Design, synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2018.01.017

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro 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 lines with IC₅₀ values in range of 3.42–8.05 μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.

Full text of DOI:10.1016/j.bmcl.2018.01.017

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
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
and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their
potential application as anticancer agents. The structure of these compounds was characterized by 1H
NMR, 13C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro
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
Received 15 November 2017
Revised 7 January 2018
Accepted 12 January 2018
Available online xxxx
Keywords:
Matrine
Derivatives
Pyrrole
Indole
lines with IC50 values in range of 3.42–8.05 lM, which showed better activity than the parent compound
(Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed
that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a
dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle
arrest of SMMC-7721 and CNE2 cells at G2/M phase.
Anticancer
Structure-activity relationship
Apoptosis
Ó 2018 Elsevier Ltd. All rights reserved.
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
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
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).
Contributed equally.
d
https://doi.org/10.1016/j.bmcl.2018.01.017
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Li Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.017

2
Z. Li et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
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,
DMF, alkyl halide, 0 °C ? RT, 30 min; (b) NaH, dry THF, reflux, 24 h.
lM), while compound A2 possessing a 1-benzyl-2-pyrrolemethy-
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
benzylic substituents upon 1-nitrogen atom, resulting in 21 new
14-(N-substituted-2-pyrrolemethylene)matrine (A3–A23) deriva-
tives. They were tested to explore the structure–activity
relationship (SAR) of the substituent group variation. Among the
benzyl-substituted derivatives, it was found that compounds
and was about 115–172 times lower than that of matrine. It could
be inferred that the introduction of a benzyl moiety on the nitro-
gen atom of pyrrole could significantly improve the anticancer
activity indicating that benzyl might interact with a large pocket
within the binding site.
Please cite this article in press as: Li Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.017

Z. Li et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
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 M), suggesting that methoxy-
benzyl at N-position is benefit to anticancer activity improvement.
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 M, suggesting that fluorobenzyl, methylbenzyl,
l
l
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,
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.
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
Please cite this article in press as: Li Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.017

4
Z. Li et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Table 1
The anti-proliferative activities of matrine derivatives A1-A23 and B1-B35.
Compd.
IC50
(l
M) SDa
ClogPc
SMMC-7721b
A549b
CNE2b
A1
A2
A3
A4
A5
A6
A7
A8
>100
>100
>100
2.802
4.320
4.239
4.239
5.242
4.328
3.620
4.769
4.819
4.819
5.318
6.146
7.972
5.033
5.033
5.033
5.183
4.178
5.183
4.463
5.348
6.007
5.494
5.704
5.623
5.623
5.712
5.004
6.153
6.203
6.203
7.530
6.417
6.418
6.417
6.567
6.732
7.391
6.878
7.322
7.783
7.637
6.474
6.474
6.474
6.935
6.916
7.378
7.172
7.487
6.474
6.935
6.417
5.623
7.530
6.417
7.530
6.878
1.361
38.42 3.05
13.41 1.42
41.61 2.69
12.25 1.05
4.65 0.23
13.26 1.51
22.42 2.03
30.68 1.23
27.91 2.67
49.36 5.59
16.00 1.15
>40
42.88 5.08
29.83 0.95
39.11 2.11
14.52 2.12
8.05 0.56
18.93 1.64
29.32 1.92
44.33 3.99
24.39 3.03
>50
45.67 4.35
7.05 5.21
28.81 2.23
11.59 0.71
3.55 0.18
7.83 0.93
28.42 1.58
24.46 1.91
21.94 1.08
32.11 4.21
13.85 2.01
>40
A9
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A21
A22
A23
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
B13
B14
B15
B16
B17
B18
B19
B20
B21
B22
B23
B24
B25
B26
B27
B28
B29
B30
B31
B32
B33
B34
B35
Matrine
Cisplatin
15.83 0.88
>40
25.97 2.32
20.93 1.56
21.56 2.41
15.12 1.26
16.21 1.23
17.58 3.08
34.03 4.25
36.57 2.68
12.93 1.20
20.30 2.12
11.94 1.23
13.68 1.11
8.009 0.67
11.81 1.09
15.45 1.25
11.95 0.84
8.52 0.54
9.12 0.86
9.55 0.45
17.56 1.76
7.58 0.63
11.21 1.05
16.81 2.01
6.82 0.38
9.76 0.81
5.65 0.32
9.81 0.67
8.65 1.02
11.45 0.65
6.21 0.43
3.95 0.34
5.65 0.64
6.89 0.81
8.35 0.56
3.26 0.21
23.68 2.65
9.73 0.78
8.73 0.76
9.06 0.59
6.83 0.73
28.21 3.01
13.78 1.23
25.78 3.11
10.74 1.23
27.03 3.21
6591 521
6.08 0.43
26.22 2.84
22.33 2.41
21.55 2.06
12.01 1.05
13.8 2.01
22.95 1.58
31.57 3.95
47.06 5.21
13.09 1.51
23.91 1.96
13.89 1.31
15.32 1.43
11.20 0.98
12.51 1.54
>50
12.06 1.16
9.24 0.85
9.84 0.94
9.68 0.67
18.34 1.54
7.53 0.47
12.13 1.54
18.08 1.45
7.03 0.65
12.56 1.43
8.53 0.19
16.84 1.54
9.74 1.21
9.04 0.89
6.33 0.63
4.96 0.54
7.12 0.56
7.45 0.68
9.13 0.78
5.04 0.43
26.32 2.76
5.24 0.89
10.06 1.11
13.21 1.23
7.07 0.32
28.45 2.43
15.45 1.12
29.87 2.71
10.89 1.31
30.22 2.61
5725 602
8.56 0.58
26.32 3.26
16.33 1.84
15.17 1.84
17.34 1.62
14.97 0.98
17.84 1.42
26.43 2.15
23.91 2.64
10.84 0.65
14.71 1.68
10.83 1.02
9.31 0.87
8.43 0.75
11.59 0.97
19.98 2.03
10.83 0.79
7.91 0.47
8.91 0.67
7.73 0.68
17.43 0.98
6.36 0.56
10.98 1.23
14.74 1.23
6.64 0.54
11.72 1.53
4.56 0.28
8.50 0.97
12.5 1.01
6.04 0.54
6.06 0.45
3.42 0.23
4.65 0.39
6.72 0.48
11.8 1.02
3.53 0.21
23.74 1.96
3.52 0.41
6.84 0.71
5.42 0.34
6.64 0.48
15.53 1.65
9.75 1.04
14.56 1.21
8.99 1.02
14.32 1.31
5278 498
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).
ClogP values produced by Chemdraw software.
c
Moreover, after changing the linking position of matrine
attached to the indole from 3-position to 4-position or 5-position,
respectively, compounds B30–B35 showed decreased activities
compared with their analogues respectively.
It was further revealed that compound 1 and A1 with low ClogP
values of 1.361, 2.802, respectively, exhibited weaker antiprolifera-
tive potency. However, compounds having slightly high ClogP val-
ues showed potent antiproliferative effect. These results suggested
Please cite this article in press as: Li Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.017

Z. Li et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
that the ClogP values of all molecules seemed to be a very impor-
tant determinant factor of the antiproliferative properties.
and B21 for further investigation to explore its anti-cancer mecha-
nisms on CNE2 and SMMC-7721 cancer cells.
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
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.
Please cite this article in press as: Li Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.017

6
Z. Li et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
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%
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
(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-
increased from 19.8% (control) to 29.5% (5
and 81.1% (30 M). Consistently, the percentage of G2/M phase
in SMMC-7721 cells increased from 18.4% (control) to 24.1% (5
M), 78.9% (10 M) to 79.1% (30 M). 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
lM), 89.4% (10 lM)
l
7721 increased from 2.60% (control) to 19.93% (5
M) and 61.50% (30 M), 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 M), 38.60% (20
M) and 74.20% (50 M) respectively after treatment with differ-
lM), 53.58% (10
l
l
l
l
l
l
l
l
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
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.
Please cite this article in press as: Li Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.017

Z. Li et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
7
3. Sun Q, Ma W, Gao Y, Zheng W, Zhang B, Peng Y. Afr J Tradit Complement Altern
Med Ajtcam. 2011;9:178.
4. Wang C-Y, Bai X-Y, Wang C-H. Am J Chin Med. 2014;42:543.
5. Wei R, Yang DY, Jiang WZ, Dai YY, Wan LY, Yang Z. Zhonghua Zhong Liu Za Zhi.
2011;33:391.
and SMMC-7721 cells. More studies are needed to explore the
precise antitumor mechanism.
Acknowledgments
6. Liu J, Xue M, Huang X, Wang S, Jiang Z, Zhang L. Zhongguo Zhong yao za zhi.
2012;37:1845.
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.
7. Qi L, Zhang J, Zhang Z. Chin J Chromatogr. 2013;31:249.
8. Tian J, Wang WH, Gao HM, Wang ZM. Zhongguo Zhong Yao Za Zhi. 2007;32:222.
9. Yong J, Wu X, Lu C. Curr Pharm Des. 2015;21:3673.
10. Liu TY, Yan S, Hua C, Pan SH, Sun XY. Biol Pharm Bull. 2010;33:1740.
11. Li H, Li X, Bai M, Suo Y, Zhang G, Cao X. Int J Clin Exp Path. 2015;8:14793.
12. Li H, Tan G, Jiang X, et al. Am J Chin Med. 2010;38:1115.
13. Zhou W, Xu X, Gao J, et al. Int J Clin Exp Med. 2015;8:9004.
14. Wang HQ, Jin JJ, Wang J. Oncol Rep. 2015;33:2561.
15. Peng-Yi HU, Qin Z, Hui C, Zhen-Feng WU, Yue PF, Ming Y. Chin J New Drugs.
2012;21:2662.
16. Li Y, Min G, Xue Q, Chen L, Liu W, Chen H. Biomed Chromatogr BMC.
2004;18:619.
17. Ye G, Zhu HY, Li ZX, et al. Biomed Chromatogr. 2007;21:655.
18. Wang L, You Y, Wang S, et al. Bioorg Med Chem Lett. 2012;22:4100.
19. Xie M, Yi X, Wang R, et al. Cell Physiol Biochem. 2014;33:1475.
20. Wu L, Wang G, Wei J, et al. Oncotarget. 2016;8.
A. Supplementary data
21. Xu H, Tang H, Feng H, Li Y. Eur J Med Chem. 2014;73:46.
22. Boger DL, Boyce CW, Labroli MA, Jin CASQ. J Am Chem Soc. 1999;121.
23. Yu PF, Chen H, Wang J, et al. Cheminform. 2008;39:831.
24. Wu LC, Wen ZS, Qiu YT, et al. ACS Med Chem Lett. 2013;4:921.
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.01.017.
25. Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A.
1991;34:725.
26. Rajan S, Indu S, Manish Kumar J, Naidu VGM, Wahid K, Ramakrishna S. Int J
Pharm. 2015;486:287.
J Med Chem.
References
1. Zhong LY, Wu H. Zhongguo Zhong Yao Za Zhi. 2006;31:1561.
2. Sun M, Cao H, Sun L, et al. Evid Based Complement Alternat Med.
2012;2012:373219.
Please cite this article in press as: Li Z., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.017