Synthesis of (-)-epigallocatechin-3-gallate derivative containing a triazole ring and combined with cisplatin/paclitaxel inhibits NSCLC cancer cells by decreasing phosphorylation of the EGFR

Article abstract of DOI:10.1177/1747519820910390

Non-small-cell lung cancer is one of the principal causes of cancer-related death around the world. Chemotherapy is commonly used to treat wild type of epidermal growth factor receptor non-small-cell lung cancer. (-)-Epigallocatechin-3-gallate is the most abundant and active catechin. However, (-)-epigallocatechin-3-gallate has limited clinical application due to its poor stability and absorption. Herein, we report that a glycosylated azide undergoes a click reaction with the terminal alkyne of (-)-epigallocatechin-3-gallate to yield a triazole-linked glucose-(-)-epigallocatechin-3-gallate derivative and have evaluated its in vitro anticancer activity against human non-small-cell lung cancer cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The product inhibits human non-small-cell lung cancer cell lines with wild type of epidermal growth factor receptor and in combination with cisplatin/paclitaxel results in more pronounced proliferation inhibition than when used alone. Stability investigations indicates that the conjugated glucose residue can improve the stability of the (-)-epigallocatechin-3-gallate scaffold. Our studies suggest that the combination of the glucose-(-)-epigallocatechin-3-gallate derivative and chemotherapeutic drugs may provide a novel strategy for the treatment of non-small-cell lung cancer.

Full text of DOI:10.1177/1747519820910390

910390CHL0010.1177/1747519820910390Journal of Chemical ResearchZi et al.
research-article2020
Research Paper
Journal of Chemical Research
1–6
© The Author(s) 2020
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Synthesis of (-)-epigallocatechin-3-gallate
derivative containing a triazole ring and combined
with cisplatin/paclitaxel inhibits NSCLC cancer
cells by decreasing phosphorylation of the EGFR
https://doi.org/10.1177/1747519820910390
DOI: 10.1177/1747519820910390
journals.sagepub.com/home/chl
Cheng-Ting Zi1,2* , Pei-Yuan Sun1*, Ning Zhang1, Han Tang1, Hao-Nang Yang1,
Qi Wang1, Yu-Na Wang1, Jing Wang1, Xuan-Jun Wang1,2,3 and Jun Sheng1,3
Abstract
Non-small-cell lung cancer is one of the principal causes of cancer-related death around the world. Chemotherapy is
commonly used to treat wild type of epidermal growth factor receptor non-small-cell lung cancer. (-)-Epigallocatechin-
3-gallate is the most abundant and active catechin. However, (-)-epigallocatechin-3-gallate has limited clinical application
due to its poor stability and absorption. Herein, we report that a glycosylated azide undergoes a click reaction with the
terminal alkyne of (-)-epigallocatechin-3-gallate to yield a triazole-linked glucose-(-)-epigallocatechin-3-gallate derivative and
have evaluated its in vitro anticancer activity against human non-small-cell lung cancer cells using the 3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide assay. The product inhibits human non-small-cell lung cancer cell lines with wild type
of epidermal growth factor receptor and in combination with cisplatin/paclitaxel results in more pronounced proliferation
inhibition than when used alone. Stability investigations indicates that the conjugated glucose residue can improve the stability
of the (-)-epigallocatechin-3-gallate scaffold. Our studies suggest that the combination of the glucose-(-)-epigallocatechin-3-
gallate derivative and chemotherapeutic drugs may provide a novel strategy for the treatment of non-small-cell lung cancer.
Keywords
combination, (-)-epigallocatechin-3-gallate derivative, wild type of epidermal growth factor receptor, non-small-cell
lung cancer, synthesis
Date received: 28 October 2019; accepted: 11 February 2020
(-)-epigallocatechin-3-gallate derivative combined with cisplatin/paclitaxel inhibits non-small-cell lung cancer cells
1Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan
Agricultural University, Kunming, P.R. China
2College of Science, Yunnan Agricultural University, Kunming, P.R.
China
Corresponding authors:
Jing Wang, Key Laboratory of Pu-er Tea Science, Ministry of Education,
Yunnan Agricultural University, Kunming 650201, P.R. China.
Email: wangjingzb4321@163.com
3State Key Laboratory for Conservation and Utilization of Bio-
Resources in Yunnan, Yunnan Agricultural University, Kunming, P.R.
China
Xuan-Jun Wang, Key Laboratory of Pu-er Tea Science, Ministry of
Education, Yunnan Agricultural University, Kunming 650201, P.R. China.
Email: wangxuanjun@gmail.com
*These authors contributed equally to this work
Jun Sheng, Key Laboratory of Pu-er Tea Science, Ministry of Education,
Yunnan Agricultural University, Kunming 650201, P.R. China.
Email: shengj@ynau.edu.cn

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Journal of Chemical Research 00(0)
click-chemistry strategy,27 the glycosylated azide 5 was
reacted with alkyne 2 in the presence of copper (II) acetate
and sodium ascorbate in tert-butyl alcohol/water (1:1) at
room temperature for 2h to afford the EGCG glycoside 6 in
Introduction
Lung cancer is a very common malignancy with thousands
of cancer-related deaths reported worldwide, and non-
small-cell lung cancer (NSCLC) accounts for 85% of all
cases of lung cancer.1 The epidermal growth factor receptor
(EGFR) is a well-established critical target for the treat-
ment of NSCLC.2 Overexpression of EGFR, as a result of
abnormal activation of the anti-apoptotic signaling path-
way and abnormal cell proliferation, is known to be impor-
tant in NSCLC.3 The epidermal growth factor receptor
tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib
and erlotinib, play a key role in treating NSCLC harboring
EGFR with activating mutations.4 Unfortunately, most
patients have wild-type EGFR (wtEGFR) tumors, and the
efficacy of EGFR-TKIs for the treatment of these patients
is still contentious.5 Nevertheless, EGFR-TKIs are
approved for second-line treatment of patients with wtEGFR
tumors.6 Chemotherapy, as a conventional treatment for
many types of cancer, is one of the first-line treatments for
NSCLC patients harboring wtEGFR.7,8 However, it has no
significant therapeutic effect.9 Therefore, new therapeutic
strategies are urgently required.
Green tea is one of the most popular types of daily bever-
ages worldwide.10,11 (-)-Epigallocatechin-3-gallate (EGCG),
is the most abundant catechin (accounting for approximately
50% of total catechins), is the most active phenolic constitu-
ent of green tea catechins and has been extensively reported
to treat various cancers including liver, lung, breast, throat,
prostate, and bladder cancer.11–15 Astudy showed that EGCG
can inhibit EGFR tyrosine kinase activity in the A549
human epidermal carcinoma cell line with wtEGFR.16
However, the use of EGCG is often hindered by problems
such as easy oxidation, ready degradation in aqueous solu-
tions, and poor intestinal absorbance.17,18
1
75% yield. The product was characterized by H-NMR,
13C-NMR, ESI-MS, and HRESI-MS.
Reagents and conditions: (a) Ac2O, NaOAc, 100°C,
20min, 99%; (b) HBr, AcOH, CH2Cl2, 0°C, 8h, 96%; (c)
NaN3, DMF, 12h, 90%; (d) CH3ONa, CH3OH, rt, 12h,
78%; (e) propargyl bromide, NaH, DMF, 0°C–rt, 12h,
40%; and (f) copper(II) acetate, sodium ascorbate (1 M, in
H2O), t-BuOH-H2O (1:1), THF, rt, 2h, 75%.
Compound 6 decreases cell viability in
NSCLC cells
Our previous study suggested that glucosylated EGCG
derivatives combined with gefitinib inhibited the prolifera-
tion of NSCLC cells (NCI-H1975).19 To test whether com-
pound 6 inhibits cell proliferation in NSCLC cells, we
chose four human NSCLC cell lines harboring wtEGFR
(NCI-H292, NCI-H441, NCI-H1781, and A549) and one
human NSCLC cell line with the L858R/T790M mutation
(NCI-H1975) to measure cell viability using the MTT assay
(Figure 1). As shown in Figure 1(a)–(d), compound 6 sig-
nificantly inhibited the cell viability of NCI-H292, NCI-
H441, NCI-H1781, and A549 at different concentrations.
By contrast, compound 6 did not inhibit the cell viability of
NCI-H1975 cells. These results indicate that compound 6
inhibits human NSCLC cell lines with wtEGFR compared
to the EGFR L858R/T790M mutation.
Compound 6 combined with cisplatin/
paclitaxel decreases cell viability in
NCI-H1781 cells
In our previous study, we synthesized a series of EGCG
glucoside derivatives by a chemical modification strategy
and evaluated their antitumor activity.17,19 Since the
1,2,3-triazole ring is a widespread functional group in many
drugs,20–25 it is of interest to attach 1,2,3-triazoles to EGCG
derivatives. Herein, we report the chemical synthesis of a
triazole-linked glucose EGCG derivative, its in vitro anti-
cancer activity against human NSCLC cell lines (NCI-
H292, NCI-H441, NCI-H1781, A549, and NCI-H1975),
and tested this synthetic compound combined with chemo-
therapeutic drugs (cisplatin/paclitaxel) on proliferation in
cancer cells. In addition, we tested the stability of triazole-
linked glucose EGCG derivative compared to EGCG.
It has been reported that almost all tumors acquire resistance
to chemotherapeutic drugs after periods of treatment.28,29
Given that compound 6 inhibited NSCLC cells with
wtEGFR, we hypothesized that compound 6 combined with
a chemotherapeutic drug would exhibit greater anticancer
activity potential than when used alone. Thus, we treated
NCI-H1781 cells with compound 6 (60μM) alone and in
combination with cisplatin/paclitaxel (12μM) by using a
cell proliferation assay (Figure 2). As shown in Figure 2(a)
and (b), compound 6 combined with cisplatin resulted in
more pronounced proliferation inhibition than 6 or cisplatin
alone. The combination of compound 6 and paclitaxel indi-
cated similar proliferation inhibition.
Results and discussion
Click-chemistry strategy for the synthesis of
the EGCG derivative
Compound 6 combined with cisplatin/
paclitaxel inhibits phosphorylation of EGFR
in NCI-H1781 cells
Glucosylated EGCG (compound 6) was synthesized
according to Scheme 1. The preparation of EGCG terminal
alkyne 2 was carried out in 45% yield by the reaction of
EGCG (1) with sodium hydride and propargyl bromide.
D-Glucose was readily converted into glycosylated azide 5
according to a known procedure.26 Finally, according to a
It is well known that the EGFR signal pathway plays a key
role in the treatment of NSCLC.19,30 Therefore, we treated
NCI-H1781 cells with the combination of compound 6 and
cisplatin/paclitaxel and examined the phosphorylation lev-
els of the EGFR by western blotting (WB; Figure 3). As

Zi et al.
3
Scheme 1. Click-chemistry strategy for the synthesis of a triazole-linked glucose EGCG derivative.
Figure 1. Effect of compound 6 on the proliferation of NSCLC cell lines. (a) NCI-H292, (b) NCI-H441, (c) NCI-H1781, (d) A549,
and (e) NCI-H1975. All cells were treated with increasing doses of compound 6 at the indicated concentrations (0, 30, 60, 90, 120,
and 150μM) for 48h. Cell proliferation was measured by the MTT assay and expressed as the proliferation rate.
shown in Figure 3, treatment of the combination of com- derivative with a triazole ring 6 showed greater stability
pound 6 and cisplatin/paclitaxel inhibited the phosphoryla- than EGCG. It appears that incorporation of the glucose
tion of EGFR more significantly than compound 6 alone, moiety slows down the hydrolysis and improves the stabil-
while the total protein levels of EGFR remained unchanged. ity of the EGCG scaffold.
These results indicate that compound 6 combined with cis-
platin/paclitaxel may inhibit proliferation in NCI-H1781
cells through the EGFR signal pathway.
Conclusion
In conclusion, we have used a glycosylated azide in a click
reaction with the terminal alkyne of EGCG to yield a tria-
Compound 6 showed more stability than
zole-linked glucose-EGCG derivative 6 in high yield.
EGCG
Compound 6 was screened for anticancer activity against a
In our previous study, we found that glucosylated EGCG panel of five human NSCLC cells (NCI-H292, NCI-H441,
derivatives had improved chemical stability and absorption NCI-H1781, A549, and NCI-H1975) and was found to
compared to EGCG.17 To investigate whether compound 6 inhibit human NSCLC cell lines with wtEGFR compared to
showed more stability than EGCG, we tested the stability the EGFR mutation. In addition, compound 6 combined
of compound 6 and EGCG according to the amount of with cisplatin/paclitaxel resulted in more pronounced pro-
hydrogen peroxide (H2O2) which is a by-product of bio- liferation inhibition than when used alone, which may
logical oxidation processes (Figure 4). Glucosylated EGCG occur through an EGFR signal pathway. Finally, stability

4
Journal of Chemical Research 00(0)
Figure 2. Compound 6 combined with cisplatin/paclitaxel decreases cell viability in NCI-H1781 cells. (a) Compound 6 (60µM)
combined with cisplatin (12μM) and (b) compound 6 (60µM) combined with paclitaxel (12μM). Cell proliferation was measured
by the MTT assay and expressed as the proliferation rate. Data represent the average of three independent experiments
(mean±SEM). **p<0.01, ***p<0.001.
Figure 3. Compound 6 combined with cisplatin/paclitaxel
inhibits phosphorylation of EGFR in NCI-H1781 cells.
Compound 6 (60μM), cisplatin/paclitaxel (12μM) alone, or with
compound 6 plus cisplatin/paclitaxel, after 12h. NCI-H1781
Figure 4. The stability compound 6 according to the amount
cells were stimulated with 10ng/mL EGF for 10min. The
of hydrogen peroxide (H2O2). H2O2 concentrations of EGCG
expression levels of the proteins were determined by western
and compound 6 were tested using a H2O2 Quantitative Assay
blotting (WB). β-Tubulin was tested as the loading control.
Kit (water-compatible). ***p < 0.001. EGCG was taken as the
control drug.
investigation indicated that a conjugated glucose residue
seems to improve the stability of the EGCG scaffold. Our
studies suggest that the combination of compound 6 and
chemotherapeutic drugs may provide a novel strategy for
the treatment of NSCLC.
performed on an Agilent 6540 Q-Tof ESIMS (Agilent
1
Technologies, Santa Clara, CA, USA). H-NMR and 13C-
NMR spectra were recorded on a Bruker AVANCE III
500MHz (Bruker BioSpin GmbH, Rheinstetten, Germany)
instrument, using tetramethylsilane (TMS) as an internal
standard. Silica gel (200–300 mesh) for column chromatog-
raphy and silica GF254 for thin-layer chromatography (TLC)
were produced by Qingdao Marine Chemical Company
(Qingdao, China).
The human NSCLC cell lines (NCI-H292, NCI-H441,
NCI-H1781, NCI-H1975, and A549) were obtained from
the American Type Culture Collection (ATCC). Antibodies
against phospho-EGFR (Tyr1068) and EGFR were obtained
from Abcom (Lake Placid, NY, USA). The anti-β-tubulin
antibody was obtained from Proteintech (Rosemont, IL,
USA). Anti-mouse IgG peroxidase-linked whole antibodies
and anti-rabbit IgG peroxidase-linked species-specific
Experimental
Materials
EGCG was purchased from Chengdu Proifa Technology
Development Co., Ltd (Chengdu, China); D-glucose was
purchased from Sinopharm Chemical Reagent Co., Ltd.
(Shanghai, China);andcisplatin, paclitaxel, and3-(4,5-dimeth-
ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were
obtained from Sigma-Aldrich (St. Louis, MO, USA). All rea-
gents were commercially available and used without further
purification unless indicated otherwise. Mass spectrometry
(MS) and high-resolution mass spectrometry (HRMS) were

Zi et al.
5
whole antibodies were obtained from Thermo Fisher streptomycin (Solarbio, Beijing, China), and 10% of fetal
Scientific (Waltham, MA, USA).
bovine serum (HyClone, Los Angeles, CA, USA) at 37°C
in a humidified 5% CO2 incubator.
Synthesis of (2R,3R)-5,7-dihydroxy-2-(3′,4′,5′-trihydroxyphenyl)
chroman-3-yl 3″,5″-dihydroxy-4″-(prop-2-yn-1-yloxy)benzoate 2.
To a solution of EGCG (458mg, 1mM) in dry DMF (5mL),
Cell viability assay
sodium hydride (60mg, 1.5mM) was added at 0 ºC under Cell viability was evaluated by the MTT assay. The NSCLC
nitrogen. The mixture was stirred at room temperature for cells (NCI-H292, NCI-H441, NCI-H1781, A549, and NCI-
0.5h, propargyl bromide (0.1mL, 1mM) was quickly added, H1975) were seeded in 96-well plates (5×104 cells/well) and
and the reaction mixture stirred at 80°C for 12h. The solvent then treated with compound 6 (0, 30, 60, 90, 120, or 150µM),
was evaporated under vacuum and the residue was purified cisplatin/paclitaxel (12μM), compound 6 (60µM) plus vary-
by flash column chromatography on silica gel (CHCl3/ ing cisplatin/paclitaxel (12μM) for 48h. Then, 20μL of MTT
CH3OH, 9:1) to afford the major product 2 (183mg, 40%). was added to the each well and the plates were incubated for
1H-NMR (CD3OD, 500MHz): δ=6.90 (s, 2H, C2″–H, C6″– a further 4h. After removal of the culture medium, the pro-
H), 6.50 (s, 2H, C2′–H, C6′–H), 5.96 (s, 2H, C6–H, C8–H), duced MTT formazan crystals were dissolved in 150µL of
5.53 (m, 1H, C3–H), 4.97 (d, 1H, J=4.6 Hz, C2–H), 4.78 (d, dimethyl sulfoxide (DMSO). The optical density (OD) at
2H J=2.4Hz, C12–CH2), 3.29 (t, 1H, J=1.6Hz, C14–H), 492nm was measured using a microplate reader. The percent-
2.96 (dd, 1H, J=4.6Hz, 12.0Hz, C4–CHa), 2.85 (dd, 1H, age of inhibition was calculated as follows: inhibition ratio
J=4.6Hz,12.0Hz,C4–CHb);13C-NMR(CD3OD,125MHz): (IR, %)=(1−OD(sample)/OD(control))×100%.
δ=167.0 (C-11), 157.9 (C-7), 157.8 (C-5), 157.2 (C-9),
151.9 (C-3″, C-5″), 146.7 (C-3′, C-5′), 138.4 (C-4″), 133.8
(C-4′), 130.7 (C-1′), 127.1 (C-1″), 110.1 (C-2″, C-6″), 106.8
WB analysis
(C-2′, C-6′), 99.3 (C-10), 96.5 (C-6), 95.9 (C-8), 80.4 (C-2), Samples containing equal amounts of proteins as indi-
79.5 (C≡CH), 78.5 (C≡CH), 70.3 (C-3), 60.0 (C-14), 26.8 cated in the text were resolved by sodium dodecyl sul-
(C-4); ESIMS: m/z=495 [M−H]–.
fate (SDS) polyacrylamide gel electrophoresis and
transferred to polyvinylidene fluoride (PVDF) mem-
Synthesis of (2R,3R)-5,7-dihydroxy-2-(3′,4′,5′-trihydroxyphenyl) branes. The membranes were blocked with 5% bovine
chroman-3-yl 3″,5″-dihydroxy-4″-((1″′-β-((2S,3R,4S,5S,6R)-3′″, serum albumin (BSA) at room temperature for 1 h and
4′″,5′″-trihydroxy-6′″-(hydroxymethyl)tetrahydro-2H-pyran- then probed with primary antibodies overnight at 4°C
2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzoate 6. To a solution and incubated with the horseradish peroxidase (HRP)-
of the glycosylated azide 5 (20.5mg, 0.1mM) and EGCG conjugated secondary antibodies for 1 h at room temper-
terminal alkyne 2 (49.6mg, 0.1mM) in THF (1.0mL) and ature. HRP was detected using a Pro-light HRP
t-BuOH-H2O (1:1, 1mL) were added copper(II) acetate Chemiluminescent Kit (Tiangen Biotech, Beijing, China)
(1.8mg, 0.01mM) and sodium ascorbate (1.0M in H2O, and FluorChem E System (ProteinSimple, Santa Clara,
0.1mL). The reaction mixture was stirred at room tempera- CA, United States).
ture for 2h until the disappearance of the starting material
was complete as indicated by TLC. The mixture was then
evaporated and the residue was purified by column chroma-
Stability assay
tography to afford the product compound 6 (52mg, 75%). The H2O2 concentrations of EGCG and compound 6 were
1H-NMR (CD3OD, 500MHz): δ=8.11 (s, 1H, C14–H), detected using a H2O2 Quantitative Assay Kit (Water-
6.91 (s, 2H, C2″–H, C6″–H), 6.53 (s, 2H, C2′-H, C6′-H), 5.96 Compatible; Sangon Biotech Co., Ltd.). Briefly, 20μL
(s, 1H, C6–H), 5.95 (s, 1H, C8–H), 5.58 (d, 1H, J=7.6Hz, samples and 100μL of working solution were added to
C1′″–H), 5.21 (m, 1H, C3–H), 5.11 (s, 1H, C2–H), 4.78 (d, each well of a 96-well microtiter plate (Thermo Scientific,
2H, J=10.4Hz, C12–CH2), 3.89–3.86 (m, 2H, C3′′′-H, Waltham, MA, USA) and incubated for 20min on a rotary
C2′′′-H), 3.72–3.69 (m, 1H, C4′′′-H–H), 3.57–3.53 (m, 2H, shaker at room temperature. The absorbance was recorded
C6′′′-H–CH2), 3.51–3.48 (m, 1H, C5′′′–H–H), 2.99–2.87 on a microplate reader at a wavelength of 595nm.
(m, 1H, C4–CHa), 2.85–2.82 (m, 1H, C4–CHb); 13C-NMR
(CD3OD, 125MHz): δ=167.1 (C–11), 157.9 (C–7), 157.8
(C–5), 157.0 (C–9), 151.9 (C–3″, C–5″), 151.7 (C–3′, C–5′),
Statistical analysis
146.7 (C–13), 139.4(C–4″), 136.3 (C–4′), 127.0 (C–1′), All results are expressed as the mean ± the standard error
124.9 (C–1″), 124.9 (C–14), 110.4 (C–2″, C–6″), 106.9 (C–2′, of the mean (SEM) from three or more independent repli-
C–6′), 106.8 (C–1′″),99.3 (C–10), 96.6 (C–6), 95.9 (C–8), 81.1 cates. The data were statistically analyzed with either the
(C–2), 78.4 (C–3′″), 74.1 (C–4′″), 70.8 (C–2′″), 70.2 (C–12), Student’s t-test or one-way analysis of variance (ANOVA).
66.0 (C–5′″), 62.4 (C–3), 60.0 (C–6′″), 26.7 (C–4); ESIMS: p < 0.05 was considered statistically significant. All of the
m/z=702 [M+H]+.
statistical analyses were performed using GraphPad Prism
5.0 software (San Diego, CA, USA).
Cell cultures
Declaration of conflicting interests
All the cell lines used in this study were cultured in RPMI-
1640 medium (Thermo Fisher Scientific, Pittsburgh, PA,
USA) supplemented with 50IU/mL of penicillin, 1% of
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.

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Journal of Chemical Research 00(0)
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Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was financially supported by the National Nature Science
Foundation of China for financial support (Nos 21602196 and
31760226), the Yunnan Provincial Science and Technology
Department (Nos 2017ZF003, 2017FD084, and 2017FG001-
046), and National Key R&D Program of China (No.
2016YFE0117700).
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