Bioorganic & Medicinal Chemistry Letters 28 (2018) 677–683

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier.com/locate/bmcl

Design, synthesis and biological evaluation of matrine derivatives as

potential anticancer agents
Zheng Li a,d, Mengyang Luo a,d, Bin Cai c, Lichuan Wu b, Mengtian Huang a, Haroon-Ur-Rashid a, Jun Jiang a,⇑,
Lisheng Wang b,⇑
a
School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi 530004, PR China
b
Medical College of Guangxi University, Guangxi 530004, PR China
c
Suzhou Galaxy biopharma, CO., LTD., Suzhou, Jiangsu 215000, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine
Received 15 November 2017 and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their
Revised 7 January 2018 potential application as anticancer agents. The structure of these compounds was characterized by 1H
Accepted 12 January 2018
NMR, 13C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro
Available online 31 January 2018
cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed
that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell
Keywords:
lines with IC50 values in range of 3.42–8.05 lM, which showed better activity than the parent compound
Matrine
Derivatives
(Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed
Pyrrole that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a
Indole dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle
Anticancer arrest of SMMC-7721 and CNE2 cells at G2/M phase.
Structure-activity relationship Ó 2018 Elsevier Ltd. All rights reserved.
Apoptosis
Cell cycle arrest

Matrine (Fig. 1) is one of the main active ingredients in Fufang-
Kushen injection. In combination with other anticancer agents
such as vinorelbine, taxol and cisplatin, matrine was also approved
by CFDA in 1995 as an adjuvant to treat non-small cell lung cancer
(NSCLC), liver cancer and gastric cancer.1–8 It has been found that
matrine displayed potent anticancer activity and induced apopto-
sis in cancer cells via downregulation of Bcl-2, upregulation of
Bax and suppression of b-catenin/survivin pathway.9–14
Owing to its multiple drug like properties, such as special scaf-
fold, simple structure and high solubility, matrine has been consid-
ered as an ideal lead compound for further structural modifications
and optimizations.15–17
In our previous study, we selected matrine as a lead compound
and successfully identified that introduction of double bond and
aromatic ring at 14 site of matrine skeleton could largely increase
its anticancer activity.18–20 The representative compound YF18
(Fig. 1), 14-napthylmethylene matrine, exhibited a significantly
enhanced anticancer activity in three human lung cancer cell lines
i.e. A549, H1975 and 95D, with IC50 ranging from 10 to 15 lM.
⇑ Corresponding authors.
E-mail addresses: jiangjun@gxu.edu.cn (J. Jiang), lswang@gxu.edu.cn (L. Wang).
d
Contributed equally.
Thus, compound YF18 showed much better anticancer activity
than matrine.20
Moreover, the introduction of nitrogen-containing heterocycle
is a ubiquitous strategy towards the structure modification of nat-
ural products as nitrogen atom can influence the interaction
between the molecule and its target.21 It is also reported that an
N-substituted pyrrole scaffold (Fig. 1) is essential to enhance anti-
cancer activity of several natural products, such as lukianol A and
lamellarin O.22 And it is well-known that a N-benzyl indole scaf-
folds possess various biological activities and continues to be a per-
vasive structural feature of many pharmacologically active
compounds, such as a newly discovered anticancer agent Indibu-
lin.23 Based on this idea, it provoked our strong interest to
introduce N-substituted pyrrole and indole group into 14 site of
matrine in order to discover a novel class of anticancer candidates
(Fig. 1).
Therefore, a variety of N-substituted pyrroles and indole were
introduced on the 14 site of matrine skeleton which resulted in
designing two series of new matrine derivatives. These derivatives
were synthesized, and biologically evaluated for their anticancer
activities. In this study, structure–activity relationship (SAR) was
first conducted to focus on the variations of the N-substitution of
pyrrole, while keeping the 14-(2-pyrrolemethylene) matrine

https://doi.org/10.1016/j.bmcl.2018.01.017
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
678 Z. Li et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 677–683

Fig. 1. Chemical structure of matrine, 14-(1-naphthalenylmethylene)matrine (YF18), lukianol A, lamellarin O, indidulin and design strategy for matrine derivatives.

scaffold intact. Similarly, N-benzyl indole group (Fig. 1), as a func-

tional group for antitumor activity, was also added on the 14 site of
matrine and then another series of 35 new 14-(N-substituted-indo-
lemethylene) matrine derivatives were designed, synthesized, and
examined for their anticancer activities. Moreover, cell death and
cell cycle of the representative compounds were explored.
As described in Scheme 1, twenty-three target compounds were
prepared using commercially available 1 as the original material.
Compounds of N-substituted pyrrole-2-carboxyaldehyde a1–a23
and N-substituted indole-carboxyaldehyde b1–b35 were obtained
by the reaction of pyrrole-2-carboxyaldehyde using alkyl halides in
the presence of NaH through a simple after-treatment and were
then directly applied in the next step without further purification.
The 14-pyrrolemethylene matrine A1–A23 (Scheme 1) and 14-
indolemethylene matrine B1–B35 (Scheme 2) were obtained
through further aldol reaction of various aromatic aldehyde with
1 in 19%–54% yields. All the synthesized compounds were purified
by silica gel column chromatography using ethyl acetate and pet-
roleum ether as gradient eluents and their structures were charac-
terized by 1H NMR, 13C NMR and ESI-MS.
As illustrated in Table 1, all the desired compounds were eval-
uated for their cytotoxic activities in three human cancer cell lines
utilizing MTT assay with matrine being tested as a comparative
compound and Cisplatin as the positive control.24
Replacing 14-H of 1 with a 1-methyl-2-pyrrolemethylene group
offered compound A1, which showed a poor activity (IC50 > 100
Scheme 1. Synthetic route for matrine derivatives. Reaction conditions: (a) NaH,
lM), while compound A2 possessing a 1-benzyl-2-pyrrolemethy- DMF, alkyl halide, 0 °C ? RT, 30 min; (b) NaH, dry THF, reflux, 24 h.
lene group at the same position exhibited a greatly improved anti-
cancer activity with an IC50 of 38.42 ± 3.05, 42.88 ± 5.08, 45.67 ±
4.35 lM against SMMC-7721, A549 and CNE2 cells respectively, Encouraged by these results, we further introduced a variety of
and was about 115–172 times lower than that of matrine. It could benzylic substituents upon 1-nitrogen atom, resulting in 21 new
be inferred that the introduction of a benzyl moiety on the nitro- 14-(N-substituted-2-pyrrolemethylene)matrine (A3–A23) deriva-
gen atom of pyrrole could significantly improve the anticancer tives. They were tested to explore the structure–activity
activity indicating that benzyl might interact with a large pocket relationship (SAR) of the substituent group variation. Among the
within the binding site. benzyl-substituted derivatives, it was found that compounds
 Z. Li et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 677–683
Scheme 2. Synthetic route for matrine derivatives. Reaction conditions: (i) NaH, DMF, alkyl halide, 0 °C ? RT, 30 min; (ii) NaH, dry THF, reflux, 36 h.
A3, A6 and A7 showed prominent cytotoxic activities against at
least one cancer cell line (IC50 < 10 lM), suggesting that methoxy-
benzyl at N-position is benefit to anticancer activity improvement.
A5, A12, A17, A18 and A22 also showed moderate anticancer activ-
ity against the three cancer cells with IC50 < 20 lM. Bearing meth-
oxy group at m-position of phenyl ring (compounds A3, A5, A6, A7)
has increased the cytotoxicity against all the three cell lines.
Among them, compound A6 decorated with 3,5-dimethoxy units
on phenyl ring exhibited the most potent cytotoxic activity against
SMMC-7721, A549 and CNE2 cells with IC50 values of 4.65 ± 0.23,
8.05 ± 0.56 and 3.55 ± 0.18 lM, respectively, stronger than those
of positive control. The compounds A2, A4, A8, A10, A14, A15,
A16, A19, A20, A21 and A23 have shown cytotoxicity in the range
of 20–40 mM against all the three cell lines.
Then, SAR analysis was focused on the substituents at the 1-
nitrogen atom of the 14-[(indol-3-yl)methylene]-matrine moiety.
In this part, a variety of benzyl were introduced into the 1-nitrogen
atom, by which 16 new 14-(N-substituted-3-indolemethylene)
matrine (compounds B1–B16) were generated and tested. All the
679
substituents were globally well tolerated and the compound B7,
B8, B9, B11, B14 and B16 is active against all the cancer cell lines
with IC50 < 10 lM, suggesting that fluorobenzyl, methylbenzyl,
tert-butylbenzyl, chlorobenzyl, trifluoromethoxybenzyl and 2-
naphthalenylmethyl at N position is beneficial for the activity.
Next, we retained the fluorobenzyl, methylbenzyl, tert-butyl-
benzyl, chlorobenzyl, trifluoromethoxybenzyl and 2-Naphthalenyl-
methyl at N-position of indolemethylene as a pharmacophore for
activity, and changed the substituents of indole or the attachment
position to the matrine core to explore the SAR. Therefore, 19
new 14-(N-substituted-3-indolemethylene) matrine were made
and tested.
We first evaluated the effects of substitutents at the positions of
the indole ring. Replacing the halogen atom of compound B17 and
B18 with a lipophilic and electron-releasing methoxyl in situ
afforded derivative B21 and B23, resulting in an dramatically
increased cytotoxicity. Changing the position of the methoxyl
group of compound B22–B23 from C-5 to C-6 of the indole ring
conferred decreased cytotoxicity on isomer B28–29.
680 Z. Li et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 677–683

Table 1
The anti-proliferative activities of matrine derivatives A1-A23 and B1-B35.

Compd. IC50 (lM) ± SDa Clog Pc

b b b
SMMC-7721 A549 CNE2
A1 >100 >100 >100 2.802
A2 38.42 ± 3.05 42.88 ± 5.08 45.67 ± 4.35 4.320
A3 13.41 ± 1.42 29.83 ± 0.95 7.05 ± 5.21 4.239
A4 41.61 ± 2.69 39.11 ± 2.11 28.81 ± 2.23 4.239
A5 12.25 ± 1.05 14.52 ± 2.12 11.59 ± 0.71 5.242
A6 4.65 ± 0.23 8.05 ± 0.56 3.55 ± 0.18 4.328
A7 13.26 ± 1.51 18.93 ± 1.64 7.83 ± 0.93 3.620
A8 22.42 ± 2.03 29.32 ± 1.92 28.42 ± 1.58 4.769
A9 30.68 ± 1.23 44.33 ± 3.99 24.46 ± 1.91 4.819
A10 27.91 ± 2.67 24.39 ± 3.03 21.94 ± 1.08 4.819
A11 49.36 ± 5.59 >50 32.11 ± 4.21 5.318
A12 16.00 ± 1.15 15.83 ± 0.88 13.85 ± 2.01 6.146
A13 >40 >40 >40 7.972
A14 25.97 ± 2.32 26.22 ± 2.84 26.32 ± 3.26 5.033
A15 20.93 ± 1.56 22.33 ± 2.41 16.33 ± 1.84 5.033
A16 21.56 ± 2.41 21.55 ± 2.06 15.17 ± 1.84 5.033
A17 15.12 ± 1.26 12.01 ± 1.05 17.34 ± 1.62 5.183
A18 16.21 ± 1.23 13.8 ± 2.01 14.97 ± 0.98 4.178
A19 17.58 ± 3.08 22.95 ± 1.58 17.84 ± 1.42 5.183
A20 34.03 ± 4.25 31.57 ± 3.95 26.43 ± 2.15 4.463
A21 36.57 ± 2.68 47.06 ± 5.21 23.91 ± 2.64 5.348
A22 12.93 ± 1.20 13.09 ± 1.51 10.84 ± 0.65 6.007
A23 20.30 ± 2.12 23.91 ± 1.96 14.71 ± 1.68 5.494
B1 11.94 ± 1.23 13.89 ± 1.31 10.83 ± 1.02 5.704
B2 13.68 ± 1.11 15.32 ± 1.43 9.31 ± 0.87 5.623
B3 8.009 ± 0.67 11.20 ± 0.98 8.43 ± 0.75 5.623
B4 11.81 ± 1.09 12.51 ± 1.54 11.59 ± 0.97 5.712
B5 15.45 ± 1.25 >50 19.98 ± 2.03 5.004
B6 11.95 ± 0.84 12.06 ± 1.16 10.83 ± 0.79 6.153
B7 8.52 ± 0.54 9.24 ± 0.85 7.91 ± 0.47 6.203
B8 9.12 ± 0.86 9.84 ± 0.94 8.91 ± 0.67 6.203
B9 9.55 ± 0.45 9.68 ± 0.67 7.73 ± 0.68 7.530
B10 17.56 ± 1.76 18.34 ± 1.54 17.43 ± 0.98 6.417
B11 7.58 ± 0.63 7.53 ± 0.47 6.36 ± 0.56 6.418
B12 11.21 ± 1.05 12.13 ± 1.54 10.98 ± 1.23 6.417
B13 16.81 ± 2.01 18.08 ± 1.45 14.74 ± 1.23 6.567
B14 6.82 ± 0.38 7.03 ± 0.65 6.64 ± 0.54 6.732
B15 9.76 ± 0.81 12.56 ± 1.43 11.72 ± 1.53 7.391
B16 5.65 ± 0.32 8.53 ± 0.19 4.56 ± 0.28 6.878
B17 9.81 ± 0.67 16.84 ± 1.54 8.50 ± 0.97 7.322
B18 8.65 ± 1.02 9.74 ± 1.21 12.5 ± 1.01 7.783
B19 11.45 ± 0.65 9.04 ± 0.89 6.04 ± 0.54 7.637
B20 6.21 ± 0.43 6.33 ± 0.63 6.06 ± 0.45 6.474
B21 3.95 ± 0.34 4.96 ± 0.54 3.42 ± 0.23 6.474
B22 5.65 ± 0.64 7.12 ± 0.56 4.65 ± 0.39 6.474
B23 6.89 ± 0.81 7.45 ± 0.68 6.72 ± 0.48 6.935
B24 8.35 ± 0.56 9.13 ± 0.78 11.8 ± 1.02 6.916
B25 3.26 ± 0.21 5.04 ± 0.43 3.53 ± 0.21 7.378
B26 23.68 ± 2.65 26.32 ± 2.76 23.74 ± 1.96 7.172
B27 9.73 ± 0.78 5.24 ± 0.89 3.52 ± 0.41 7.487
B28 8.73 ± 0.76 10.06 ± 1.11 6.84 ± 0.71 6.474
B29 9.06 ± 0.59 13.21 ± 1.23 5.42 ± 0.34 6.935
B30 6.83 ± 0.73 7.07 ± 0.32 6.64 ± 0.48 6.417
B31 28.21 ± 3.01 28.45 ± 2.43 15.53 ± 1.65 5.623
B32 13.78 ± 1.23 15.45 ± 1.12 9.75 ± 1.04 7.530
B33 25.78 ± 3.11 29.87 ± 2.71 14.56 ± 1.21 6.417
B34 10.74 ± 1.23 10.89 ± 1.31 8.99 ± 1.02 7.530
B35 27.03 ± 3.21 30.22 ± 2.61 14.32 ± 1.31 6.878
Matrine 6591 ± 521 5725 ± 602 5278 ± 498 1.361
Cisplatin 6.08 ± 0.43 8.56 ± 0.58 3.89 ± 0.23

The bold values represent the IC50 values of the representative compounds which were further explored for their cell death and cell cycle.
a
Cytotoxicity (as IC50 for each cell line) is the concentration of compound which reduced by 50% the optical density of treated cells with respect to untreated cells using the
MTT assay. IC50 values are taken as a mean from three experiments. Mean ± SD.
b
Cell lines include human hepato carcinoma (SMMC-7721), lung carcinoma (A549) and nasopharyngeal carcinoma (CNE2).
c
Clog P values produced by Chemdraw software.

Moreover, after changing the linking position of matrine It was further revealed that compound 1 and A1 with low Clog P
attached to the indole from 3-position to 4-position or 5-position, values of 1.361, 2.802, respectively, exhibited weaker antiprolifera-
respectively, compounds B30–B35 showed decreased activities tive potency. However, compounds having slightly high Clog P val-
compared with their analogues respectively. ues showed potent antiproliferative effect. These results suggested
 Z. Li et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 677–683 681

that the Clog P values of all molecules seemed to be a very impor-
tant determinant factor of the antiproliferative properties.
Interestingly, most derivatives possessed the strongest cytotox-
icity against CNE2 cells, followed by SMMC-7721 cells, and were
least cytotoxic to A549 cells. Thus, we subsequently selected A6
and B21 for further investigation to explore its anti-cancer mecha-
nisms on CNE2 and SMMC-7721 cancer cells.
In order to investigate whether compound A6 and B21 could
induce cell apoptosis, CNE2 and SMMC-7721 cells treated with 0,
5, 10, 30 lM of A6 and 0, 10, 20, 50 lM of B21, were subjected

Fig. 2. Compound A6 could induce apoptosis in CNE2 and SMMC-7721 cells in a dose-dependent manner.

Fig. 3. Compound B21 could induce apoptosis in CNE2 and SMMC-7721 cells in a dose-dependent manner.
682 Z. Li et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 677–683

to AnnexinV-FITC/propidium iodide (PI) dual staining and quanti-
fied by flow cytometry.25 As shown in Fig. 2, the percentage of
apoptotic cells (Lower right quadrant, AV+/PI and Upper right
quadrant, AV+/PI+) in CNE2 significantly increased from 4.93%
(control) to 11.96% (5 lM), 34.04% (10 lM) and 50.50% (30 lM)
respectively after treatment with different concentrations of com-
pound A6 for 24 h. And the percentage of apoptotic cells in SMMC-
7721 increased from 2.60% (control) to 19.93% (5 lM), 53.58% (10
lM) and 61.50% (30 lM), respectively. Consistently, as shown in
Fig. 3, the percentage of apoptotic cells of in CNE2 significantly
increased from 5.29% (control) to 17.52% (10 lM), 38.60% (20
lM) and 74.20% (50 lM) respectively after treatment with differ-
ent concentrations of compound B21 for 24 h. And the percentage
of apoptotic cells in SMMC-7721 increased from 2.60% (control) to
39.00% (10 lM), 58.80% (20 lM) and 95.00% (50 lM), respectively.
The results revealed that compound A6 and B21 could induce the
apoptosis of CNE2 and SMMC-7721 cells in a dose-dependent
manner.
To reveal whether the inhibition of cancer cells growth by com-
pound A6 and B21 was in associate with cell cycle arrest, CNE2 and
SMMC-7721 cells were treated with different concentrations of
compound A6 (0, 5, 10 and 30 lM) and B21 (0, 10, 20 and 50
lM) for 24 h. Cell cycle distribution was investigated by flow cyto-
metric analysis using propidium iodide staining method.26 Com-
pound B21 did not show significant cell cycle arrest (data not
shown), while compound A6 significantly cell cycle arrest as
shown in Fig. 4. The percentage of G2/M phase in CNE2 gradually
increased from 19.8% (control) to 29.5% (5 lM), 89.4% (10 lM)
and 81.1% (30 lM). Consistently, the percentage of G2/M phase
in SMMC-7721 cells increased from 18.4% (control) to 24.1% (5
lM), 78.9% (10 lM) to 79.1% (30 lM). These results confirmed that
compound A6 could arrest the cell cycle of CNE2 and SMMC-7721
cells at G2/M phase.
In summary, 58 new matrine derivatives A1–A23 and B1–B35
were synthesized, and their anti-proliferative activities against
human cancer cell lines such as SMMC-7721, A549 and CNE2 were
investigated. SAR analysis revealed that suitable nitrogen-contain-
ing heterocycle groups on 14 site of matrine were benefit to anti-
cancer activity improvement. In MTT assay, compound A6 and
B21 exhibited the most significant growth inhibition of cancer
cells. Further studies indicated that A6 exerted its anti-cancer
activity by inducing the apoptosis of CNE2 and SMMC-7721 cells
and G2/M cell cycle arrest in a dose dependent manner. B21
exerted its anti-cancer activity by inducing the apoptosis of CNE2

Fig. 4. Compound A6 could induce G2/M cell cycle arrest in CNE2 and SMMC-7721 cancer cells. (A) A6 induces G2/M cell cycle arrest in CNE2 and SMMC-7721 cells in a
dose-dependent manner. (B) Distributions of G1, S and G2/M in CNE2 and SMMC-7721 cells under A6 treatment.
 Z. Li et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 677–683
and SMMC-7721 cells. More studies are needed to explore the
precise antitumor mechanism.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21402032, 21262005), the high level
innovation team and outstanding scholar project of Guangxi
institutions of higher education (guijiaoren [2014] 49 hao),
Guangxi Natural Science Foundation (2014GXNSFBA118031,
2017GXNSFBA198240) and the State Key Laboratory for Chemistry
and Molecular Engineering of Medicinal Resources, Guangxi
Normal University (CMEMR2017-B14). We also thank Professor
Cai Bin of Suzhou Galaxy biopharma, CO., LTD. for the experiment
support.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.01.017.
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