Discovery of novel VEGFR-2 inhibitors embedding 6,7-dimethoxyquinazoline and diarylamide fragments

Article abstract of DOI:10.1016/j.bmcl.2021.127788

VEGF/VEGFR-2 signaling plays a critical part in tumor angiogenesis. Inhibition of this pathway has been considered as a promising approach for cancer treatment. In this work, a series of 6,7-dimethoxy-4-anilinoquinazoline derivatives bearing diarylamide moiety were designed, synthesized and evaluated as potent inhibitors of VEGFR-2 kinase. Their in vitro antiproliferation activities against two human cancer cell lines Hep-G2 and MCF-7 have also been determined. Among them, compound 14b exhibited the most potent inhibitory activity against VEGFR-2 with IC₅₀ value of 0.016 ± 0.002 μM and it showed the most potent antiproliferative effect against Hep-G2 and MCF-7 with IC₅₀ values at low-micromolar range. Molecular docking studies revealed that these compounds represented by the most potent compound 14b could bind well to the ATP-binding site of VEGFR-2, which suggested that compound 14b could be a potential anticancer agent targeting VEGFR-2.

Full text of DOI:10.1016/j.bmcl.2021.127788

Bioorg. Med. Chem. Lett. 36 (2021) 127788
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel VEGFR-2 inhibitors embedding 6,7-dimethoxyquinazo-
line and diarylamide fragments
Ru Wanga, Hu Liua, Yuan-Yuan Youa, Xin-Yu Wanga, Bing-Bing Lva, Li-Qin Caoa, Jia-Yu Xueb,
,
,*
Yun-Gen Xua *, Lei Shia
a Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
b Jiangsu Provincial Key Laboratory for Plant Ex Situ Conservation, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
VEGF/VEGFR-2 signaling plays a critical part in tumor angiogenesis. Inhibition of this pathway has been
considered as a promising approach for cancer treatment. In this work, a series of 6,7-dimethoxy-4-anilinoqui-
nazoline derivatives bearing diarylamide moiety were designed, synthesized and evaluated as potent in-
hibitors of VEGFR-2 kinase. Their in vitro antiproliferation activities against two human cancer cell lines Hep-G2
and MCF-7 have also been determined. Among them, compound 14b exhibited the most potent inhibitory ac-
tivity against VEGFR-2 with IC50 value of 0.016 ± 0.002 µM and it showed the most potent antiproliferative
effect against Hep-G2 and MCF-7 with IC50 values at low-micromolar range. Molecular docking studies revealed
that these compounds represented by the most potent compound 14b could bind well to the ATP-binding site of
VEGFR-2, which suggested that compound 14b could be a potential anticancer agent targeting VEGFR-2.
VEGFR-2
Inhibitor
6,7-Dimethoxy-4-anilinoquinazoline
Diarylamide
Cancer
Protein kinases constitute one of the largest protein families. By
multisite phosphorylation, they direct the activity, localization and
function of many proteins, and serve to regulate a wide variety of
cellular processes.1 However, deregulation of protein kinases, which
trigger alteration in kinase-mediated signal transduction, is closely
related to many diseases, such as cancer, diabetes, and immunological,
inflammatory, degenerative and cardiovascular disorders.2 The estab-
lished druggability and the clinical safety profile of approved protein
kinase inhibitors make protein kinases attractive as drug targets.3
Angiogenesis, the growth of new blood vessels from existing vascu-
lature, is essential for normal organ growth and wound repair.4,5
However, an imbalance in this process is involved in a multitude of
pathological events, including cancer, psoriasis, rheumatoid arthritis,
endometriosis, multiple sclerosis, diabetic retinopathy, obesity, and
asthma.4–6 In terms of cancer, solid tumors cannot grow beyond a crit-
ical size without developing new blood vessels to provide oxygen and
nutrients and to dispose of metabolic wastes.7 Hence, blocking angio-
genesis could be a strategy to arrest tumor growth. A number of
proangiogenic regulators, such as vascular endothelial growth factor
(VEGF), epidermal growth factor (EGF), platelet-derived growth factor
(PDGF), transforming growth factor–β (TGF-β), fibroblast growth factor
(FGF), angiopoietins, integrins, and matrix metalloproteinases (MMPs),
have been identified.8,9 Among them, VEGF has been identified as the
most important regulator of tumor angiogenesis, mainly mediated
through a specific receptor tyrosine protein kinase — vascular endo-
thelial growth factor 2 (VEGFR-2, also known as KDR or FLK1).10
Binding of VEGF to VEGFR-2 leads to receptor dimerization, followed by
autophosphorylation of specific tyrosine residues in the intracellular
kinase domain, which initiates a typical receptor signal transduction
cascade and activates a network of distinct downstream signaling
pathways, ultimately leading to angiogenesis, vascular permeability
enhancement, tumor proliferation, and tumor migration.11,12 The
expression of VEGF is commonly upregulated in tumor microenviron-
ment characterized by insufficient oxygenation (hypoxia), acidic pH
(acidosis), and elevated levels of reactive oxygen species (ROS), which is
correlated with tumor progression and poor prognosis in patients with
solid tumors.13 Besides, VEGFR-2 is overexpressed in some malignancies
such as breast cancer, ovarian cancer, thyroid cancer, and hepatocellular
carcinoma.14–17 Therefore, inhibition of VEGF/VEGFR-2 signaling has
been considered one of the most attractive approaches for the treatment
of cancer. Indeed, several VEGFR-2 kinase inhibitors, namely sorafenib
(1), sunitinib (2), pazopanib (3), vandetanib (4), axitinb (5), lenvatinib
(6), regorafenib (7) and cabozantinib (8) (Fig. 1), have been approved
by the Food and Drug Administration (FDA) for the treatment of various
* Corresponding authors.
E-mail addresses: xyg@cpu.edu.cn (Y.-G. Xu), shilei@cpu.edu.cn (L. Shi).
https://doi.org/10.1016/j.bmcl.2021.127788
Received 9 September 2020; Received in revised form 1 January 2021; Accepted 10 January 2021
Available online 16 January 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

R. Wang et al.
Bioorganic & Medicinal Chemistry Letters 36 (2021) 127788
Fig. 1. FDA-approved VEGFR-2 kinase inhibitors.
Fig. 2. Design of novel VEGFR-2 inhibitors bearing 6,7-dimethoxyquinazoline and diarylamide moieties.
types of cancer, such as renal cell carcinoma, colorectal cancer, hepa-
tocellular cancer, non-small cell lung cancer, gastrointestinal stromal
tumor, and thyroid cancer.18 However, current antiangiogenic drugs
including VEGFR-2 inhibitors produce modest beneficial effects and
induce drug resistance.19 Therefore, it is essential to discover novel
VEGFR-2 inhibitors with high efficiency and low toxicity to overcome
drug resistance. A high number of VEGFR-2 inhibitors have recently
been reported, highlighting the interest of medicinal chemists in this
class of therapeutic agents.20–25
activities against VEGFR-2 kinase and antiproliferative activities against
two human cancer cell lines. In addition, their structure–activity re-
lationships (SARs) and possible VEGFR-2 binding modes were further
explored.
The synthetic route of the target compounds containing 6,7-dime-
thoxyquinazoline and diarylamide moieties was outlined in Scheme 1.
Condensation of commercially available substituted benzoic acids
11a-u with 4-nitroaniline 12 in the presence of 1-ethyl-3-(3-(dimethyla-
mino)propyl)carbodiimide hydrochloride (EDCI) and dimethylamino-
pyridine (DMAP) gave the N-(4-nitrophenyl)benzamide intermediates
12a-u. Hydrogenation of 12a-u by treatment with hydrazine hydrate,
iron trichloride and activated charcoal in ethanol afforded N-(4-ami-
nophenyl)benzamide intermediates 13a-u. Condensation of 13a-u with
4-chloro-6,7-dimethoxyquinazoline in the presence of trifluoroacetic
acid in isopropanol under nitrogen atmosphere provided the title
It has been reported that compounds WHI-P180 (9)26 with 6,7-dime-
thoxyquinazoline moiety and SKLB610 (10)27 with diarylamide moiety
are potent and selective VEGFR-2 inhibitors. In this work, a series of
hybrids containing 6,7-dimethoxyquinazoline and diarylamide frag-
ments were designed as novel VEGFR-2 inhibitors (Fig. 2). All the target
compounds were synthesized and evaluated for their inhibitory
2

R. Wang et al.
Bioorganic & Medicinal Chemistry Letters 36 (2021) 127788
Scheme 1. Reagents and conditions: (a) 4-nitroaniline, EDCI, DMAP, dichloromethane, r.t.; (b) NH2NH2⋅H2O, FeCl3, activated charcoal, ethanol, 85 ◦C; (c) 4-chloro-
6,7-dimethoxyquinazoline, TFA, isopropanol, reflux.
compounds 14a-u.
withdrawing trifluoromethyl (14q) was unfavorable for the activity.
Halogen substituent was tolerated in the following order: fluorine >
chlorine > iodine. Moreover, compounds with two halogen substituents
(14s-u) displayed moderate activities. Furthermore, the activity of
compounds with mono-substituent at the para position on the terminal
phenyl ring (14c, 14e, 14f, 14i, 14l, 14 m, 14p and 14r) indicated that
larger electron-donating groups such as ethyl (14e) and tert-butyl (14f)
were well tolerated.
All the prepared N-(4-((6,7-dimethoxyquinazolin-4-yl)amino)
phenyl)benzamide derivatives 14a-u were assayed in vitro for their
enzymatic activity against VEGFR-2 kinase using Caliper motility shift
assay. The results were expressed as IC50 values (the mean values from
three independent determinations) and summarized in Table 1, using
sorafenib as a positive control.
As shown in Table 1, most of these compounds exhibited promising
activity against VEGFR-2. Among them, compound 14b showed the
most potent activity with IC50 of 0.016 µM against VEGFR-2, which was
better than that of the lead compounds WHI-P180 (IC50 = 0.074 µM) and
SKLB610 (IC50 = 0.46 µM) and positive control sorafenib (IC50 = 0.021
µM). Based on the activity data, the impact of substitution on the ter-
minal phenyl ring on the activity of the designed scaffold was investi-
gated and the structure activity relationships (SARs) was summarized as
follows.
To further elucidate the biological activities of the target compounds,
all the synthesized compounds 14a-u were tested for their anti-
proliferation activities against two human cancer cell lines including
Hep-G2 (human liver cancer) and MCF-7 (human breast cancer) by MTT
assay, using sorafenib as the positive control (Table 1). Among them,
compound 14b, the most potent VEGFR-2 inhibitor, also showed the
most potent anticancer activities against Hep-G2 and MCF-7 with IC50
values of 7.5 ± 0.5 μM and 13 ± 2.8 μM respectively, which were better
As demonstrated by compounds 14a–c, the position of the substi-
tution at the terminal benzene was important for the inhibitory activity
than the lead compounds WHI-P180 and SKLB610 and were equivalent
to sorafenib. These data indicated that the cellular potencies of these
compounds were basically consistent with their VEGFR-2 kinase inhi-
bition activities. However, small lipophilic groups such as fluorinr (14g-
i), chlorine (14j-l) and methyl (14a-c) were favorable for the cellular
activities while bigger lipophilic groups such as methoxy (14d), ethyl
(14e) and tert-butyl (14f) led to poor cell potency, despite promising or
mild enzyme activity. In addition, compounds with strong electron
withdrawing group such as trifluoromethyl (14q and 14r) showed mild
enzyme activities but weak cellular activities. Compounds with anili-
noquinazoline scaffold have been reported as multi-target kinase in-
hibitors. Besides VEGFR-2, they also exhibited inhibitory potency
against other kinases such as EGFR,28 RET26 and Aurora kianses.29
Therefore, the antiproliferation activities of the title compounds may be
attributed to their inhibition on these kinases.
against VEGFR-2. The meta- methyl-substituted compound 14b (IC50
=
0.016 µM) was more potent than ortho-methyl-substituted compound
14a (IC50 = 0.115 µM), whereas para-methyl substitution (14c) resulted
in the decrease of activity (IC50 = 3.4 µM), which indicated the position
effect of functional group on the terminal phenyl in the following order:
meta->ortho->para-. This rule was also existed in other single-
substituted derivatives with small functional group such as halogen
(14g-r). In addition, changing the size and electronic effect of substit-
uent at the specified position on the terminal benzene had a critical
impact on enzyme inhibition. Comparing the activity of compounds with
mono-substituent at the meta position on the terminal phenyl ring (14b,
14h, 14k, 14o and 14q), we observed that small electron-donating
methyl (14b) was favorable for the activity while the electron-
3

R. Wang et al.
Bioorganic & Medicinal Chemistry Letters 36 (2021) 127788
Table 1
Enzymatic and cellular activities of the target compounds.
Compound
No.
VEGFR-2
Hep-G2
MCF-7
R
(IC50, µM)
(IC50, µM)
(IC50, µM)
14a
2-CH3
3-CH3
4-CH3
2-OCH3
4-CH2CH3
4-C(CH3)3
2-F
0.115 ± 0.008
0.016 ± 0.002
3.4 ± 0.6
15 ± 1.3
7.5 ± 0.5
25 ± 1.7
>100
21 ± 0.6
13 ± 2.8
19 ± 1.2
>100
14b
14c
14d
5.4 ± 0.5
14e
0.38 ± 0.07
0.26 ± 0.03
0.08 ± 0.01
0.047 ± 0.004
>10
72 ± 20
>100
65 ± 13
>100
14f
14g
13 ± 0.8
8.2 ± 1.4
15 ± 3.1
26 ± 4
11 ± 2.3
13.6 ± 0.5
27 ± 2
14h
3-F
14i
4-F
14j
2-Cl
0.32 ± 0.02
0.075 ± 0.016
>10
36 ± 4.8
18 ± 2.6
30 ± 4.4
43 ± 2.5
37 ± 3.9
30 ± 1.4
48 ± 3.5
>100
14k
3-Cl
12 ± 1.9
28 ± 6
14l
4-Cl
14m
14n
4-Br
2.2 ± 0.3
35 ± 7.2
33 ± 0.8
28 ± 4.5
40 ± 1.2
83 ± 16
>100
2-I
0.42 ± 0.09
0.25 ± 0.04
1.6 ± 0.35
1.4 ± 0.21
8.6 ± 1.3
14o
3-I
14p
4-I
14q
3-CF3
4-CF3
2,6-di-F
3,4-di-Cl
2-Br, 5-F
14r
>100
14s
0.58 ± 0.05
0.35 ± 0.029
0.36 ± 0.015
0.074 ± 0.013
0.46 ± 0.03
0.021 ± 0.004
17 ± 2.6
28 ± 4.5
22 ± 1.7
18 ± 1.5
8.4 ± 0.8
6.5 ± 1.6
24 ± 4
14t
25 ± 3.3
26 ± 5
14u
WHI-P180
SKLB610
Sorafenib
24 ± 0.9
21.5 ± 1.8
15 ± 4
To further understand the binding mode of the target compounds
with VEGFR-2, target compounds were docked into the ATP binding site
of VEGFR-2 (PDB: 3B8Q) by using Discovery Studio 4.5/CDOCKER
protocol. The binding mode of the most potent compound 14b with
VEGFR-2 was depicted in Fig. 3, which revealed that compound 14b was
embedded into the ATP-binding site of VEGFR-2 via hydrogen bonds,
derivatives possessing diarylamide moiety have been designed, pre-
pared and evaluated as novel VEGFR-2 inhibitors. Their in vitro anti-
proliferative activities against two human cancer cell lines (Hep-G2 and
MCF-7) have also been investigated using the MTT-based assay. Com-
pound 14b showed the most potent inhibitory activity against VEGFR-2
with IC50 of 0.016 ± 0.002 μM, which was better than the positive
π
-cation interactions,
π
-anion interactions,
π-
π
stacked interactions,
control sorafenib. It also displayed the most potent antiproliferative
activities against Hep-G2 and MCF-7 cancer cell lines with IC50 values of
alkyl interactions, and van der Waals interactions with amino acid res-
idues of VEGFR-2.
7.5 ± 0.5 μM and 13 ± 2.8 μM, respectively, which were similar to the
The nitrogen atom at 1 position of quinazoline nucleus formed a
reference drug sorafenib. SARs studies revealed that introduction of
substituent at the mata position of the terminal phenyl ring was
preferred. Electron-donating substituent such as methyl at the terminal
phenyl ring was favorable for the activity while the electron-
withdrawing substituent such as trifluoromethyl led to the decrease of
activity. Halogen substituent at the terminal phenyl ring was well
tolerated. Molecular docking studies of all the target compounds into the
active sit of VEGFR-2 were performed using Discovery Studio 4.5/
CDOCKER protocol. The binding mode of the most potent inhibitor 14b
with VEGFR-2 demonstrated that compound 14b could bind tightly to
the active site of VEGFR-2 by various types of interactions with amino
acid residues of VEGFR-2. All the above results suggested that com-
pound 14b could be a potential anticancer agent targeting angiogenesis
and deserves further investigation.
–
–
conventional hydrogen bond with the N H of CYS919 (N… H N: 2.30
◦
–
Å, 131.36 ). The amide N H of compound 14b formed another con-
–
ventional hydrogen bond with the oxygen atom of ASP1046 (O… H N:
◦
–
2.04 Å, 143.27 ). The C H at 2 position of quinazoline nucleus formed a
–
carbon hydrogen bond with the oxygen of GLU917 (O… H C: 2.34 Å,
◦
–
108.05 ) Additionally, the C H of methoxy group at 7 position formed a
–
carbon hydrogen bond with the oxygen of CYS919 (O… H C: 2.48 Å,
◦
–
162.59 ) while the C H of GLY922 formed another carbon hydrogen
–
bond with the oxygen of this methoxy group (O… H C: 2.82 Å,
141.47◦).
The phenyl ring linked to quinazoline moiety formed a π-cation
interaction with the terminal quaternary ammonium cation of LYS868
(4.55 Å) while the terminal phenyl ring formed a -anion interaction
with the terminal carboxylate anion of ASP1046 (4.80 Å). Moreover, the
phenyl ring of quinazoline moiety formed a stacked interaction with
the phenyl ring of PHE918 (5.73 Å) while the phenyl ring linked to
π
π-
π
Declaration of Competing Interest
quinazoline moiety formed a
π
-
π
T-shaped interaction with the phenyl
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
ring of PHE1047 (5.50 Å). Besides, The methyl group at the terminal
phenyl ring formed three alkyl interactions with ILE892 (5.39 Å),
VAL898 (4.69 Å) and LEU1019 (5.01 Å).
In summary,
a series of 6,7-dimethoxy-4-anilinoquinazoline
4

R. Wang et al.
Bioorganic & Medicinal Chemistry Letters 36 (2021) 127788
Fig. 3. (A) 3D molecular docking modeling of compound 14b with VEGFR-2. (B) 2D model of the interaction between compound 14b and VEGFR-2. The hydrogen
bonds are displayed as green dotted lines. The π-cation and π-anion interactions are displayed as yellow dotted lines. The π-π stacked interaction is displayed as pink
dotted line. The akyl interactions are displayed as pale pink dotted lines.
Acknowledgements
Appendix A. Supplementary data
This work was supported by Fundamental Research Funds for the
Central Universities (Grant No. 2632018ZD09), College Students Inno-
vation Project for the R&D of Novel Drugs (Grant No. 201910316100),
and Excellent Science and Technology Innovation Team of Jiangsu
Province Universities in 2015, China.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127788.
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