Design, synthesis and anticancer activities evaluation of novel 5H-dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-oxadiazole units

Article abstract of DOI:10.1016/j.bmcl.2018.02.008

Rucaparib and PJ34 were used as the structural model for the design of novel 5H-dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-oxadiazole units. And target compounds were successfully synthesized through a 3-step synthetic strategy. All target compounds were screened for their anti-proliferative effects against OVCAR-3 cell line. Preliminary biological study of these compounds provided potent compounds d21 and d22 with better activities than Rucaparib.

Full text of DOI:10.1016/j.bmcl.2018.02.008

Accepted Manuscript
Design, Synthesis and Anticancer Activities Evaluation of Novel 5H-diben-
zo[b,e]azepine-6,11-dione Derivatives Containing 1,3,4-oxadiazole Units
Xin He, Xin-yang Li, Jing-wei Liang, Chong Cao, Shuai Li, Ting-jian Zhang,
Fan-hao Meng
PII:
S0960-894X(18)30097-0
https://doi.org/10.1016/j.bmcl.2018.02.008
BMCL 25604
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 December 2017
4 February 2018
7 February 2018
Please cite this article as: He, X., Li, X-y., Liang, J-w., Cao, C., Li, S., Zhang, T-j., Meng, F-h., Design, Synthesis
and Anticancer Activities Evaluation of Novel 5H-dibenzo[b,e]azepine-6,11-dione Derivatives Containing 1,3,4-
oxadiazole Units, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.
2018.02.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
Design, Synthesis and Anticancer Activities Evaluation
of Novel 5H-dibenzo[b,e]azepine-6,11-dione Derivatives
Containing 1,3,4-oxadiazole Units
Xin He, Xin-yang Li, Jing-wei Liang, Chong Cao, Shuai Li, Ting-jian Zhang, Fan-hao Meng*
1

Bioorganic & Medicinal Chemistry Letters
Design, Synthesis and Anticancer Activities Evaluation of Novel 5H-
dibenzo[b,e]azepine-6,11-dione Derivatives Containing 1,3,4-oxadiazole Units
Xin He , Xin-yang Li , Jing-wei Liang , Chong Cao , Shuai Li , Ting-jian Zhang , Fan-hao Meng
Department of Medicinal Chemistry, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenbei District, Shenyang, 110122, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Rucaparib and PJ34 were used as the structural model for the design of novel 5H-
dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-oxadiazole units. And target
compounds were successfully synthesized through a 3-step synthetic strategy. All target
compounds were screened for their anti-proliferative effects against OVCAR-3 cell line.
Preliminary biological study of these compounds provided potent compounds d21 and d22 with
better activities than Rucaparib.
Keywords:
5H-dibenzo[b,e]azepine-6,11-dione
PARP-1 inhibitors
anticancer
2009 Elsevier Ltd. All rights reserved.
Cancer is one of the most serious threats against human health
in the world, and the clinical prognosis remains relatively poor.1
Surpassing heart diseases, it is taking the position of number one
killer due to various worldwide factors.2 Nowadays there is no
absolute effective treatment for cancer patients in clinical
practice, but chemotherapy is still the most widely used form of
treatment for cancer. However, the majority of cancers are either
resistant to chemotherapy or acquire resistance during treatment.3
As a result, designing and discovering new, safe and efficient
chemical classes of agents aiming at the treatment of cancer are
the prime targets for contemporary medicinal chemistry
researchers.
indispensible role player in tumor cell development and PARP-1
targeted therapy can positively predict the outcome in cancer
therapy.
Poly(ADP-ribose) polymerase-1 (PARP-1) is the most
abundant and best-characterized member of the PARP family of
nuclear enzymes, with an important role in the cellular life
cycle.4 It is involved in various cellular processes including DNA
repair, telomere regulation, transcription, genomic stability and
regulation of cell death. It is widely accepted that the catalytic
activity of PARP-1 is stimulated by DNA damage caused by
peroxidation, irradiation and DNA-damaging chemicals, for
example, chemotherapeutic agent.5 PARP-1 plays a critical role
in the repair of single-strand breaks (SSB) by base excision repair
(BER) and has also been implicated in other roles in DNA
repair.6
Figure. 1 Structural connection between pharmacophore of
PARP1 inhibitors and NAD+
In view of the key role of the PARP-1 in maintaining the
genomic integrity, particularly in the repair of single-strand DNA
30 lesions which caused by ionizing radiation, chemotherapy, or
products of cellular and oxidative metabolism, PARP-1 is an
———
Inhibitors of ADP-ribosyltransferases (ARTs) of the poly
(ADP-ribose) polymerase (PARP) family are promising
 Corresponding author. Tel.: +86 13386887693; e-mail: fhmeng@cmu.edu.cn
2

candidates for treatment of cancer.7 Various PARP-1 inhibitors
\are being pursued into different stages of clinical trials and some
have even been approved for clinical anticancer therapy
including E7016, AZD-2281 (Olaparib), BMN-673(Tlazoparib),
MK-4827 (Niraparib), ABT-888 (Veliparib) and AG-014699
(Rucaparib).8 Most currently available structure of PARP-1
inhibitors is based on the benzamide as pharmacophore, which
mimics the structure of nicotinamide in NAD+ to form the
substrate-protein interaction of NAD+ with PARP-1 (Fig.1).4, 9
dibenzo[b,e]azepine-6,11-dione derivatives bearing carboxyl
group at the 4-position and the subsequent N-acylation followed
by cyclization to deliver
5H-dibenzo[b,e]azepine-6,11-dione
derivatives containing 1,3,4-oxadiazole units. To that end, a 4-
step synthetic strategy was designed starting from anthranilic
acids and phthalic anhydride. The synthetic route is illustrated in
Scheme 2.
Rucaparib (Rubraca, produced by Clovis Oncology Company)
such as 8-fluoro-2-{4-[(methyllamino)methyl]phenyl}-1,3,4,5-
terahydro-6H-azepino[5,4,3-cd]indol-6-one, is an intravenous
PARP-1 inhibitor with no significant toxicities when used alone.
In 2016, the U.S. Food and Drug Administration (FDA) have
accelerated the approval of Rucaparib for the treatment of
advanced ovarian cancer associated with mutations in the BRCA
gene. 10
In the present letter, Rucaparib was considered as the parent
compound for the design of our target compounds in order to find
a series of small molecule compounds with high potent, low
toxicity as candidates for discovery of clinical anticancer drugs.
By observing the chemical structure of Rucaparib, it can be
regarded as one compound of three-fused ring structure which is
based on the structure of of benzoazepin and pyrrole. We
obtained the skeleton of benzoazepin according to the open loop
strategy in drug design by taking C-C bond of the pyrrole ring as
the cutting point to open the pyrrole ring (Scheme 1).
Furthermore, referring to the structural features of the PJ34
Scheme 2. : 1) DMAP, THF, 70℃; 2) i. SOCl2, CHCl3, 50℃; ii.
AlCl3, CHCl3, 50℃; 3) i. SOCl2, DCM; ii. acylhydrazines, Et3N,
DCM, 35℃; iii. TsCl, DCM, 35℃.
The first step involved N-acylation of anthranilic acids with
phthalic anhydride in refluxing THF in the presence of DMAP as
a catalyst to give the amide derivative a. The amide derivative a
was then reacted with SOCl2 in chloroform followed by AlCl3 to
give the 5H-dibenzo[b,e]azepine-6,11-dione derivative b with
carboxyl group at 4 position. After the 5H-dibenzo[b,e]azepine-
11
molecule (a general PARP inhibitor) which is a derivative of
phenanthridin-6(5H)-one, we got Segment I of our target
compounds by incorporating the aromatic ring in the branched
chain into the heterocyclic side of the benzoazepin. Then we
integrated the amino group in the aromatic ring of the Rucaparib
6,11-dione derivative
b
was treated with SOCl2 in
dichloromethane, the carboxyl group at 4 position converted into
the acyl chloride. The acyl chloride was then reacted with
hydrazine derivatives resulting in the intermediate c by using
triethylamine as acid-binding agent in dichloromethane. Finally,
structure
into
a five-
membered heterocyclic ring containing both N and O, so that
Segment II of our target compounds was obtained (Scheme 1).
our target compounds
d were synthesized through the
intermediate c without being separated from dichloromethane
reacted with p-toluenesulfonyl chloride via elimination
reaction.14 Crude products were purified by recrystallization.
With this set of compounds in hand, the anticancer activity
spectrum of these molecules was investigated in the next part.
The antitumor activities of all of our target compounds (d1-22)
against human ovarian cancer cell line (OVCAR-3) were
evaluated
by
using
3-(4,5-dimethyldiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) assay according to the
literature protocol Table 1 and Table 2.
Table 1. Anticancer activities Assays of Compounds d1-11
against OVCAR-3 cell line
Scheme 1. Design of 5H-dibenzo[b,e]azepine-6,11-dione
derivatives containing 1,3,4-oxadiazole units
The synthetic strategy deployed in this work was primarily
based on the method for synthesis of 2,5-disubstituted-1,3,4-
oxadiazoles. N’-aromatic carbonyl acylhydrazine derivatives
were prepared as intermediates by N-acylation of acylhydrazine
with carbonyl chlorides substituted with aromatic ring, followed
by the cyclization step in the presence of p-toluenesulfonic
chloride to give 2,5-disubstituted-1,3,4-oxadiazoles.12 5H-
dibenzo[b,e]azepine-6,11-dione could be obtained via the ring-
closing reaction of 2-(phenylcarbamoyl)benzoic acid under acidic
conditions.13 In the present work, a convenient process for
preparation of 2-(2-carboxybenzamido)benzoic acid derivatives
as intermediates was described to provide an entry into 5H-
Compd
R1
R2
IC50a(μM)
10.08±0.52
d1
3

H
H
6.28±0.13
>100
d14
d15
4.19±0.46
NAb
d2
d3
11.40±0.93
NA
d4
d5
H
>100
d16
H
H
12.13±0.99
8.99±0.55
d17
d18
17.70±1.11
10.67±0.72
d6
d7
H
H
>100
>100
d19
d20
>100
>100
NA
d8
d9
H
H
1.66±0.23
d21
d10
1.40±0.30
3.31±0.21
d22
NA
d11
Rucaparib
a
See the footnotes in Table 1.
Rucaparib
3.31±0.21
a
Data were shown as mean ± SED.
No activity.
To our delight, about half of compounds (d1-2, d4, d6-7, d14,
b
d17-18 and d21-22) showed varying a degree of inhibitory
activity. Compound d21 and d22 were found to reveal good
activities (IC50 = 1.66±0.23 μM and IC50 = 1.40±0.30 μM)
against OVCAR-3 cell line comparable to Rucaparib (IC50 = 3.31
±0.21 μM) (Fig. 2). By comparing chemical structures of d6-11
and d17-22, it was an obvious discovery that most compounds
without methyl group at the 2-position of 5H-
dibenzo[b,e]azepine-6,11-dione displayed high potency. The
detrimental effect of methyl substituted 5H-dibenzo[b,e]azepine-
6,11-dione was even more evident that compound d10 and d11
(compared to d21 and d22)were devoid of any activity against
OVCAR-3 cell line. Introduction of the electron-donating group
to substituted aromatic rings (methoxyl group, d18) could
enhance biologic activity, displaying IC50 = 8.99 ± 0.55 μM,
while no substituted group (d17) showed IC50 = 12.13±0.99 μM.
Among compounds d19-22 with halogen atoms, containing
fluorine and chlorine atoms (d19 and d20) showed only little
potency, while d21 and d22 were 100-fold more active,
indicating that compounds with bromo atoms were more
necessary for inhibitory properties.
Table 2. Anticancer activities Assays of Compounds d12-22
against OVCAR-3 cell line
Compd
R1
H
R2
IC50a(μM)
>100
d12
H
>100
d13
4

1.0
0.8
0.6
0.4
0.2
0.0
0.304
NA
d4
d5
Rucaparib
d21
d22
** *
** **
0.446
0.147
d6
d7
0.625
1.250
2.500
5.000
10.000
Conc. (μM)
Figure. 2 The inhibitory effect of d21, d22 and Rucaparib on
OVCAR-3 cell line. Values were expressed by mean ± SED.
n=3; *P <0.05, compared to Rucaparib; **P <0.01, compared to
Rucaparib.
1.055
1.191
NA
d8
d9
Interestingly, d1, d2 and d4 showed a certain extent of
inhibitory activities, while compound d12, d13 and d15 without
methyl substituent on 5H-dibenzo[b,e]azepine-6,11-dione were
not observed to provide obvious activities. It was presumably due
to the number of atoms connected between the 1,3,4-oxadiazole
ring and substituted aromatic rings in the side chain. The link
chain consisting of two atoms between the 1,3,4-oxadiazole ring
and substituted aromatic rings was likely to be necessary for the
apparent activities of those without methyl substituent. The
conjecture was well proved that d3 displayed no inhibition
activity comparable to d14 with an IC50 = 6.28±0.13 μM.
d10
0.939
0.026
d11
Rucaparib
a
To verify the potency targeting PARP-1, all compounds were
tested in the PARP-1 enzyme assay shown in Table 3 and Table
4. Fortunately, most compounds displayed different levels of
inhibition to PARP-1. And it was obvious that the trend of
inhibition to PRAP-1 was basically the same as that of antitumor
activities. Both d21 (IC50 = 0.047 μM) and d22 (IC50 = 0.025 μM)
showed higher potency against PARP-1 than other 20 compounds
(d1-20). It was revealed that d22 almost have the same potency
as Rucaparib with an IC50= 0.026μM.
The assays were performed as described in Supporting
Information.
b No activity.
Table 4. PARP-1 Enzymatic Assays of Compounds d12-22
Table 3. PARP-1 Enzymatic Assays of Compounds d1-11
Compd
R1
H
R2
IC50a(μM)
NA
d12
Compd
R1
R2
IC50a(μM)
H
H
1.101
0.099
d13
d14
0.277
d1
0.051
NAb
d2
d3
H
1.255
d15
5

Figure. 4 The expression level of Bcl-2 along with the change of
the concentration of d21 and d22. The ordinate was expressed by
the ratio of integrated optical density of Bcl-2 expression to that
of β-actin expression (Bcl-2/β-actin). n=3; *P <0.05, compared to
control group (0 μM); **P <0.01, compared to control group (0
μM).
H
0.745
d16
H
H
0.400
0.136
d17
d18
As the most potent inhibitor, d22 was docked into the active si
te of PARP-1 (PDB ID:
4RV6) to investigate its binding mode (Fig. 5). The ligand overla
pped with benzazepine skeleton of Rucaparib (blue molecule in F
ig. 5), exhibited a binding mode comparable to Rucaparib. Both
compound d22 and Rucaparib could form a H-bond interaction
H
H
0.951
1.263
d19
d20
with
1. The compound d22 appeared to interact with the region throug
h the amide group,
Gly863
located at
the binding pocket
of PARP-
which was projected toward Gly863 with a distance of 1.748 Å,
and subsequently form a better optimized H-bond interaction.
Due to a slightly longer H-bond formed between Rucaparib and
Gly863 with a distance of 2.283 Å, the results of molecular
docking
d22 in the S field was -
13.4189, which is slightly lower than the posing score of Rucapar
ib. This may contribute to its anticancer activity.
displayed
GBVI/WSA binding free energy of
H
H
0.047
d21
0.025
0.026
d22
Rucaparib
a
See the footnotes in Table 3.
From the results above, to determine whether the compounds
with activities could really enhance OVCAR-3 cell apoptosis,
compound d21 and d22 with IC50 values lower than 3.31±0.21
μM (Rucaparib) were further evaluated for their inhibition on cell
proliferation by western blot analysis (Fig. 3). Overexpression of
antiapoptotic Bcl-2 members such as Bcl-2 occurs frequently in
cancers resulting in defective apoptosis leading to enhanced cell
survival and drug resistance.15 So we took the expression of Bcl-
2 as an index to measure the level of apoptosis. Concentration
course analysis revealed that compound d21 and d22 induced a
decline in levels of Bcl-2 in OVCAR-3 cell, which was observed
after 24-hour exposure (Fig. 3 and 4). It was further indicated
that d21 and d22 had the potential to induce OVCAR-3 cell
apoptosis via the Bcl-2 related pathway.
Figure. 5 Docking conformation of d22 binding with PARP-1
(blue molecular is Rucaparib; green molecular is d22)
In conclusion, taking Rucaparib and PJ34 as structural model,
a series of novel 5H-dibenzo[b,e]azepine-6,11-dione derivatives
containing 1,3,4-oxadiazole units have been designed and finally
successfully synthesized. Structures of all target compounds were
determined by 1H-NMR, 13C-NMR and MS. We found that
compounds d1-2, d4, d6-7, d14, d17-18 and d21-22 could inhibit
OVCAR-3 cancer cell growth. Among these, d21 and d22
showed better inhibitory activities against OVCAR-3 cell line
comparable to Rucaparib. Due to the significant results we
obtained, chemical studies aiming at improving the anticancer
activity of these compounds and the study of pharmacological
mechanism are currently underway and will be reported in due
course.
d21 (μM)
d22 (μM)
0
0.625 1.25 2.5
5
10
0
0.625 1.25 2.5
5
10
Bcl-2
β-actin
Figure. 3 Western blot analysis in OVCAR-3 cells exposed to
d21 and d22 for 24 hours.
Acknowledgments
*
*
**
This work was supported by the National Natural Science
Foundation of China (No. 81274182) and the project of Liaoning
distinguished professor.
*
*
*
6

phthalic anhydride (2.06 g, 13.89 mmol), DMAP (20 mg, 0.13
mmol) and THF (20 mL) was heated under reflux in an oil bath at
70 ℃ for 4 h. After completion of the reaction, THF was removed
under vacuum to obtain brown liquids. Then ice-cold water (50
mL) was poured into the brown liquids. The precipitate was
filtered off and dried to get the crude product a. a was dissolved
in chloroform (50 mL), then thionyl chloride (3.88 g, 29.11 mmol)
and catalyst DMF (10 mg, 0.13 mmol) were added. The reaction
mixture was heated at 50 ℃ for 2 h. AlCl3 (3.46 g, 29.11 mmol)
was added to this mixture for 3 additional hours at this
temperature. The reaction fixture was poured into ice-cold
aqueous acid (100 mL) under stirring. After keeping stirring for
0.5 h, the aqueous phase of the mixture was separated and
extracted with chloroform (20 mL×3). Then the organic phase was
dried over Na2SO4 and evaporated under vacuum. The residue was
purified by crystallization in dichloromethane to afford 2.2 g of 2-
methyl-6,11-dioxo-6,11-dihydro-5H-dibenzo[b,e]azepine-4-
carboxylic acid as off-white solids b (59﹪). Finally, in a dry
flask, thionyl chloride (0.51 g, 4.27 mmol) was added to the
mixture of 6,11-dioxo-6,11-dihydro-5H-dibenzo[b,e]azepine-4-
carboxylic acid b (1 g, 3.56 mmol) and dichloromethane (30 mL).
After catalyst DMF (10 mg, 0.13 mmol) was added, the reaction
mixture was heated at 35 ℃ for about 5 h and then cooled to 0 ℃.
Benzohydrazide (0.47 g, 3.48 mmol) was added, and then the
solution of triethylamine (1.62 g, 16 mmol) in dichloromethane (5
mL) was added dropwise to this reaction mixture at this
References and notes
1.
2.
B. Kocyigit-Kaymakcioglu, R. G. Aker, K. Tezcan, E. Sakalli, S.
Ketenci, E. E. Oruc-Emre, D. Akin, A. Gurbanova, B. Terzioglu
and F. Onat, Med. Chem. Res., 2011, 20, 607.
X. Hou, J. Zhang, X. Zhao, L. Chang, P. Hu and H. Liu, Chin. J.
Chem., 2014, 32, 538.
3.
4.
P. Cozzi, Farmaco., 2003, 58, 213.
(a) J. Chen, H. Peng, J. He, X. Huan, Z. Miao and C. Yang,
Bioorg. Med. Chem. Lett., 2014, 24, 2669; (b) E. M. Horvath and
C. Szabo, Drug News Perspect., 2007, 20, 171.
5.
(a) J. M. de Murcia, C. Niedergang, C. Trucco, M. Ricoul, B.
Dutrillaux, M. Mark, F. J. Oliver, M. Masson, A. Dierich, M.
LeMeur, C. Walztinger, P. Chambon and G. de Murcia, P. Natl.
Acad. Sci. USA, 1997, 94, 7303; (b) C. Szabo, B. Zingarelli, M.
O'Connor and A. L. SALzMAN, P. Natl. Acad. Sci.USA, 1996, 93,
1753
6.
8.
(a) M. Anwar, H. M. Aslam and S. Anwar, Hered. Cancer Clin.
Pr., 2015, 13, 4; (b) R. S. Meehan and A. P. Chen,
Gynecologic oncology research and practice, 2016, 3,3.
T. Helleday, E. Petermann, C. Lundin, B. Hodgson and R. A.
Sharma, Nat. Rev. Cancer, 2008, 8, 193.
(a) N. J. Curtin and C. Szabo, Mol. Aspects Med., 2013, 34, 1217;
(b) K. A. Menear, C. Adcock, R. Boulter, X. –l. Cockcroft, L.
Copsey, A. Cranston, K. J. Dillon, J. Drzewiecki, S. Garman, S.
Gomez, H. Javaid, F. Kerrigan, C. Knights, A. Lau, V. M. Loh, I.
T. W. Matthews, S. Moore, M. J. O’Connor, G. C. M. Smith and
N. M. B. Martin, J. Med. Chem., 2008, 51, 6581; (c) Y. Shen, F.
L. Rehman, Y. Feng, J. Boshuizen, I. Bajrami, R. Elliott, B.
Wang, C. J. Lord, L. E. Post and A. Ashworth, Clin. Cancer Res.,
2013, 19, 5003; (d) P. Jones, S. Altamura, J. Boueres, F. Ferrigno,
M. Fonsi, C. Giomini, S. Lamartina, E. Monteagudo, J. M.
Ontoria, M. V. Orsale, M. C. Palumbi, S. Pesci, G. Roscilli, R.
Scarpelli, C. Schultz-Fademrecht, C. Toniatti and M. Rowley, J.
Med. Chem., 2009, 52, 7170; (e) M. J. O’Connor, Mol. Cell, 2015,
60, 547; (f) J. Murai, S.-y. N. Huang, B. Brata Das, A. Renaud, Y.
Zhang, J. H. Doroshow, J. Ji, S. Takeda and Y. Pommier, Cancer
Res., 2012, 72, 5588; (g) Y. Shen, F. L. Rehman, Y. Feng, J.
Boshuizen, I. Bajrami, R. Elliott, B. Wang, C. J. Lord, L. E. Post
and A. Ashworth, Clin. Cancer Res., 2013, 19, 5003.
Y. Pommier, M. J. O’Connor and J. de Bono, Sci. Transl. Med.,
2016, 8, 362.
temperature, followed by stirring at 35 ℃ for a further 10h. After
addition of p-toluenesulfonyl chloride (0.75 g, 3.91 mmol),
mixture was kept stirring overnight at 35 ℃. After the solvent was
evaporated under reduce pressure, ice-cold water (50 mL) was
added and filtered off. The filter cake was dried and purified by
crystallization in methanol to give 0.78 g of the pure product d1
(57﹪). A representative compound d1 and its spectrum data are
as follows:
2-methyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)-5H-dibenzo[b,e]-
azepine-6,11-dione (d1): White solid, 0.78 g, yield 57﹪; 1H NMR
(600MHz, DMSO-d6) δ 8.19 (d, 1 H, J = 0.8 Hz), 8.04 - 7.92 (m,
4 H), 7.87 - 7.82 (m, 2 H), 7.67 - 7.57 (m, 3 H), 7.53 - 7.47 (m, 2
H), 2.53 (s, 3 H); 13C NMR (151MHz, DMSO-d6) δ 167.6, 164.0,
162.2, 140.7, 135.3, 133.7, 132.6, 132.3, 131.7, 129.9, 129.7,
127.7, 126.9, 124.0, 123.1, 122.1, 21.0; MS (API-ESI) found
382.1 [M+H]+.
9.
10. (a) J. Murray, H. Thomas, P. Berry, S. Kyle1, M. Patterson, C.
Jones, G. Los, Z. Hostomsky, E. R. Plummer, A. V. Boddy and N.
J. Curtin, Br. J. Cancer, 2014, 110, 1977; (b) S. S. Canan Koch, L.
H. Thoresen, J. G. Tikhe, K. A. Maegley, R. J. Almassy, J. Li, X.-
H. Yu, S. E. Zook, R. A. Kumpf, C. Zhang, T. J. Boritzki, R. N.
Mansour, K. E. Zhang, A. Ekker, C. R. Calabrese, N. J. Curtin, S.
Kyle, H. D. Thomas, L.-Z. Wang, A. H. Calvert, B. T. Golding, R.
J. Griffin, D. R. Newell, S. E. Webber and Z. Hostomsky, J. Med.
Chem., 2002, 45, 4961; (c) J. Murai, S.-Y. N. Huang, A. Renaud,
Y. Zhang, J. Ji, S. Takeda, J. Morris, B. Teicher, J. H. Doroshow
and Y. Pommier, Mol. Cancer Ther., 2014, 13, 433.
15. M. Rahmani, M. M. Aust, E. Attkisson, D. C. Williams Jr., A.
Ferreira-Gonzalez and S. Grant, Cancer Research, 2013, 73, 1340.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
11. T. Ekblad and H. Schueler, Chem. Biol. Drug Des., 2016, 87,
478.
12. (a) P. Stabile, A. Lamonica, A. Ribecai, D. Castoldi, G. Guercio
and O. Curcuruto, Tetrahedron Lett., 2010, 51, 4801; (b) S. L.
Harbeson, WO 2009009531, 2009; (c) G. I. Elliott, J. R. Fuchs, B.
S. J. Blagg, H. Ishikawa, H. Tao, Z. Yuan and D. L. Boger, J. Am.
Chem. Soc., 2006, 128, 10589.
Click here to remove instruction text...
13. V. G. Pawar, S. R. Bhusare, R. P. Pawar and B. M. Bhawal, Synth.
Commun., 2002, 32, 1929.
14. As an example, the synthesis of 4-(1,3,4-oxadiazol-2-yl)-5H-
dibenzo[b,e]azepine-6,11-dione derivatives d1 is described here.
A mixture of 2-amino-5-methylbenzoic acid (2 g, 13.23 mmol),
7