Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents

Article abstract of DOI:10.1016/j.bmcl.2017.09.040

Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC₅₀ = 7.5 μM) and showed better activity than the lead compound (xanthotoxin, IC₅₀ > 100 μM) and the reference drug (5-fluorouracil, IC₅₀ = 29.6 μM) did. The IC₅₀ value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents.

Full text of DOI:10.1016/j.bmcl.2017.09.040

Accepted Manuscript
Design and synthesis of new triazoles linked to xanthotoxin for potent and highly
selective anti-gastric cancer agents
Qing-Kun Shen, Chuan-Feng Liu, Hong-Jian Zhang, Yu-Shun Tian, Zhe-Shan
Quan
PII:
S0960-894X(17)30936-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.09.040
BMCL 25304
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
15 June 2017
8 September 2017
16 September 2017
Please cite this article as: Shen, Q-K., Liu, C-F., Zhang, H-J., Tian, Y-S., Quan, Z-S., Design and synthesis of new
triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents, Bioorganic & Medicinal
Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.09.040
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Design and synthesis of new triazoles linked to xanthotoxin for
potent and highly selective anti-gastric cancer agents
Qing-Kun Shen, Chuan-Feng Liu, Hong-Jian Zhang, Yu-Shun Tian* and Zhe-Shan
Quan*
Key Laboratory of Natural Resources and Functional Molecules of the Changbai
Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University,
Yanji, Jilin, 133002, China.
*Corresponding author: Tel: + 86 433 243-6020; Fax: + 86 433 243-5026.
E-mail: zsquan@ybu.edu.cn (Z. S. Quan).
*Corresponding author: Tel: + 86 433 243-6028; Fax: + 86 433 243-5026.
E-mail: ystian@ybu.edu.cn (Y. S. Tian).

Abstract
Two series of xanthotoxin-triazole derivatives were designed, synthesized, and
studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds
in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay.
Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-
4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest
antiproliferative activity against AGS cells (IC50 = 7.5 µM) and showed better activity
than the lead compound (xanthotoxin, IC50 > 100 µM) and the reference drug
(5-fluorouracil, IC50 = 29.6 µM) did. The IC50 value of 6p in L02 cells was 13.3 times
higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic
activity and specificity compared with the positive control 5-fluorouracil. Cell cycle
analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase
arrest in AGS cells. Compound 6p was identified as a promising lead compound for the
further development and identification of 1,2,3-triazole-based anticancer agents.
Keywords: Xanthotoxin; Triazole; AGS cells; Antiproliferation

Over the past few decades, cancer has been the second most common
life-threatening disease after cardiovascular disease. Gastric cancer is one of the most
frequent causes of cancer-related deaths1. Despite the enormous advances in cancer
treatment, it remains the second most common cause of death worldwide because of
ineffective chemotherapy, caused by drug resistance, and the inability of many drugs to
differentiate between normal cells and cancerous cells2. Thus, there is an urgent need for
a systematic approach to the development of new chemotherapeutic agents with superior
efficacy, lower toxicity, and better selectivity.
Furanocoumarins occupy an important place in the subject of natural products and
synthetic organic chemistry. They possess antileukodermal, vasodilatory, and anticancer
activities3-5. Xanthotoxin and imperatorin (Fig. 1) are two important derivatives of
furanocoumarin: it has been reported that xanthotoxin and its derivatives clearly inhibited
the growth of tumor cells4 and the administration of imperatorin was reported to inhibit
tumor growth and block tumor angiogenesis in a xenograft tumor model6.
Nitrogen heterocycles have been extensively investigated in the literature owing to
their role as active pharmacophores. Among them, substituted 1,2,3-triazoles are an
indispensable structural motif of compounds that display a broad spectrum of biological
activities and are widely used in organic synthesis, medicinal chemistry, and material
science. For example, 1,2,3-triazoles are reported to possess diverse pharmacological
effects, including anticancer7-8 (compound A and B; Fig. 1), immunosuppressant9,
antimicrobial10-11, antimalarial12, and anti-inflammatory13 activities. Compounds
containing 1,2,3-triazole actively participate in hydrogen bonding and dipole-dipole
interactions owing to their strong dipole moments; moreover, it is extremely resistant to
hydrolysis and remains stable in oxidative and reductive conditions14. Recently, a
molecular hybridization approach that combines two pharmacophores to yield a single
molecule with the additive biological properties has been favored by medicinal
chemists15. These hybrids combine two active moieties in a single molecule with the goal

of creating a chemical entity that is medically more effective than the individual
constituents. We envisaged that the integration of the xanthotoxin and 1,2,3-triazole
moieties into one molecular platform could potentially produce novel compounds with
significant synergistic antitumor properties. Additionally, 1,2,4-triazole is an isostere of
1,2,3-triazole. Herein, we have described our work towards the design, synthesis, and
evaluation of new xanthotoxin-linked 1,2,3-triazoles (6a–6r) (Fig. 1) and new
xanthotoxin-linked 1,2,4-triazoles (9a–9g) (Fig. 1) for their cytotoxicity in the gastric
cancer cell line, AGS, and the human normal liver cell line, L-02.
O
Ο
Ο
O
Ο
Ο
O
O
Imperatorin
Xanthotoxin
HIF-1 inhibitor
O
Isostere
O
Molecular
Ο
Ο
Ο
Ο
O
N
O
N
N
O
O
Hybridization
N
O
R
Ν
N
N
N
N
R
Compound A
9a-9g
6a-6g
Ο
O
O
N
Ν
N
Compound B
Fig. 1. Design of target compound 6a-6r and 9a-9g.
The synthetic outlines for the synthesis of the starting and target compounds are
presented in Scheme 1. First, xanthotoxin (3) was treated with 1 M BBr3 in anhydrous
methylene chloride at 0
to yield 9-hydroxy-7H-furo[3,2-g]chromen-7-one (4) via a
reported procedure16. In the next step, 9-(prop-2-ynyloxy)-7H-furo[3,2-g]chromen-7-one
(5) was obtained by the reaction of propargyl bromide and compound 4 in the presence of
anhydrous potassium carbonate and dry acetone at 56
for 12 h17. Then, the target

compounds 6a–6r were obtained by the reaction of various intermediates (1a–1k or
2l–2r), sodium ascorbate, and CuSO4·5H2O in dichloromethane:water (5:1) at 40 for
12–24 h18-19. Additionally, 9-hydroxy-7H-furo[3,2-g]chromen-7-one (4) was treated with
ethyl bromoacetate in the presence of anhydrous potassium carbonate in dry acetone at
56
for 12 h to yield intermediate 7. Hydrazinolysis of the latter afforded the acid
hydrazides 8, which were mingled with N,N-dimethylformamide dimethyl acetal and
aniline to yield the target compounds 9a–9g20.
N3
a
NH2
Cl
b
N3
R
R
R
R
1a-1k
2l-2r
e
d
c
O
O
O
O
O
O
O
O
O
O
O
N
O
O
O
OH
4
O
3
N
5
N
R
6a-6r
f
g
h
O
O
O
O
O
O
O
O
O
O
O
O
O
N
NHNH2
O
7
R
O
N
N
8
9a-9g
Scheme 1. Reagents and conditions: (a) NaN3, DMF, rt; (b) (i) NaNO2, HCl, 0 oC, 45min; (ii) NaN3,
o
H2O, 0 C; (c) BBr3, CH2Cl2, 0 C, 12h ; (d) K2CO3, propargyl bromide, acetone, 56 C; (e) 1a-1k or
o
o
.
o
2l-2r, CuSO4 5H2O, sodium ascorbate, CH2Cl2/H2O (1:1), 40 C; (f) K2CO3, ethyl bromoacetate,
acetone, 56 oC; (g) hydrazine hydrate, ethyl alcohol, 78oC; (h) (i) dimethylacetal, acetonitrile, 60 oC, 1
h; (ii) various aromatic amine, glacial acetic acid, 120 oC.
The synthetic outlines for the synthesis of the starting and compared compounds
10-11 are presented in Scheme 2. 1-(4-(trifluoromethyl)phenyl)-4-methyl-1H-1,2,3-
triazole (10) was obtained by the reaction of propionaldehyde, malononitrile,
21
1-azido-4-(trifluoromethyl)benzene (2p) and DBU in DMSO at 50
.

4-Fluorobenzenamine was mingled with N,N-dimethylformamide dimethyl acetal and
acetohydrazide to yield the target compound 4-(4-fluorophenyl)-3-methyl-4H-1,2,4-
triazole (11)20. All compounds submitted for biological testing were recrystallized to
consistent melting point and judged as >95% pure by HPLC and identified via IR,
1H-NMR, and 13C-NMR spectrometry and high resolution mass spectrometry (HRMS).
CF3
N3
i
H
N
N
NC
CN
F3C
O
N
10
2p
F
NH2
O
O
j
N
N
N
NHNH2
N
O
F
11
Scheme 2. Reagents and conditions: (i) DBU, DMSO, 50 oC, 8h; (j) (i) acetonitrile, 60 oC, 1 h; (ii)
glacial acetic acid, 120 oC.
The antiproliferative activity of the synthesized compounds was evaluated against
the cultured human AGS cell line, with xanthotoxin tested as a comparative compound.
In addition, the clinically prescribed powerful antineoplastic drug 5-fluorouracil (5FU)
was used as a reference drug. The screening procedure was based on a standard MTT
method22 and the growth inhibition percentages after 100 µM treatment are summarized
in Table 1. In the AGS cell line, 100 µM xanthotoxin resulted in 35.3% the growth
inhibition; it is evident from the activity essay that most of the xanthotoxin-linked
triazoles showed better antiproliferative activity. Compounds 6g, 6h, 6j, 6n–6r, 9b, and
9e exhibited good activity, with growth inhibition percentages greater than 50%.

Table 1. The antiproliferative activity of compounds 6a-r and 9a-g
O
O
N
O
O
O
O
O
N
O
N
R
N
N
N
R
6a-6r
9a-9g
% Growth Inhibition at 100 µM
Compound
R
AGSa
6a
6b
6c
6d
6e
6f
-CH2C6H5
24.4 0.2
25.5 0.4
30.1 0.5
43.1 0.4
33.2 0.8
49.5 0.9
-CH2C6H4(o-F)
-CH2C6H4(m-F)
-CH2C6H4(p-F)
-CH2C6H4(o-Cl)
-CH2C6H4(m-Cl)
6g
6h
6i
-CH2C6H4(p-Cl)
-CH2C6H4(2,4-Cl)
-CH2C6H4(2,6-Cl)
-CH2C6H4(m-CF3)
-CH2C6H4(p-CH3)
-C6H5
53.2 0.7
67.7 1.0
32.5 0.3
51.7 0.3
47.0 0.5
46.4 0.4
39.6 0.2
70.4 0.7
89.6 0.4
92.4 1.1
65.6 0.4
6j
6k
6l
6m
6n
6o
6p
6q
-C6H4(o-F)
-C6H4(P-F)
-C6H4(P-Cl)
-C6H4(p-CF3)
-C6H4(p-CH3)
6r
9a
9b
9c
9d
9e
9f
-C6H4(p-OCH3)
-C6H5
53.2 0.7
40.1 0.8
72.3 1.0
45.2 0.3
40.3 0.4
52.9 0.3
39.4 0.2
-C6H4(p-F)
-C6H4(o-Cl)
-C6H4(p-Cl)
-C6H4(p-CF3)
-C6H4(p-CH3)
9g
-C6H4(p-OCH3)
34.4 0.1
35.3 0.2
74.9 0.8
Xanthotoxin
5-FUb
-
-
a Human gastric cancer cells.
b 5-fluorouracil

Table 2. IC50 values ( µM) of some active compounds in AGS cancer cell lines and L02
cell lines
In vitro anti-proliferative activities (IC50, µM)a
Compound
SIb (L02/AGS)
AGS
L02
6g
93.2 3.5
26.5 1.4
>100
> 100
90.2 3.8
> 100
> 1.1
3.4
6h
6j
-
6n
10.7 1.2
8.2 1.9
7.5 1.1
33.2 1.9
94.6 3.1
13.1 1.6
41.0 2.5
>100
> 100
> 9.3
> 12.2
> 13.3
> 3.0
> 1.1
7.2
6o
> 100
6p
> 100
6q
> 100
6r
> 100
9b
9e
94.2 2.8
> 100
> 2.4
-
Xanthotoxin
> 100
5-FU
29.6 1.4
19.1 1.0
0.7
a represents the concentration of compound that is required for 50% inhibition using the MTT assay.
Data are expressed as the mean SD from the dose response curves of at least three independent
experiments.
b selectivity indexe.
One of the major obstacles to the druggability of compounds with effective
antitumor activity is their toxicity to normal cells23. Thus, it is necessary to evaluate the
cytotoxicity to normal cells as part of the anticancer drug development. To evaluate the
selective antiproliferative activity of the promising compounds, the cell growth inhibitory
activities (IC50) against the AGS cell line and the L02 normal cell line were measured and
are summarized in Table 2. The selectivity indices (SI) were calculated by the dividing
the IC50 values in cancer cells by the IC50 values in normal cells. The activities of 6h, 6n,
6o, 6p, and 9b against AGS cells were superior to that of 5FU (IC50 = 29.61 µM); the IC50
values were 26.51, 10.7, 8.2, 7.5 and 13.1 µM, respectively. Remarkably, these
compounds displayed clear antitumor activity in AGS cells and low toxicity L02 cells,
which supported the rationale of the drug design. For example, compounds 6o and 6p

exhibited more than 12.2-fold and 13.3-fold cytotoxicity towards AGS cells than the L02
normal cell line. 5FU had similar effective and toxic doses, with IC50 values of 29.6 µM
(AGS) and 19.1 µM (L02), respectively, which indicated that both cancer cells and
normal cells would be killed.
The structure-activity relationship (SAR) analysis revealed that the
phenyl-substituted derivatives showed better activity compared with the
benzyl-substituted derivatives and highlighted the importance of the substituted benzene
of this molecular modification for the antiproliferative activity in xanthotoxin-linked
1,2,3-triazoles. Among the phenyl-substituted derivatives 6n–6r, the order of potency
was p-CF3 > p-Cl > p-F > p-CH3 > p-OCH3. Additionally, for the phenyl-substituted
xanthotoxin-linked 1,2,4-triazoles, the order of potency was p-F > p-CF3. Thus,
compounds with an electron-withdrawing group (-CF3, -Cl, -F) at the 4-position of the
benzyl moiety displayed better antitumor activity. Compound 6p and Compound 9b were
the most active compounds in the 1,2,3- triazoles linked to xanthotoxin and 1,2,4-
triazoles linked to xanthotoxin, respectively. 1-(4-(Trifluoromethyl)phenyl)-4-methyl-1H-
1,2,3-triazole (10) was the structure containing 1, 2, 3-triazole of compound 6p and
4-(4-fluorophenyl)-3-methyl-4H-1,2,4-triazole (11) was the structure containing 1, 2, 4-
triazole of compound 9b. Therefore, in order to evaluate the antiproliferative activity of
1,2,3-triazoles and 1,2,4-triazoles without the xanthotoxin, compound 10 and compound
11 were synthesized. Their cell growth inhibitory activities (IC50) against the AGS cell
line and the L02 normal cell line were measured and are summarized in Table 3. The
results suggested that xanthotoxin and the triazoles did not show significant
antiproliferative activity, respectively. Remarkably, we found that the integration of the
xanthotoxin and triazole moieties into one molecular platform could potentially produce
novel compounds with significant synergistic antitumor properties. So we suspect that
there are two reasons to explain this phenomenon. First, compare to xanthotoxin,triazoles
linked to xanthotoxin showed stronger water solubility. Second, compounds containing

triazole actively participate in hydrogen bonding and dipole-dipole interactions owing to
their strong dipole moments, as a result, it can be better combined with the receptor.
Table 3. The antiproliferative activity of the compared compounds Xanthotoxin, 10 ,11 and some
active compounds 6p, 9b in AGS cancer cell lines and L02 cell lines
AGS cell
L02
Compound
structure
aInhibition rate bIC50(µM)
Inhibition rate %
IC50 (µM)
>100
%
O
Xanthotoxin
10
35.3 0.2
44.5 1.9
>100
>100
3.3 0.5
9.4 0.3
O
O
O
CF3
>100
N
N
N
O
O
O
O
6p
11
92.4 1.1
7.5 1.1
33.9 1.6
>100
N
N
N
F3C
F
13.9 1.2
>100
16.9 1.8
53.1 2.1
>100
N
N
N
O
O
O
O
F
9b
72.3 1.0
13.1 1.6
94.2 2.8
N
N
N
Among all the tested compounds, 6p was found to be the most active in the tested
cell lines (AGS, IC50 = 7.5 µM; L02, IC50 > 100 µM). The IC50 value of 6p in L02 cells
was 13.3 times higher than in AGS cells. Therefore, based on the therapeutic activity and
specificity, we selected 6p for further investigation and explored its mechanism of action
on cell death in detail.

Fig. 2. A. Flow cytometry analyses of cell cycle distribution of breast cancer cell AGS after treatment
of compound 6p (0.1 and 10 µM), no treatment (Ctrl) as reference control for 48 h. B. Apoptosis
induction in lung carcinoma cell AGS after 12 h treatment with 6p (0.1 and 10 µM) and no treatment
(Ctrl) as reference control for 48 h.
Many cytotoxic compounds exert their antiproliferative effect by the arrest of the
cell cycle at a particular cell cycle checkpoint, the induction of apoptosis, or by a
combination of these two effects24. Because compound 6p showed the highest
antiproliferative activity of all the synthesized compounds, its effects on AGS cells were
evaluated by a flow cytometry assay after propidium iodide (PI) staining25. As shown in
Fig. 2A, in comparison with the control group, the treatment of compound 6p (0.1–10
µM) increased the percentage of AGS cells in both the G2 and S phases after 12 h.
Specifically, 10 µM compound 6p led to a decrease in the G1 phase (from 77.02% to
49.76%) and a dramatic increase in the G2 phase (from 16.41% to 38.17%) and the S
phase (from 6.57% to 12.08%). This demonstrated that compound 6p inhibited cell
growth in AGS cells via the induction of S/G2 phase arrest. In order to identify whether
compound 6p induced cell death through apoptosis, we stained the cells with annexin
V-FITC and PI and examined the staining by flow cytometry. The combined results of

three independent experiments are presented in Fig. 2B. Our results suggested that
compound 6p induced cell death, but this was not clearly attributable to the induction of
apoptosis in AGS cells.
Hypoxia inducible factor (HIF)-1 inhibitor has emerged as an attractive target for
anticancer agents as it is a transcription factor that controls the expression of genes such
as vascular endothelial growth factor (VEGF), erythropoietin (EPO), and insulin-like
growth factor26-27. VEGF and EPO are key factors in tumor growth and pathological
angiogenesis. Therefore, drugs targeting HIF-1 may represent a novel approach to cancer
therapy27-30. Imperatorin (Fig. 1) potently inhibited hypoxia-induced HIF-1 activation in
various human cancer cell lines. Therefore, we suspected that the anticancer activity of
compound 6p anticancer occurred through the inactivation of HIF-1; however, study into
this mechanism is in progress.
In conclusion, two series of xanthotoxin-linked triazole derivatives have been
designed, synthesized, and examined for their antiproliferative properties. The
antiproliferative activity of the test compounds was evaluated against the human AGS
cell line and the human L02 normal cell line. Compound 6p possessed the strongest
antiproliferative active against the AGS cells (IC50 = 7.5 µM) and showed better activity
than the lead compound (xanthotoxin, IC50 > 100 µM) and the reference drug (5FU, IC50
= 29.6 µM). The IC50 value of 6p in L02 cells was 13.3 times higher than in the AGS cell.
Therefore, it exhibited better therapeutic activity and specificity compared with the
positive control (5FU). Cell cycle analysis revealed that compound 6p inhibited cell
growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified
as a promising lead compound for the further development and identification of
1,2,3-triazole-based anticancer agents.
Acknowledgments

This work was supported by the National Natural Science Foundation of China (No.
81360468, 21662036).
Supplementary data
Supplementary data associated with this article can be found in the online version
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Highlights:
• Τwo novel series of xanthotoxin-triazole were designed and synthesized.
• Compound 6p was found to have the better antiproliferative activity than the lead
compound and the reference drug.
• All compounds did not exhibit any remarkable cytotoxic activity against L02 normal
cell.
• Compound 6p exhibited better therapeutic activity and specificity compared with 5-Fu
• Compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells.

Design and synthesis of new triazoles linked to xanthotoxin for
potent and highly selective anti-gastric cancer agents
Qing-Kun Shen, Chuan-Feng Liu, Hong-Jian Zhang, Yu-Shun Tian* and Zhe-Shan
Quan*
Key Laboratory of Natural Resources and Functional Molecules of the Changbai
Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University,
Yanji, Jilin, 133002, China.
O
O
O
O
O
N
O
O
O
O
O
N
O
N
O
R
AGS: IC50 > 100 µM
N
N
N
R
6a-6r
9a-9g
6p:R = -C6H4(p-CF3)
9b:R = -C6H4(p-CF3)
AGS: IC50 = 7.5 µM
L02: IC50 > 100 µM
AGS: IC50 = 13.1 µM
L02: IC50 = 94.2 µM
Two novel series of xanthotoxin-triazole derivatives were designed, synthesized,
characterized and evaluated for their antiproliferative activity