Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2020.127036

Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamid

Full text of DOI:10.1016/j.bmcl.2020.127036

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Design, Synthesis and Anticancer Activities of Novel Dual Poly(ADP-ribose)
Polymerase-1/Histone Deacetylase-1 Inhibitors
Yongbin Tian, Zhouling Xie, Chenzhong Liao
PII:
S0960-894X(20)30108-6
DOI:
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https://doi.org/10.1016/j.bmcl.2020.127036
BMCL 127036
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Bioorganic & Medicinal Chemistry Letters
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13 February 2020
Please cite this article as: Tian, Y., Xie, Z., Liao, C., Design, Synthesis and Anticancer Activities of Novel Dual
Poly(ADP-ribose) Polymerase-1/Histone Deacetylase-1 Inhibitors, Bioorganic & Medicinal Chemistry Letters
(2020), doi: https://doi.org/10.1016/j.bmcl.2020.127036
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Design, Synthesis and Anticancer Activities of Novel
Dual Poly(ADP-ribose) Polymerase-1/Histone
Deacetylase-1 Inhibitors
Leave this area blank for abstract info.
Yongbin Tian1, Zhouling Xie1,*, Chenzhong Liao*
IC50 (nM)
Compd
PARP-1
HDAC-1
4
4.23
4.19
-
340
-
Olaparib
Chidamide
Compound 4
Dual PARP-1/HDAC-1 inhibitor
160

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Design, Synthesis and Anticancer Activities of Novel Dual Poly(ADP-ribose)
Polymerase-1/Histone Deacetylase-1 Inhibitors
Yongbin Tian1, Zhouling Xie1,*, Chenzhong Liao*
School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone
deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by
combining critical pharmacophores in approved drugs olaparib and chidamide, a series of novel
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid derivates were designed and
synthesized. All efforts led to a good dual PARP-1/HDAC-1 inhibitor, compound 4, with IC50
values of 4.2 and 340 nM against PARP-1 and HDAC-1, which were as potent as olaparib and
chidamide respectively. The MTT assay further demonstrated that compound 4 had potent
inhibitory activities against BRCA1/2-proficient K562 and MDA-MB-231 cells with GI50 values
of 5.6 and 4.3 μM, respectively. Therefore, our results suggested that compound 4 could be a
promising dual PARP-1/HDAC-1 inhibitor for further studies. In addition, a few excellent
PARP-1 inhibitors such as 7-9 and HDAC-1 inhibitors such as 12 were serendipitously
discovered, which also could be further studied in our next work.
Keywords:
Poly(ADP-ribose) polymerase-1
Histone deacetylase-1
Anticancer
Dual target inhibitor
Structure activity relationship
2019 Elsevier Ltd. All rights reserved.
Poly(ADP-ribose) polymerase-1 (PARP-1) is the most
abundant and most widely investigated among the 17 members of
PARPs family1. PARP is an enzymatic protein containing a DNA
binding domain, a catalytic domain and an auto-modification
domain2. Once damaged DNA is recognized by the DNA binding
domain of PARP, its catalytic domain then catalyzes the substrate
nicotinamide adenine dinucleotide to form nicotinamide and
ADP-ribose. ADP-ribose units are further transferred onto
acceptor proteins (histones and PARP itself), participating in
DNA damage repair through the base excision repair pathway3-5.
The overexpression of PARP-1 has been observed in multiple
cancer cells such as breast and ovarian cancer cells6. On the basis
of PAPR-1’s mechanism, PARP-1 inhibitors have been attractive
anticancer drugs in combination with chemotherapeutic drugs
such as temozolomide and cisplatin7, 8. In addition, PARP-1
inhibitors could be used as monotherapy for BRCA1/2- deficient
(has homologous recombination repair deficient) cancers by
synthetic lethality mechanism9. Up to now, four PARP-1
inhibitors, olaparib, rucaparib, niraparib and talazoparib have
been approved by the FDA (Figure 1). Olaparib, as the first-in-
class approved PARP-1 inhibitor, has been used for the treatment
of BRCA1/2-mutated ovarian cancer10. To further improve
therapeutic efficacy of olaparib, extend its treatments to
homologous recombination repair proficient cancers and even
overcome its drug resistance, researchers have focused on finding
suitable combination therapies with other anticancer drugs or
designing dual or multiple-target anticancer drugs by
simultaneously inhibiting PARP-1 and other critical regulated
proteins11.
Human histone deacetylases (HDACs), a class of Zn
metalloenzymes having 18 different isoforms, represent
important epigenetic modifications. They catalyze the
deacetylation from lysine residues in histones tails, resulting in
chromatin condensation and are overexpressed in various cancer
types12, 13. HDACs inhibition has been confirmed as an effective
method for cancer treatment by reducing tumor cell metastasis,
angiogenesis and proliferation, inducing tumor cell apoptosis and
inhibiting DNA repair14, 15. Five HDACs inhibitors have reached
the market to date. In addition, researchers found that inhibition
of HDACs with other kinases or proteins such as c-Met, JAK and
PI3K has synergistic antitumor effect. Several dual inhibitors
such as CUDC-907 have even been entered into clinical trials16.
Interestingly, synergistic effect of PARP-1 inhibition with
HDACs inhibition has been observed in many studies. For
example, Koeffler H. P. et al reported that HDACs inhibition
could sensitize triple-negative breast cancer to the PARP-1
inhibitor olaparib17. Goodman Jr O.B. et al reported that
combination of HDACs inhibition and PARP-1 inhibition could
decrease homologous recombination-related protein expression
and increase DNA damage in prostate cancer cell18. Hamerlik P.
et al reported that HDACs inhibitor SAHA in combination with
PARP-1 inhibitor olaparib could enhance inhibitory activity
against glioblastoma cancer cells by inducing apoptosis and
———
1
These authors contributed to this work equally.
*Corresponding authors.
E-mail addresses: zhoulingxie@hfut.edu.cn (Xie Z.), czliao@hfut.edu.cn (Liao C.).

the main part of olaparib, i.e., 2-fluoro-5-((4-oxo-3,4-
dihydrophthalazin-1-yl)methyl)benzoic acid to the ZBG moiety
of chidamide were also investigated by employing 5-
aminopentanoic acid, 6-aminohexanoic acid, tranexamic acid,
piperidine-4-carboxylic acid and 4-(aminomethyl)benzoic acid.
All efforts led to compounds 1-13 and their synthesis is depicted
in schemes 1 and 2.
As shown in scheme 1, the critical intermediates 3a and 3b
were firstly synthesized. Protection of 1a-1b with t-butyloxy
carbonyl (Boc) group afforded 2a and 2b, which were further
reduced to 3a and 3b by Pd/C. As outlined in scheme 2, 4a-4e
were esterified to intermediates 5a-5e which were further
condensed with 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-
yl)methyl)benzoic acid and hydrolyzed to give 7a-7e. Then, 7a-
7e, on the one hand, were reacted with ortho-phenylenediamine,
providing final compounds 1, 4, 7, 10, 12; On the other hand, 7a-
7e were condensed with 3a-3b to afford compounds 2, 3, 5, 6, 8,
9, 11, 13 following the removal of the N-Boc protecting group.
Figure 1. Chemical structures of approved PARP-1 inhibitors, HDACs
inhibitors and compound P1.
Scheme 1. Reagents and conditions: a) Boc2O, Et3N, DMAP, DCM, rt, 10 h;
b) Pd/C, H2, rt, 8 h.
impairing cell cycle progression19. All results suggested that
synchronous inhibition of PARP-1 and HDACs could be a
promising approach for cancer treatment. To avoid several side
effects induced by drug-drug interactions, developing PARP-
1/HDACs hybrid inhibitors has become a new trend in recent
years. Jiang Y. et al reported several olaparib hydroxamic acid
derivatives as dual PARP-1/HDAC inhibitors in 201720.
Compound P1, among them, displayed potent inhibitory activity
against PARP-1 (IC50 = 68.15 nM) and HDAC-1 (IC50 = 27.26
nM). However, its potencies against these two targets were lower
than olaparib and SAHA respectively. In addition, studies
showed that the hydroxamic acid fragment of SAHA, as a zinc
binding group (ZBG), results in several drawbacks including
short half-time, lacking selectivity over metalloproteases which
may lead to poor druggability21. Therefore, to overcome these
potential limitations, our group designed and synthesized a series
of novel olaparib derivatives to identify more effective and safer
novel dual PARP-1/HDACs inhibitors.
°
Scheme 2. Reagents and conditions: a) MeOH, SOCl2, 0 C to rt; b) EDCI,
HOBT, Et3N, DMF, rt, overnight; c) LiOH, THF/H2O, rt, overnight; d)
HBTU, Et3N, DMF, rt, overnight; e) HBTU, Et3N, DMF, rt, overnight; f)
TFA, DCM, rt, overnight.
All synthesized compounds were evaluated for PARP-1
inhibitory activity and HDAC-1 inhibitory activity and the results
are shown in Table 1. Olaparib and chidamide were used as the
positive drugs. As the linker is 5-aminopentanoic acid, compound
1 showed modest inhibitory activity against PARP-1 (39.3%
inhibition at 20 nM) and HDAC-1 (IC50 = 740 nM). Introducing
F atom to the phenyl ring of benzamide in compound 1 decreased
PARP-1 and HDAC-1 inhibitory activities (see compounds 2 and
3), demonstrating that F substitution is not favorable for the
improvement of potency. To extend the linker, 6-aminohexanoic
acid was introduced to replace 5-aminopentanoic acid, providing
compounds 4-6. Delightedly, compound 4 showed strong
inhibitory activity against PARP-1 (IC50 = 4.2 nM), which was
17-fold more potent than P1 and as potent as olaparib;
simultaneously, it also displayed potent inhibitory activity against
HDAC-1 (IC50 = 340 nM), only slightly less potent than
chidamide, which indicating that compound 4 was a promising
dual PARP-1/HDAC-1 inhibitor. Next, a F atom was added to the
4’ or 5’ position of the phenyl ring of benzamide in compound 4,
Figure 2. Design strategy of novel dual PARP-1/HDAC-1 inhibitors.
Chidamide, a drug approved in 2014 in China for the
treatment of relapsed or refractory peripheral T-cell lymphoma, is
a potent HDACs inhibitor with a benzamide group chelating the
Zn2+ at the bottom of the active sites of HDACs22. We then used
benzamide or fluorine substituted benzamide as ZBGs to replace
hydroxamic acid, affording a series of novel potential dual
PARP-1/HDAC-1 inhibitors (Figure 2). Linkers, which connect

which led to significantly decreased inhibitory activity over
PARP-1 and HDAC-1 (see compounds 5 and 6). This effort
further confirmed that F substitution is no benefit to PARP-1
820 nM) was decreased by 2-3 folds compared with 4. Similarly,
introducing F atom to the phenyl ring of benzamide still had
slightly or no effect on inhibitory activities (see compounds 8 and
9). As the linker is tranexamic acid (one more carbon than
piperidine-4-carboxylic acid), compound 10 showed potent
HDAC-1 inhibitory activity with an IC50 value of 340 nM, which
was as potent as compound 4 and only ~2 folds less potent than
chidamide. Unfortunately, its inhibitory activity against PARP-1
was sharply decreased (inhibition ratio = 41.3% at 20 nM). A F
atom substituted compound 11 displayed less potent toward
HDAC-1 than compound 10. Finally, as the linker is 4-
(aminomethyl)benzoic acid (contains aromatic ring), the
inhibitory activity of compound 12 against HDAC-1 was
improved with an IC50 value of 140 nM, which was as potent as
chidamide; while, its potency over PARP-1 (inhibition ratio =
37.3% at 20 nM) was much lower than compound 4. A F atom
substitution within compound 13 still led to decreased potency.
These results demonstrated that rigid linkers may be
disadvantage for the balance between PARP-1 inhibitory activity
and HDAC-1 inhibitory activity. In addition, F atom substitution
may affect the electrical and physical properties of compounds,
weakening the affinity to PARP-1 or HDAC-1. Overall, through
this work, we gotten a promising dual PARP-1/HDAC-1
inhibitor, compound 4; in addition, unexpectedly, we obtained
excellent PARP-1 inhibitors (compounds 7-9) and HDAC-1
inhibitor (compound 12) which could be for further studied.
Table 1. The HDAC-1 and PARP-1 inhibitory activities of our
final compounds.
IC50 (nM)a
(inhibition% at 20 nMb)
Compd
Linker (R1)
R2
R3
PARP-1
HDAC-1
H
F
H
H
F
H
H
F
H
H
F
H
F
H
F
-
(39.36)
740
1
(42.35)
(64.73)
4.23
910
1000
340
520
810
820
950
940
340
890
140
340
27.26 c
160
NA
2
H
H
F
3
4
(65.86)
(46.23)
1.94
5
H
H
F
6
Table 2. Antiproliferative activities of compounds 1 – 13 against
three different human cancer cell lines.
7
GI50 (μM)a
Compd
1.81
8
K562
62.4 ±3.37
NA
MCF-7
NAb
MDA-MB-231
61.58 ± 3.98
31.29 ± 2.34
25.40 ± 0.92
4.35 ± 0.58
13.91 ± 1.64
40.50 ±3.51
2.31 ± 1.39
1.03 ± 0.53
4.49 ± 2.43
50.45 ± 1.75
49.19 ± 1.69
59.27 ± 2.91
78.72 ± 3.20
2.88 ± 1.10
4.23 ± 0.96
H
H
H
H
H
-
2.58
9
1
NA
2
(41.31)
(49.66)
(37.38)
(22.06)
68.15c
NAd
10
11
1520 ±4.32
5.62 ±0.61
8.13 ±0.55
14.7 ±1.34
NA
NA
3
NA
4
NA
5
12
NA
6
13
NA
7
NA
NA
8
-
-
-
P1
NA
NA
9
10
Chidamide
Olaparib
-
-
2.92 ±0.32
6.61 ±0.73
0.408 ±0.11
2.21 ±0.23
0.45 ±0.13
NA
11.1 ±0.25
NA
-
-
4.19
11
aEach IC50 is the mean from three experiments. Standard error of the IC50 was
generally less than 10%.
1.91 ±0.22
11.5 ±1.03
1.43 ±0.16
13.2 ±1.05
12
bEach inhibition ratio is the mean from three experiments. Standard error of
the inhibition ratio was generally less than 10%.
cPrevious reported inhibitory activity against PARP-1 and HDAC-1.
dNA: not active.
13
Chidamide
Olaparib
aEach GI50 is the mean ± SEM from three experiments. Standard error of the
IC50 was generally less than 10%.
and HDAC-1 inhibitory activity. To limit spatial rotation of the
fat chains within compounds 1-6 and then identify more effective
dual PARP-1/HDAC-1 inhibitors, we used several linkers
containing cyclic structures such as 4-(aminomethyl)benzoic
acid, tranexamic acid and piperidine-4-carboxylic acid to replace
6-aminohexanoic acid to explore the impact of these rigid linkers
on potencies against PARP-1 and HDAC-1. As the linker is
piperidine-4-carboxylic acid (see compound 7), the inhibitory
activity against PARP-1 was significantly enhanced (IC50 = 1.9
nM), which was ~2 folds more potent than compound 4 and
bNA: not active.
Subsequently, all compounds were further evaluated for
antiproliferative activities in the MTT assay using three different
human tumor cell lines including K562 (human chronic myeloid
leukemia cell line), MCF-7 (breast cancer cell line) and MDA-
MB-231 (breast cancer cell line). None of these cell lines have
mutant BRCA1/2 gene. As shown in Table 2, almost all
compounds displayed no cytotoxic activity toward MCF-7 cell
and only compound 12, a potent HDAC-1 inhibitor, showed
olaparib; while, the inhibitory activity against HDAC-1 (IC50
=

potent antiproliferative activity with a GI50 value of 1.9 μM
which was as potent as chidamide. Compound 12 also
significantly inhibited the growth of K562 cell (GI50 = 0.4 μM),
as potent as chidamide; while showed weakly cytotoxic activity
against MDA-MB-231 cell. Similarly, compounds 10 and 13
having good HDAC-1 inhibitory activity, showed potent
inhibition against K562 and MCF-7 cells. Compound 4, the best
dual PARP-1/HDAC-1 inhibitor in this study, showed potent
inhibition against K562 and MDA-MB-231 cells with GI50 values
of 5.6 and 4.3 μM respectively. Compared with olaparib, the
cytotoxic activity of 4 toward K562 cell was markedly enhanced.
Compounds 7-9 as potent PARP-1 inhibitors, displayed weak or
no cytotoxic activity toward K562 and MCF-7 cells, which is an
unsurprising result due to that PARP-1 inhibition is insensitive to
BRCA1/2-proficient cells. Unexpectedly, against MDA-MB-231
cell, 7-8 displayed more potent cytotoxic activity than olaparib.
In this work, our identified dual PARP-1/HDAC-1 inhibitor 4,
really showed good antiproliferative activities for BRCA1/2-
proficient cell, K562 cell, extending antitumor spectrum of
classical PARP-1 inhibitor, olaparib.
distorted a little bit and the π-π stacking interaction between this
moiety and Tyr896 is undermined, which is not good for binding,
however, this fault is made up by the 2-aminobenzamide moiety
which can be accommodated well in a subpocket of the active
site of PARP-1 (Figure 3B).
Regarding HDACs, most HDAC inhibitors chelate the zinc
ion in the active site using their ZBGs. It is very interesting to
find that for some isoforms of HDACs, their inhibitors form
bidentate complex with the zinc ion; whereas, some HDAC
inhibitors form monodentate chelating complexes with the zinc
ion in other isoforms of HDACs, even though the zinc-binding
groups are same. For example, both of the two oxygen atoms of
the negatively charged hydroxamic acid of SAHA chelate the
Zn2+ in HDAC-2 (PDB ID: 4LXZ), establishing an exceptionally
stable 5-membered ring13, nevertheless, in a crystal structure of
the HDAC-1:MTA1 complex with a peptide inhibitor having a
hydroxamic acid function group (PDB ID: 5ICN), this
hydroxamic acid chelates the zinc ion using only one oxygen
atom. Crystal structure of an analog of chidamide binding to
HDAC-2 (PDB ID: 4LY1) demonstrates that the amino group of
2-aminobenzamide is deprotonated and negatively charged,
chelating the Zn2+ in a dentate fashion with a coordination
number of 5. Based on this information, we investigated how
compound 4 binds to HDAC-1. Modeling results indicated that
amino group of 2-aminobenzamide of compound 4 could chelate
the Zn2+ very well, whereas the oxygen atom in the amide group
does not have direct interaction with the Zn2+ (Figure 3C). It
forms a hydrogen bond with Try303 and leads to a monodentate
chelating complex. The fatty chain of compound 4 functions as a
linker and has hydrophobic interactions with surrounding
residues of HDAC-1 as well. The phthalazin-1(2H)-one moiety
could form three possible hydrogen bonds with Gly97 and
Cys100; it also may have extra hydrophobic interactions with
few residues around it, as demonstrated in Figure 3C and 3D.
To explore the binding modes of compound 4 to PARP-1
and HDAC-1, this compound was docked into the active sites of
PARP-1 (PDB ID: 5DS3)23 and HDAC-1 (PDB ID: 5ICN )24
respectively by employing the program of Glide 6.7 in the
Schrödinger Suite.
Modeling results on PARP-1 indicated that compound 4 has
very similar interactions as olaparib with the target of PARP-1
(Figure 3A and 3B): the binding poses are similar, and five
hydrogen bonds between and PARP-1 are maintained. These
hydrogen bonds include three formed by the phthalazin-1(2H)-
one moiety with Gly863 and Ser904 and two formed by the two
amide groups with Arg878 and Tyr896. One main binding
difference is that the fluorobenzyl moiety of compound 4 is
Figure 3. Putative binding modes of compound 4 (yellow ball and stick model) to PARP-1 (A and B) and HDAC-1 (C and D). Hydrogen bonds are shown as
magenta dotted lines. In A and C, bound olaparib to PARP-1 (PDB ID: 5DS3) and a peptide inhibitor to HDAC-1 are shown as dark green line modes; in B and
D, they are shown as dark green stick modes, respectively.

Overall, 13 novel compounds were designed and synthesized
to be dual PARP-1/HDAC-1 inhibitors based on olaparib and
chidamide. Among them, compound 4 was identified as a
promising dual PARP-1/HDAC-1 inhibitor and showed
comparable PARP-1 and HDAC-1 inhibitory activities as
olaparib and chidamide with IC50 values of 4.2 nM and 340 nM
respectively. Moreover, compound 4 extended the antitumor
spectrum of olaparib for BRCA-proficient cells such as K562
cell. Serendipitously, we also found several potent PARP-1
inhibitors and HDAC-1 inhibitors. For example, compounds 7-9
displayed excellent PARP-1 inhibitory activity and were more
potent than olaparib; compound 12 showed good HDAC-1
inhibitory activity and was almost as potent as chidamide. In our
next work, compounds having excellent potency will be further
evaluated for their selectivity over other PARP and HDAC
subtypes, and anticancer activities using more different type
tumor cell lines or animal tumor models. We surely believed that
more effective novel dual PARP-1/HDAC-1 inhibitors could be
discovered in the near future.
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The work was supported by National Natural Science
Foundation of China (81803352 and 21672050) and Fundamental
Research Funds for the Central Universities (JZ2018HGBZ0167
and JZ2018HGTA0225). The authors declare no other conflicts
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Highlights
Synergistic inhibition of PARP-1 and HDACs is a potential effective strategy for cancer treatment.
Compound 4 showed comparable potency against PARP-1 and HDAC-1 with olaparib and
chidamide respectively.
Compound 4 extended the antitumor spectrum of olaparib.
A few excellent PARP-1 inhibitors and HDAC-1 inhibitors were serendipitously discovered.