Synthesis and Antiproliferative Activities of Novel Substituted 5-Anilino-α-Glucofuranose Derivatives

Article abstract of DOI:10.1002/cbdv.201900739

In order to find novel antitumor candidate agents with high efficiency and low toxicity, 14 novel substituted 5-anilino-α-glucofuranose derivatives have been designed, synthesized and evaluated for antiproliferative activities in vitro. Their structures were characterized by NMR (¹H and ¹³C) and HR-MS, and configuration (R/S) at C(5) was identified by two-dimensional ¹H,¹H-NOESY-NMR spectrum. Their antiproliferative activities against human tumor cells were investigated by MTT assay. The results demonstrated that most of the synthesized compounds had antiproliferative effects comparable to the reference drugs gefitinib and lapatinib. In particular, (5R)-5-O-(3-chloro-4-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}anilino)-5-deoxy-1,2-O-(1-methylethylidene)-α-glucofuranose (9da) showed the most potent antiproliferative effects against SW480, A431 and A549 cells, with IC₅₀ values of 8.57, 5.15 and 15.24 μm, respectively. This work suggested 5-anilino-α-glucofuranose as an antitumor core structure that may open a new way to develop more potent anti-cancer agents.

Full text of DOI:10.1002/cbdv.201900739

Title: Synthesis and Antiproliferative Activities of Novel Substituted 5-
Anilino-α-Glucofuranose Derivatives
Authors: Yaling Zhang, Lili Wang, Baoli Sun, Xiabing Li, Qiaoli Hou,
Wei Wang, and Baolin Li
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To be cited as: Chem. Biodiversity 10.1002/cbdv.201900739
Link to VoR: http://dx.doi.org/10.1002/cbdv.201900739

Chemistry & Biodiversity
10.1002/cbdv.201900739
Synthesis and Antiproliferative Activities of Novel Substituted 5-Anilino-α-
Glucofuranose Derivatives
Yaling Zhang a, ‡, Lili Wang , Baoli Sun b, ‡, Xiabing Li , Qiaoli Hou , Wei Wang ,
b, ‡
*, b
b
b
*, a, b
Baolin Li
a
National Engineering Laboratory for Resource Development of Endangered Crude
Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural
Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences,
Shaanxi Normal University, Xi’an, 710119, China.
b
School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi’an,
7
10119, China.
*
Corresponding author:
xiabingli@snnu.edu.cn (Dr. Xiabing Li)
baolinli@snnu.edu.cn (Prof. Baolin Li)
‡
These authors contributed equally to this work.
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Chemistry & Biodiversity
10.1002/cbdv.201900739
Abstract
In order to find novel antitumor candidate agents with high efficiency and low toxicity,
4 novel substituted 5-anilino-α-glucofuranose derivatives have been designed,
synthesized and evaluated for antiproliferative activities in vitro. Their structures were
1
1
13
characterized by NMR ( H and C) and HRMS, and configuration (R/S) at C-5 was
1
1
identified by two-dimensional H- H NOESY-NMR spectrum. Their antiproliferative
activities against human tumor cells were investigated by MTT assay. The results
demonstrated that most of the synthesized compounds had antiproliferative effects
comparable to the reference drugs gefitinib and lapatinib. In particular, (5R)-5-(3-
chloro-4-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-isopropylidene-α-
glucofuranose (9da) showed the most potent antiproliferative effects against SW480,
A431 and A549 cells, with IC50 values of 8.57, 5.15 and 15.24 µM, respectively. This
work suggested 5-anilino-α-glucofuranose as an antitumor core structure that may open
a new way to develop more potent anti-cancer agents.
Keywords: substituted 5-anilino-α-glucofuranoses; antiproliferative activities; MTT
assay; structure-activity relationship (SAR)
1
. Introduction
Cancer is complex because of its genetics, its versatile responses to an environment in
which it has to compete to survive and thrive, and also reigns beyond the boundary of
a tumor.[1] Nowadays, kinds of approaches were used to treat cancer, targeted drugs
were one of them, especially small molecule compounds, which have been popular and
used for the therapy of various cancers in clinic. For example, many quinazoline
st
derivaties, including gefitinib, erlotinib and lapatinib, known as the 1 generation of
tyrosine kinase inhibitors (TKIs), have been used for treatment of various cancers.
Gefitinib is a selective small-molecule epidermal growth factor receptor (EGFR)-TKI
indicated for the treatment of adults with locally advanced or metastatic non-small cell
lung cancer (NSCLC) with activating mutations of EGFR tyrosine kinase.[2-4] Erlotinib,
also as an EGFR-TKI, remains the only regimen recommended by the National
Comprehensive Cancer Network for third-line treatment of NSCLC.[5] Lapatinib, as a
dual target TKI of human epidermal growth factor receptor 2 (HER-2) and EGFR, uses
in combination with capecitabine for the treatment of patients with HER-2-
overexpressing metastatic breast cancer.[6] However, they all have some limits in
clinical using, such as drug resistance of gefitinib and erlotinib,[7, 8] hepatotoxicity of
lapatinib.[9-11] Today, the 2 generation (such as afatinib, neratinib, and dacomitinib),
3rd generation (such as osimertinib and rociletinib),[12] even more 4 generation (such
as TQB3804)[13] of TKIs have been developed, and give a hope to inhibit the mutants
nd
th
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Chemistry & Biodiversity
10.1002/cbdv.201900739
of kinase, but drug resistance is still present. So, there is an urgent demand for
developing and discovering novel lead compounds for cancer therapy.
Dapagliflozin and canagliflozin (Figure 1) are sodium-dependent glucose
transporters 2 (SGLT2) inhibitors, and they are used to treatment of diabetes.[14, 15]
Recently, a new potential role for dapagliflozin and canagliflozin as an anti-cancer
agents was reported. For example, dapagliflozin can reduce the cell number of HCT116
cells, and the cause of decrease was apoptosis independent cell death, which indicate it
can be used as an anticancer reagent in tumor cell populations such as HCT116 that do
not express UGT1A9.[16] Canagliflozin can directly inhibit the growth of SGLT2-
expressing liver cancers by reducing glucose uptake and inhibiting glycolytic
metabolism in cancer cells, which suggested it can be used for treatment of
hepatocellular carcinoma.[17] Meanwhile, canagliflozin can not only lower blood
glucose but also inhibit complex-I supported respiration and cellular proliferation in
prostate and lung cancer cells.[18] Some canagliflozin derivatives were synthesized and
their anti-cancer effects were evaluated.[19] Moreover, we also reported four
dapagliflozin analogues 5-arylamino-α-glucofuranoses (Figure 1: 1aa, 1ab, 1ba and
1
bb) as anti-cancer agents.[20]
Figure 1. Structures of reported compounds and design of target compounds
Given the above facts, herein, we further optimized the structure of 1aa, using 5-
anilino-α-glucofuranose as core structure. 14 Novel substituted 5-anilino-α-
1
glucofuranose derivatives were designed through assignment different R (chlorin,
3
methyl) and R (ethoxybenzyl, ((4-fluorophenyl)thienyl)methyl) referenced from
dapagliflozin and canagliflozin as shown in Figure 1 and Table 1. Finally, they were
synthesized and their in vitro antiproliferative activities against human colon cancer
cell lines SW480, epidermoid carcinoma cell lines A431 and NSCLC cell lines A549
were evaluated.
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Chemistry & Biodiversity
10.1002/cbdv.201900739
2
2
. Results and discussion
.1. Chemistry
According to our previously reported results,[20] the synthetic route for the
substituted 5-anilino-α-glucofuranoses is outlined in Scheme 1. Firstly, four
commercially available nitrobenzoic acid derivatives (2a-2d) as starting materials
o
reacted respectively with the mixture of thionyl chloride and pyridine at 50 C for 3 h
to afford corresponding acyl chlorides 3a-3d. Compounds 3a-3d were used for the next
step reaction without further purification. They were immediately reacted with
phenetole or 2-(4-fluorophenyl)thiophene in the presence of anhydrous AlCl by
3
o
Friedel-Crafts reaction in CH
2
Cl
2
at 0 C and compounds 4a-4g were obtained in
1
9%~78% yields. Compounds 4a-4g were dissolved in CH
Et SiH in the presence of BF •Et O to provide 5a-5g in 47%~97% yields. Further, 5a-
g were reduced with NH NH •H O in the presence of FeCl and activated carbon to
give intermediates 6a-6g in 77%~97% yields. Meanwhile, the 5-hydroxyl group of 1,2-
O-isopropylidene-α- -glucofuranose (7) was selectively oxidized with (Bu Sn) O/Br
to afford 1,2-O-isopropylidene-5-keto-α-glucofuranose (8) in 98% yield. Finally, the
reductive amination of compound 8 with arylamine (6a-6g) using NaBH CN as a
3
CN and were reduced by
3
3
2
5
2
2
2
3
D
3
2
2
3
reductant gave the target compounds 5-anilino-α-glucofuranoses (9a-9g). It is worth to
mention that C-5 in compound 8 is a prochiral carbon, and the reductive amination of
6
9
and 8 can generate two configuration R and S at C-5 of 9a-9g. Thus diastereoisomers
aa-9ga and 9ab-9gb were afforded in all reductive amination, and optically pure
diastereoisomers 9aa-9ga and 9ab-9gb were finally obtained in 14%~56% yields after
silica gel chromatographic separation.
The determination of absolute configurations at C-5 of the obtained compounds
1
1
was illustrated with 9fb as an example by two-dimensional (2D) H- H NOESY NMR
1
1
spectrum. Firstly, all hydrogen resonance signals of 9fb were assigned by 2D H- H
1
COSY spectrum and the coupling constants from one dimensional H NMR. Three
resonance peaks at δ 5.25, 5.15 and 4.52 ppm were generated respectively from the H
of 3-OH, the H of 5-NH and the H of 6-OH in glucofuranose moiety. Above three
1
1
hydrogen atoms exhibited obvious NOESY correlation in H- H NOESY spectrum
Figure 2). This indicated that they are close to each other in space. Meanwhile the
(
preferential configurations of two molecules 9fa and 9fb, with 5R- and 5S-C absolute
configuration, were obtained by energy optimization using SYBYL-X2.1.1 software.
As shown in Figure 3, when the absolute configuration of C-5 is in S (Figure 3B), the
interaction distances of H of 3-OH, H of 5-NH and H of 6-OH were obviously shorter
than that in molecule with 5R- configuration (Figure 3A). These clearly suggested the
C-5 in compound 9fb is S configuration. In addition, the H of 3-OH, H of 5-NH and H
of 6-OH in molecule 9fb also exhibited NOESY correlation with the hydrogens (at δ
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Chemistry & Biodiversity
10.1002/cbdv.201900739
3
.37 ppm) of H
with H O in solution by the H-bond interactions of H
and H of 6-OH.
2
O from DMSO-d6 solvent. This indicated compound 9fb can associate
2
2
O with H of 3-OH, H of 5-NH
Scheme 1. Synthetic route of target compounds 9aa～9ga, 9ab～9gb
o
Reagents and conditions: (I) thionyl chloride, pyridine, 50 C, 3 h. (II) phenetole or 2-(4-
o
o
fluorophenyl)thiophene, AlCl
3
, CH
2
Cl
2
, 0 C. (III) CH
3
CN, Et
3
SiH, BF
3
•Et
2
O, 40 C, 2 h. (IV)
3
Sn) O/Br , CHCl ,
o
NH
2
NH
2
•H
2
O, FeCl
3
•H
2
O, activated carbon, C
2
H
5
OH, 80 C, 40 min. (V) (Bu
3
2
2
0 oC. (VI) NaBH
CN, MeOH, 70-80 C, 1 h.
o
3
1
1
Figure 2. H- H NOESY of 9fb
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Chemistry & Biodiversity
10.1002/cbdv.201900739
Figure 3. The preferential configurations of compound 9fa (A) and 9fb (B).
2
.2. Antiproliferative activity
All the synthesized compounds were evaluated for their ability to inhibit the
proliferation of the three different human tumor cell lines, including SW480, A431 and
A549, using methyl thiazolyl tetrazolium (MTT) assay.[9, 21-23] Clinical drugs, gefitinib
and lapatinib, were used as reference compounds. The indicated compound was serially
diluted with dimethyl sulfoxide (DMSO), and then diluted with the cell culture medium.
The IC50 values of these compounds are listed in Table 1. Meanwhile, previous reported
compounds 1aa, 1ab, 1ba and 1bb were also tested for their antiproliferative activities
against cancer cells in order to analyze the structure-activity relationship (SAR) of
substituted 5-anilino-α-glucofuranoses.
When SW480 (human colon cancer) cells were treated with targeted compounds,
most compounds showed certain antiproliferative activities with IC50 values in the
range of 8.57-115.70 µM except compounds 1bb and 9fb. Compounds 1aa and 9da
were the most potent agents with IC50 values of 14.72 and 8.57 µM, respectively.
Compared with gefitinib (IC50 = 12.50 µM ) and lapatinib (IC50 = 12.58 µM ), 1aa was
less potent, but 9da was more potent. Assay against A431 (human epidermoid
carcinoma) cells was also performed, and as shown in Table 1, except compounds 9aa
and 9fa, the most of tested compounds showed certain antiproliferative activities
against A431 cells, the IC50 values of them were in the range of 5.15-105.90 µM, which
were all less potent than gefitinib and lapatinib (with IC50 values of 4.45 and 4.80 µM ,
respectively). Compound 9da was the most potent agent among the synthesized
compounds. We then assessed the antiproliferative efficacy of these compounds against
A549 (human NSCLC) cells. When 100 µM compounds 9aa, 9ab, 9ba, 9fa, 9fb, 9ga
and 9gb were co-incubated with A549 cells 72 h, there was less than 50% inhibition of
the cell proliferation. Other compounds exhibited certain antiproliferative effect against
A549 cells, with the IC50 values in the range of 15.24-106.20 µM, and compounds 1aa,
9
da (IC50 values of 19.49 and 15.24 µM , respectively) showed higher antiproliferative
effect compared gefitinib (IC50 = 21.17 µM ), but lower antiproliferative effect than
lapatinib (IC50 = 14.90 µM ).
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Chemistry & Biodiversity
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Table 1. Antiproliferative activities of synthesis compounds against human cancer cell lines
IC50 (µM) a
SW480
Absolute
configuration
Compound
R
R1
R3
A431
A549
gefitinib
lapatinib
12.50±0.28
12.58±1.35
14.72±4.65
26.12±8.24
46.12±3.25
>100 b
4.45±0.25
4.80±0.71
11.25±1.76
11.60±5.16
34.62±0.96
21.17±0.47
14.90±1.21
19.49±1.32
47.48±0.31
43.33±9.30
1
1
1
1
9
9
9
9
9
9
9
aa
ab
ba
bb
aa
ab
ba
bb
ca
(5R)-
(5S)-
(5R)-
(5S)-
(5R)-
(5S)-
(5R)-
(5S)-
(5R)-
(5S)-
(5R)-
CH
CH
Cl
3
3
Cl
82.90±22.40 >100 b
>100 b
3´-Cl
3´-Cl
3´-Cl
3´-Cl
4´-Cl
4´-Cl
3´-Cl
4´-(4-ethoxybenzyl)
4´-(4-ethoxybenzyl)
4´-(2-ethoxybenzyl)
4´-(2-ethoxybenzyl)
3´-(2-ethoxybenzyl)
3´-(2-ethoxybenzyl)
115.70±15.34 >100 b
79.46±8.46
63.19±0.57
52.28±8.78
35.27±0.16
39.22±4.27
8.57±2.80
78.71±25.30 >100 b
83.58±28.89 106.20±33.81
34.99±2.18
18.84±3.27
21.01±1.41
5.15±0.40
70.88±8.14
48.43±0.27
57.28±4.25
15.24±6.64
cb
da
4
´-(5-(4-fluorophenyl)
thienyl)methyl
´-(5-(4-fluorophenyl)
thienyl)methyl
´-(5-(4-fluorophenyl)
thienyl)methyl
´-(5-(4-fluorophenyl)
thienyl)methyl
´-(5-(4-fluorophenyl)
thienyl)methyl
´-(5-(4-fluorophenyl)
thienyl)methyl
´-(5-(4-fluorophenyl)
thienyl)methyl
´-(5-(4-fluorophenyl)
thienyl)methyl
The values are mean ± SD of at least three independent experiments.
4
9
9
9
9
9
9
9
db
ea
eb
fa
(5S)-
(5R)-
(5S)-
(5R)-
(5S)-
(5R)-
(5S)-
3´-Cl
30.04±14.31 16.85±1.05
30.57±0.79
3
4´-Cl
60.75±3.35
22.37±4.26
97.38±30.02 48.02±14.64
3
4´-Cl
20.08±0.93
68.85±22.24
>100 b
3
4´-CH
4´-CH
2´-CH
2´-CH
3
3
3
3
67.06±14.17 >100 b
3
>100 b
105.90±7.62 >100 b
102.70±3.40 >100 b
91.61±3.28
>100 b
fb
3
ga
gb
46.44±2.78
49.55±9.94
3
[
[
a]
b]
IC50 was not calculated because less than 50% inhibition was observed at the highest concentration (100 µM).
Furthermore, compounds with ethoxybenzyl, 4´-CH substituent (1aa and 1ab)
3
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Chemistry & Biodiversity
10.1002/cbdv.201900739
could give more potent effect than 4´-Cl or 3´-Cl substituent (1ba, 1bb, 9aa～9cb), and
(
(
5R)-5-anilino-α-glucofuranose (1aa) showed a higher antiproliferative effects than
5S)-5-anilino-α-glucofuranose (1ab) against SW480, A431 and A549 cells.
Compounds with 5-(4-fluorophenyl)thienyl methyl, Cl substituent (9da, 9db and 9eb)
showed more potent effects than CH substituents (9fa～9gb) when against three tested
3
cell lines, and also, substituted (5R)-5-anilino-α-glucofuranoses (9da, 9fa, 9ga) showed
a higher antiproliferative effect than substituted (5S)-5-anilino-α-glucofuranoses (9db,
9
fb, 9gb) against SW480 cell line. So, CH - group combined with ethoxybenzyl or Cl
3
combined with 5-(4-fluorophenyl)thienyl methyl may be the advantage groups for
substituted 5-anilino-α-glucofuranose as anti-cancer agents.
Notably, compound 9da with 3´-Cl and 4´-(5-(4-fluorophenyl)thienyl)methyl
groups showed the highest antiproliferative activities against all tested cancer cells,
SW480, A431 and A549 (with IC50 values of 8.57, 5.15 and 15.24 µM , respectively).
In addition, as shown in Figure 4, compound 9da exhibited a good dose-response
relationship when three tumor cells were treated with different concentration of 9da for
7
2 h (Figure 4).
Figure 4. Dose response curve of inhibition rate to series concentrations of 9da, gefitinib and
lapatinib against human cancer cell lines.
(
A) SW480 cells, (B) A431 cells, (C) A549 cells. Cells were treated with 9da or gefitinib or lapatinib
at the series indicated concentrations, and viable cells were measured after 72 h of treatment. All
error bars represent in mean±SEM.
3
. Conclusions
1
4 novel substituted 5-anilino-α-glucofuranose derivatives have been designed and
synthesized. Their antiproliferative activities against human tumor cell lines in vitro
were investigated. The results demonstrated that all synthesized compounds had certain
antiproliferative effects compared to the reference drugs gefitinib and lapatinib.
Compound 9da showed the most potent antiproliferative effects against SW480, A431
and A549 cell lines (with IC50 values of 8.57, 5.15 and 15.24 µM , respectively).
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Chemistry & Biodiversity
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Preliminary SAR analysis indicated that CH combined with ethoxybenzyl or Cl
3
combined with 5-(4-fluorophenyl)thienyl methyl maybe the advantage groups for
substituted 5-anilino-α-glucofuranoses as anti-cancer agents. 5-anilino-α-
glucofuranose as a core structure may give a new way to development more potent anti-
cancer agents. Further investigations of this novel class of compounds are underway in
our laboratory.
4
4
. Experimental section
.1. General
Human cancer cell lines SW480, A431 and A549 were purchased from the Cell
Bank of the Chinese Academy of Sciences (Shanghai, China). Dulbecco’s Modified
Eagle’s Medium (DMEM) and fetal bovine serum (FBS) were purchased from Gibco.
Trypsin, penicillin-streptomycin (P/S) and L-glutamate were purchased from Sigma-
Aldrich. All other reagents and solvents were analytical grade; they were supplied by
local commercial suppliers and used without further purification unless otherwise
noted.
NMR spectra were obtained using a Super-conducting Fourier Digital NMR
spectrometer 300, 400, 600 MHz (BrukerAvance III) instrument at room temperature,
and chemical shifts were reported in parts per million (ppm, d) downfield from
tetramethylsilane (TMS). Coupling constants (J) were reported in Hz. Spin
multiplicities were described as s (singlet), brs (broad singlet), d (double), t (triplet), q
(quartet), and m (multiplet). The high-resolution mass spectra (HRMS) were measured
using Bruker Esquire 3000plus mass spectrometer. Melting point (m.p) was determined
using a digital melting point apparatus (Beijing Tektronix Instrument Co. Ltd.,
Zhengzhou, China).
4
4
.2. Chemistry
.2.1. General procedure for the preparations of 4a-4g.
A suspension of nitrobenzoic acid derivatives 2a-2d (25 mmol) in 8 mL thionyl
chloride containing 100 μL pyridine was heated at 50 °C for 3 h, then the solvent was
removed under reduced pressure to provide 3a-3d, which was used for the next step
without further purification.
At 0 °C , the crude 3a dissolved in CH
mixture (anhydrous AlCl (37 mmol) and phenetole (27 mmol)) dissolved in 45 mL
CH Cl . The resulting mixture continued to react at 0-5 °C to give a dark green solution.
2
Cl (14 mL) was added to the stirring
2
3
2
2
After completion of the reaction as indicated by TLC, the solution was poured into 80
mL 2 N HCl aqueous solution and stirred at room temperature for 20 min. The mixture
was extracted with CH
2
Cl , then the organic phase was washed with water and brine,
2
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Chemistry & Biodiversity
10.1002/cbdv.201900739
dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified
by silica column chromatography (ethyl acetate: petroleum ether = 1 : 20) to provide
compound 4a and 4b. Products 4c were prepared from 3c with phenetole, while
products 4d-4g were created from 3a-3d with 2-(4-fluorophenyl)thiophene according
to the same method of 3a.
(
2-Chloro-4-nitrophenyl)(4-ethoxyphenyl)methanone (4a). White solid, yield
1
5
5%. m.p.: 94.6~96.2 ℃. H NMR (600 MHz, CDCl
3
) δ: 8.34 (d, J = 2.1 Hz, 1H), 8.23
(
dd, J = 8.3, 2.1 Hz, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 6.95 (d, J
1
3
=
9.0 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H). C NMR (151 MHz,
) δ: 191.7, 164.3, 148.7, 145.0, 132.5, 132.4, 129.5, 128.1, 125.2, 121.9, 114.7,
4.1, 14.6.
CDCl
3
6
(
2-Chloro-4-nitrophenyl)(2-ethoxyphenyl)methanone (4b). White solid, yield
1
2
0%. m.p.: 86.7~88.7 ℃. H NMR (600 MHz, CDCl
3
) δ: 8.27 (d, J = 2.1 Hz, 1H), 8.17
(
dd, J = 8.4, 2.1 Hz, 1H), 7.91 (dd, J = 7.8, 1.8 Hz, 1H), 7.59~7.53 (m, 1H), 7.51 (d, J
8.4 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.84 (q, J = 7.0 Hz,
=
1
3
2
1
H), 0.85 (t, J = 7.0 Hz, 3H). C NMR (151 MHz, CDCl
3
) δ: 192.6, 158.9, 148.2,
47.9, 135.7, 131.9, 131.2, 128.9, 125.8, 124.7, 121.7, 121.0, 112.3, 63.8, 13.8.
(
2-Chloro-5-nitrophenyl)(2-ethoxyphenyl)methanone (4c). White solid, yield
1
1
7
9%. m.p.: 86.5~88 ℃. H NMR (600 MHz, CDCl
3
) δ: 8.21 (dd, J = 7.7, 2.3 Hz, 2H),
.90 (dd, J = 7.8, 1.8 Hz, 1H), 7.61~7.50 (m, 2H), 7.14~7.04 (m, 1H), 6.88 (d, J = 8.4
1
3
Hz, 1H), 3.84 (q, J = 7.0 Hz, 2H), 0.85 (t, J = 7.0 Hz, 3H). C NMR (151 MHz, CDCl
δ: 192.0, 158.8, 146.3, 143.1, 137.8, 135.6, 131.3, 130.6, 125.9, 124.7, 123.6, 121.0,
12.3, 63.7, 13.9.
2-Chloro-4-nitrophenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone
3
)
1
(
(4d).
1
White solid, yield 75%. m.p: 62.8~63.4 ℃. HNMR (600 MHz, CDCl
3
) δ: 8.36 (d, J =
2
7
1
1
.1 Hz, 1H), 8.25 (dd, J = 8.3, 2.1 Hz, 1H), 7.68~7.63 (m, 3H), 7.34 (d, J = 4.0 Hz, 1H),
1
3
.28 (d, J = 4.0 Hz, 1H), 7.14 (t, J = 8.6 Hz, 2H). CNMR (151 MHz, CDCl ) δ: 184.6,
3
64.4, 162.8, 154.8, 149.0, 143.9, 140.9, 137.3, 132.7, 129.5, 129.2, 129.1, 128.4,
28.4, 125.5, 124.4, 121.8, 116.5, 116.7.
(
2-Chloro-5-nitrophenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone (4e). Light
1
yellow solid, yield 78 %. m.p.: 155.4~156.1 ℃. HNMR (600 MHz, CDCl
3
) δ: 8.32 (s,
1
H), 8.28 (d, J = 6.4 Hz, 1H), 7.70~7.60 (m, 3H), 7.38~7.32 (m, 1H), 7.27 (s, 1H), 7.11
1
3
(
t, J = 8.3 Hz, 2H). C NMR (151 MHz, CDCl
3
) δ: 184.9, 165.3, 163.6, 155.7, 147.1,
41.8, 140.1, 139.2, 138.3, 132.4, 129.3, 128.5, 127.5, 126.7, 125.4, 124.9, 117.4,
17.3.
5-(4-Fluorophenyl)thiophen-2-yl)(2-methyl-5-nitrophenyl)methanone (4f). Light
1
1
(
1
yellow solid, yield 76 %. H NMR (400 MHz, CDCl
3
) δ: 8.33 (d, J = 2.4 Hz, 1H), 8.25
(
dd, J = 8.4, 2.4 Hz, 1H), 7.66 (dd, J = 8.8, 5.2 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.38
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1
3
(
d, J = 4.0 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 2.51 (s, 3H). C
NMR (101MHz, CDCl ) δ: 187.3,164.7, 162.2, 154.1, 145.6, 144.5, 142.1, 139.2,
36.9, 132.2, 132.2, 129.3, 128.3, 124.9, 124.3, 122.8, 116.5, 116.3, 19.9.
3
1
(
5-(4-Fluorophenyl)thiophen-2-yl)(2-methyl-3-nitrophenyl)methanone
(4g).
) δ:
1
Light yellow solid, yield 73 %. m.p.: 126.8~127.4 ℃. HNMR (600 MHz, CDCl
3
7
.87 (d, J = 8. 0 Hz, 1H), 7.59~7.53 (m, 3H), 7.37 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 4.0
1
3
Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 7.04 (t, J = 8.5 Hz, 2H), 2.40 (s, 3H). C NMR (151
MHz, CDCl ) δ: 188.0, 164.3, 162.7, 154.2, 150.9, 142.3, 141.6, 137.1, 131.3, 130.8,
29.3, 129.3, 128.3, 128.3, 126.5, 125.7, 124.3, 116.5, 116.3, 16.3.
.2.2. General procedure for the preparations of 5a-5g
CN (6 mL), then triethylsilane (3
3
1
4
Compound 4a (0.63 g, 2 mmol) was dissolved in CH
3
mL) and the solution of boron trifluoride in diethyl ether (1.5 mL) were added. The
mixture was headed to 40 ℃ for 2 h. After cooling to room temperature, the reaction
mixture was neutralized with saturated aqueous NaHCO solution and extracted with
3
ethyl acetate. The organic layer was washed with water and saturated brine, dried and
concentrated in vacuo to give 5a of a pale yellow solid, yield 92%. Products 5b～5g
were prepared according to the same method of 5a.
2
-Chloro-1-(4-ethoxybenzyl)-4-nitrobenzene (5a). Yellow solid, yield 92%. m.p.:
1
5
8
2
1.4~52.7 ℃. H NMR (600 MHz, CDCl
3
) δ: 8.23 (d, J = 2.1 Hz, 1H), 8.00 (dd, J =
.5, 2.3 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz,
1
3
H), 4.09 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). C NMR (151
) δ: 157.9, 146.9, 146.8, 134.9, 131.2, 130.1, 129.4, 124.7, 121.8, 114.8,
3.5, 38.5, 14.9.
MHz, CDCl
3
6
2
-Chloro-1-(2-ethoxybenzyl)-4-nitrobenzene (5b). Yellow solid, yield 45%. m.p.:
1
2
3~24.5℃. H NMR (600 MHz, CDCl
3
) δ: 8.24 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.25
(
d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.2
1
3
Hz, 1H), 4.14 (s, 2H), 4.00 (tt, J = 6.9, 3.5 Hz, 2H), 1.33 (td, J = 6.9, 1.2 Hz, 3H). C
NMR (151 MHz, CDCl ) δ: 156.8, 146.6, 146.6, 134.9, 131.1, 130.7, 128.4, 126.21,
24.4, 121.4, 120.5, 111.4, 63.5, 34.1, 14.8.
3
1
1
-Chloro-2-(2-ethoxybenzyl)-4-nitrobenzene (5c). Yellow solid, yield 41%. m.p.:
1
9
8
0.8~92.5 ℃. H NMR (300 MHz, CDCl
3
) δ: 8.10 (d, J = 2.4 Hz, 1H), 7.97 (dd, J =
.7, 2.5 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.20 (dd, J = 12.8, 8.1 Hz, 2H), 6.89 (dd, J
13.8, 7.6 Hz, 2H), 4.14 (s, 2H), 4.02 (dd, J = 13.9, 6.9 Hz, 2H), 1.38 (t, J = 6.9 Hz,
=
1
3
3
1
H). C NMR (75 MHz, CDCl
3
) δ: 156.8, 146.5, 141.1, 140.7, 130.8, 130.0, 128.5,
26.1, 126.0, 122.1, 120.4, 111.4, 63.5, 34.1, 14.8.
2
-(2-Chloro-4-nitrobenzyl)-5-(4-fluorophenyl)thiophene (5d). Yellow solid, yield
1
9
8
7%. m.p.: 131.6~132.2 ℃. H NMR (600 MHz, CDCl
3
) δ: 8.27 (d, J = 2.3 Hz, 1H),
.07 (dd, J = 8.5, 2.3 Hz, 1H), 7.48 (dd, J = 8.7 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 7.07
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1
3
(
d, J = 3.6 Hz, 1H), 7.03 (t, J = 8.7 Hz, 2H), 6.81 (d, J = 3.6 Hz, 1H), 4.33 (s, 2H). C
NMR (151 MHz, CDCl ) δ: 163.1, 161.5, 147.2, 145.2, 142.8, 139.2, 134.7, 131.0,
30.5, 130.4, 127.5, 127.3, 127.3, 124.8, 123.0, 122.0, 115.9, 115.8, 33.82.
3
1
2
-(2-Chloro-5-nitrobenzyl)-5-(4-fluorophenyl)thiophene (5e). Yellow solid, yield
1
9
6%. m.p.: 81.6~82.3 ℃. HNMR (600 MHz, CDCl
3
) δ: 7.28 (d, J = 2.6 Hz, 1H), 7.17
(
dd, J = 8.7, 2.6 Hz, 1H), 6.66 (d, J = 8.7 Hz, 1H), 6.60 (dd, J = 8.6 Hz, 2H), 6.19 (d, J
1
3
=
3.5 Hz, 1H), 6.15 (t, J = 8.6 Hz, 2H), 5.94 (d, J = 3.5 Hz, 1H), 3.44 (s, 2H). C NMR
) δ: 163.9, 162.2, 147.5, 143.5, 141.5, 140.5, 140.1, 131.3, 131.2,
31.2, 128.1, 128.1, 128.0, 126.1, 123.8, 123.7, 116.7, 116.5, 34.6.
-(4-Fluorophenyl)-5-(2-methyl-5-nitrobenzyl)thiophene (5f). Yellow solid, yield
(151 MHz, CDCl
3
1
2
1
9
6%. H NMR (600 MHz, DMSO-d ) δ: 8.13 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.3, 2.5
6
Hz, 1H), 7.61 (dd, J = 8.8, 5.3 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 3.6 Hz,
1
3
1
H), 7.21 (t, J = 8.9 Hz, 2H), 6.89 (d, J = 3.6 Hz, 1H), 4.31 (s, 2H), 2.43 (s, 3H). C
NMR (151 MHz, DMSO-d ) δ: 162.3, 160.7, 145.9, 144.9, 141.6, 140.9, 140.4, 131.4,
30.3, 127.2, 127.0, 123.6, 121.7, 115.9, 115.8, 32.8, 19.2.
6
1
2
-(4-Fluorophenyl)-5-(2-methyl-3-nitrobenzyl)thiophene (5g). Yellow solid, yield
1
9
6
=
7%. m.p.: 97.4~98.2 ℃. HNMR (600 MHz, CDCl
3
) δ: 6.42 (d, J = 8.0 Hz, 1H),
.24~6.17 (m, 3H), 6.03 (t, J = 8.0 Hz, 1H), 5.77 (dd, J = 15.0, 6.1 Hz, 3H), 5.40 (d, J
1
3
3.2 Hz, 1H), 2.95 (s, 2H), 1.17(s, 3H). C NMR (151 MHz, CDCl ) δ: 157.8, 156.2,
3
1
1
46.3, 137.0, 136.2, 135.8, 128.4, 125.5, 125.3, 125.3, 122.0, 121.9, 121.3, 121.3,
17.6, 117.5, 110.7, 110.5, 29.1, 9.7.
4
.2.3. General procedure for the preparations of 6a-6g
The mixture of compound 5a (2.92 g, 10 mmol), activated carbon (1.5 g) and
FeCl3·6H O (0.20 g) was added to EtOH (30 mL), then NH O (4.0 mL) was
2
2
NH2 · H
2
dropwise added. The reaction mixture was stirred under reflux for 40 min, and the hot
solution was filtered. A large amount of white crystals was precipitated with ice water,
collected by suction filtration, washed with water and dried to give 6a. Products 6b-6g
were prepared according to the same method of 6a.
3
-Chloro-4-(4-ethoxybenzyl)aniline (6a). White solid, yield 90%. m.p.:
1
8
7.1~88.6 ℃. H NMR (600 MHz, CDCl
3
) δ: 7.09 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.2
Hz, 1H), 6.87~6.78 (m, 2H), 6.72 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.2, 2.4 Hz, 1H),
1
3
4
.01 (q, J = 7.0 Hz, 2H), 3.93 (s, 2H), 3.57 (s, 2H), 1.41 (t, J = 7.0 Hz, 3H). C NMR
151 MHz, CDCl ) δ: 157.3, 145.7, 134.5, 132.4, 131.5, 129.7, 128.8, 115.8, 114.4,
13.9, 63.4, 37.5, 14.9.
(
3
1
3
-Chloro-4-(2-ethoxybenzyl)aniline (6b). Light yellow solid, yield 77%. m.p.:
1
5
8.4~59.5 ℃. H NMR (300 MHz, CDCl
3
) δ: 7.16 (t, J = 7.0 Hz, 1H), 6.99 (d, J = 6.8
Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 7.1, 4.2 Hz, 2H), 6.70 (d, J = 2.1 Hz,
1
H), 6.46 (dd, J = 8.1, 2.1 Hz, 1H), 4.01 (dd, J = 15.9, 9.0 Hz, 4H), 3.44 (s, 2H), 1.38
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1
3
(
t, J = 6.9 Hz, 3H). C NMR (75 MHz, CDCl
3
) δ: 156.8, 145.5, 134.8, 131.8, 130.1,
1
29.0, 128.1, 127.3, 120.3, 115.7, 113.8, 111.2, 63.6, 32.5, 14.9.
4
-Chloro-3-(2-ethoxybenzyl)aniline (6c). Light yellow solid, yield 85%. m.p.:
1
1
19~120 ℃. H NMR (600 MHz, CDCl
3
) δ: 7.18 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 8.4
Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.85 (t, J = 7.3 Hz, 2H), 6.44 (dd, J = 8.4, 2.8 Hz,
1
1
1
H), 6.41 (d, J = 2.7 Hz, 1H), 4.02 (dd, J = 13.9, 7.0 Hz, 2H), 3.99 (s, 2H), 3.37 (s, 2H),
1
3
.37 (dt, J = 6.9, 1.3 Hz, 3H). C NMR (151 MHz, CDCl
3
) δ: 156.8, 145.0, 139.2,
30.3, 129.7, 128.3, 127.4, 123.6, 120.3, 117.5, 114.2, 111.3, 63.6, 33.3, 14.9.
3
-Chloro-4-((5-(4-fluorophenyl)thiophen-2-yl)methyl)aniline (6d). White solid,
1
yield 97%. m.p.: 163.4~164.1 ℃. H NMR (600 MHz,DMSO-d
6
) δ: 7.56 (dd, J = 8.3,
5
6
.5 Hz, 2H), 7.23 (d, J = 3.5 Hz, 1H), 7.17 (t, J = 8.2 Hz, 2H), 7.04 (d, J = 8.3 Hz, 1H),
.79 (d, J = 3.5 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 6.51 (dd, J = 8.2, 1.8 Hz, 1H), 5.31
1
3
(
s, 2H), 4.03 (s, 2H). C NMR (151 MHz, DMSO-d
6
) δ: 162.2, 160.6, 149.0, 144.0,
40.2, 133.0, 131.3, 130.6, 130.6, 126.9, 126.1, 123.8, 123.4, 123.3, 115.9, 115.8,
13.8, 113.8, 113.1, 39.5, 32.3.
1
1
4
-Chloro-3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)aniline (6e). White solid,
1
yield 92%. m.p.: 145.7~146.2 ℃. HNMR (600 MHz, DMSO-d
6
) δ: 7.62 (dd, J = 8.8
Hz, 2H), 7.30 (d, J = 3.6 Hz, 1H), 7.22 (t, J = 8.8 Hz, 2H), 7.11 (d, 1H), 6.89 (d, J = 3.6
1
3
Hz, 1H), 6.66 (d, J = 2.7 Hz, 1H), 6.58~6.54 (m,1H), 5.73 (s,2H), 4.12 (s,2H). C NMR
151 MHz, DMSO-d ) δ: 162.2, 160.6, 147.0, 142.3, 140.6, 137.6, 130.5, 130.5, 129.6,
27.0, 126.9, 126.8, 123.4, 119.4, 116.3, 115.9, 115.8, 114.6, 33.2.
(
6
1
3
-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylaniline (6f). Light yellow
1
solid, yield 94%. H NMR (400 MHz, DMSO-d
6
) δ: 7.59 (dd, J = 8.6, 5.4 Hz, 2H), 7.26
(
d, J = 3.5 Hz, 1H), 7.19 (t, J = 8.8 Hz, 2H), 6.81 (dd, J = 9.2, 5.8 Hz, 2H), 6.48 (d, J =
1
3
2
.2 Hz, 1H), 6.40 (dd, J = 8.0, 2.3 Hz, 1H), 4.83 (s, 2H), 3.97 (s, 2H), 2.12 (s, 3H). C
) δ: 162.6, 160.1, 146.7, 144.0, 140.1, 138.4 130.6, 130.6,
30.5, 126.9, 126.8, 126.2, 123.3, 122.5, 115.9, 115.7, 115.2, 112.6, 33.5, 18.1.
NMR (101 MHz, DMSO-d
6
1
4
-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-3-methylaniline (6g). Light yellow
1
solid, yield 96%. m.p.: 116.8~117.3 ℃. H NMR (600 MHz, DMSO-d
6
) δ: 7.57 (dd, J
=
8.9, 5.3 Hz, 2H), 7.24 (d, J = 3.6 Hz, 1H), 7.18 (t, J = 8.9 Hz, 2H), 6.87 (t, J = 7.7
Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H),
1
3
4
1
4
.84 (s, 2H), 4.05 (s, 2H), 2.01 (s, 3H). C NMR (151 MHz, DMSO-d ) δ: 162.1, 160.5,
6
46.9, 144.6, 115.9, 115.7, 113.3, 34.1, 12.8.
.2.4. Preparation of 1,2-O-isopropylidene-5-keto-α-glucofuranose (8).
According to reference methods,[24] a mixture of 1,2-O-isopropylidene-α-D-
glucofuranose (7, 2.20 g, 10 mmol) and bis(tributyltin) oxide (11.91 g, 20 mmol) were
dissolved in CHCl (60 mL), then was refluxed with stirring for 1 h until dissolved
3
completely. The solution was cooled to room temperature, and bromine was dropwise
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Chemistry & Biodiversity
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added under ice bath, then stirred for about 5 min. After the completion of the reaction
monitored by TLC), the mixture was directly concentrated and purified by silica
(
column chromatography (ethyl acetate: acetone = 1: 1) to provide a light yellow syrupy
liquid 8.
1
,2-O-isopropylidene-5-keto-α-glucofuranose (8). Light yellow syrupy liquid,
1
yield 98%. H NMR (300 MHz, D
2
O) δ: 6.05 (d, J = 3.5 Hz, 1H), 4.86 (d, J = 3.6 Hz,
1
H), 4.69 (s, 1H), 4.63 (d, J = 3.6 Hz, 1H), 4.56 (s, 1H), 4.42 (d, J = 3.6 Hz, 1H), 1.43
1
3
(
s, 3H), 1.29 (s, 3H). C NMR (75 MHz, D O) δ: 207.1, 112.2, 104.2, 83.8, 83.6, 74.4,
2
6
5.7, 25.2, 24.6.
.2.5. General procedure for the preparation of 9aa-9ga and 9ab-9gb
CN (0.66 g, 10.4 mmol) were
OH (10 mL), compound 8 (4.10 g, 19 mmol) and 4 A molecular sieve
0.80 g) were added, and the resulting mixture was refluxed for 1 h. The solvent was
4
After compound 6a (0.69 g, 2.6 mmol) and NaBH
3
dissolved in CH
3
(
removed under reduced pressure. After that the resulting mixture was mixed with water,
extracted by ethyl acetate. The organic phase was washed with brine, dried over
anhydrous sodium sulfate, flitered and evaporated. The residue was purified by silica
column chromatography (methanol:chloroform = 1:80, V/V) to give target compounds
9
aa and 9ab. Compounds 9ba-9gb were prepared according to the same method of 9aa
and 9ab.
5R)-5-(3-Chloro-4-(4-ethoxybenzyl)anilino)-1,2-O-isopropylidene-α-
(
2
4
glucofuranose (9aa). White solid, yield 17%. m.p.: 130.4~131.7 ℃. [α] -20 (c 0.02,
D
1
DMSO). H NMR (600 MHz, DMSO-d
6
) δ: 7.05 (d, J = 8.50 Hz, 2H), 6.94 (d, J = 8.4
Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.4, 2.2 Hz,
H), 5.81 (d, J = 3.7 Hz, 1H), 5.63 (d, J = 8.6 Hz, 1H), 5.28 (d, J = 5.0 Hz, 1H), 4.82
t, J = 5.3 Hz, 1H), 4.43 (d, J = 3.8 Hz, 1H), 4.07 (dd, J = 8.7, 2.4 Hz, 1H), 4.01 (dd, J
4.8, 2.6 Hz, 1H), 3.95 (q, J = 7.0 Hz, 2H), 3.79 (s, 2H), 3.61~3.54 (m, 1H), 3.54~3.46
1
(
=
1
3
(
m, 2H), 1.39 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H), 1.23 (s, 3H). C NMR (151 MHz,
DMSO-d ) δ: 156.7, 148.5, 133.2, 132.5, 131.2, 129.3, 124.5, 114.1, 112.1, 111.7,
10.2, 103.9, 85.1, 81.1, 73.4, 62.8, 60.6, 53.7, 36.6, 26.6, 26.1, 14.7. IR νmax(KBr) cm-
6
1
1:
3423, 3308, 2985, 2918, 1619, 1582, 1515, 1475, 1442, 1390, 1305, 1246, 1161,
486.1659
1
120, 1057, 1006, 965, 924, 858, 814, 762. HRMS calcd for C24
H
30ClNO
6
+
[
M+Na] , found 486.1644.
(
5S)-5-(3-Chloro-4-(4-ethoxybenzyl)anilino)-1,2-O-isopropylidene-α-
2
4
glucofuranose (9ab). White solid, yield 49%. m.p.: 114.5~115.2 ℃. [α] -1.3 (c 0.02,
D
1
DMSO). H NMR (600 MHz, DMSO-d
6
) δ: 7.05 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.4
Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 2.3 Hz, 1H), 6.55 (dd, J = 8.4, 2.3 Hz,
H), 5.82 (d, J = 3.7 Hz, 1H), 5.57 (d, J = 9.4 Hz, 1H), 5.27 (d, J = 5.0 Hz, 1H), 4.58
1
(t, J = 5.3 Hz, 1H), 4.37 (d, J = 3.7 Hz, 1H), 4.07 (dd, J = 9.2, 2.4 Hz, 1H), 3.98 (dd, J
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Chemistry & Biodiversity
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=
4.9, 2.7 Hz, 1H), 3.95 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 3.66 (dd, J = 13.1, 9.2, 3.7
Hz, 1H), 3.63~3.57 (m, 1H), 3.50~3.42 (m, 1H), 1.39 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H),
1
3
1
1
2
1
.23 (s, 3H). C NMR (151 MHz, DMSO-d
6
) δ: 156.7, 148.1, 133.1, 132.5, 131.1,
29.3, 124.7, 114.1, 112.7, 112.0, 110.4, 104.3, 84.8, 79.2, 72.9, 62.8, 60.5, 51.9, 36.6,
-1
6.7, 26.1, 14.7. IR νmax(KBr) cm : 3426, 3345, 3197, 2929, 1770, 1609, 1578, 1503,
379, 1309, 1249, 1218, 1162, 1069, 923, 887, 858, 803, 705. HRMS calcd for
+
C
24
H
30ClNO
6
486.1659 [M+Na] , found 486.1644.
(
5R)-5-(3-Chloro-4-(2-ethoxybenzyl)anilino)-1,2-O-isopropylidene-α-
2
4
glucofuranose (9ba). White solid, yield 24%. m.p.: 135.2~136.6 ℃. [α] -2.2 (c 0.01,
D
1
CHCl
3
). H NMR (600 MHz, DMSO-d
6
) δ: 7.14 (t, J = 7.5 Hz, 1H), 6.96~6.85 (m, 3H),
6
5
3
1
.81 (t, J = 7.3 Hz, 1H), 6.67 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 5.81 (d, J = 3.2 Hz, 1H),
.62 (d, J = 8.4 Hz, 1H), 5.29 (d, J = 4.7 Hz, 1H), 4.83 (t, J = 4.9 Hz, 1H), 4.43 (d, J =
.3 Hz, 1H), 4.08 (d, J = 8.5 Hz, 1H), 4.02 (d, J = 6.6 Hz, 3H), 3.81 (s, 2H), 3.59 (s,
1
3
H), 3.51 (d, J = 3.7 Hz, 2H), 1.40 (s, 3H), 1.33 (t, J = 6.8 Hz, 3H), 1.23 (s, 3H). C
) δ: 156.1, 148.3, 133.4, 131.3, 129.3, 128.5, 127.1, 123.2,
19.9, 112.0, 111.5, 111.3, 110.2, 103.8, 85.1, 81.1, 73.4, 63.0, 60.5, 53.7, 31.7, 26.5,
NMR (151 MHz, DMSO-d
6
1
2
1
-1
6.0, 14.7. IR νmax(KBr) cm : 3430, 3310, 2979, 2937, 2890, 1615, 1496, 1448, 1389,
330, 1295, 1246, 1166, 1048, 1003, 930, 888, 861, 808,746. HRMS calcd for
+
C
24
H
30ClNO
6
486.1659 [M+Na] , found 486.1638.
(
5S)-5-(3-Chloro-4-(2-ethoxybenzyl)anilino)-1,2-O-isopropylidene-α-
2
4
glucofuranose (9bb). White solid, yield 53%. m.p.: 54.5~55.2 ℃. [α] -1.6 (c 0.01,
D
1
CHCl
3
). H NMR (600 MHz, DMSO-d
6
) δ: 7.17~7.11 (m, 1H), 6.93 (d, J = 8.1 Hz, 1H),
6
.88 (dd, J = 10.4, 8.9 Hz, 2H), 6.81 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 6.53
dd, J = 8.4, 2.3 Hz, 1H), 5.82 (d, J = 3.6 Hz, 1H), 5.56 (d, J = 9.4 Hz, 1H), 5.28 (d, J
4.8 Hz, 1H), 4.59 (t, J = 5.2 Hz, 1H), 4.37 (d, J = 3.6 Hz, 1H), 4.08 (dd, J = 9.0, 2.4
Hz, 1H), 4.05~3.97 (m, 3H), 3.81 (s, 2H), 3.71~3.57 (m, 2H), 3.51~3.42 (m, 1H), 1.39
(
=
1
3
(
s, 3H), 1.34 (t, J = 7.0 Hz, 3H), 1.23 (s, 3H). C NMR (151 MHz, DMSO-d
6
) δ: 156.2,
1
1
2
8
48.1, 133.4, 131.3, 129.4, 128.5, 127.2, 123.4, 119.9, 112.6, 111.9, 111.4, 110.4,
-1
04.3, 84.8, 79.2, 72.9, 63.1, 60.4, 51.9, 31.7, 26.7, 26.1, 14.7. IR νmax(KBr) cm : 3395,
991, 2929, 1615, 1503, 1452, 1379, 1332, 1215, 1169, 1072, 1044, 1005, 955, 928,
+
52, 753. HRMS calcd for C24
H
30ClNO
6
486.1659 [M+Na] , found 486.1638.
(
5R)-5-(4-Chloro-3-(2-ethoxybenzyl)anilino)-1,2-O-isopropylidene-α-
2
4
glucofuranose (9ca) White solid, yield 18%. m.p.: 120.0~120.6 ℃. [α]D +8.4 (c 0.01,
1
CHCl
3
). H NMR (600 MHz, DMSO-d
6
) δ: 7.20~7.13 (m, 1H), 7.05 (d, J = 8.7 Hz, 1H),
6
2
4
.98~6.89 (m, 2H), 6.83 (t, J = 7.7 Hz, 1H), 6.50 (dd, J = 8.7, 2.8 Hz, 1H), 6.46 (d, J =
.7 Hz, 1H), 5.77 (d, J = 3.8 Hz, 1H), 5.54 (d, J = 8.6 Hz, 1H), 5.25 (d, J = 4.9 Hz, 1H),
.78 (t, J = 5.3 Hz, 1H), 4.41 (d, J = 3.8 Hz, 1H), 4.10~3.98 (m, 4H), 3.85 (s, 2H), 3.55
(
dd, J = 12.6, 8.5, 3.9 Hz, 1H), 3.51~3.43 (m, 2H), 1.38 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H),
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Chemistry & Biodiversity
10.1002/cbdv.201900739
1
3
1
1
6
2
8
.22 (s, 3H). C NMR (151 MHz, DMSO-d
6
) δ: 156.2, 147.6, 137.6, 129.4, 129.0,
27.8, 127.4, 120.01, 118.8, 114.8, 111.7, 111.5, 110.3, 103.9, 85.1, 81.0, 73.3, 63.2,
-1
0.2, 53.56, 32.67, 26.6, 26.1, 14.7. IR νmax(KBr) cm : 3438, 3383, 3324, 2985, 2958,
931, 2876, 1602, 1519, 1473, 1458, 1413, 1375, 1314, 1239, 1163, 1106, 1011, 932,
+
90, 860, 818, 753. HRMS calcd for C24
H30ClNO
6
486.1659 [M+Na] , found 486.1648.
(
5S)-5-(4-Chloro-3-(2-ethoxybenzyl)aniline)-1,2-O-isopropylidene-α-
2
4
glucofuranose (9cb). White solid, yield 50%. m.p.: 105.6~106.8 ℃. [α]D +0.4 (c 0.01,
1
CHCl
3
). H NMR (600 MHz, DMSO-d
6
) δ: 7.21~7.13 (m, 1H), 7.04 (d, J = 8.7 Hz, 1H),
6
.95 (t, J = 8.3 Hz, 2H), 6.83 (t, J = 7.5 Hz, 1H), 6.51 (dd, J = 8.8, 2.4 Hz, 1H), 6.46 (d,
J = 2.3 Hz, 1H), 5.80 (d, J = 3.6 Hz, 1H), 5.50 (d, J = 9.3 Hz, 1H), 5.23 (d, J = 4.9 Hz,
1
2
3
1
8
3
H), 4.53 (s, 1H), 4.36 (d, J = 3.6 Hz, 1H), 4.08 (d, J = 8.9 Hz, 1H), 4.03 (q, J = 6.9 Hz,
H), 3.97 (s, 1H), 3.84 (s, 2H), 3.67~3.54 (m, 2H), 3.43 (d, J = 10.2 Hz, 1H), 1.38 (s,
1
3
H), 1.33 (t, J = 6.9 Hz, 3H), 1.22 (s, 3H). C NMR (151 MHz, DMSO-d
6
) δ: 156.2,
47.3, 137.5, 129.5, 129.0, 127.7, 127.4, 120.1, 118.9, 115.4, 112.0, 111.5, 110.4, 104.2,
-1
4.8, 79.0, 72.9, 63.2, 59.9, 51.8, 32.7, 26.7, 26.1, 14.7. IR νmax(KBr) cm : 3491, 3463,
384, 3310, 2983, 2939, 2877, 1595, 1516, 1498, 1484, 1451, 1383, 1319, 1247, 1172,
1111, 953, 889, 864, 828, 799, 756. HRMS calcd for C24
H
30ClNO
486.1659 [M+Na]+,
6
found 486.1648.
(
5R)-5-(3-Chloro-4-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-
isopropylidene-α-glucofuranose (9da). Light yellow solid, yield 16%. m.p.:
2
D
4
1
1
28.5~129.6 ℃. [α] +15.9 (c 1, CHCl
3
). H NMR (600 MHz, CDCl
3
) δ: 7.50 (dd, J
=
7.8, 5.4 Hz, 2H), 7.15 (d, J = 8.2 Hz, 1H), 7.05 (dd, J = 14.1, 5.7 Hz, 3H), 6.90 (s,
1
H), 6.77 (d, J = 3.4 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.01 (d, J = 3.4 Hz, 1H), 4.56
(
d, J = 3.2 Hz, 1H), 4.41~4.36 (m, 2H), 4.17 (s, 2H), 3.89~3.85 (s, 1H), 3.83 (d, J =
1
3
1
2.3 Hz, 1H), 3.73 (dd, J = 10.7, 6.2 Hz, 1H), 1.53 (s, 3H), 1.36 (s, 3H). C NMR
) δ: 163.9, 162.3, 146.3, 143.7, 142.7, 135.7, 132.4, 131.9, 130.7,
28.2, 127.3, 123.75, 117.9, 116.8, 116.7, 116.3, 112.9, 106.0, 86.3, 80.4, 63.2, 56.3,
(151 MHz, DMSO-d
6
1
3
8
-1
4.1, 27.8, 27.1. IR νmax(KBr) cm : 3427, 3304, 2915, 1601, 1513, 1223, 1068, 1004,
+
34, 788. HRMS calcd for C26
H
27ClFNO
5
S 542.1175 [M+Na] , found 542.1159.
(
5S)-5-(3-Chloro-4-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-
isopropylidene-α-glucofuranose (9db). Light yellow solid, yield 56%. m.p.:
2
D
4
1
1
7
75.4~176.3 ℃. [α] +7.8 (c 1, CHCl
3
). H NMR (600 MHz, CDCl
3
) δ: 7.45 (s, 2H),
.12~6.94 (m, 4H), 6.73 (d, J = 9.4 Hz, 2H), 6.5 (d, J = 7.9 Hz, 1H), 5.91 (d, J = 2.2
Hz, 1H), 4.48 (d, J = 2.0 Hz, 1H), 4.24 (s, 1H), 4.19 (d, J = 6.4 Hz, 1H), 4.09 (s, 2H),
1
3
3
1
1
2
.84~3.72 (m, 3H), 1.46 (s, 3H), 1.28 (s, 3H). C NMR (151 MHz, DMSO-d ) δ: 162.9,
6
61.3, 146.8, 143.2, 141.6, 134.6, 131.4, 130.9, 130. 9, 127.3, 127.2, 127.1, 126.1,
22.7, 115.8, 115.6, 114.7, 113.2, 111.8, 104.7, 85.1, 80.2, 75.0, 61.3, 53.3, 33.0, 26.7,
-1
6.8. IR vmax(KBr) cm : 3427, 3328, 2927, 1616, 1514, 1380, 1232, 1163, 1074, 833,
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Chemistry & Biodiversity
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+
8
08. HRMS calcd for C26
5R)-5-(4-Chloro-3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-
isopropylidene-α-glucofuranose (9ea). Light yellow solid, yield 15%. m.p.:
H
27ClFNO
5
S 542.1175 [M+Na] , found 542.1162.
(
2
D
4
1
1
7
18.3~123.2 ℃. [α] +17.2 (c 1, CHCl
3
). H NMR (600 MHz, CDCl
3
) δ: 7.40 (s, 2H),
.12 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 10.0 Hz, 3H), 6.68 (s, 1H), 6.62 (s, 1H), 6.56 (d,
J = 8.4 Hz, 1H), 5.88 (s, 1H), 4.44 (s, 1H), 4.25 (d, J = 10.8 Hz, 2H), 4.07 (q, J = 15.9
Hz, 2H), 3.7 (s, 1H), 3.7 (d, J = 11.0 Hz, 1H), 3.59~3.54 (m, 1H), 1.41 (s, 3H), 1.23 (s,
1
3
3
1
7
1
H). C NMR (151 MHz, CDCl
3
) δ: 162.9, 161.3, 144.6, 141.9, 141.7, 138.7, 130.8,
30.4, 127.2, 126.7, 124.8, 122.8, 118.2, 115.8, 115.7, 115.4, 111.9, 104.9, 85.2, 79.4,
-1
6.7, 61.94, 55.1, 33.9, 26.8, 26.1. IR vmax(KBr) cm : 3475, 3277, 2923, 1601, 1502,
377, 1231, 1151, 1060, 1004. HRMS calcd for C26 27ClFNO
S 542.1175 [M+Na]+,
H
5
found 542.1159.
5S)-5-(4-Chloro-3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-
isopropylidene-α-glucofuranose (9eb). Light yellow solid, yield 54%. m.p.:
(
2
D
4
1
1
10.8~111.3 ℃. [α] +10.4 (c 1, CHCl
3
). HNMR (600 MHz, DMSO-d ) δ: 7.60 (dd,
6
J = 8.8, 5.3 Hz, 2H), 7.28 (d, J = 3.6 Hz, 1H), 7.21 (t, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8
Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 6.56 (dd, J = 8.8, 2.8 Hz,
1
H), 5.82 (d, J = 3.7 Hz, 1H), 5.61 (d, J = 9.3 Hz, 1H), 5.25 (d, J = 4.9 Hz, 1H), 4.55
(s, 1H), 4.37 (d, J = 3.7 Hz, 1H), 4.08 (s, 3H), 4.00 (s, 1H), 3.69 (s, 1H), 3.62 (d, J =7.5
1
3
Hz, 1H), 3.47 (d, J = 7.5 Hz, 1H), 1.38 (s, 3H), 1.23 (s, 3H). C NMR (151 MHz,
DMSO-d ) δ: 162.2, 160.6, 147.6, 142.5, 140.4, 137.2, 130.5, 130.5,129.3, 127.0,
27.0, 126.7, 123.4, 118.2, 115.9, 115.8, 114.9, 112.7, 110.4, 104.3, 84.9, 79.1, 72.9,
6
1
6
1
5
-
1
0.1, 51.9, 33.4, 26.7, 26.1. IR vmax(KBr) cm : 3450, 3355, 2925, 1604, 1514, 1232,
+
159, 1076, 837, 804. HRMS calcd for C26
42.1162.
H
27ClFNO
5
S 542.1175 [M+Na] , found
(
5R)-5-(4-Methyl-3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-
isopropylidene-α-glucofuranose (9fa). Light yellow solid, yield 17%. m.p.:
2
D
4
1
1
04.2~104.8 ℃. [α] +26.8 (c 1, CHCl
3
). HNMR (600 MHz, DMSO-d
6
) δ: 7.47~7.42
(m, 2H), 7.03~7.69 (m, 4H), 6.68 (d, J = 2.1 Hz, 1H), 6.66~6.63 (m, 2H), 5.96 (d, J =
3
4
.6 Hz, 1H), 4.50 (d, J = 3.6 Hz, 1H), 4.37 (t, J = 2.6 Hz, 1H), 4.34 (d, J = 2.6 Hz, 1H),
.01 (s, 2H), 3.85~3.80 (m, 1H), 3.75 (dd, J = 11.1, 2.4 Hz, 1H), 3.66 (dd, J = 11.1, 6.4
1
3
Hz, 1H), 2.20 (s, 3H), 1.48 (s, 3H), 1.30 (s, 3H). C NMR (151 MHz, DMSO-d
6
): 57.7,
56.0, 138.2, 137.9, 136.3, 134.0, 126.2, 125.6, 123.4, 121.9, 120.8, 117.47, 113.0,
10.54, 110.40, 109.9, 106.6, 99.8, 80.1, 73.9, 71.9, 56.9, 50.5, 28.9, 21.6 , 20.9, 13.32.
1
1
-1
IR vmax(KBr) cm : 3440, 2934, 1612, 1502, 1377, 1212, 1068, 996, 807, 743. HRMS
+
calcd for C27
H30FNO
5
S 522.1721 [M+Na] , found 522.1709.
(
5S)-5-(4-Methyl-3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-
isopropylidene-α-glucofuranose (9fb). Light yellow solid, yield 53%. m.p.:
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Chemistry & Biodiversity
10.1002/cbdv.201900739
2
D
4
1
1
40.8~141.3 ℃. [α] +15.6 (c 1, CHCl
3
). H NMR (600 MHz, CDCl
3
) δ: 7.46 (dd, J
=
8.8, 5.2 Hz, 2H), 7.07~6.95 (m, 4H), 6.67 (d, J = 3.5 Hz, 1H), 6.61 (d, J = 2.4 Hz,
1
4
7
H), 6.57 (dd, J = 8.1, 2.4 Hz, 1H), 5.91 (d, J = 3.7 Hz, 1H), 4.48 (d, J = 3.7 Hz, 1H),
.24 (d, J = 2.6 Hz, 1H), 4.20 (dd, J = 7.1, 2.4 Hz, 1H), 4.01 (s, 2H), 3.80 (dt, J = 14.1,
1
.8 Hz, 3H), 2.20 (s, 3H), 1.47 (s, 3H), 1.29 (s, 3H). H NMR (600 MHz, DMSO-d6)
δ: 7.68 – 7.51 (m, 2H), 7.28 (d, J = 3.6 Hz, 1H), 7.20 (dd, J = 12.3, 5.4 Hz, 2H), 6.84
d, J = 8.2 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 6.47 (dd, J = 8.2,
(
2
4
2
3
.2 Hz, 1H), 5.82 (d, J = 3.7 Hz, 1H), 5.25 (d, J = 4.4 Hz, 1H), 5.15 (d, J = 9.4 Hz, 1H),
.52 (s, 1H), 4.38 (d, J = 3.7 Hz, 1H), 4.12 (dd, J = 8.8, 2.7 Hz, 1H), 4.03 (dd, J = 4.4,
.7 Hz, 1H), 3.98 (d, J = 1.8 Hz, 2H), 3.76 – 3.65 (m, 1H), 3.61 (d, J = 10.4 Hz, 1H),
1
3
.49 (d, J = 10.4 Hz, 1H), 2.12 (s, 3H), 1.39 (s, 3H), 1.23 (s, 3H). C NMR (151 MHz,
) δ: 157.7, 156.0, 139.7, 138.1, 136.3, 134.1, 126.2, 125.6, 125.6, 121.9, 121.9,
21.5, 120.8, 117.5, 111.2, 110.5, 110.4, 108.0, 106.5, 99.5, 79.8, 75.4, 70.0, 56.3, 49.0,
CDCl
3
1
2
-1
9.0, 21.5, 20.9, 13.2. IR vmax(KBr) cm : 3427, 3306, 2927, 1616, 1514, 1380, 1232,
163, 1074, 833, 808. HRMS calcd for C27 S 500.1901 [M+H], found
1
5
H30FNO
5
00.1902.
5R)-5-(2-Methyl-3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-
isopropylidene-α-glucofuranose (9ga). Light yellow solid, yield 14%. m.p.:
(
2
D
4
1
1
46.8~147.3 ℃. [α] +23.8 (c 1, CHCl
3
). H NMR (600 MHz, CDCl
3
) δ: 7.46 (dd, J
=
8.8, 5.3 Hz, 2H), 7.10 (t, J = 7.8 Hz, 1H), 7.01 (dd, J = 10.6, 6.8 Hz, 3H), 6.83 (t, J =
7
4
.6 Hz, 2H), 6.64 (d, J = 3.6 Hz, 1H), 6.00 (d, J = 3.6 Hz, 1H), 4.53 (d, J = 3.6 Hz, 1H),
.43 (t, J = 2.7 Hz, 1H), 4.38 (d, J = 2.7 Hz, 1H), 4.12 (d, J = 4.5 Hz, 2H), 3.94~3.90
(
m, 1H), 3.79 (dd, J = 11.1, 2.1 Hz, 1H), 3.65 (dd, J = 10.8, 6.1 Hz, 1H), 2.16 (s, 3H),
1
3
1
1
1
3
7
.51 (s, 3H), 1.33 (s, 3H). C NMR (151 MHz, CDCl
3
) δ: 162.9, 161.2, 143.9, 143.6,
41.5, 139.14, 130.84, 127.11, 126.7, 125.8, 124.1, 122.7, 122.4, 115.7, 115.6, 113.8,
-1
11.8, 105.1, 85.2, 79.4, 77.1, 62.3, 55.6, 34.9, 26.8, 26.1, 12.8. IR vmax(KBr) cm :
567, 3421, 2923, 1593, 1502, 1457, 1367, 1321, 1212, 1177, 1060, 1004, 834, 796,
35. HRMS calcd for C27
5S)-5-(2-Methyl-3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)anilino)-1,2-O-
isopropylidene-α-glucofuranose (9gb). Light yellow solid, yield 56%. m.p.:
H30FNO
5
S 500.1901 [M+H], found 500.1902.
(
2
D
4
1
1
2
5
61.3~161.8 ℃. [α] +9.4 (c 1, CHCl
3
). H NMR (600 MHz, CDCl ) δ: 7.49~7.27 (m,
3
H), 6.96 (dt, J = 16.8, 8.2 Hz, 4H), 6.65 (t, J = 7.8 Hz, 2H), 6.57 (d, J = 2.8 Hz, 1H),
.86 (s, 1H), 4.43 (d, J = 3.2 Hz, 1H), 4.21 (s, 2H), 4.03 (s, 2H), 3.84 (s, 1H), 3.74 (d,
1
3
J = 2.2 Hz, 2H), 2.03 (s, 3H), 1.41 (s, 3H), 1.22 (s, 3H). C NMR (151 MHz, CDCl
3
)
δ: 157.6, 156.0, 139.9, 138.7, 136.1, 133.7, 125.7, 125.6, 121.9, 121.8, 121.6,
1
2
1
20.5,117.4, 116.7, 115.3, 110.5, 110.4, 106.5, 105.9, 99.6, 79.7, 75.5, 70.2, 56.1, 48.7,
-1
9.8, 21.5, 20.9, 7.6. IR vmax(KBr) cm : 3456, 3207, 2920, 1591, 1514, 1226, 1060,
+
014, 827, 790. HRMS calcd for C27
H30FNO
5
S 522.1721 [M+Na] , found 522.1709 .
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Chemistry & Biodiversity
10.1002/cbdv.201900739
4
4
.3. Biology
.3.1. Cell culture
Cells were cultured using DMEM supplemented with 10% FBS, 100 units/mL
penicillin, 100 μg/mL streptomycin and 2 mM L-glutamate at 37 °C and 5% CO with
2
9
5% humidity.
4
.3.2. Antiproliferative Activity in Vitro
The antiproliferation activities of targeted compounds against SW480, A549, and A431
cells were evaluated in vitro by the MTT assay according to reported methods.[9, 23, 25]
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of
China (grant number 21272144), and the Fundamental Research Funds for the Central
Universities (grant numbers GK201906010, GK201706005 and GK201603034).
Author Contributions Statement
Xiabing Li and Baolin Li designed the experiments. Lili Wang and Baoli Sun
synthesized the compounds. Yaling Zhang tested the anti-tumor activity of the
derivatives. Yaling Zhang drafted the manuscript with support from Qiaoli Hou,
Xiabing Li and Wei Wang. Yaling Zhang and Baolin Li contributed to the discussion
section and revised the manuscript.
Supporting Information
NMR and HRMS spectra of all the target compounds. The Supporting Information is
available free of charge via the Internet at
Conflicts of interest
The authors declare no competing financial interest.
References
[
1] Anon, 'Cancer: The Road Ahead', Cell 2017, 168, 545-546.
[
2] S. Dhillon, 'Gefitinib: a review of its use in adults with advanced non-small cell lung cancer',
Targeted oncology 2015, 10, 153-170.
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Chemistry & Biodiversity
10.1002/cbdv.201900739
[
[
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