Bioorganic & Medicinal Chemistry Letters
Design, synthesis and biological evaluation of novel molecules as potent
PARP-1 inhibitors
a,
†
b,
†
a
a
a,
b,
*
a,b,*
Hui Shen , Yiran Ge , Junwei Wang , Hui Li , Yungen Xu
, Qihua Zhu
a
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target
compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition
activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive
results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against
HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited
good metabolic stability in vitro with t1/2 of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular
properties and protein docking were applied to structure design. Our study provides potential lead compounds
and design directions for the development of PARP-1 inhibitors.
Antitumor drug
DNA repair
PARP-1 inhibitors
Drug design
Poly (ADP-ribose) polymerase (PARP) is a ubiquitous DNA repair
enzyme in eukaryotic cells with a critical role in base-excision repair
Besides, various PARP inhibitors are under different clinical trial stages
as a single agent or combinatorial therapy with other antitumor agents.
With the success of PARP inhibitors as antitumor agents in clinical
practice, it is still a very active area of investigation.
(
BER) of single-strand breaks (SSB), which was first reported by
1
Chambon and his team in 1963. In 1980, Durkacz reported that
dimethyl sulfate’s cytotoxic activity could be potentiated by inhibiting
PARP, prompting the possibility to use PARP inhibitors and cytotoxic
drugs as a combination therapy for cancer treatment.2 The enzymes of
PARP family play essential roles in multiple cellular processes beyond
DNA repair, including cellular differentiation, gene transcription,
inflammation, mitosis, cell death, and metabolism.3 To date, 18 mem-
bers of PARP family have been identified and characterized. Among
them, PARP-1 shares the largest proportion of the family and is
responsible for about 90% of the function.4 Several studies confirmed
the involvement of PARP-1 in many pathological conditions, including
apoplexy, neurodegenerative disease, myocardial ischemia, inflamma-
tion, diabetes, cancer, and other diseases.5 It has validated that PARP
inhibition could achieve resultant killing cancer cells with BRCA1/2
mutation through synthetic lethality. Thus, PARP-1 is considered a
significant antitumor target and attracted much attention from aca-
demics and pharmaceutical companies.
To discover novel PARP inhibitors, our group has disclosed two novel
series of compounds with scaffolds of imidazole[4,5-c]pyridine car-
boxamide and 8,9-dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6(7H)-
one as PARP-1 inhibitors in our previous works and culminated in
obtaining two lead compounds XZ-1203121
2,13
and XZ-160811
14
(Fig. 1). However, they are still inferior to Olaparib and unsatisfied PK
properties also hinder further study. Hence, there is a continued need for
developing more potent PARP-1 inhibitors with improved druggable
properties. Herein, we described the discovery of novel potent com-
pounds as PARP-1 inhibitors and culminated in obtaining compound II-
4 which exhibited high potency against PARP-1 enzyme and cancer cell
lines in vitro.
Firstly, compounds of I series were prepared according to the pro-
cedures as shown in Scheme 1–4. Compounds I-1 ~ I-3 were synthesized
from key intermediates 1a ~ 1c and 2-fluoro-5-((4-oxo-3,4-dihydroph-
thalazin-1-yl)methyl)benzoic acid (2) by condensation reaction using
PyBOP as coupling agent (Scheme 1). In Scheme 2, the key intermediate
6, which was synthesized from starting material 2 via esterification,
chlorination, alkoxy substituted and hydrolysis reaction, condensed
To date, five PARP inhibitors, including Olaparib, Rucaparib,7
6
Niraparib,8,9 Talazoparib and Fluzoparib, have been approved to
10
11
treat ovarian or breast cancer harboring BRCA1 or BRCA2 mutations.
*
†
Both authors contributed equally to this work.
Received 8 April 2021; Received in revised form 19 May 2021; Accepted 29 May 2021
Available online 6 June 2021
0
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