Synthesis and evaluation of new thiourea derivatives as antitumor and antiangiogenic agents

Article abstract of DOI:10.1016/j.tetlet.2020.152366

A series of novel thiourea derivatives were synthesized and evaluated by biological activities. Among them, compound 10e containing 3,5-bis(trifluoromethyl)phenyl moiety (R₁) at the terminal thiourea and phenylamino (R₂) at the terminal acyl position showed the best cytotoxic activities against seven cancer cell lines (NCI-H460, Colo-205, HCT116, MDA-MB-231, MCF-7, HepG2, PLC/PRF/5) and HUVECs. Moreover, compound 10e moderately inhibited various RTKs such as VEGFR2, VEGFR3, and PDGFRβ. Notably, 10e exhibited much better inhibitory effect of tumor formation and antiangiogenic activities than Sorafenib and Regorafenib at the same concentration. Further docking studies suggested that 10e could serve as potential candidate for cancer therapy.

Full text of DOI:10.1016/j.tetlet.2020.152366

Tetrahedron Letters 61 (2020) 152366
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and evaluation of new thiourea derivatives as antitumor and
antiangiogenic agents
Wenjing Bai a,b, Jianxin Ji a, Qiang Huang d, Wei Wei c,
⇑
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b University of the Chinese Academy of Sciences, Beijing 100049, China
c Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Qinghai 810008, China
d Department of Clinical Pharmacy, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel thiourea derivatives were synthesized and evaluated by biological activities. Among
them, compound 10e containing 3,5-bis(trifluoromethyl)phenyl moiety (R1) at the terminal thiourea
and phenylamino (R2) at the terminal acyl position showed the best cytotoxic activities against seven
cancer cell lines (NCI-H460, Colo-205, HCT116, MDA-MB-231, MCF-7, HepG2, PLC/PRF/5) and HUVECs.
Moreover, compound 10e moderately inhibited various RTKs such as VEGFR2, VEGFR3, and PDGFRb.
Notably, 10e exhibited much better inhibitory effect of tumor formation and antiangiogenic activities
than Sorafenib and Regorafenib at the same concentration. Further docking studies suggested that 10e
could serve as potential candidate for cancer therapy.
Received 18 July 2020
Revised 9 August 2020
Accepted 11 August 2020
Available online 20 August 2020
Keywords:
Thiourea derivatives
Antitumor
Antiangiogenesis
RTK inhibitors
Ó 2020 Elsevier Ltd. All rights reserved.
Introduction
(PDGFR) and fibroblast growth factor receptor (FGFR) have been
used as targets in the antitumor drug screening [11–15]. Many small
Tumorigenesis is a multistage process involving a series of
events and occurs over an extended period [1]. In comparison with
normal cells, cancer cells acquire several abilities, uncontrolled cell
growth is the most fundamental trait [2]. Angiogenesis also play a
crucial role in cancer progression because tumor can’t grow more
than 1–2 mm without a vascular supply [3,4]. Currently, blockade
of angiogenesis and regression of rapidly growing tumor are two
major cancer chemotherapies [5]. Although multiple antiangio-
genic combination therapies have obtained some encouraging
findings, current results also show that the combination therapies
associated with increasing toxicity on normal cells [6]. Single agent
with both anti-tumor and antiangiogenic functions is superior to
the combination therapy [7]. Therefore, it is still highly desirable
to design and synthesize new medicines that have the ability of
both antitumor and antiangiogenic activities.
Receptor tyrosine kinases (RTKs), a subclass of tyrosine kinases,
which involved in cell proliferation, cell death and cell differentia-
tion [8,9]. Dysregulation of RTK signaling often results in cell trans-
formation, which is observed in various malignancies [10].
Targeting RTKs provides revolutionized treatment for cancer ther-
apy. At present, various RTKs such as vascular endothelial growth
factor receptors (VEGFR), platelet-derived growth factor receptor
molecule receptor tyrosine kinase inhibitors have been approved to
be potent antitumor agents such as Sorafenib, Regorafenib, Axitinib,
Lenvatinib, and Sunitinib [16–20]. The advantage of broad spectrum
antitumor treatment has proved in clinic trials. However, the heavy
adverse side effects of these agents indicating there is still a great
demand for receptor tyrosine kinases inhibitors discovery [21].
Thiourea derivatives have variety of biological properties
including antitubercular, antiviral, antimalarial, anti-inflamma-
tory, and especially, antitumor activities [22–25]. To develop
potent and selective agents that have both antiangiogenic and anti-
tumor activities, herein, a series of thiourea derivatives were
designed and synthesized, and their biological activities were fur-
ther evaluated. Among various synthesized thiourea derivatives,
compound 10e bearing 3,5-bis(trifluoromethyl)phenyl moiety at
the terminal thiourea and phenylamino at the terminal acyl posi-
tion was found to exhibit excellent antitumor and antiangiogenic
properties, which might be considered as a promising candidate
for cancer therapy (Figure.1).
Results and discussion
Chemistry
⇑
In order to evaluate the antiproliferative effects of substituents
(R1) attached to the thiourea moiety, compounds 4a-p and 5a-p
Corresponding author.
E-mail address: weiweiqfnu@163.com (W. Wei).
https://doi.org/10.1016/j.tetlet.2020.152366
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
W. Bai et al. / Tetrahedron Letters 61 (2020) 152366
10a-h were synthesized by the addition reaction of 3,5-bis(trifluo-
romethyl)phenyl isothiocyanate with compounds 9a-h.
Biological evaluation
In vitro antiproliferative activity analysis
The newly synthesized compounds were evaluated for their
antiproliferative activities against human endothelial cells (Human
umbilical vein endothelial cells, HUVEC) and cancer cells including
human large cell lung cancer cell line (NCI-H460), human colorec-
tal adenocarcinoma cell line (Colo-205), human colon carcinoma
cell line (HCT116), human breast adenocarcinoma cell line (MDA-
MB-231), human breast adenocarcinoma cell line (MCF-7), human
hepatoma cell line (HepG2) and human hepatoma cell line (PLC/
PRF/5). All of them were tested by CCK-8 assay using Sorafenib
and Regorafenib as positive control. As presented in Table 1 and
Table 2, antiproliferative activities were shown as the percent of
Figure 1. Structure of synthesized potent compound 10e.
were firstly synthesized by the reaction of 4-(4-aminophenoxy)-N-
methylpicolinamide or 4-(4-amino-3-fluorophenoxy)-N-
1
methylpicolinamide 2 with various isothiocyanates 3a-p (phenyl
isothiocyanate, 4-fluorophenyl isothiocyanate, 2,4-difluorophenyl
isothiocyanate,
4-bromophenyl
isothiocyanate,
4-(trifluo-
romethyl)phenyl isothiocyanate, 4-chloro-3-(trifluoromethyl)phe-
nyl isothiocyanate, 3,5-bis(trifluoromethyl)phenyl isothiocyanate,
3-nitrophenyl isothiocyanate, 4-carboxyphenyl isothiocyanate, 3-
ethoxycarbonylphenyl isothiocyanate, 4-(trifluoromethoxy)phenyl
isothiocyanate, 4-(methylthio)phenyl isothiocyanate, 4-tert-butyl-
phenyl isothiocyanate, 4-fluoro-2-methylphenyl isothiocyanate,
4-(benzyloxy)phenyl isothiocyanate, 3,4-methylenedioxyphenyl
isothiocyanate) in the presence of THF, DMF or ACN (Scheme 1)
[26,27].
inhibition values at 10 lM.
Initially, we evaluated the effects of substituents (R1) attached
to the thiourea moiety on the antiproliferative activity against
the tested cell lines. As shown in Table 1, compound 4a with a phe-
nyl ring in the absence of any substituent failed to exhibit antipro-
liferative effects at the concentration of 10
lM, which indicated
Furthermore, to assess the effects of R2 groups on the antiprolif-
erative activity, compounds 10a-h were synthesized as described
in Scheme 2 [26,28,29]. Firstly, 4-chloro-pyridine-2-carbonyl chlo-
ride 7 was prepared from 2-Picolinic acid 6 and SOCl2 in the pres-
ence of DMF. Subsequently, various substituted amines (i.e.
cyclopentylamine, cyclopropylamine, N,N-dimethylethylenedi-
amine, benzylamine, aniline, pyrrolidine, piperidine, 4-aminote-
trahydropyran) were treated with 7 to generate compounds 8a-
h. Then, the key intermediates 9a-h were obtained by coupling
of compounds 8a-h with 4-aminophenol in the presence of
K2CO3 with potassium tert-butoxide. Finally, the target compounds
that the important role of substituent on the aromatic ring. Then,
various thiourea derivatives with electron-withdrawing or elec-
tron-donating groups on aromatic ring were examined. Generally,
the compounds 4d-4j bearing electron withdrawing group on the
phenyl ring showed good antiproliferative activities. Moreover,
compound 4 g with the 3,5-bis(trifluoromethyl)phenyl exhibited
the best antiproliferative activities against cancer cell lines and
HUVECs, which indicated that trifluoromethyl moiety increased
the antiproliferative activity. Compounds 4 k-4p containing elec-
tron-donating groups showed relative weaker activity against cell
lines, which suggested that the electron-donating group on the
Scheme 1. Reagents and conditions: (a) THF, DMF, ACN, 25℃, 2 h.
Scheme 2. Reagents and conditions: (a) SOCl2, DMF, 70℃, 16 h; (b) RNH2 / Pyrrolidine / Piperidine, DCM, Et3N, 0℃, 6 h; (c) 4-aminophenol, DMF, tBuOK, K2CO3, 100℃, 12 h;
(d) 3,5-bis(trifluoromethyl)phenyl isothiocyanate, THF, DMF, ACN 25℃, 2 h.

W. Bai et al. / Tetrahedron Letters 61 (2020) 152366
3
Table 1
Structures and activities of target compounds 4a-p and 5a-p.
Comp.
R1
X
Inhibition (%) of compounds at 10 lM
HUVEC
NCI-H460
Colo-205
6.4 4.2
HCT 116
MDA-MB-231
16.4
MCF-7
10.1
HepG2
PLC/PRF/5
0 0.2
4a
4b
4c
H
H
H
23.2 1.1
À0.3 0.7
À8 1.5
2
2
15.6 1.6
24.1 1.5
16.1 0.4
3.1 0.4
3.5 1.1
À5.6
À2.9
1
2
22 2.2
11.7 1.8
16.3 1.6
16.5
1
2.7 0.8
3.2 2.4
À0.8 0.3
17.4 7.5
18.6 1.1
8.8 1.9
4d
4e
4f
H
H
H
H
50 0.6
9.5 1.9
13.1 1.9
13.5 0.9
47 1.9
À4.9 0.3
0.7
34
3
19.2 1.9
24.4 0.3
50.7 1.7
49.1 1.2
23.2 3.6
27.9 1.9
68.8 0.6
13.6 0.7
57.9 1.3
75.2 0.3
80.1 0.9
29.2 3.2
85.2 0.3
83.1 0.2
6
27.6 0.7
79.6 0.6
82.3 0.6
3
2.9
51.1 3.3
53.3 1.9
20.2 0.7
41.6 1.6
4g
74.4 0.6
67
1
4h
4i
H
H
H
28.8 0.5
À4 1.9
7.3 3.2
À0.2 2.4
3.4 1.6
79.1 3.1
3.8 3.1
11.3 0.9
48.4
4
14.6 2.9
13.7 1.4
1.7 2.1
52.2 3.2
À0.6 4.4
17.8 0.7
29.5 1.8
6.9 2.5
21.2 0.6
47
1
À1.3 3.9
À2 0.6
0.8 0.9
7.9 0.6
4j
27.2 0.3
4k
4l
H
H
H
34.8 3.8
56 0.4
21.2 2.4
À0.7 0.6
9.8 3.6
14.2 11.6
9.9 3.4
À2.7 1.3
À9.9 1.2
6.8 5.6
23.3 0.7
37.6 3.8
8.3 2.9
31.8 1.4
7.2 2.2
14.8 3.7
23.6 6.7
16.6 4.4
7.7 4.5
6.8 1.1
16 0.9
1.5 1.4
4m
51.8 1.3
36.2 11.2
4n
4o
H
H
1.8 3.7
0.2 1.5
8.1 0.7
0
2.2
À0.5 2.8
14.6 1.7
13.7 3.6
10.4 1.1
26.8 1.7
À0.7 1.9
1.5 1.6
5.5 1.3
20.5 3.2
À0.9 0.6
9.9 1.7
7.6 3.3
4p
5a
5b
5c
H
F
29.8 1.5
7.8 0.4
14.8 0.4
1.6 2.4
0.6 1.2
16.6 7.6
14.8 6.6
20.9 7.1
4.2 0.9
1.5 3.6
À4.7 2.7
À7 1.7
19.3
4
6.2 3.5
13.2 0.8
8.1 2.2
8.5 2.2
12.8 3.5
3.6 4.2
7.3 0.5
14.8 0.7
0.6 2.2
17.1 2.1
18.3 0.1
23.3 1.2
F
4
1.6
5.1
2
F
14.6
33.5
2
1
2.6 0.6
4.2
2
7
2.6
2.7 0.9
5d
5e
F
F
12.4 1.7
27.2 3.9
2.7 1.6
14.2 0.5
19 0.9
22.1
1
20.7 3.3
23.5 1.7
8.2 2.6
59.8 2.7
45.3
1
14.6
1
16.4 4.1
35.5 0.3
14.9 1.8
5f
F
F
75.6 0.7
80.9 0.5
67.9 0.9
85 0.8
32.5 3.2
76.7 0.4
40.9 1.5
68.8 1.5
69.9 2.1
82.8 0.5
34.7 1.8
58.1 4.2
60 2.7
24.8 2.3
47.2 0.6
5g
67.8 0.8
5h
5i
F
F
25.1 0.3
28.7 4.8
75.3 3.4
40.7 4.4
0.2 2.8
12.2 3.2
13.8 4.3
50.4 1.3
23.2
3
45.5 0.4
3.2 2.2
À3.5 1.1
À1.7 1.1
6
4.4
3
5.8
7.8 3.8
5j
F
23.2 1.4
2.3 1.7
17.6 7.5
À0.9
2
5.2 1.8
16.2 1.6
11.6 2.2
7.9 1.5
5k
5l
F
F
F
F
50.4 2.2
38.1 1.2
31.1 1.5
11.9 0.9
5.8 1.8
0.6 0.3
7.8 2.8
4.9 1.9
14.9 4.9
15.9 8.7
4.1 3.4
3.4 0.9
À5.1 2.3
À2.8 1.7
32.4 1.9
20.3 1.6
19.1 0.8
10.1 2.9
13.5 3.3
17.7 3.7
15.7 4.3
18.2 2.1
5.6 7.1
7.2 0.6
À3.5 2.7
0.7 0.3
2.2 1.8
4.3
1
7.1 0.8
4.1 0.1
10.4 1.2
99.4 0.1
5m
5n
À2.6
3
Sora
Rego
–
–
–
–
94.1 0.4
84.5 0.5
85.4 0.1
85.8 0.9
88.7 0.8
82.1 0.8
98.1 0.1
84.7 0.8
98 0.3
82 0.7
93.4 0.3
85.2 0.1
79.3 0.8
78.4
1
78.9
2
All values are expressed as Mean SEM.

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W. Bai et al. / Tetrahedron Letters 61 (2020) 152366
Table 2
Structures and activities of target compounds 10a-h.
Comp.
10a
R2
Inhibition (%) of compounds at 10 lM
HUVEC
NCI-H460
88.5 0.8
Colo-205
79.9 0.7
HCT116
71 1.2
MDA-MB-231
79.1 1.2
MCF-7
HepG2
PLC/PRF/5
85.8 0.2
86.2 0.8
29.6 0.8
57.9 0.6
10b
10c
72.8 0.6
62.5 0.8
71 0.9
54 1.8
51.8 1.1
65 1.3
38 0.7
2.7 2.8
49.4 0.6
67.8 1.1
50.3 2.5
62.4 1.6
52.8 0.4
56.2 0.4
58.3 0.9
30.4 0.4
10d
10e
87.7 0.1
89.2 0.4
92.8 0.6
97.3 0.7
87.9 0.4
85 1.6
79.7 0.2
87.6 0.4
86.5 0.4
85 0.6
57.1 0.9
78.8 0.7
65.8 2.8
87.3 0.7
89.9 0.3
90.7 0.1
10f
87.1 0.1
89.1 0.6
76.8 0.7
73.8 1.1
58.7 0.4
72.3 0.2
38.2 3.6
69.5 0.5
35.5 0.5
33 2.7
68.3 2.1
65.5 0.3
78.8 1.1
46.1 3.4
10g
61.1
1
12.7 1.3
10h
64.1 0.7
82.6 0.6
73.6 0.8
63.2 0.5
59.9 0.7
22.5 2.9
62.9 0.9
73.3 0.2
sora
rego
–
–
93 0.5
80.8 0.7
81.8 0.4
79.9
85.3 2.1
1
95.4 0.2
78.5 0.7
96 0.7
54.5 3.3
82.3 0.1
77.7 0.7
77.6 1.4
71.5 2.8
96.7 0.4
69.3 0.5
81.5
1
All values are expressed as Mean SEM.
terminal aromatic ring decreased the antiproliferative activities. In
addition, the introduction of fluoro atoms at X position displayed
no significant impact on the antiproliferative activity (5 vs 4).
Based on the above results, 4 g was selected as precursor. Keep-
ing R1 as 3,5-bis(trifluoromethyl)phenyl moiety to assess the
effects of R2 groups attached to the acyl position on the antiprolif-
erative activity. As the results outlined in Table 2, most of com-
pounds bearing alkyl or aromatic amino groups showed
significant antiproliferative activities. Compound 10e with pheny-
lamino group showed the best activity against all of the tested cell
lines compared with other compounds bearing cycloalkylamino or
alkylamino group. The IC50 values of 10e are depicted in Table 3.
Compound 10e showed excellent activity against the HUVECs
pound showed weaker inhibition of RTK than Sorafenib and Rego-
rafenib, 10e still had excellent multi-kinase inhibitory activities at
low concentration.
Inhibition of clone formation
Clone formation can partly represent the malignant potential of
cancer cell [30]. Based on the result of antiproliferation, compound
10e as the potential compound was chosen to test the inhibitory
ability of neoplastic transformation. Cancer cells HepG2 and
endothelial cells HUVECs were treated with compounds at the final
concentration 5
lM for 14 days, respectively. As result shown in
Figure 2A and B, compound 10e totally inhibited HepG2 and
HUVECs clone formation, which showed much better inhibition
than Sorafenib and Regorafenib. The results indicated that com-
pound 10e has the potential to inhibit cancer cell growth, malig-
nant transformation and vascular endothelial cell proliferation.
(IC50 = 2.81
M), MDA-MB-231 (IC50 = 8.21
HepG2 (IC50 = 6.21 M), PLC/PRF/5 (IC50 = 7.82
l
M), NCI-H460 (IC50 = 1.86
M), MCF-7 (IC50 = 9.19
M), which is more
l
M), HCT116 (IC50 = 6.42-
l
l
l
M),
l
l
potent than Sorafenib and Regorafenib. Therefore, compound 10e
was selected as a new starting point for further optimization.
Inhibition of angiogenesis
To explore the antiangiogenic activity of compound 10e, tube
formation assay was conducted [31]. To mimic in vivo angiogene-
sis, HUVECs were plated on Matrigel and then treated with DMSO
(control), Sorafenib, Regorafenib and 10e at the final concentration
Inhibition of RTKs
Based on the role of RTK inhibitors in antitumor and antiangio-
genesis, the most active antiproliferative compound 10e was fur-
ther evaluated for their inhibitory activities against VEGFR2,
VEGFR3, PDGFRb and FGFR1 kinase. As result depicted in Table 4,
compound 10e inhibited VEGFR2, VEGFR3 and PDGFRb kinase
activities with the inhibition percentage values of 38%, 49% and
45%, respectively at the concentration 800 nM. Although com-
5
lM. As shown in Figure 3, compound 10e could significantly
inhibit the formation of the reticulation of tube-like structures.
When HUVECs were exposed to compound 10e, the tube structures
were destroyed and the morphological characteristics were evi-
dently inhibited, which is more obviously inhibition than Sorafenib
Table 3
The IC50 values of selected compounds against HUVECs and cancer cell lines.
Comp.
IC50(lM)
HUVEC
NCI-H460
Colo-205
HCT 116
MDA-MB-231
MCF-7
HepG2
PLC/PRF/5
10e
Sora
Rego
2.81
7.69
9.01
1.86
3.95
4.7
9.92
9.76
9.7
6.42
9.39
6.24
8.21
12.83
17.38
9.19
14.9
16.11
6.21
11.19
7.56
7.82
11.76
11.75

W. Bai et al. / Tetrahedron Letters 61 (2020) 152366
5
Table 4
Receptor tyrosine kinase inhibitory activities of compound 10e.
Comp.
Inhibition (%) of compounds at 800 nM
VEGFR2
VEGFR3
PDGFR-b
FGFR1
10e
Sora
Rego
38.7 1.4
90 0.5
87.5 0.8
49.5
91.3 0.6
91.8 0.2
3
44.8 2.9
79.3 0.1
77.1 0.4
7.6 2.8
59.9 2.2
78.7 1.6
All values are expressed as mean SEM.
Figure 2. Compound 10e inhibited cell clone formation (A) Clones of HepG2 cells after treatment with Control, Sorafenib, Regorafenib, 10e at the final concentration 5
14 days. (B) Clones of HUVECs after treatment with Control, Sorafenib, Regorafenib, 10e at the final concentration 5 M for 14 days.
lM for
l
Figure 3. Compound 10e inhibited tube formation. The tube formation of HUVEC cells treated with control, Sorafenib, Regorafenib, 10e at the final concentration 5 lM for
12 h, respectively.
and Regorafenib. Considering that proliferation and tube formation
of endothelial cells are properties in process of angiogenesis, these
results demonstrated that compound 10e has the ability to block
blood vessel formation.
The final binding conformation was selected with the lowest
energy conformation. Due to the X-ray crystallographic structures
of VEGFR3 and PDGFRb were not fully resolved, compound 10e was
docked with VEGFR2 (PDB ID: 3WZE) to identify the key interac-
tions [34,35].
Molecular docking studies
In general, the binding mode of 10e with VEGFR2 was similar
with Sorafenib as shown in Figure 4A. The terminal phenylamino
moiety occupies the adenine pocket, and the 3,5-bis(trifluo-
romethyl)phenyl group binds hydrophobic allosteric pocket. Simi-
lar with Sorafenib, the NH of compound 10e formed a hydrogen
bone with conserved Glu885 (3.18 Å) at the hinge region of the
kinase (Figure 4B and C). In addition, the binding affinity was also
evaluated by hydrophobic interactions. Compound 10e had the
hydrophobic interactions with the residues such as Leu1035,
Val899, Val916, Phe918, and Leu889, which indicated that 10e
could be considered as novel candidate for further discovery of
VEGFR2 inhibitor.
Sorafenib is a Type II inhibitor blocking VEGFR2 DFG-out. As
reported, Sorafenib formed five hydrogen bones with VEGFR2
[32]. The 4-chloro-3-(trifluoromethyl)phenyl group of Sorafenib
binds a deep hydrophobic allosteric pocket and the urea group
lying in an allosteric channel forms hydrogen bonds with N-lobe
residue Glu885 and the activation-loop residue Asp 1046 [33].
Moreover, the terminal picolinamide group of Sorafenib formed
the conserved hinge bond with Cys919.
In order to better understand the interaction between com-
pounds and kinases, molecular docking studies on the potent rep-
resentative compound 10e was performed using AutoDock vina.

6
W. Bai et al. / Tetrahedron Letters 61 (2020) 152366
Figure 4. Interaction between 10e and VEGFR2 by docking analysis (A) Superimposition of 10e (cyan) and Sorafenib (yellow) at VEGFR2 binding site. (B) The LigPlus
schematic 2-dimensiona represents 10e and VEGFR2 interaction. (C) 3-Dimensional binding modes of 10e docked into VEGFR2 kinase. Hydrogen bonds between 10e and
VEGFR2 are represented by yellow dashed line.
Conclusion
In summary, we designed and synthesized three series (4, 5, 10)
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152366.
of thiourea derivatives. All synthesized compounds were investi-
gated for their cytotoxic activities against HUVECs and multiple
cancer cell lines. Among them, compound 10e containing 3,5-bis
(trifluoroMethyl)phenyl moiety (R1) at the terminal thiourea and
phenylamino (R2) at the terminal acyl position showed higher
antiproliferative activities than Sorafenib and Regorafenib. Fur-
thermore, compound 10e was also proved to be a moderate RTK
inhibitor against VEGFR2, VEGFR3 and PDGFRb. In addition to
antiproliferative activities, 10e also showed the potency of inhibit-
ing clone formation against cancer cells or endothelial cells. More-
over, compound 10e has exhibited excellent antiangiogenic
activities according to tube formation assay. In addition, molecular
docking of the compound 10e into the active site of VEGFR-2 was
performed, and the result suggested the compound could bind well
at the active site. The above studies showed that compound 10e
exhibited significant antitumor and antiangiogenic activities,
which has the potential to be considered as a promising candidate
for antitumor agent.
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This work was supported by the Institute of Drug Innovation,
Chinese Academy of Sciences (CASIMM0420152013 and
CASIMM0420151009); the International Cooperation Project of
Qinghai Province (2018-HZ-806), Strategic Biological Resources
Service Network Program of Chinese Academy of Sciences (ZSTH-
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Exploration Project (No. CK-1149-011).

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