Design, synthesis and biological evaluation of 3,4-dihydronaphthalen-1(2H)-one derivatives as Bcl-2 inhibitors

Article abstract of DOI:10.1007/s11164-017-2972-x

Abstract: A series of new 3,4-dihydronaphthalen-1(2H)-one derivatives (6a–f) were designed, and synthesized by the Claisen–Schmidt condensation reaction. Their structures were characterized by NMR, FTIR, and MS spectroscopy. Their antitumor activities against human neoplastic cell lines Hela, Hepg2, K562, THP-1, SW1990, MIA PaCa-2, NCI-H460 and SK-BR-3 by the MTT method exhibited obvious anticancer activities and their cytotoxicities for LO2 cell lines were lower than DOX, especially for 6b and 6d. The inhibition activities against the Bcl-2 protein for 6b was evaluated and the result shows that lipophilic 3,4-dimethoxybenzylidene and 3,4-dihydronaphthalen-1(2H)-one could bind slightly to the active pockets of the Bcl-2 protein.

Full text of DOI:10.1007/s11164-017-2972-x

Res Chem Intermed
DOI 10.1007/s11164-017-2972-x
Design, synthesis and biological evaluation of 3,4-
dihydronaphthalen-1(2H)-one derivatives as Bcl-2
inhibitors
Fuli Wang1 Rongxiang Zhang2 Yong Cui3
•
•
•
Liping Sheng4 Yinping Sun1 Wei Tian1
Xiao Liu1 Shuzeng Liang5
•
•
•
•
Received: 21 January 2017 / Accepted: 2 May 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract A series of new 3,4-dihydronaphthalen-1(2H)-one derivatives (6a–f) were
designed, and synthesized by the Claisen–Schmidt condensation reaction. Their struc-
tures were characterized by NMR, FTIR, and MS spectroscopy. Their antitumor activ-
ities against human neoplastic cell lines Hela, Hepg2, K562, THP-1, SW1990, MIA
PaCa-2, NCI-H460 and SK-BR-3 by the MTT method exhibited obvious anticancer
activities and their cytotoxicities for LO2 cell lines were lower than DOX, especially for
6b and 6d. The inhibition activities against the Bcl-2 protein for 6b was evaluated and
the result shows that lipophilic 3,4-dimethoxybenzylidene and 3,4-dihydronaphthalen-
1(2H)-one could bind slightly to the active pockets of the Bcl-2 protein.
&
Shuzeng Liang
shuzengliang01@163.com
1
2
3
4
5
Department of Oncology, The Central Hospital of Zibo, Zibo 255036, Shandong, People’s
Republic of China
Department of Outpatient Service, The Shouguang People’s Hospital,
Shouguang 262799, Shandong, People’s Republic of China
Department of Oncology, The Shouguang People’s Hospital, Shouguang 262799, Shandong,
People’s Republic of China
Outpatient Operating Room, The Shouguang People’s Hospital, Shouguang 262799, Shandong,
People’s Republic of China
Operating Room, Qianfoshan Hospital Affiliated to Shandong University, Jingshi Road, Lixia
District, Jinan 250014, Shandong, People’s Republic of China
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F. Wang et al.
Graphical Abstract
Keywords Anticancer activity Á Cytotoxicity Á Bcl-2 inhibitors
Introduction
Malignant tumors seriously impact on human health. Currently, surgery and
chemotherapy can prolong life for up to a few years in some patients [1–3]. Many
chemotherapy drugs on the market are used for clinical applications. In the process
of treatment, apoptosis is triggered by internal or external cellular stimuli, and the
evasion of apoptosis is a hallmark of human cancer and contributes to the resistance
to conventional therapies. Therefore, targeting key apoptosis regulators is a most
promising strategy of the treatment for malignant tumors [4, 5].
The Bcl-2 (B cell lymphoma 2) family of proteins [6, 7] are very important
therapeutic targets for malignant tumors and include Bcl-2, Bcl-xL, Mcl-1, Bfl-1/
A1, Bcl-B and Bcl-w, and pro-apoptotic proteins, such as BAK, BAX, BID, BIM
and BAD. The study and development of Bcl-2 inhibitors has become one of the
important strategies for treating malignant tumors. Recently, some small-molecule
Bcl-2 inhibitors, such as ABT-199 [8], Gossypol [9] and Obatoclax [10], have been
used as antitumor agents in clinical trials [11]. However, these antitumor agents
have some problems in clinical application, such as relatively low bioavailability,
high toxicity, and so on.
Some 3,4-dihydronaphthalen-1(2H)-one derivatives have been investigated as
novel modulators of allergic and inflammatory phenomena [12] and inhibitors of
retinoic acid (RA)-metabolizing enzymes as potential agents for the treatment of skin
conditions and cancer [13]. 3,4-dihydronaphthalen-1(2H)-one is a very potential
active fragment in antitumor agents, but it is certainly rare for 3,4-dihydronaphthalen-
1(2H)-one derivatives to be potent Bcl-2 family inhibitors. In addition, some
antiproliferative drugs containing the pharmacophore of a,b-unsaturated keto can
interact as the primary binding site to bio-thiols from susceptible neoplasms while
having lower toxicity toward normal cells [14–16]. It will provide greater
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Design, synthesis and biological evaluation of…
antiproliferative activities against tumor cell lines when they can be combined
between 3,4-dihydronaphthalen-1(2H)-one and a,b-unsaturated keto.
With this aim in mind, in this study, a series of new 3,4-dihydronaphthalen-
1(2H)-one derivatives were designed and synthesized by the Claisen–Schmidt
condensation reaction. Their antitumor activities against human neoplastic cell lines
Hela, Hepg2, K562, THP-1, SW1990, MIA PaCa-2, NCI-H460, SK-BR-3 and
against anti-apoptotic Bcl-2 proteins have been evaluated by the MTT method.
Experimental section
Materials and methods
Anisole, succinic anhydride, aluminum chloride, hydrazine hydrate, diethylene
glycol (DEG), polyphosphoric acid (PPA), 2-methoxybenzaldehyde, 3,4-
dimethoxybenzaldehyde, 2-fluorobenzaldehyde, 4-fluorobenzaldehyde, furfural,
2-thenaldehyde were purchased from Sinopharm Chemical Reagent (Shanghai,
China). R(-)-gossypol (AT-101) was purchased from Selleckchem (Shanghai,
China). They were used as obtained without further purification. NMR spectra were
obtained on a Bruker Avance 400 MHz spectrometer (1H NMR at 400 Hz, 13C
NMR at 100 Hz) in CDCl3 using TMS as an internal standard. Chemical shifts (d)
are given in ppm and coupling constants (J) in Hz. Infrared (IR) spectra were
obtained in the 400–4000 cm-1 range using a Bruker tensor-27 FTIR Spectrometer.
All melting points were measured on a digital melting point apparatus and were
uncorrected. The docking mode was simulated using the SYBYLX 2.0 software
(Tripos; Certara, St. Louis, MO, USA).
Synthesis of 6a–f: general procedure [16]
7-Methoxy-3,4-dihydronaphthalen-1(2H)-one (5) was obtained following literature
reports: 5- (1.76 g, 10.0 mmol) and 2-methoxybenzaldehyde (1.36 g, 10.0 mmol),
or 3,4-dimethoxybenzaldehyde (1.66 g, 10.0 mmol), or 2-fluorobenzaldehyde
(1.24 g, 10.0 mmol), or 4-fluorobenzaldehyde (1.24 g, 10.0 mmol), or furfural
(0.96 g, 10.0 mmol), or 2-thenaldehyde (1.12 g, 10.0 mmol) were dissolved in
15 mL of methanol. Next, 5.0 mL 10% NaOH solution added, and the mixture was
stirred for 3–4 h at ambient temperature (monitored by TLC). The solvent was
removed through a pouring process, and the residues were purified on silica gel by a
column using petroleum ether/EtOAc (4:1, v/v) as the eluent to afford light yellow
powders 6a–f.
(E)-7-methoxy-2-(2-methoxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one (6a) Yellow
powder, yield: 87%; m.p. 132–134 °C. IR (cm-1): 2944(m), 2839(m), 1662(s),
1595(s), 1483(s), 1423(s), 1292(s), 1234(s),1107(m), 1014(s), 979(m), 889(m),
1
809(m), 773(s). H NMR: d 8.00 (s, 1H), 7.65 (s, 1H), 7.30 (m, 2H), 7.18 (d, 1H),
7.01 (d, 1H), 6.98 (d, 1H), 6.94 (m, 2H), 3.88 (d, 6H), 3.04 (t, J = 5.8 Hz, 2H), 2.89
(t, J = 5.8 Hz, 2H). 13C NMR: d 187.82, 158.53, 158.19, 136.09, 135.41, 134.33,
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F. Wang et al.
132.73, 130.14, 130.09, 129.41, 124.85, 121.33, 119.98, 110.61, 110.23, 55.52,
55.44, 28.20, 27.73. HRMS: calcd for C19H19O3 [M ? H?] 295.1334; found
295.1338.
(E)-2-(3,4-dimethoxybenzylidene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (6b) Yel-
low solid, yield: 88%; m.p. 32–34 °C. IR (cm-1): 2943(m), 2841(m), 1668(s),
1585(s), 1509(s), 1472(s), 1270(s), 1130(s), 1020(m), 887(m), 796(m), 744(s). H
1
NMR: d 7.82 (s, 1H), 7.61 (s, 1H), 7.17 (d, 1H), 7.09 (m, 2H), 7.01 (d, 1H), 6.92 (m,
2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.14 (t, J = 5.9 Hz, 2H), 2.89 (t,
J = 5.9 Hz, 2H). 13C NMR: d 187.62, 158.58, 149.51, 148.65, 136.88, 135.68,
134.33, 133.72, 129.31, 128.62, 123.25, 121.27, 113.16, 110.83, 110.24, 55.89,
55.88, 55.49, 27.89, 27.42. HRMS: calcd for C20H21O4 [M ? H?] 325.1440; found
325.1443.
(E)-2-(2-fluorobenzylidene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (6c) Yellow
powder, yield: 82%; m.p. 124–126 °C. IR (cm-1): 2938(m), 2842(m), 1669(s),
1595(s), 1295(s), 1222(s), 1145(s), 1098(s), 1024(m), 972(m), 922(m), 775(s). H
1
NMR: d 7.83 (s, 1H), 7.65 (s, J = 2.5 Hz, 1H), 7.37 (m, J = 7.2 Hz, 2H), 7.18 (m,
3H), 7.10 (m, 1H), 3.89 (d, 3H), 2.98 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 5.9 Hz, 2H).
1
13C NMR: d 187.39, 161.84, 159.36, 158.62, 136.18, 135.83 (d, JCF = 362.0 Hz),
130.70 (d, JCF = 3.0 Hz), 130.28 (d, JCF = 8.3 Hz), 129.51, 129.35 (d,
3
3
2
4JCF = 2.7 Hz), 123.80 (d, JCF = 14 Hz), 123.79, 121.69, 115.81 (d,
2JCF = 22 Hz), 110.21, 55.54, 28.06, 27.80. HRMS: calcd for C18H16FO2
[M ? H?] 283.1134; found 283.1131.
(E)-2-(4-fluorobenzylidene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (6d) Yel-
low powder, yield: 87%; m.p. 123–125 °C. IR (cm-1): 2938(m), 2836(m),
1665(s), 1595(s), 1496(s), 1429(s), 1295(s), 1228(s), 1149(m), 1027(s), 979(m),
1
915(m), 812(m), 734(s). H NMR: d 7.79 (s, 1H), 7.60 (s, J = 2.7 Hz, 1H), 7.39
(dd, J = 8.4, 5.5 Hz, 2H), 7.16 (d, J = 8.3 Hz, 1H), 7.08 (dt, J = 9.7, 5.7 Hz, 3H),
3.86 (d, 3H), 3.06 (t, J = 5.8 Hz, 2H), 2.88 (t, J = 5.8 Hz, 2H). 13C NMR: d
187.64, 163.81, 161.33, 158.64, 135.79, 135.54, 134.67 (d, JCF = 105.0 Hz),
1
4
3
131.89 (d, JCF = 4.0 Hz), 131.72 (d, JCF = 8.0 Hz), 129.43, 121.56, 115.52 (d,
2JCF = 22.0 Hz), 110.24, 55.53, 27.92, 27.27. HRMS: calcd for C18H16FO2
[M ? H?] 283.1134; found 283.1129.
(E)-7-methoxy-2-(thiophen-2-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (6e) Yel-
low powder, yield: 85%; m.p. 98–100 °C. IR (cm-1): 2954(m), 2839(m), 1659(s),
1586(s), 1496(s), 1426(s), 1289(s), 1226(s), 1094(m), 1027(s), 963(m), 825(m),
1
708(s). H NMR: d 8.05 (s, 1H), 7.61 (s, 1H), 7.52 (d, 1H), 7.41 (d, 1H), 7.20 (m,
1H), 7.15 (d, 1H), 7.07 (m, 1H), 3.88 (s, 3H), 3.19 (t, J = 5.9 Hz, 2H), 2.98 (t,
J = 5.9 Hz, 2H). 13C NMR: d 187.07, 158.62, 139.11, 135.67, 134.41, 133.24,
131.75, 129.48, 129.34, 129.31, 127.54, 121.27, 110.25, 55.52, 27.26, 27.18.
HRMS: calcd for C16H15O2S [M ? H?] 271.0793; found 271.0787.
(E)-2-(furan-2-ylmethylene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (6f) Yellow
powder, yield: 89%; m.p. 89–91 °C. IR (cm-1): 2954(m), 2832(m), 1659(s),
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Design, synthesis and biological evaluation of…
1585(s), 1499(s), 1426(s), 1292(s), 1247(s), 1167(m), 1100(s), 1027(s), 935(m),
882(m), 822(m), 776(s). 1H NMR: d 7.58 (d, 2H), 7.54 (s, 1H), 7.05 (d, 1H), 7.02 (d,
1H), 6.68 (s, 1H), 6.50 (s, 1H), 3.83 (s, 3H), 3.26 (t, J = 5.9 Hz, 2H), 2.91 (t,
J = 5.9 Hz, 2H). 13C NMR: d 187.12, 158.52, 152.41, 144.32, 136.15, 134.24,
131.76, 129.35, 122.81, 121.14, 116.50, 112.21, 110.22, 55.42, 27.42, 26.81.
HRMS: calcd for C16H15O3 [M ? H?] 255.1021; found 255.1026.
Anticancer testing with MTT method
Compounds 6a–f were screened against human neoplastic cell lines: human cervical
carcinoma cells (HeLa), human liver hepatocellular carcinoma cell line (HePG2),
human chronic myelogenous leukemia cell line (K562), human acute mononuclear
granulocyte leukemia (THP-1), human pancreatic cancer cells (SW1990 and MIA
PaCa-2), human non-small cell lung cancer (NCI-H460) and human breast
carcinoma cells (SK-BR-3) and human normal heptical cell line (LO2) by MTT
assay (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide; MTT;
Dojindo Laboratories, Tokyo, Japan). The cells were seeded in a 96-well plate at a
density of 1 9 104 cells/well with 200 lL medium per well for 24 h. The cells were
treated with the compounds (10, 8, 5, 3, 2, 1, 0.5, 0.1, 0.05 and 0.01 lg/mL) and
incubated for 24 h. Cells with only culture media were used as a negative control.
After removal of the media, MTT (20 lL, 5 mg/mL) was added and the plates were
incubated for 4 h at 37 °C. The media were removed and 150 lL DMSO was added
to dissolve the dark-blue formazan crystals. The optical density was measured by a
¨
multi-well plate reader (TECAN, Mannedorf, Switzerland) at 540 nm. The
experiments were examined in triplicate, and the IC50 values are expressed in
Table 1. Doxorubicin (DOX) was used as a positive control at the concentrations of
1.5, 1.2, 1.0, 0.8, 0.5, 0.3, 0.1, 0.05 and 0.01 lg/mL.
Binding assay for Bcl-2 protein [11]
A 26-residue Bid-BH3 peptide (QEDIIRNIARHLAQVGDSMDRSIPPG) was
labeled at the N-terminus by 5-carboxyfluorescein succinimidyl ester (FAM) as
the fluorescence-labeled peptide (5-FAMQEDIIRNIARHLAQVGDSMDRSIPPG).
The 5-FAM-Bid-BH3 peptide had a Kd value of 58 nM to bind to the Bcl-2 protein
[17]. In the competitive binding experiments, the Bcl-2 protein and compounds
were preincubated in the PBS assay solution for 30 min at room temperature. Then,
the 5-FAM-Bid-BH3 peptide was added into the solution and incubated for 20 min.
The volume of the total solution was 200 lL. Finally, the solutions were transferred
into 96-well plates with 60 lL per well and three wells per sample. The polarization
values (milipolarization units, mpol) were measured at 540 nm using the multi-well
plate reader (TECAN). In the binding experiments, compounds 6a–f were prepared
in DMSO at nine concentrations: 100, 50, 10, 5, 1, 0.5, 0.1, 0.05 and 0.01 lg/mL.
Each value was reproduced in three independent assays and expressed with standard
deviations. Doxorubicin (DOX) and R(-)-gossypol (AT-101) were used as a positive
control at the concentrations of 100, 50, 10, 5, 1, 0.5, 0.1, 0.05 and 0.01 lg/mL.
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Design, synthesis and biological evaluation of…
Molecular docking
A molecular docking program using the SYBYLX 2.0 software was used with
default values. The structures of 6b and the Bcl-2 protein were optimized according
to Ref. [11].
Results and discussion
Structural analysis
Our synthetic route to the target compounds is shown in Scheme 1. A vital
intermediate 7-methoxy-3,4-dihydronaphthalen-1(2H)-one (5) as a white solid was
prepared in an overall yield of 50% for the three steps based on the method in the
literature [18, 19]. First, anisole and succinic anhydride were reacted by F–C
acylation to generate 4-(4-methoxyphenyl)-4-oxobutanoic acid (3) by catalysis of
Lewis acid (AlCl3) in 92% yield. Secondly, after Wolff–Kishner–Huang–Minlon
reduction, 4-phenoxybutanoic acid (4) was generated in 90% yield. Then, the key
compound 5 was prepared for the cyclization in the presence of PPA in the lower
yield of 61%. Lastly, 5 and arylaldehydes was subjected to Claisen–Schmidt
condensation to yield a series of new 3,4-dihydronaphthalen-1(2H)-one derivatives
(6a–f), which have been characterized by NMR, FTIR, and MS spectroscopy. Some
selected spectral data are discussed below.
In the 1H NMR spectra of 6a–f, the chemical shifts of 8.00, 7.82, 7.83, 7.79, 8.05,
and 7.58 ppm, respectively, appear as a singlet attributed to the proton of a,b-
unsaturated ketone pharmacophore. All the compounds characteristically show two
groups of triplets from the two intra-annular methylene groups at d 3.19–2.88 ppm.
From the FTIR spectra, the characteristic absorption bands in the range of
2954–2832 cm-1 correspond to the stretching vibration band of methyl and
methylene of 6a–f. The characteristic bands at around 1669–1659 cm-1 are
attributed to –C=O group in a,b-unsaturated ketone. The strong bands at around
Scheme 1 Synthetic strategy of asymmetric compounds 6a–f
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F. Wang et al.
1595–1585 cm-1 are attributed to the stretching vibration of –C=C bonds in a,b-
unsaturated ketone pharmacophore. The strong stretching vibration bands of C-O
can be found in the range of 1295 and 1222 cm-1. Additionally, 13C NMR, MS
spectroscopy further confirm the correctness of their structures.
Anticancer activity and cytotoxicity
The anticancer activities against human carcinoma cell lines Hela, Hepg2, K562,
THP-1, SW1990, MIA PaCa-2, NCI-H460 and SK-BR-3 were evaluated by the
MTT method. Doxorubicin (DOX) was selected as the positive control. As shown in
Table 1, their anticancer activities for 6a and 6c with the o-substituent group (–
OCH3 and –F) and 6e–f with the heterocyclic substituent (thiophene and furan ring)
are very poor against all the experimental cells, which can be proved from the high
IC50 values ([8 lM). The results display weaker anticancer activity than the
positive control DOX. Fortunately,the target compounds of 6b with the 3,4-
dimethoxy substituent group and 6d with the para-fluoro substituent group against
Hela, K562 and THP-1 cells were better than that against the others. Their IC50
values can be below 5.0 lM. Therefore, compounds 6b and 6d display better
anticancer activity than DOX, and their IC50 values are only 0.56 0.18 and
0.61 0.05 lM, respectively. In order to evaluate the cytotoxicity of the target
compounds, the LO2 cell line was selected as the experimental cells. The results
suggested that their IC50 values were higher than 12 lM, which cytotoxicities are
lower than DOX. Structure analysis shows that the 3,4-dihydronaphthalen-1(2H)-
one scaffold substituted by para-substituents, such as 6b and 6d, are more
beneficial for improved anticancer activity and decreased cytotoxicity toward
human carcinoma cell lines.
Inhibition activities against Bcl-2 protein
The study of inhibiting anti-apoptotic Bcl-2 proteins was explored for 3,4-
dihydronaphthalen-1(2H)-one derivatives. The binding affinities for Bcl-2 with Ki
values are about 1.89 0.15 lM of 6b and 2.05 0.11 lM of 6d, respectively,
while the binding affinities for other compounds are more than 10 lM (Table 2).
Compounds 6b and 6d are close to the positive control DOX (1.84 0.21 lM), but
Table 2 The binding affinities
of 6a–f to the Bcl-2 protein
Compd
Ki (lM)
6a
10.43 0.71
1.89 0.15
17.54 1.03
1.84 0.21
2.05 0.11
46.21 3.12
37.18 1.18
0.41 0.32
6b
6c
DOX
6d
6e
6f
AT-101
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Design, synthesis and biological evaluation of…
Fig. 1 The docking mode of compound 6b in the active site of the Bcl-2 protein
significantly higher than AT-101 (0.41 0.32 lM). To better study the interactions
of 3,4-dihydronaphthalen-1(2H)-one derivatives with the Bcl-2 protein, compound
6b with better anticancer activity and lower cytotoxicity was selected to dock with
the Bcl-2 protein in the active site using the SYBYLX 2.0 software. As shown in
Fig. 1, the 3,4-dimethoxybenzylidene group as the lipophilic group in 6b could
reasonably bind to the largest active pocket of the Bcl-2 protein, while the 3,4-
dihydronaphthalen-1(2H)-one scaffold can also orient to the other active pocket of
the Bcl-2 protein.
Conclusions
In this study, a series of new 3,4-dihydronaphthalen-1(2H)-one derivatives (6a–
f) were designed, synthesized and evaluated for their antitumor activities against
Hela, Hepg2, K562, THP-1, SW1990, MIA PaCa-2, NCI-H460 and SK-BR-3 by the
MTT method. Compounds 6b and 6d exhibited obvious anticancer activities and
lower cytotoxicities for LO2 than DOX. The inhibition activities against the Bcl-2
protein for 6b shows that lipophilic 3,4-dimethoxybenzylidene and 3,4-dihydron-
aphthalen-1(2H)-one could bind to the active pockets of the protein.
Acknowledgement Our thanks for the binding assay for Bcl-2 proteins by Prof. Xi Hu from Yantai
University in China.
References
1. Y. Komohara, M. Jinushi, M. Takeya, Cancer Sci. 105, 1 (2014)
2. E.A. Mellon, G.M. Springett, S.E. Hoffe, P. Hodul, M.P. Malafa, K.L. Meredith, W.J. Fulp, X. Zhao,
R. Shridhar, Cancer 120, 1171 (2014)
3. A. Bhatt, O. Glehen, Indian J. Surg. Oncol. 7, 188 (2016)
4. L. Wei, X. Zhang, X.Y. Hu, A.R. Hu, Med. Sci. Monit. 22, 1872 (2016)
123

F. Wang et al.
5. A.B. Cook, D.R. Ziazadeh, J. Lu, T.L. Jackson, Math. Biosci. Eng. 12, 1219 (2015)
6. Z.N. Oltvai, C.L. Milliman, S.J. Korsmeyer, Cell 74, 609 (1993)
7. Y.H. Yee, S.J. Chong, S. Pervaiz, Biol. Chem. 397, 585 (2016)
8. A.J. Souers, J.D. Leverson, E.R. Boghaert, S.L. Ackler, N.D. Catron, J. Chen et al., Nat. Med. 19, 202
(2013)
9. Y.B. Mao, W.J. Cai, J.W. Wang, G.J. Hong, X.Y. Tao, L.J. Wang, Y.P. Huang, X.Y. Chen, Nat.
Biotechnol. 25, 1307 (2007)
10. S. Trudel, Z.H. Li, J. Rauw, R.E. Tiedemann, X.Y. Wen, A.K. Stewart, Blood 109, 5430 (2007)
11. Y. Wan, S. Wu, G. Xiao, T. Liu, X. Hou, C. Chen, P. Guan, X. Yang, H. Fang, Bioorg. Med. Chem.
23, 1994 (2015)
12. J.W. Barlow, T. Zhang, O. Woods, A.J. Byrne, J.J. Walsh, Med. Chem. 7, 213 (2011)
13. A.J. Kirby, L.R. Le, F. Maharlouie, P. Mason, P.J. Nicholls, H.J. Smith, C. Simons, J. Enzyme Inhib.
Med. Chem. 18, 27 (2003)
14. A.D. Kumar, M.P. Kumar, Med. Res. Rev. 30, 818 (2010)
15. S. Das, U. Das, H. Sakagami, N. Umemura, S. Iwamoto, T. Matsuta, M. Kawase, J. Molnar, J. Serly,
´
D.K.J. Gorecki, Eur. J. Med. Chem. 51, 193 (2012)
16. Q. Chen, Y. Hou, G.G. Hou, J.F. Sun, N. Li, W. Cong, F. Zhao, H.J. Li, C.H. Wang, Res. Chem.
Intermed. 42, 8119 (2016)
17. B. Zhou, X. Li, Y. Li, Y. Xu, Z. Zhang, M. Zhou, X. Zhang, Z. Liu, J. Zhou, C. Cao, B. Yu, R. Wang,
ChemMedChem 6, 904 (2011)
18. H.A. Aisa, W. Lu, J.C. Cai, Chin. J. Chem. 21, 720 (2003)
19. F. Ameer, R.G.F. Giles, I.R. Green, R. Pearce, Synth. Commun. 34, 1247 (2004)
123