Synthesis of novel xanthone analogues and their growth inhibitory activity against human lung cancer a549 cells

Article abstract of DOI:10.2147/DDDT.S217827

Purpose: Xanthones demonstrated an array of pharmacological activities via non-covalent DNA interaction and have been widely utilized in new drug research. The introduction of the polar 1,2,3-triazole ring located at the C3-position of xanthone has not been reported thus far. Methods: In the present study, a series of xanthone derivatives were designed, synthesized, and characterized through¹H NMR,¹³C NMR, and MS. The methyl thiazolyl tetrazolium method was used to evaluate the cytotoxic activity of compounds. Furthermore, the structure– activity relationship and the potential mechanism of target compounds were investigated. Results: The IC₅₀ showed that the inhibitory activity of 18 target compounds was higher than that of the original xanthone intermediate 4. In particular, compound 1j was the most active agent against A549 cancer cells (IC₅₀ = 32.4 ± 2.2 μM). Moreover, apoptosis analysis indicated different contributions of early/late apoptosis to cell death for compounds 1h and 1j. The results of Western blotting analysis showed that compound 1j significantly increased the expression of caspase 3, Bax, and c-Jun N-terminal kinase, and regulated p53 to a better healthy state in cancer cells. Conclusion: We synthesized several derivatives of xanthone and evaluated their cytotoxicity. The evidence suggested that compound 1j possessed greater anticancer potential for further evaluations.

Full text of DOI:10.2147/DDDT.S217827

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Open Access Full Text Article
O R I G I N A L R E S E A R C H
Synthesis of Novel Xanthone Analogues and Their
Growth Inhibitory Activity Against Human Lung
Cancer A549 Cells
This article was published in the following Dove Press journal:
Drug Design, Development and Therapy
Junqi Wu,1,2,* Jinwei Dai,1,3,
*
Purpose: Xanthones demonstrated an array of pharmacological activities via non-covalent
Yuyang Zhang, 1,3 Jing Wang,1
Lei Huang,1 Hongmei Ding,1
Tiejun Li,1,4 Yuefan Zhang,1,5
Junqin Mao,6 Shichong Yu1
DNA interaction and have been widely utilized in new drug research. The introduction of the
polar 1,2,3-triazole ring located at the C3-position of xanthone has not been reported thus far.
Methods: In the present study, a series of xanthone derivatives were designed, synthesized,
1
and characterized through H NMR, 13C NMR, and MS. The methyl thiazolyl tetrazolium
method was used to evaluate the cytotoxic activity of compounds. Furthermore, the structure–
activity relationship and the potential mechanism of target compounds were investigated.
Results: The IC50 showed that the inhibitory activity of 18 target compounds was higher
than that of the original xanthone intermediate 4. In particular, compound 1j was the most
active agent against A549 cancer cells (IC50 = 32.4 2.2 μM). Moreover, apoptosis analysis
indicated different contributions of early/late apoptosis to cell death for compounds 1h and
1j. The results of Western blotting analysis showed that compound 1j significantly increased
the expression of caspase 3, Bax, and c-Jun N-terminal kinase, and regulated p53 to a better
healthy state in cancer cells.
1College of Pharmacy, Naval Medical
University, Shanghai 200433, People’s
Republic of China; 2Department of
Thoracic Surgery, Shanghai Pulmonary
Hospital, Tongji University School of
Medicine, Shanghai 200433, People’s
Republic of China; 3Department of
Pharmacology, School of Life Science and
Biopharmaceutics, Shenyang
Pharmaceutical University, Shenyang
110016, People’s Republic of China;
4Department of Pharmacy, Punan
Hospital, Shanghai 200125, People’s
Republic of China; 5Biomedical
Innovation R&D Center, School of
Medicine, Shanghai University, Shanghai,
20444, People’s Republic of China;
6Department of Pharmacy, Shanghai
Pudong New Area People’s Hospital,
Shanghai 201299, People’s Republic of
China
Conclusion: We synthesized several derivatives of xanthone and evaluated their cytotoxi-
city. The evidence suggested that compound 1j possessed greater anticancer potential for
further evaluations.
Keywords: synthesis, xanthone, derivatives, lung cancer cell, apoptosis
Introduction
Lung cancer is currently the most common type of cancer affecting both men and
women, owing to the high prevalence of smoking worldwide.1,2 According to the
American Cancer Society, lung cancer was the leading cause of cancer-related mor-
tality in 2016 in the United States of America, with estimated 158,080 deaths (~27%).3
Conventional treatments against cancer, such as surgery and radiation therapy, are not
feasible in advanced lung cancer mainly owing to the location of the cancer cells in the
body.4 Chemotherapy is an effective systemic treatment option; chemotherapeutic
drugs can disrupt the cell cycle/division and angiogenesis or induce apoptosis of
cancer cells through several signaling pathways.5 Nevertheless, owing to the high
rate of cancer-related mortality, development of resistance, and occurrence of serious
adverse effects, continuous efforts are exerted by scientists to develop new drugs for
the treatment of cancer.6
*These authors contributed equally to
this work
Correspondence: Junqin Mao
Email maojq204@163.com
Shichong Yu
Tel/Fax +86-21-81871228
Email yuscc1008@163.com
Xanthones are bioactive substances isolated and extracted from plants and
microorganisms.7 Their basic skeleton had been confirmed as a biphenyl pyranone
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with a planar three-ring structure (Figure 1A). Notably, the DNA targeting compounds, such as xanthones.25,26 Cu(I)-
derivatives of xanthone possess an array of pharmacological catalyzed azide-alkyne cycloaddition (Click Reaction)
activities (e.g., antitumor, antibacterial, antioxidant, hypoli-
pidemic, etc.).8,9 Based on their planar structure, they act as
efficient DNA intercalators and show anticancer activity via
non-covalent DNA interaction.10 Previous studies have
rapidly yields bioactive molecules linked through 1,2,3-tria-
zole with high atom economy, and have been widely applied
to combinatorial synthesis and bio-conjugate chemistry.27
However, to the best of our knowledge, the incorpora-
reported structures of natural xanthones, such as tion of the polar 1,2,3-triazole ring located at the
5,6-dimethylxanthone-4-acetic acid (DMXAA; IC50 = 48.4
μM for MDA-MB-231 cells) (Figure 1) and globosux-
anthone A, which showed outstanding anti-proliferative
activity.11,12 In particular, DMXAA can interact with various
biological targets via diverse actions. DMXAA is currently
entering the phase III clinical trial stage; consequently, the
synthesis of xanthone derivatives with excellent anticancer
activity has attracted considerable attention. A series of
xanthone analogues were reported and demonstrated
improved in vitro antitumor activity versus the parent
xanthone and drug-like properties.13,14 For example,
a caged xanthone (Figure 1B; IC50 = 3.60 μM for A549
cells) was synthesized using the prenyl moiety of its parent
C3-position of xanthone has not been reported in prior
studies. Therefore, 22 heterocyclic xanthone derivatives
were designed and synthesized to explore the antiprolifera-
tive effect associated with the 1,2,3-triazole and substituent
benzyls of the xanthone framework (1a–v, Figure 1). The
antiproliferative effects of all derivatives were evaluated
in vitro using the MTT colorimetric method against
human lung cancer cell line A549.28,29 Furthermore, we
carefully selected potential compounds to examine the
main mechanism involved in cancer cell death.
Materials and Methods
Chemistry
xanthone,15,16 while 3-phenylxanthone (Figure 1C; IC50
=
Target compounds 1a–v were synthesized on the basis of
a reasonable synthetic route strategy (Scheme 1). In this
method, synthesis of compound 4 was achieved by apply-
ing Eaton’s reagents starting from 2-hydroxybenzoic acid
2 and 1, 3, 5-trihydroxybenzene 3. Compound 5 was
synthesized through the O-alkylation reaction, in the pre-
sence of K2CO3, KI, and propargyl bromide in acetonitrile
at room temperature. The target compounds 1a–v were
obtained by performing a click reaction with variously
substituted benzyl azides. All compounds were
6.27 μM for QGY-7703 cells) was identified as a potent and
promising antitumor agent.17
In the side chain, 1,2,3-triazole could serve as
a privileged building block for the synthesis of bioconju-
gates owing to its high stability, selectivity, and fewer
adverse reactions.18 It exhibited formidable stability under
basic and acid hydrolysis, including oxidative and reductive
reactions. Moreover, this heterocycle was the bioisostere of
amide and interacted with biomolecular targets through
hydrogen-bonding.19 This attractive chromophore showed
diverse activities (e.g., antibacterial, antiallergic, antiviral,
antimalarial, antifungal, and anticancer).20–24 In addition, it
interacted with DNA and acted as a supporting motif for
Scheme 1 Synthesis of compounds 1a-v. Reagents and conditions: (A) P2O5/CH3
SO3H, 85°C, 2.5 h; (B) Propargyl bromide, K2CO3, KI, acetonitrile, 6 h; (C)
Corresponding benzyl azide, DMSO, CuSO4.5H2O, Vit-Na, r.t., 2 h.
Figure 1 Chemical structures of xanthones (A) Basic structure of xanthone, (B, C)
Derivatives of xanthone.
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1
characterized through H NMR, 13C NMR, and MS. The were incubated with A549 cells for 12 h. The absorbance was
measured at 490 nm using a microplate reader (Multiskan
MK3, Thermo Scientific, USA). Cell survival in the control
group was considered 100% and that of all other groups was
normalized to this value. These procedures were performed
in triplicate.
details are provided in the Supplementary Information of
this article.
Biological Assays
We used the methyl thiazolyl tetrazolium (MTT) method to
measure the cytotoxic activity of the target compounds
against human lung cancer A549 cells. The results of this
experiment are summarized in Table 1.28,29 The A549 cells
were obtained from the Cell Bank of the Chinese Academy
of Sciences (Shanghai, China). Cells were seeded at a density
of 5×104 cells/mL, and the compounds were added to the
supernatant at different concentrations (i.e., 50 μg/mL,
30 μg/mL, 10 μg/mL, 2 μg/mL, 0.4 μg/mL). Cells not treated
with compounds served as negative control, while those
treated with pirarubicin hydrochloride served as positive
control. Twelve hours later, MTT (20 μL, 5 mg/mL) was
added to the cells, and the cells were incubated at 37°C for
4 h in the dark. Subsequently, dimethyl sulfoxide was added
and the mixture was incubated for 10 min. All compounds
Western blotting was performed to separate the pro-
teins. For the extraction of total protein, 5×105 A549 cells
were lysed in Protein Extraction Regent (Pierce, Rockford,
USA) supplemented with a protease inhibitor cocktail and
centrifuged (17,709 g) for 15 min at 4°C. Protein concen-
trations of the extracts were measured using the BCA
assay (Pierce, Rockford, IL, USA) and equalized with
the extraction reagent. Proteins were separated through
sodium dodecyl sulfate-polyacrylamide gel electrophoresis
and transferred to nitrocellulose membranes (Millipore,
MA, USA). After the transfer, the proteins were immuno-
blotted with the corresponding primary antibody against
caspase 3, p53, Bax, and c-Jun N-terminal kinase (JNK)
(Cell Signaling Technology, Danvers, MA, USA) (dilution
ratio: 1:5000). The blots were incubated with the corre-
sponding horseradish peroxidase-conjugated secondary
antibody (Kangchen, Shanghai, China) for 1 h at room
temperature (dilution ratio: 1:5000). The intensity of each
protein band was measured using Quantity One.
Table 1 Anticancer Activities of the Target Compounds in vitro
(IC50, μM)
Compounds
R
IC50(μM) A549
A549 cells (1×105 cells/mL) were seeded in six-well
plates and treated with either vehicle or the indicated
concentrations of 1j and 1h for 48 hr. The cells were
collected through centrifugation at 4°C and washed twice
with ice-cold phosphate-buffered saline. Subsequently, the
cells were stained with Annexin-V-FITC/PI (KeyGEN;
Nanjing, China) and analyzed via flow cytometry (BD
FACS Calibur, Franklin Lakes, CA, USA).
1a
4-CH3
3-CH3
2-CH3
4-F
113.8 6.2
92.5 3.9
67.3 3.3
102.3 4.1
292.4 6.0
96.8 5.5
51.5 2.6
40.2 3.8
596.6 9.8
32.4 2.2
71.5 6.3
96.4 5.8
264.1 6.2
56.0 2.8
104.8 4.7
133.2 5.4
74.2 4.3
97.1 3.8
59.2 3.6
76.4 5.4
97.7 3.4
133.2 4.2
340.7 4.8
268.4 3.5
5.8 0.3
1b
1c
1d
1e
3-F
1f
2-F
1g
4-Cl
1h
3-Cl
1i
2-Cl
1j
4-Br
3-Br
2-Br
4-OCH3
3-OCH3
2-OCH3
4-CF3
3-CF3
2-CF3
4-CN
3-CN
2-CN
H
1k
Statistical Analysis
1l
Data are presented as means standard deviation. One-way
analysis of variance was used to calculate statistical differ-
ences. All statistical analyses in this study were conducted
using SPSS for Windows, version 22.0 (IBM, Armonk, NY,
USA). A p<0.05 denoted statistical significance.
1m
1n
1o
1p
1q
1r
1s
Results and Discussion
1t
As shown in Table 1, 22 target compounds were synthesized
after the introduction of 1,2,3-triazole and the heterocycle
group. Of those, 18 compounds showed higher activity
compared with intermediate 4 (IC50 = 340.7 4.8 μM) and 5
1u
1v
4
-
5
-
Pirarubicin Hydrochloridea
-
(IC50 = 268.4
3.5 μM). The extensional structure of
Note: aPirarubicin Hydrochloride was used as a positive control.
various substituted groups resulted in a significantly
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Figure 2 1h (A) (concentration: 46 μM) and 1j (B) (concentration: 46 μM) induced cell death in human umbilical vein endothelial cells in vitro.
increased anticancer effect versus compound 1v with the possessed higher activity versus those with electron-
benzyl group (IC50 = 133.2 4.2 μM). In detail, the com- donating groups (1a–c, 1m–o). Of note, the compounds
pounds with substituted deactivating groups (1d–k, 1p–u) with weak electron-withdrawing groups (1g, 1h, 1j, 1k)
Figure 3 1h and 1j induced apoptosis in cancer A549 cells. Representative scatter diagrams. The A549 cells were pre-treated with (A) 1h at a dose of 0, 23, and 46 μM (0,
10, and 20 μg/mL), (B) 1j at a dose of 0, 17, and 34 μM (0, 8 and 16 μg/mL), respectively, for 48 h. Apoptotic cells were stained with Annexin V-FITC and PI, and measured
using flow cytometry. **p<0.01 vs Con.
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demonstrated the highest activity in this series. Among 20 μg/mL, 46 μM) and 1j (low dose: 8 μg/mL, 17 μM;
compounds with substituted halogen, the compound with high dose: 16 μg/mL, 34 μM) were selected for further
replaced para bromide exhibited the highest anticancer activ- evaluation. Firstly, their effect of these compounds on
apoptosis was investigated. Two doses (low dose, high
dose) were used in the experiment and the results are
presented in Figure 3. At the low dose, the rate of total
apoptosis induced by 1h and 1j was only 12.21% and
11.18%, respectively. Notably, at the high dose, 1j resulted
in 24.20% and 17.59% total and later apoptosis, respec-
tively. The effect of 1h on later apoptosis also markedly
contributed to cell death (19.93%). There was no signifi-
cant difference between the low and high dose groups in
terms of early apoptosis. Furthermore, A549 cells were
incubated with 1h (46 μM) and 1j (34 μM) for 72 h. The
ity (IC50 = 32.4 2.2 μM). However, the IC50 values of
compounds 1a–v were lower than that of pirarubicin hydro-
chloride, an effective anticancer drug used in clinical prac-
tice. Two representative compounds, namely 1h (IC50 = 40.2
3.8 μM) and 1j (IC50 = 32.4 2.2 μM), presented strong
activity against lung cancer A549 cells. In addition, these
compounds obviously decreased the survival rate of human
umbilical vein endothelial cells, and resulted in toxic effects
on normal cells at concentrations of 46 μM and 34 μM,
respectively (Figure 2).
Owing to their higher activity against cancer cells,
compounds 1h (low dose: 10 μg/mL, 23 μM, high dose: rate of total apoptosis increased with time (Figure 4).
##
Figure 4 1h and 1j induced apoptosis in cancer A549 cells at 24 and 72 hrs. **p<0.01 vs Con.
p<0.01 vs 24hrs.
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We used Western blotting to examine the expression significantly up-regulated the expression of Bax protein.
of caspase 3, p53, Bax, and JNK in A549 cells after Bax, belonging to the Bcl-2 gene family, was central to
the regulation of mitochondrial apoptosis. Collectively,
these findings suggest that the high expression of apopto-
sis-related factors and p53 was the main mechanism of
compound 1j.
incubation with 1h and 1j for 12 h to disclose the mechan-
ism through which compounds 1h and 1j prevented cancer
cell growth. Caspase-3 was involved in the apoptotic
process (i.e., chromatin condensation and DNA fragmen-
tation). JNK played key roles in regulating cell prolifera-
tion, apoptosis, and differentiation. As shown in Figure 5,
we found that both compounds 1j and 1h increased the
expression of caspase-3 and JNK in A549 cells.
Interestingly, these two compounds also enhanced the
expression of p53. p53 is a tumor suppressor playing
numerous roles in inducing DNA repair, senescence, cell
cycle arrest, and apoptosis. This result was consistent
with those of previous studies investigating other series
Conclusion
Most of the target compounds exerted a marked inhibitory
effect on cancer cells. The activity of 18 compounds was
higher than that of the intermediates 4 and 5. Moreover, the
extensional structure of the 1,2,3-triazole ring and hetero-
cycle groups was beneficial to anticancer activity.
Compounds 1h and 1j demonstrated the most potent inhibi-
tory activity against A549 cells. The effects of compounds
of xanthone.30,31 Noticeably, only compound 1j 1h and 1j on early apoptosis, necrosis, and late apoptosis
Figure 5 Effect of 1h (A) and 1j (B) on proteins related to cell death. A549 cells were treated with 1h (at a dose of 23 and 46 μM) and 1j (at a dose of 17 and 34 μM) for
12 hrs. The expression levels of proteins were measured using Western blotting. All data are presented as mean SE; n=3, *p<0.05 vs Con; **p<0.01 vs Con.
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Acknowledgments
This work was supported by the National Natural Science
Foundation of China (No. 21202200) and by the Project of
Shanghai Science and Technology Transformation and
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The authors declare no conflict of interests in this work.
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