that cells deficient in BRCA1 and BRCA2,
proteins involved in DNA double strand break repair by homolo-
gous recombination (HR) repair, are highly sensitive to PARP-1
inhibitors.5 These results indicate that PARPi could have clinical
benefits in cancer patients as monotherapy in individuals with
cancers bearing specific defects in HR repair, in addition to chemo-
sensitizers in combination with DNA damaging agents as well as in
several other therapeutic areas.
The past few decades have witnessed much research in the field
of PARPi and most of the compounds in development mimic the
nicotinamide moiety of NAD+. To date several compounds have en-
tered clinical trials, including: ABT-888,6 AZD-2281,7 AG014699,8
and MK-48279 (Fig. 1), in addition to several other derivatives
whose structures have not been revealed.
A research program was started in our company with the aim of
developing PARPi suitable for clinical development in BRCA mutant
cancer patients. Although extensive data exists on the design of po-
tent PARP enzyme inhibitors, there is minimal SAR published
describing the optimization of cell based activity for the inhibition
of BRCA deficient cells, whilst maintaining good selectivity over
BRCA wild type cells. This manuscript describes the optimization
of a novel series of PARP inhibitors, focusing on the optimization
of their cellular activity and selectivity.
On the basis of the proposed binding of NAD+ to PARP-1, to-
gether with X-ray crystal structures of PARP-1 with bound inhibi-
tors,10 we designed
a novel pyrrolo[1,2-a]pyrazin-1(2H)-one
scaffold. We envisaged that this heterocycle could bind in the nic-
otinamide pocket, the five-membered ring sandwiched between
Tyr-896 and Tyr-907 amino acids and the lactam of the pyrazinone
making three H-bonds to the enzyme. The pendant fluorobenzyl
* Corresponding author. Fax: +39 06 91093654.
E-mail address: giovanna.pescatore@gmail.com (G. Pescatore).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.026

G. Pescatore et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1094–1099
1095
Table 1
O
SAR on the pyrrolo[1,2-a]pyrazin-1(2H)-one portion
NH
N
O
NH2
O
O
F
N
N
R =
NH
N
N
H
N
H
F
N
Compd
No.
R
PARP1
IC50 (nM)
BRCA 1-
CC50 (nM)
BRCA wt
CC50 (nM)
a,b
c,b
d,b
O
ABT-888
AZD-2281
O
H
N
NH
1
2
3
1.8
>20
l
M
>20
>20
>20
l
l
l
M
M
M
O
NH2
O
N
NH
N
NHMe
R
N
N
O
R
N
H
F
NH
1.6
1.0
3400
2500
AG014699
MK-4827
Figure 1. PARP inhibitors currently being evaluated in the clinic.
O
NH
NH
group could then reach down into the adenine binding
pocket allowing any substituent to make further binding interac-
tions there to improve affinity. Gratifyingly as reported in
Figure 2, 1 demonstrated that the pyrrolo[1,2-a]pyrazin-1(2H)-
one scaffold is an excellent enzyme inhibitor with IC50 = 1.8 nM
against PARP-1. Unfortunately this compound failed to demon-
strate any anti-proliferative effects in BRCA1 deficient cells at
Cl
Cl
N
R
O
4
2.6
170
220
>20
lM
N
20
l
M.11
Knowing that excellent PARP inhibition is required to inhibit
Cl
Cl
R
O
proliferation of cells defective in BRCA9 we sought to improve
the activity of this series intrinsically and also to increase the lipo-
philicity given the hydrophilic nature of 1 (log D = À0.89) in the
hope to improve cell permeability. We recognized that substitution
on the pyrrole ring should be possible, and also allow us to im-
prove the contact surface area with the enzyme. Also given the
hydrophobic nature of this part of the enzyme it should be possible
to incorporate hydrophobic substituents.
NH
Cl
Cl
5
6
1.6
4.0
>20
>20
l
M
M
N
R
O
R
NH
A small improvement in cellular potency was observed when
increasing the lipophilic character of the pyrrole moiety by intro-
ducing a methyl (2) or a chloro group (3) in the 7 position
(Table 1). The effect due to the chlorine substitution was more
evident compared to the methyl, as 3 exhibited improved anti-pro-
18,000
l
N
Cl
a,c–d
b
The assays were performed as described in Ref. 9.
Values are means of at least four experiments (standard deviations were within
25% of the mean value).
liferative effects in BRCA1 deficient cells compared to
2
Nicotinamide
Binding Pocket
Ser-904
Gly-863
Ser-904
Gly-863
N
Tyr-907
N
H
Tyr-907
H
O
H
O
H
O
O
O
O
HO
HO
H
OH
HO
H
OH
N
N
H
N
N+
O
O
F
N
NH2
O
Tyr-896
NH
1.8
Tyr-896
H
N
1
N
N
HO
O
O
P
O
78
g-8
Ar
N
O
-O
-O
O
O
P
PARP-1 IC 50 (nM)
BRCA 1- CC50 (nM)
OH
Adenine
O
H
> 20,000
OH
O
Binding Pocket
O
766
Asp-
Figure 2. Binding mode of NAD+ in PARP active site,10 and proposed binding mode of the pyrrolo[1,2-a]pyrazin-1(2H)-one scaffold. PARP and BRCA1- assays conducted as
described in Refs. 9 and 11.

1096
G. Pescatore et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1094–1099
(CC50 = 2.5
l
M vs 3.4
l
M) reflective the larger pi value of the chlo-
nitrogen with the piperidine 12 and the morpholine 13 was detri-
mental as both compounds lost more than 20-fold enzymatic
activity.
Further elaboration of the piperazine series was then undertaken
with a view to pick up additional binding interactions in the adenine
pocket and thereby improve activity further (Table 3). Addition of
rine group (pi = 0.71 vs 0.56). The incorporation of a second chlo-
rine at either the 6 (4) or 8 (5) position confirmed the observed
trend and significantly improved cellular activity with both com-
pounds displaying CC50 <250 nM in BRCA1 deficient cells. This
finding tracks the lipophilicity as confirmed by increased log D val-
ues (log D = 0.58 and 0.91 for 3 and 4, respectively). Remarkably,
the 6,7-dichloropyrrolo analogue (4) was 15-fold more potent than
3 on BRCA1 deficient cells (CC50 = 170 nM) and displayed optimal
selectivity with no anti-proliferative activity in BRCA wild type
Table 3
SAR study on the piperazine portion: alkyl- and acyl-substituted analogues
O
HeLa cells at 20
(6) though maintaining PARP-1 inhibitory activity, significantly
lost cellular activity (CC50 = 18 M).
lM. Surprisingly, the 6,8-dichloropyrrolo analogue
NH
Cl
N
l
O
Cl
On the basis of the encouraging cellular data for 4, the 6,7-
dichloropyrrolo[1,2-a]pyrazin-1(2H)-one was selected for further
investigation. Optimization focused on the homopiperazine substi-
tuent, and in a logical extension substituted homopiperazine and a
number of corresponding piperazine analogs were explored
(Table 2). The unsubstituted homopiperazine and piperazine (4
and 9) showed similar PARP-1 inhibitory activity in the nanomolar
range and similar potency in the cell based assays. Alkylation in the
homopiperazine series (7) was tolerated but a significant loss in
N
N
F
R
a,b
Compd
No.
R
PARP1 IC50
(nM)
BRCA 1-
CC50 (nM)
BRCA wt
CC50 (nM)
c,b
d,b
14
14
13
250
>10,000
>10,000
15
1600
cellular activity was observed (CC50 = 1.1 lM), while in the pipera-
zine series it resulted in a marked loss of enzymatic activity (10:
16
14
970
>5000
IC50 = 41 nM).
N
17
18
18
13
>10,000
>5000
>10,000
>10,000
Acylation to produce the 4-acetyl-homopiperazine 8 resulted in
sevenfold decrease in PARP-1 inhibitory activity compared to the
unsubstituted analogue 4 and the acetamide showed only marginal
activity in cells, losing 30-fold. Instead the 4-acetyl-piperazine 11
still displayed good PARP-1 inhibitory activity and submicromolar
cellular activity (IC50 = 6.3 nM, CC50 = 700 nM). Removal of the
OH
19
20
3.2
2.1
1200
150
>5000
>5000
O
O
O
Table 2
First SAR on the pendant anilide
21
22
1.0
3.7
340
270
>5000
>5000
O
NH
Cl
N
O
O
Cl
R
F
23
24
2.4
3.1
150
500
>5000
>5000
N
N
Compd
No.
R
PARP1
IC50 (nM)
BRCA1-
CC50 (nM)
BRCA wt
CC50 (nM)
O
O
a,b
c,b
d,b
HN
N
N
N
N
4
7
2.6
5.0
170
>20
>20
lM
lM
lM
lM
NH
N
25
26
27
7.2
9.0
2.4
670
>10,000
>5000
1100
O
S
O
3000
910
8
9
19
2.3
41
5700
180
ND
>20
>20
ND
N
O
O
O
N
N
N
N
>10,000
S
NH
O
O
10
28
2.0
1800
>10,000
N
N
N
N
O
O
11
6.3
700
>10
lM
29
30
2.5
5.1
3500
200
>10,000
>5000
O
N
N
N
12
13
200
59
ND
ND
ND
ND
O
31
N
H
2.1
53
>5000
O
O
a–d
a–d
See footnotes of Table 1. ND = not determined.
See footnotes of Table 1.

G. Pescatore et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1094–1099
1097
larger lipophilic chains to the piperazine such as 14–16 resulted in a
more than fivefold loss of enzymatic activity and an even larger loss
of cellular activity.
ortho-fluorophenyl 32 showed weaker enzyme potency and lost
significant cellular activity. Installation of a polar heterocycle such
as 2-pyridyl recovered this activity and 33 displayed high enzy-
matic inhibitory activity and moderate potency in cells
(IC50 = 2.8 nM and CC50 = 430 nM) while the isomeric 3-pyridyl
(34) lost fourfold in enzymatic activity and was inactive in cell
In contrast, amides 19–31 all showed single digit nanomolar
inhibition of PARP-1. Although aliphatic amides 20–22 show
anti-proliferative effects in BRCA deficient cells in the 150–
350 nM range, no further improvement could be achieved. The iso-
propyl derivative 20 is the most encouraging with CC50 = 150 nM
and more than 30-fold selectivity over BRCA wild type cells. The
addition of a weakly basic center, either a basic heterocycle, like
pyridine 23 and imidazole 24, as well as aliphatic amine, like 29–
31, was promising. In particular the 2-pyridyl derivative (23) dis-
played good anti-proliferative activity in BRCA1 deficient cells with
CC50 = 150 nM, and showing 30-fold selectivity. The amino acid
derivative 31 displayed double-digit nanomolar anti-proliferative
against BRCA1 deficient cells (CC50 = 53 nM) with more than 100-
based assay at 5 lM.
The corresponding 2-pyrimidine 35 showed a further improve-
ment in the anti-proliferative effect on BRCA1 deficient cells; how-
ever activity was also observed against the BRCA wild type cell line
(CC50 = 2800 nM), and 35 displayed only 22-fold selectivity. A
fourfold increase in enzymatic activity and sevenfold increase in
cellular potency was gained when a CN group was introduced
in 3 position of the pyridyl analogue (36, IC50 = 0.7 nM and
CC50 = 62 nM), but again this derivative displayed only 25-fold
selectivity between BRCA1 deficient and proficient cells.
fold selectivity over BRCA proficient (CC50 >5
l
M) and this partic-
Substitution in the 5 position of the pyridine was less tolerated
and significantly decreased the enzymatic potency (37 vs 36,
IC50 = 14 nM vs 0.7 nM) although some cellular activity was main-
tained (CC50 = 200 nM). Other modifications such as the introduc-
ular analogue was one of the most interesting derivatives.
Fujisawa (Astellas) have previously described N-aryl pipera-
zines to be fragments that significantly improve the potency of
PARPi,12 therefore an investigation around this fragment was per-
formed (Table 4). Substituted phenyl derivatives exemplified by
Table 5
SAR study on the benzamide portion: piperidinyl-substituted analogues and spiro-
substituted analogues
Table 4
SAR study on the piperazine portion: aryl- and heteroaryl-substituted analogues
O
O
NH
Cl
N
NH
Cl
O
N
Cl
O
R
Cl
N
F
N
F
R
Compd No.
R
PARP1
IC50 (nM)
BRCA 1-
BRCA wt
a,b
CC50c,b(nM)
CC50d,b(nM)
Compd
No.
R
PARP1
IC50 (nM)
BRCA 1-
BRCA wt
CC50 (nM)
a,b
c,b
d,b
CC50 (nM)
N
N
42
43
7.1
2.3
3800
400
>10,000
>5000
F
NH2
32
24
>10,000
>10,000
N
H
N
33
34
35
2.8
12
430
>10,000
>5000
2800
N
N
44
45
46
2.6
22
1600
1100
120
>10,000
>5000
>5000
N
N
N
>5000
130
N
3.1
N
CN
N
36
37
38
0.7
14
15
62
1600
4200
>5000
5.4
N
N
N
N
N
N
200
2700
47
48
49
50
51
1.0
6.2
2.5
8.2
9.0
180
>10,000
>5000
CN
OMe
220
HN
N
N
N
N
N
N
48
>10,000
>5000
39
40
1.8
1.0
320
190
1200
770
HN
HN
HN
N
2300
>2500
O
41
1.4
60
920
>5000
NH
N
N
a–d
a–d
See footnotes of Table 1.
See footnotes of Table 1.

1098
G. Pescatore et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1094–1099
Table 6
Dialkylation to give 44 resulted in no improvement in enzymatic
activity but was detrimental for cellular activity (CC50 = 1.6 M)
Profile of compounds 31, 46 and 49
l
and homologation to diethylamino 45 resulted in a 10-fold loss
in enzymatic activity (IC50 = 28 nM). Noticing this steric constraint
the dimethylamino was constrained in an azetidine (47) or pyrrol-
idine (46), and encouragingly both derivatives displayed CC50
<200 nM in BRCA deficient cells with more than 50-fold selectivity
over BRCA wild type cells. The cyclization strategy could also be
applied to the 4-position of the piperidine to give spirocycles 48–
51. The spiro-pyrrolidine 49 proved to have the best cellular activ-
ity with CC50 = 48 nM being fivefold more active than piperidine 48
and 40-fold more active than the spiro azetidine 50. Incorporation
of further functionality into the spiro ring as in the case of 51 was
Compounds
31
46
49
PARP-1 IC50 (nM)
BRCA1-CC50 (nM)
BRCAwt CC50 (nM)
Rat liver microsomes
2.1
53
>5000
5.4
120
>5000
2.5
48
>10,000
CLint
(l
l/min/mg)
122
>200
11,000
135
94
8000
65
130
12,000
Rat Clearance (mL/min/kg)
hERG IC50 (nM)
CYP inhibition
(% at 10
l
M)
3A4: 25
3A4: 30
2D6: 35
not tolerated loosing all cellular activity at 2.5 lM.
tion of a methoxy group were detrimental, as 39 displayed signif-
icantly lower activity both in enzyme and cellular assays
(IC50 = 15 nM and CC50 = 2700 nM). Similarly, benzo fusion of 34
and 35 was also detrimental, and although isoquinoline 39 and iso-
meric quinazolines 40 and 41 proved to be very potent PARP-1
inhibitors, these compounds showed an undesirable profile in cells
with minimal selectivity between BRCA deficient and wild type
cells. In contrast to 34 and 35 which displayed 20-fold selectivity
the benzofused analogs demonstrated only around fourfold selec-
tivity suggesting underlying off-target activity.
Knowing the amino group on the piperazine was important for
activity, exploration was also undertaken in a related series, the 4-
amino piperidines, to explore the effect of a nitrogen in an exocy-
clic position, and a series of analogs were investigated including al-
kyl substitution on the external nitrogen (43–45), or incorporation
of the nitrogen into a cycle (46–47) or a spiro-structure (48–51)
(Table 5). Simple 4-amino piperidine (42) was tolerated displaying
PARP-1 IC50 = 7.1 nM and micromolar activity in BRCA deficient
The discovery of the 6,7-dichloropyrrolo[1,2-a]pyrazin-1(2H)-
one class of PARPi enabled several sub-classes of compounds to
be developed that showed good levels of PARP inhibition, and
which are able to inhibit the proliferation of BRCA1-silenced HeLa
cells with CC50 <200 nM, for example, 31, 46, and 49. These com-
pounds demonstrate excellent selectivity over BRCA proficient
cells, typically at least 50-fold. However, the pharmacokinetic
properties of these compounds were suboptimal and despite mod-
est stability in rat microsomes, 31, 46, and 49 were characterized
with high plasma clearance in rats (Table 6). They also demon-
strated micromolar binding to the hERG ion channel and weak
CYP inhibition.
The general synthesis of the key intermediate dichloropyrrol-
o[1,2-a]pyrazin-1(2H)-one acid scaffold is outlined in Scheme 1
and was constructed according to a novel DBU-catalyzed intramo-
lecular hydroamination reaction which was recently developed in
our laboratories.13,14 Further synthetic manipulations then enabled
construction of the desired final compounds as illustrated.
In summary we have reported the identification of a series of
pyrrolo[1,2-a]pyrazin-1(2H)-ones PARP inhibitors; the physical
cells (CC50 = 3.8 lM). Enzymatic activity could be improved three-
fold by alkylation, as 43 displayed IC50 = 2.3 nM and showed
around 10-fold improvement in cellular activity (CC50 = 400 nM).
O
F
O
F
O
F
N
N
N
N
n
R2
N
R1
NMe
n
O
O
11, 20-22, 25-27: n = 1
8: n = 2
10: n = 1
7: n = 2
19, 23-24, 28-31
g
h
i
DMB
HN
O
O
O
O
CN
F
DMB
R
R
R
NH
R
NH
N
NH
R
N
O
N
NH
N
c
e
b
O
F
O
CN
F
N
H
OH
N
a
OH
NH
n
F
F
CN
1- 6: n = 2
9: n = 1
e
d
d
O
O
O
O
N
N
N
N
N
F
X
NR1R2
F
R
NH
F
F
48-51
42-43
44, 46 (d)
(
e)
12: X = CH2
13: X = O
14-18, 32-41
45, 47 (f)
Scheme 1. Reagents and conditions: (a) TBTU, TEA, DMF; (b) (i) 30 mol % DBU, DCM, reflux; (ii) iPr3SiH, TFA, 110 °C; (c) 10% aq NaOH, reflux; (d) amine, TBTU, DIPEA, DMF; (e)
(i) Boc-amine, TBTU, DIPEA, DMF; (ii) TFA/DCM; (f) (i) piperidin-4-one, TBTU, DIPEA, DMF; (ii) NHR1R2, Ti(O-iPr)4 NaBH3CN, DCE, MeOH; (g) R2COCl, TEA, DCM; (h) H2CO,
NaBH3CN, NaOAc, MeOH; (i) R1CO2H, HBTU, DIPEA, DCM.

G. Pescatore et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1094–1099
1099
Swift, S.; Giavara, S.; O’Connor, M. J.; Tutt, A. N.; Zdzienicka, M. Z.; Smith, G. C.
M.; Ashworth, A. Cancer Res. 2006, 66, 8109.
6. Penning, T. D.; Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Liu, X.; Shi, Y.; Klinghofer, V.;
Johnson, E. F.; Donawho, C. K.; Frost, D. J.; Bontcheva-Diaz, V.; Bouska, J. J.;
Osterling, D. J.; Olson, A. M.; Marsh, K. C.; Luo, Y.; Giranda, V. L. J. Med. Chem.
2009, 52, 514.
7. Fong, P. C.; Boss, D. S.; Yap, T. A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.;
Mortimer, P.; Swaisland, H.; Lau, A.; O’Connor, M. J.; Ashworth, A.; Carmichael,
J.; Kaye, S. B.; Schellens, J. H. M.; De Bono, J. S. N. Eng. J. Med. 2009, 361, 123.
8. Thomas, H. D.; Calabrese, C. R.; Batey, M. A.; Canan, S.; Hostomsky, Z.; Kyle, S.;
Maegley, K. A.; Newell, D. R.; Skalitzky, D.; Wang, L. Z.; Webber, S. E.; Curtin, N.
J. Mol. Cancer Ther. 2007, 6, 945.
chemical properties were modified to improve the cellular activity
of these compounds resulting in compounds that inhibit the prolif-
eration of BRCA deficient cells in the low double-digit nanomolar
range and show excellent selectivity over BRCA proficient cancer
cells. The efforts to improve the pharmacokinetics of these com-
pounds will be the subject of a future paper.
Acknowledgments
The authors thank Mauro Cerretani, Claudia Giomini, Monica
Bisbocci, Maria Orsale, Massimiliano Fonsi, Fabrizio Fiore, Anna Al-
fieri, and Simona Cianetti for their support of this work.
9. Jones, P.; Altamura, S.; Boueres, J. K.; Ferrigno, F.; Fonsi, M.; Gavory, G.; Giomini,
C.; Lamartina, S.; Monteagudo, E.; Ontoria, J. M.; Orsale, M. V.; Roscilli, G.;
Rowley, M.; Scarpelli, R.; Schultz-Fademrecht, C.; Toniatti, C. J. Med. Chem.
2009, 52, 7170.
10. (a) Ruf, A.; Rolli, V.; de Murcia, G.; Schulz, G. E. J. Mol. Biol. 1998, 278, 57;
(b) Canan-Koch, S. S.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K. A.; Almassy,
R. J.; Li, J.; Yu, X.-H.; Zook, S. E.; Kumpf, R. A.; Zhang, C.; Boritzki, T. J.;
Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese, C. R.; Curtin, N. J.; Kyle,
S.; Thomas, H. D.; Wang, L.-Z.; Calvert, A. H.; Golding, B. T.; Griffin, R. J.;
Newell, D. R.; Webber, S. E.; Hostomsky, Z. J. Med. Chem. 2002, 45, 4961;
(c) Costatino, G.; Macchiarulo, A.; Camaioni, E.; Pellicciari, R. J. Med. Chem.
2001, 44, 3786.
11. The ability of compounds to inhibit the growth of cervical cancer HeLa cells
where BRCA-1 had been silenced with a lentivirus expressing a short hairpin
interfering RNA (shRNA) targeting BRCA-1 was tested in 7-day proliferation
assays. In parallel, the cytotoxicity against a matched pair cell line expressing
an empty lentivector was also measured.
12. Hattori, K.; Kido, Y.; Yamamoto, H.; Ishida, J.; Iwashita, A.; Mihara, K. Bioorg.
Med. Chem. Lett. 2007, 17, 5577.
13. Llauger Bufi, L.; Bergami, C.; Kinzel, O. D.; Lillini, S.; Pescatore, G.; Torrisi, C.;
Jones, P. Tetrahedron Lett. 2009, 50, 172.
14. Jones, P.; Kinzel, O. D.; Llauger Bufi, L.; Muraglia, E.; Pescatore, G.; Torrisi, C.
WO 2007/138355, 2007.
References and notes
1. (a) Jagtap, P.; Szabó, C. Nat. Rev. Drug Disc. 2005, 4, 421; (b) Schreiber, V.;
Dantzer, F.; Amé, J.-C.; de Murcia, G. Nat. Rev. Mol. Cell Biol. 2006, 7, 517.
2. (a) Hassa, P. O.; Hottiger, M. O. Front. Biosci. 2008, 13, 3046; (b) Amé, J. C.;
Spenlehauer, C.; de Murcia, G. BioEssays 2004, 26, 882.
3. (a) Horwáth, E. M.; Szabó, C. Drug News Perspect. 2007, 20, 171; (b) Tentori, L.;
Graziani, G. Pharmacol. Res. 2005, 52, 25; (c) Rodon, J.; Iniesta, M. D.;
Papadopoulos, K. Expert Opin. Investig. Drugs 2009, 18, 31; (d) Ratnam, K.;
Low, J. A. Clin. Cancer Res. 2007, 13, 1383.
4. (a) Moroni, F. Curr. Opin. Pharmacol. 2008, 8, 96; (b) Pacher, P.; Szabó, C.
Cardiovasc. Drug Rev. 2007, 25, 235.
5. (a) 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 (London, U.K.) 2005, 434,
913; (b) Farmer, H.; McCabe, N.; Lord, C. J.; Tutt, A. N. J.; Johnson, D. A.;
Richardson, T. B.; Santarosa, M.; Dillon, K. J.; Hickson, I.; Knights, C.; Martin, N.
M. B.; Jackson, S. P.; Smith, G. C. M.; Ashworth, A. Nature (London, U.K.) 2005,
434, 917; (c) McCabe, N.; Turner, N. C.; Lord, C. J.; Kluzek, K.; Bialkowska, A.;