Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold

Article abstract of DOI:10.1016/j.bmcl.2013.12.048

Poly(ADP-ribose)polymerase-I (PARP-1) enzyme is involved in maintaining DNA integrity and programmed cell death. A virtual screening of commercial libraries led to the identification of five novel scaffolds with inhibitory profile in the low nanomolar range. A hit-to-lead optimization led to the identification of a group of new potent PARP-1 inhibitors, acyl- piperazinylamides of 3-(4-oxo-3,4-dihydro-quinazolin-2-yl)-propionic acid. Molecular modeling studies highlighted the preponderant role of the propanoyl side chain.

Full text of DOI:10.1016/j.bmcl.2013.12.048

Accepted Manuscript
Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold
Giuseppe Giannini, Gianfranco Battistuzzi, Loredana Vesci, Ferdinando M.
Milazzo, Francesca De Paolis, Marcella Barbarino, Mario Berardino Guglielmi,
Valeria Carollo, Grazia Gallo, Roberto Artali, Sabrina Dallavalle
PII:
S0960-894X(13)01420-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.12.048
BMCL 21156
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
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10 December 2013
11 December 2013
Please cite this article as: Giannini, G., Battistuzzi, G., Vesci, L., Milazzo, F.M., De Paolis, F., Barbarino, M.,
Guglielmi, M.B., Carollo, V., Gallo, G., Artali, R., Dallavalle, S., Novel PARP-1 inhibitors based on a 2-
propanoyl-3H-quinazolin-4-one scaffold, Bioorganic & Medicinal Chemistry Letters (2013), doi: http://dx.doi.org/
10.1016/j.bmcl.2013.12.048
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold
Giuseppe Giannini,a* Gianfranco Battistuzzi,a Loredana Vesci,a Ferdinando M. Milazzo,a Francesca De
Paolis,a Marcella Barbarino,a Mario Berardino Guglielmi,a Valeria Carollo,a Grazia Gallo,a Roberto Artali,b
Sabrina Dallavalle.c
a R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.,Via Pontina Km 30,400, I-00040, Pomezia (RM), Italy
b Scientia Advice di Roberto Artali, 20832, Desio (MB), Italy
c
Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di
Milano, Via Celoria 2, 20133 Milano, Italy.
Corresponding Author
Phone, +39-0691393640; fax: +39-0691393638; e-mail: giuseppe.giannini@sigma-tau.it
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Poly(ADP-ribose)polymerase-I (PARP-1) enzyme is involved in maintaining DNA
integrity and programmed cell death. A virtual screening of commercial libraries led to
the identification of five novel scaffolds with inhibitory profile in the low nanomolar
range. A Hit-to-lead optimization led to the identification of a group of new potent
PARP-1 inhibitors, acyl-piperazinylamides of 3-(4-oxo-3,4-dihydro-quinazolin-2-yl)-
propionic acid. Molecular modeling studies highlighted the preponderant role of the
propanoyl side chain.
Keywords:
PARP-1 inhibitors Anticancer
3-(4-Oxo-3,4-dihydro-quinazolin-2-yl)-
propionamides Molecular Modeling
Virtual screening of commercial libraries
Hit-to-lead optimization
2009 Elsevier Ltd. All rights reserved.
Poly (ADP-ribose) polymerases (PARPs) are a family of
proteins whose main roles involve maintaining DNA integrity
and programmed cell death. So far 18 members have been
recognized, but PARP-1 and PARP-2 are the two most studied
isoforms. PARP-mediated DNA repair utilizes base excision
repair pathway.1 Blocking PARP’s activity prevents DNA
damage repair, which finally leads to cell death through induction
of DNA double-strand breaks (DSBs). Lately, however, new
mechanisms of action of PARP inhibitors have been discovered,
demonstrating that when bound to some inhibitors, PARP
proteins, , instead of being released from DNA once the repair
process has started, remain trapped on DNA preventing its
replication and consequent cell division.2
PARP-mediated repair process involves the binding of
damaged DNA to N-terminal zinc finger motif of PARP, which
in turn causes activation of the catalytic C-terminal domain
allowing the enzyme to hydrolyze NAD+, ultimately resulting in
the production of linear and branched poly-ADP-ribose chains.
Enhanced PARP-1 expression and/or activity, has been also
observed in different human tumor cell lines such as

hepatocellular carcinoma, colorectal carcinoma, cervical
carcinoma, malignant lymphomas, and leukaemia. Moreover, it
has been reported that PARP catalytic activity is also stimulated
in response to DNA damage.3
now beginning pivotal trials of PARP inhibitors in breast and
ovarian cancer.9
X-Ray crystal structures10,11 and molecular modeling
studies12-15 indicate that the amide of nicotinamide makes three
key hydrogen bonds with the hydroxyl group of S904 and the
amide backbone of G863, and that there is a stacking interaction
with a conserved Y907. Conformationally constrained cyclic
inhibitors demonstrate an anti-disposition of the amide bond.
Attempts to improve PARP inhibitors’ affinity to the binding site
have been made locking the carboxamide group which is usually
free to rotate. This locking can be made either inserting on the
aromatic ring heteroatoms or groups able to give an
intramolecular hydrogen bond with the amide NH, or enclosing
the amide group into a two (or more)-ring heterocycle.10
Based on these findings, we created a pharmacophore query
in which the presence of three structural features were imposed:
1) an aromatic ring, 2) a carboxamide moiety with at least one
NH group locked into the desired anti-conformation, 3) a side
chain extending into the deep pocket located in the auto-
modification domain of PARP-1.
It is well-known that many anti-cancer therapies, such as
those involving temozolomide (TMZ), platinum-based drugs,
topoisomerase inhibitors and radiotherapy, implicate DNA
damage. These therapies are however shadowed by the
emergence of resistance, notably due to DNA repair through
PARP pathway, undermining therefore their efficacy. Such
observation led to the development of combination therapies
wherein resistance to the mechanism of action of the DNA
damaging drugs was hampered by PARP inhibition. It has even
been shown that PARP inhibition could potentiate the effect of
DNA damaging agents,4,5 as well as radiotherapy. Cancer cells
presenting at least one of BRCA1 and BRCA2 mutated genes,
two well-known tumor-suppressor genes, are very sensitive to
PARP-1 inhibition, resulting in cell cycle arrest and apoptosis.
This suggests an efficacious role for PARP inhibitors, as single
agents, against tumors exhibiting BRCA1 and/or BRCA2
mutations.6-8
O
locked carboxamide group
NH
Few PARP-1 inhibitors have been discovered and assessed
in advanced clinical trials, either as stand-alone monotherapies or
aromatic ring
R
long side chain
in combination therapies. All these compounds have
a
nicotinamide-based structure aimed at competing with NAD+ for
the binding to PARP-1 catalytic site [e.g., olaparib (AZD2281),
veliparib (ABT-888), niraparib (MK-4827), BMN-673, and
rucaparib (AG-014699/ PF-01367338)] (Figure 1).
Figure 2. Pharmacophore query
Virtual screening of commercial libraries led to the
identification of few scaffolds containing appropriate chains
and/or groups that satisfied the pharmacophore query, i.e.
4-(methylene)-4H-isoquinoline-1,3-dione
(group
A),
3H-quinazoline-4-one, (B) 1H-quinazoline-2,4-dione (C),
2H-phthalazine-1-one (D) and 2-oxomethylenebenzamide (E)
derivatives (Figure 3).
Niraparib (MK4827)
Tesaro (licensed from Merck)
BMN-673
BioMarin Pharmaceuticals
Veliparib (ABT-888)
AbbVie
Group A
Group B
Group D
Group C
Group E
O
O
O
O
O
NH
NH
NH2
R
NH
NH
N
Rucaparib (AG-014699/PF-01367338)
Clovis Oncology (licensed from Pfizer)
Olaparib (KU-59436/AZD-2281)
AstraZeneca (after KuDOS Pharm. acquisition)
O
O
N
R
3
O
N
R
R
R
1
2
4
5
Figure1: Structure of some PARP inhibitors
Figure 3. Scaffolds selected from virtual screening of commercial libraries.
Although a series of setbacks almost caused the demise of
PARP inhibitors, as predicted by many observers in 2011; more
recent analyses show an invigorated interest in this target, with a
possible regulatory approval within 3 years. A few companies are
Three derivatives from group A, seven from each of groups B
and C, nine from group D, and six from group E were evaluated
for their inhibitory activity against recombinant human PARP-1,

expressed as GST fusion protein, by means of a highly sensitive
fluorescent enzymatic assay (see Supporting Information).
Moreover, based on the hypothesis that PARP-1 inhibitors
could represent a monotherapy option against tumors with
mutated BRCA1/2 genes, as suggested by several experiments
performed in vitro and in vivo on human tumor cell lines or
xenograft models,15-17 the most active compounds of each group
(Figure 4) were subjected to further investigation, i.e.
cytotoxicity against the triple-negative and BRCA-1 deficient
breast tumor cell line MDA-MB436.
All tested compounds appeared to be potent PARP-1
inhibitors showing a two-digit nM activity (Figure 4). Such an in-
vitro profil was however not corroborated by an adequate
antiproliferative activity on the above mentioned breast cancer
cell line (i.e., IC50> 10 μM).
Figure 5. Representation of 2a binding mode with the key residues
The presence of one or more carbonyl groups in the side chain
also appeared to largely contribute to the binding through
hydrogen bonds. Considering again 2a, the carbonyl group of the
propanoyl chain forms a very strong hydrogen bond with the
S203 hydroxyl group (1.70 Å). The pattern of interaction with
PARP-1 is further completed by a hydrogen bond between the
second carbonyl group and the hydroxyl group of Y228 with a
distance of 1.80Å. In this orientation, the furan moiety is placed
in front of the aromatic ring of Y228, thus enabling a strong pi-pi
stacking interaction (Figure 5).
O
O
O
O
O
NH
NH
N
NH
NH2
NH
N
N
O
O
O
O
O
O
HN
N
N
NH
N
HN
O
N
N
O
O
N
O
COCH3
3a
5a
42.9 nM
4a
1a
2a
28.5 nM
87.4 nM
49.8 nM
87.6 nM
Figure 4. Structure and PARP-1 inhibitory activity (IC50) of the selected
compounds.
Recent reports appeared once this work was already completed,
indicate similar interactions of this carbonyl group with N387
(through a water molecule) of isoform PARP-323 and with Y1213
of Tankyrase-1.24
A hit-to-lead optimization was undertaken on most active
compound of the series, 2a.
Although a number of quinazolinone derivatives with
PARP inhibiting properties have already been reported,18-22 none
of them contain a propanoyl chain attached to the position 2 of
the quinazolinone nucleus. We hypothesized that the CO group
on this chain could have been an important point of interaction
with a suitable hydrogen bond donating group in the binding site.
The importance of the carbonyl group for the activity of the
herein described compounds was confirmed by studying
analogues lacking the carbonyl moiety. Indeed, the replacement
of the carbonyl group with a methylene group preclude any
interaction, leading to a 10- to 100-fold increase in the calculated
free energy. The observed effect is mainly due to the inability of
the methylene group to get close to region delimited by S203 and
N207. The different orientation within the binding site leads to
the lack of the interactions with S203 and Y228, resulting in a
dramatic fall of the affinity for the PARP-1 receptor. (Fig. S1 in
SI)
This hypothesis was confirmed by docking experiments with
PARP-110 protein and optimization through QM/MM mixed
approach. All of the tested compounds behave as PARP-1
inhibitors, being anchored to the nicotinamide binding site in a
very similar way. The compounds sat inside the cavity with the
main heterocyclic ring inserted between Y246 and H201, thus
forming a strong pi-pi interaction with Y246. The ring
carboxamide group gives rise to hydrogen bond interaction with
the S243 OH group, and two with the G202 backbone. This
situation is depicted for hit compound 2a in Figure 5.
Therefore the hit-to-lead program was performed keeping
intact the nucleus, the propanoyl-piperazino chain (2a), and
modifying the acyl moiety (2-furanoyl in the case of 2a),
introducing cycloalkyl or aromatic groups (2b-c, 2h) or
heterocycles (tetrahydrofuran, thiophene, pyrrole, benzofuran,
piperidine) (2d-g, 2l-k) (Scheme 1).

The key intermediate in the synthesis of the series of
compounds 2 was quinazolin-4(3H)-one-2-propanoic acid 8, in
turn prepared from anthranilamide and succinic anhydride in
refluxing toluene,25 followed by ring closure with NaOH.
The acylpiperazines reagents were obtained by coupling
commercial N-Boc-protected piperazine with the appropriate acid
by means of standard peptide chemistry (PyBOP, DIPEA, DMF,
rt),26 followed by deprotection with TFA/CH2Cl2 to give the
corresponding trifluoroacetates 11. These were coupled with acid
8 by peptide coupling chemistry too. Compound 2k was obtained
from 2i by treatment with Pd(PPh3)4 and morpholine as a side
product of 2j.
the ability of the tested compounds to affect PARylation of
nuclear proteins following a strong DNA damage induced by
treatment with H2O2.27
As shown in Table 2, all compounds showed relevant inhibitory
activity also on this cellular model, with EC50 values ranging
from 256 nM (2e) to 865 nM (2f), thus confirming their ability to
target and inhibit PARP activity.
Table 1. PARP-1 inhibiting activity of compounds 2
Cpd.
PARP-1; IC50 (nM)±SDa
2a
28.5±0.8
2b
67.1±4.6
2c
110.0±70.0
130.0±20.0
9.8±2.5
2d
2e
2f
29.5±3.7
b
2l
2g
2h
130.0±20.0
56.1±4.7
a
2i
300.0±80.0
31.9±8.4
6
7
8
e
2j
-
-
c
d
2
2b-k
2k
220.0±40.0
10±0.2
9
10
11
Olaparib
Veliparib
MK-4827
2f
2i
2j
R =
2b
2c
10±0.2
30±5
2g
2d
2e
a Values are the mean (± S.D.) of three experiments.
f
2h
2k
Table 2. Results of a PARylation assay on HeLa (human endometrial ca.)
cells.a
Scheme 1. Reagents and conditions: (a) i. Toluene, reflux; ii. NaOH 2N,
reflux (83%); (b) (4-aminophenyl)-4-morpholinylmethanone, TEA, HATU,
pyridine, 140 °C, MW (2l: 60%); (c) RCOOH, PyBOP, DIPEA, DMF, rt (47-
80%); (d) DCM/TFA=7/3, rt, quantitative; (e) PyBOP, DIPEA, DMF, rt (2b:
50%; 2c: 73%; 2d: 48%; 2e: 38%; 2f: 51%; 2g: 62%; 2h: 52%; 2i: 32%); (f)
Pd(PPh3)4, morpholine, DCM, rt (2j: 36%, 2k: 17%).
Compound
PARylation; EC50 (nM)
2b
2e
2f
707
256
865
467
Among these new derivatives, 2e was shown to inhibit PARP-1
catalytic activity with a potency 3- fold higher than that of
parental 2a (Table 1), whereas other compounds showed a
comparable (2f and 2j) or a slightly weaker (2b and 2h)
inhibitory activity with respect to 2a. This is consistent with the
presence of a ring able to interact through pi-pi stacking with
Y228, as shown by the modeling.
2h
a Values are the mean of two experiments (standard deviations were within
25% of the mean values).
Although temozolomide (TMZ), topoisomerase I poisons and
ionizing radiation (IR), as mentioned above, potentiate anticancer
activity when combined with PARP inhibitors in a wide range of
tumor models, the discovery that these inhibitors alone
selectively kill cancer cells with homologous recombination-
deficiency (HRD), represents a very significant advance. This
observation has rapidly translated into clinical trials on patients
with breast, ovarian and prostate cancer BRCA1/2 mutated.
A moderate reduction of inhibitory activity was instead observed
for derivatives 2c, 2d and 2g, whereas more pronounced was the
decrease in activity for 2k (IC50=220 nM) and 2i (IC50=300 nM).
Some of the most active compounds (2b, 2e, 2f, and 2h) were
then assessed through a functional parylation assay on a cellular
model (human endometrial carcinoma cell line HeLa), to assess

For this reason, compounds 2b, 2e, 2f, and 2h were also
investigated both alone and in combination with TMZ on triple-
negative, BRCA1-mutated, and MDA-MB436 breast carcinoma
cells. The combination index indicated a synergic effect (Table
3).
200mg/10mL/kg, according to the schedule qdx5/wx3w, was
shown to significantly inhibit (by 47%) tumor growth (P<0.01 vs.
vehicle treated group, Mann-Whitney).
In conclusion,
a
ligand-based approach aimed at
discovering novel PARP-1 inhibitors was undertaken, taking into
account pharmacophoric features of known inhibitors.
Table 3. Combination Index (CI) values of interactions between selected test
compounds and temozolomide (TMZ), on MDA-MB436, breast-triple-
negative, and BRCA1-mutated cells after 7 days of treatment.
Five thousand compounds, selected from commercial libraries,
were virtually screened against PARP-1, leading to the
identification of five new scaffolds presenting PARP-1IC50
values in the low nanomolar range (IC50 values 28.5-87.6 nM).
A 4(3H)-quinazolinone hit (2a) was selected and synthetic
efforts were made to improve the inhibitory profile. A series of
differently acylated derivatives was prepared, most of them being
active on PARP-1 in a two-digit nanomolar range. The activity of
the most potent derivatives was further confirmed in a functional
cell PARylation assays. They also showed a synergic effect when
combined with temozolomide in vivo. Moreover, compound 2e
revealed to be efficacious in inhibiting the tumor volume of a
BRCA1-deleted and BRCA2 mutated breast carcinoma. Because
PARP-1 is highly expressed in a variety of cancers, including
breast, hepatocellular carcinoma and non-small cell lung
cancer,28-30 and its expression is often correlated with poor
prognosis and drug-resistance, the identification of novel PARP
inhibitors is strongly recommended.
Cells
Compound IC50, µM
Combination
index values (CI)
ED50
ED75
0.80
0.22
0.43
0.60
ED90
MDA-
2b
2e
51.1
17.3
18.1
19.5
120
0.70
0.05
0.12
0.40
0.90
0.85
0.80
0.90
MB436
2f
2h
TMZ
The dose-response curve of each drug was determined and combination index
(CI) values for varying drug/TMZ concentration ratios were calculated
according to Chou-Talalay method using CalcuSyn software (Biosoft). CIs <
1 indicate synergism.
Compounds 2e and 2h were successively selected for pre-
ADME evaluation. In a bidirectional Caco-2 cells assay, 2e and
2h showed an efflux ratio of 5.8 and 6.0, respectively,
corresponding to a moderate permeability. Interestingly enough,
the two compounds were found not to be P-gp substrate.
Evaluation of blood/plasma distribution resulted in a ratio of
about 0.4 for both compounds after 60 minutes, whereas human
plasma stability studies (2 hour incubation) gave a recovery of
50% for 2e and 57% for 2h. Finally, evaluation of metabolic
stability on human hepatocytes gave a t1/2 of 584 min (2e) and
618 min (2h).
Taken together, these results demonstrate that the
2-propanoyl-quinazolinone nucleus is a suitable scaffold for the
development of new PARP inhibitors.
Compound 2e was selected for in vivo investigation in
athymic SCID beige mice xenografted with MX1 breast
carcinoma cells, the latter being characterized by BRCA1
deletion and BRCA2 gene mutation. As reported in Table 4, the
drug delivered intraperitoneally at the maximum tolerated dose of
Table 4. Antitumor activity of 2e against MX1 human breast carcinoma xenograft
Cpd.
Dose/route
mg/kg
0
Schedule
BWL%
Lethality
TV+
TVI%
(d +38)
/
(d +38)
781+30
Vehicle
Qdx5/wx3w
Qdx5/wx3w
0
0/8
0/8
200/ip
10
412±56
*47
2e

16. McCabe, N.; Lord, C.J.; Tutt, A.N.J.; Nial, M.B.M.; Smith,
G.C.M.; Ashworth, A. Cancer Biol. Ther. 2005, 4, 934.
17. Drew, Y.; Mulligan, E.A.; Vong, W.-T.; Thomas, H.D.; Kahn, S.;
Kyle, S.; Mukhopadhyay, A.; Los, G.; Hostomsky, Z.; Plummer,
E.R.; Edmondson, R.J.; Curtin, N.J.. J. Natl. Cancer Inst. 2011,
103, 334.
Treatments started 7 days after tumor injection.
*P<0.01 vs vehicle-treated group (Mann-Whitney’s test).
Acknowledgment.
18. Griffin, R.J.; Srinivasan, S..; Bowman,K.; Hilary Calvert, A.;
Curtin,N.J.; Newell,D.R.; Pemberton, L.C.; Golding, B.T. J.
Med. Chem. 1998, 41, 5247.
The authors would like to thank Prof. Lucio Merlini and Dr.
Gilles Pain for helpful suggestions and for assistance with the
manuscript.
19. Hattori, K.; Kido, Y.; Yamamoto, H.; Ishida, J.; Kamijo, K.;
Murano, K.; Ohkubo, M.; Kinoshita, T.; Iwashita, A.; Mihara, K.;
Yamazaki, S.; Matsuoka, N.; Teramura, Y.; Miyake, H. J. Med.
Chem. 2004, 47, 4151.
20. Iwashita, A.; Hattori, K.; Yamamoto, H-; Ishida, J.; Kido, Y.;
Kamijo, K.; Murano, K.; Miyake, H.; Kinoshita, T.; Warizaya, M.;
Ohkubo, M.; Matsuoka, N.; Mutoh, S.; FEBS Letters 2005, 579,
1389.
References
1. Rouleau M.; Patel, A.; Hendzel, M.J.; Kaufmann, S.H.; Poirier,
G,G. Nat. Rev. Cancer 2010, 10, 293.
21. Ishida, J.; Yamamoto, H.; Kido, Y.; Kamijo, K.; Murano, K.;
Miyake, H.; Ohkubo, M.; Kinoshita, T.; Warizaya, M.; Iwashita,
A.; Mihara, K.; Matsuoka, N.; Hattori, K. Bioorg. Med. Chem.
2006, 14, 1378.
2. Murai J.; Huang, S.N.; Das, B.B.; Renaud, A.; Zhang, Y.;
Doroshow, J.H.; Ji, J.; Takeda, S.; Pommier, Y. Cancer Res.,
2012, 72, 5588.
22. Le, T.V.T.;, Suh J.H.; Kim, N.; Park, H.-J. Bioorg. Med. Chem.
Lett. 2013, 23, 2642.
3. Amé J.C.; Rolli, V.; Schreiber, V.; Niedergang, C.; Apiou, F.;
Decker, P.; Muller, S.; Höger, T.; Ménissier-de Murcia, J.; de
Murcia, G. J. Biol. Chem., 1999, 274, 17860.
23. Lindgren, A.E.G.; Karlberg, T.; Thorsell,, A.-G.; Hesse, M.; Spjut,
S.; Ekblad, T.; Andersson, C.D.; Pinto, A.F.; Weigelt, J.; Hottiger,
M.O.; Linusson, A.; Elofsson, M.; Schuler, H. ACS Chem. Biol.
2013, 8, 1698.
4. Liu X.: Shi, Y.; Guan, R.; Donawho, C.; Luo, Y.; Palma, J.; Zhu,
G.-d.; Johnson, E.F.; Rodriguez, L.E.; Ghoreishi-Haack, N.;
Jarvis, K.; Hradil, V.P.; Colon-Lopez, M.; Cox, B.F.; Klinghofer,
V.; Penning, T.; Rosenberg, S.H.; Frost, D.; Giranda, V.L.; Luo,
Y. Mol. Cancer Res., 2008, 6, 1621.
24. Bregman, H.; Gunaydin, H.; Gu, Y.; Schneider, S.; Wilson, C.; Di
Mauro, E.F.; Huang, X. J. Med. Chem. 2013, 56, 1341.
25. Bavetsias, V. Synth. Comm. 1998, 28, 4547.
5. Węsierska-Gądek, J.; Zulehner, N.; Ferk, F.; Składanowski, A.;
Komina, O.; Maurer, M. Biochem. Pharmacol., 2012, 84, 1318
6. 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.
26. Kim, H.J., Kwak, W.Y., Min, J.P., Sung, S.Y., Kim, H.D., Kim,
M.K., Kim, H.S., Park, K.J., Son, M.H., Kim, S.H., Lee, B.J.
Bioorg. Med. Chem. Lett. 2012, 22, 5545.
27. Jones, P.; Altamura, S.; Boueres, J.; Ferrigno, F.; Fonsi, M.;
Giomini, C.; Lamartina, S.; Monteagudo, E.; Ontoria, J.M.; Orsale
M.V.; Palumbi, M.C.; Pesci, S.; Roscilli, G.; Scarpelli, R.;
Schultz-Fademrecht, C.; Toniatti, C.; Rowley, M. J. Med. Chem.
2009, 52, 7170.
7. 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 2005, 434, 917.
28. Shimizu, S.; Nomura, F.; Tomonaga, T.; Sunaga, M.; Noda, M.;
Ebara, M.; Saisho, H. Oncol Rep 2004, 12: 821-825
8. Ratnam K.; Low, J. Clin. Cancer Res. 2007, 13, 1383.
9. Garber, K. Nature Reviews. Drug Discovery 2013, 12, 725.
10. Ferraris, D.V. J. Med. Chem. 2010, 53, 4561.
29. Rojo, F.; Garcia-Parra, J.; Zazo, S.; Tusquets, I.; Ferrer-Lozano,
J.; Menendez, S.; Eroles, P.; Chamizo, C.; Servitja, S.; Ramirez-
Merino, N.; Lobo, F.; Bellosillo, B.; Corominas, J.M.; Yelamos,
J.; Serrano, S.; Lluch, A.; Roviea, A.; Albanell, J. Ann. Oncol.
2012, 23: 1156-1164
11. Papeo, G.; Casale, E.; Montagnoli, A.; Cirla, A. Exp. Opin. Ther.
Pat. 2013, 23, 503-514.
12. Costantino, G.; Macchiarulo, A.; Camaioni, E.; Pellicciari, R. J.
Med. Chem. 2001, 44, 3786.
30. Michels, J.; Vitale, I.; Galluzzi, L.; Adam, J.; Olaussen, K.A.;
Kepp, O.; Senovilla, L.; Talhoui, I.; Guegan, J.; Enot, D.P.;
Talbot, M.; Robin, A.; Girard, P.; Orear, C.; Lissa, D.;
Sukkurwala, A.Q.; Garcia, P.; Behnam-Motlagh, P.; Kohno, K.;
Wu, G.S.; Brenner, C.; Dessen, P.; Saparbaev, M.; Soria, J.C.;
Castedo, M.; Kroemer, G. Cancer Res. 2013, 73, 2271-80
13. Bellocchi, D.; Macchiarulo, A.; Costantino, G.; Pellicciari, R.
Bioorg. Med. Chem. 2005, 13 1151.
14. Zeng, H.; Zhang, H.; Jang, F.; Zhao, L.; Zhang, J. Chem. Biol.
Drug Des. 2011, 78, 333.
15. Fatima, S.; Bathini, R.; Sivan, S.K.; Manga, V. J. Receptors
Signal Transd. 2012, 32, 214.

Graphical Abstract
Novel PARP-1 inhibitors based on a
Leave this area blank for abstract info.
2-propanoyl-3H-quinazolin-4-one scaffold
Giuseppe Giannini, Gianfranco Battistuzzi, Loredana Vesci, Ferdinando M. Milazzo, Francesca De Paolis, Marcella Barbarino, Mario
Berardino Guglielmi, Valeria Carollo, Grazia Gallo, Roberto Artali, Sabrina Dallavalle.