Discovery of novel picolinamide-based derivatives as novel VEGFR-2 kinase inhibitors: Synthesis,: in vitro biological evaluation and molecular docking

Article abstract of DOI:10.1039/c8md00057c

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has emerged as an attractive target for cancer therapy. In our effort, a novel series of picolinamide-based derivatives were designed and synthesized as potent and effective VEGFR-2 inhibitors. All the newly prepared compounds were evaluated in vitro for their antiproliferative activity against A549 and HepG2 cell lines. Among the new compounds, 8j and 8l exhibited better activity against both A549 and HepG2 cell lines. Molecular docking was performed to investigate the binding capacity and binding mode with VEGFR-2 (PDB code: 4ASD).

Full text of DOI:10.1039/c8md00057c

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ARTICLE
Discovery of novel picolinamide-based derivatives as novel
VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation
and molecular docking
Received 00th January 20xx,
Accepted 00th January 20xx
Wuji Sun,a Shubiao Fangb and Hong Yan*a
DOI: 10.1039/x0xx00000x
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the
VEGFR-2 signaling pathway has emerged as an attractive target for cancer therapy. In our effort, a novel series of
picolinamide-based derivatives was designed and synthesized as potent and effective VEGFR-2 inhibitors. All the newly
prepared compounds were evaluated in vitro for their antiproliferative activity against A549 and HepG2 cell lines. Among
the new compounds, 8j and 8l exhibited better activity against both A549 and HepG2 cell lines. The molecular docking was
performed to investigate the binding capacity and binding mode with VEGFR-2 (PDB code: 4ASD).
www.rsc.org/
many structurally diverse VEGFR-2 kinase inhibitors have been
approved or in clinical trials for the treatment of cancers, such
Introduction
as Sorafenib,12 Regorafenib,13 Axitinib14 and ENMD-207615
(
Fig.
Cancer is the second leading cause of death worldwide. Cancer
management is an extremely challenging field for medicinal
chemists to discover effective and safer chemotherapeutic
agents targeting various biochemical processes involved in
progression of different kinds of cancers.1 Among these
targets, angiogenesis, the generation and growth of new blood
vessels from the endothelium of an existing vascular network,
is one of the critical processes that affect growth and
development of cancerous cells.2 Angiogenesis is also a
complex process regulated by multiple growth factors that
involves the migration, growth and differentiation of
endothelial cells.3, 4 Among these factors, vascular endothelial
growth factor (VEGF) and its receptors (VEGFR-1/Flt-1, VEGFR-
2/KDR/FLK-1 and VEGFR-3/Flt-4) are recognized as the major
mediator of tumor angiogenesis.5-7 Particularly, VEGFR-2, a
class of receptor tyrosine kinase, mediates the major
angiogenic function of VEGF,8 which expressed primarily in
endothelial cells and secreted by endothelial cells and various
tumor cells. Over activation of VEGFR-2 is correlated with poor
1
).
O
H
N
H
N
CF3
Cl
O
Cl
N
O
H
N
O
N
O
F
N
H
N
CF3
H
O
Sorafenib
Regorafenib
N
HN
N
N
N
N
S
HN
N
O
NH
HN
N
Axitinib
ENMD-2076
Fig. 1 VEGFR-2 inhibitors currently approved or in clinical trials
As well known, Sorafenib and Axitinib, known as tyrosine
kinase inhibitors, could significantly inhibit the activity of
VEGFR-2 and then cause the reduction of angiogenesis.12, 16
The structure-activity relationships (SARs) demonstrate
Sorafenib binds to the ATP binding site of VEGFR-2. It presents
a typical pharmacophore model where the central aryl moiety,
occupying the linker region, is bound to pyridine core
occupying the adenine pocket via an ether linker, while the
terminal aryl ring in hydrophobic pocket is bound to the
central aryl moiety via urea group in para position. The similar
model between Axitinib and VEGFR-2 can also be discovered,
where the central indazole moiety holds the linker region,
while the aryl ring and the terminal pyridine ring are linked to
the indazole.
prognosis and metastasis in the majority of solid tumor
patients.9,
10
Due to the vital roles of VEGFR-2 in tumor
angiogenesis, inhibition of VEGFR-2 activation has become a
compelling approach for developing targeted cancer
therapies.11 Hence, several kinase inhibitors targeting VEGFR-2
are acknowledged as the promising therapeutic drugs for
treatment against a wide variety of human cancers. At present,
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Journal Name
H3C
O
HO
b
HO
a
X
O
X
X
Y
CHO
Y
Y
O
4a
: X = N; Y = CH
4b: X = CH; Y = N
1a
3a
: X = N; Y = CH
1b: X = CH; Y = N
: X = N; Y = CH
3b: X = CH; Y = N
2
O
e
R
N
X
Y
O
O
N
N
HOOC
N
c
d
Cl
R
8a-8v
Cl
Cl
7a-7k
5
6
Scheme 1 Synthetic route of target compounds 8a-8v. Reagents and conditions: a) acetic anhydride/acetic acid, reflux, 72-75%;
b) KOH, EtOH, reflux, 92-94%; c) SOCl2/DMF, reflux, 100%; d) amines, dichloromethane, rt, 71-81%; e) Cu, Cs2CO3, DMF, N2, 110
℃, 54-70%.
In this paper, we report the design, synthesis and SARs of acetic anhydride/acetic acid to furnish compounds 3a-3b in
a novel series of picolinamide-based derivatives as potential 75% and 72% yield. Next, hydrolysis of compounds 3a-3b was
VEGFR-2 inhibitors. In an attempt to develop new scaffolds for achieved via potassium hydroxide in ethanol to afford the
VEGFR-2 inhibitors, we hypothesized that a hybrid scaffold corresponding compounds 4a-4b in 92% and 94% yield,
could be created by grafting 2-ethenylpyridine fragment of respectively. Furthermore, the starting material 2-picolinic acid
Axitinib onto 4-phenoxypicolinamide fragment of Sorafenib
Fig. 2). In order to further explore the SARs, a series of chloropicolinoyl chloride
picolinamide-based derivatives was designed and chloride was treated with the corresponding amine to form
5
was treated with thionyl chloride to prepare 4-
(
6. Subsequently, 4-chloropicolinoyl
8
6
synthesized as VEGFR-2 inhibitors. As expected, these 4-chloropicolinamide derivatives 7a-7k in 71-81% yield. Finally,
picolinamide derivatives displayed effective antiproliferative the target compounds 8a-8v were prepared through reaction
activity and could be considered as the promising VEGFR-2 of 4-chloropicolinamide derivatives 7a-7k and compounds 4a-
inhibitors.
4b in 54-70% yield. The final products were purified by column
chromatography and their structures were characterized by 1H
NMR, 13C NMR and HRMS. The crystal structures of 8b (CCDC
number 1588889) and 8l (CCDC number 1588886) were
confirmed by single crystal X-ray diffraction (Fig. 3 and Fig. 4).
adenine pocket
linker region
linker region
hydrophobic pocket
Cl
O
N
HN
N
O
N
O
H
S
N
HN
N
N
CF3
O
H
H
Sorafenib
Axitinib
adenine pocket
O
linker region
hydrophobic pocket
O
R
Fig. 3 ORTEP diagram of the crystal structure of 8b (drawn at
50 % thermal ellipsoids)
N
X
Y
8
Fig. 2 Design of picolinamide-based derivatives
8
Results and discussion
Chemistry
Fig. 4 ORTEP diagram of the crystal structure of 8l (drawn at 50
% thermal ellipsoids)
The synthetic route for compounds 8a-8v is depicted in
Scheme 1. Specifically, synthesis was initiated by reacting
picoline 1a-1b with 4-hydroxybenzaldehyde
2 in refluxing
2 | J. Name., 2012, 00, 1-3
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Table 1 The structures and IC50 values of target compounds against cancer cell lines
Substituent
IC50 (μM)a
Entry
selectivityb
R
X
Y
A549
HepG2
8a
8b
N
CH
17.4 ± 1.1
21.6 ± 1.3
30.2 ± 1.4
1.2
1.6
N
N
N
CH
CH
CH
19.1 ± 0.9
20.0 ± 1.5
16.2 ± 1.7
8c
30.0 ± 2.0
31.3 ± 1.3
1.5
1.9
8d
8e
8f
N
N
N
CH
CH
CH
18.8 ± 0.8
63.6 ± 2.1
＞100
27.9 ± 1.5
26.0 ± 1.0
45.1 ± 2.6
1.5
0.4
＜0.5
8g
＞100
＞4.7
1.8
8h
8i
N
N
N
CH
CH
CH
21.4 ± 0.9
17.3 ± 1.3
12.5 ± 1.0
31.0 ± 2.4
20.6 ± 1.9
8j
1.6
8k
8l
N
CH
N
15.6 ± 2.2
13.2 ± 1.6
79.7 ± 0.8
27.0 ± 2.1
18.2 ± 0.8
＞100
1.7
1.4
CH
CH
＞1.2
8m
N
＞100
＞3.9
8n
8o
CH
CH
N
N
25.6 ± 2.2
62.1 ± 2.8
56.2 ± 1.4
0.9
8p
8q
8r
CH
CH
CH
N
N
N
17.0 ± 0.7
19.3 ± 1.5
18.2 ± 1.7
28.9 ± 2.5
1.7
＞100
＞5.2
37.2 ± 1.6
2.0
8s
8t
CH
CH
CH
N
N
N
20.6 ± 2.3
35.5 ± 0.9
16.8 ± 1.2
33.7 ± 0.6
77.5 ± 2.7
22.4 ± 2.2
1.6
2.2
1.3
8u
8v
CH
-
N
-
-
18.6 ± 1.7
41.6 ± 1.5
2.2
-
-
Sorafenib
Axitinib
19.3 ± 0.9
22.4 ± 1.4
29.0 ± 2.0
38.7 ± 1.9
1.5
1.7
-
a IC50 values are the mean ± S.D. of three separate experiments.
b Selectivity=IC50 value (HepG2)/IC50 value (A549)
Biological evaluation
cell lines were stimulated by VEGF and usually used as the
tested cells in the discovery of VEGFR-2 kinase inhibitors. As
shown in Table 1, most target compounds exhibited effective
inhibitory activities against both cell lines with IC50=12.5-25.6
μM and 18.2-37.2 μM compared to Sorafenib (IC50=19.3 μM
In vitro antiproliferative activity of the 22 picolinamide
derivatives was evaluated against A549 and HepG2 cell lines by
CCK assay using Sorafenib and Axitinib as controls. And both
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and 29.0 μM) and Axitinib (IC50=22.4 μM and 38.7 μM). The receptor and Sorafenib and Axitinib would be considered as
results indicated the hybrid scaffold created by grafting 2- the reference compounds in docking study.18 All target
ethenylpyridine fragment onto 4-phenoxypicolinamide compounds were docked into the binding site, and the binding
structure could maintain even enhance the antiproliferative affinities were reported as the binding free energy (Δ
activity. Among them, 8d and 8k demonstrated better inhibition constant (Ki). The docking results were presented in
antiproliferative activities against A549 cell with IC50=16.2 μM Table 3. Compound fitted well into the binding site of
and 15.6 μM, and 8a and 8u demonstrated better inhibitory VEGFR-2, with Δ ranging from -10.52 to -8.31 kcal/mol and Ki
activities against HepG2 cell with IC50=21.6 μM and 22.4 μM ranging from 0.019 to 0.815 μM. Among the target
compared to other compounds. Moreover, 8j showed effective compounds, 8l (Δ =-10.52 kcal/mol, Ki=0.019 μM) exhibited a
G) and
8
G
G
inhibitory activities against A549 and HepG2 cell lines with better binding capacity with VEGFR-2 owing to the
IC50=12.5 μM and 20.6 μM, and 8l showed similar inhibitory introduction of methylamino in suitable positions. And the
activities against both cell lines with IC50=13.2 μM and 18.2 introduction of cyclohexylamino in 8j (Δ
μM, respectively. Ki=0.029 μM) and 8u (Δ =-10.27 kcal/mol, Ki=0.030 μM) also
In the following, the impacts of the substituent R on the resulted in better binding capacity than other compounds. It
carbonyl group and the substituents X/Y on the terminal was obvious that the docking results of 8j 8l and 8u were
G=-10.28 kcal/mol,
G
,
pyridine were investigated, which may influence the selectivity consistent with their better antiproliferative activities.
on A549 and HepG2 cell lines. As shown in Table 1, compound
Table 3 The docking results of the target compounds
8g bearing a 4-fluorobenzylamino group provided a significant
reduction of inhibition potency on A549 (IC50
＞100 μM) and
Entry
△
Ga
Kib
Entry
△
Ga
Kib
selectivity (＜0.5-fold vs HepG2). This trait was also obvious in
8a
-9.53
-8.53
-9.00
-8.95
-9.66
-9.14
-9.32
-9.37
-9.61
-10.28
-9.42
-11.03
-9.15
0.104
8l
-10.52
-9.65
-9.20
-9.56
-9.10
-8.59
-9.76
-8.59
-8.31
-10.27
-9.45
0.019
compound 8f containing 4-methoxybenzylamino. In contrast,
compound 8q containing 4-methoxybenzylamino group
showed good antiproliferative activity to A549 with IC50=19.3
8b
0.561
0.253
0.274
0.082
0.198
0.147
0.135
0.090
0.029
0.125
0.008
0.195
8m
8n
8o
8p
8q
8r
0.084
0.179
0.098
0.214
0.503
0.069
0.505
0.815
0.030
0.119
8c
μM and
＞5.2-fold selectivity against HepG2. Moreover, it was
8d
notable that compound 8h bearing an isopropylamino group
and compound 8n bearing a 4-methoxyanilino group showed
good inhibitory activities against A549 (IC50=21.4 μM and 25.6
8e
8f
μM) and selectivity (
To assess the inhibition for VEGFR-2 of target compounds,
the most active compounds 8a 8j 8l and 8u were selected to
＞3.9-fold and ＞5.2-fold vs HepG2).
8g
,
,
8h
8i
8s
further evaluated for their inhibitory activity against VEGFR-2
kinase with Sorafenib as positive control. The results indicated
that these compounds displayed good inhibitory activity on
VEGFR-2 kinase with IC50 values ranging from 0.29 to 1.22 μM
8t
8j
8u
8v
8k
(
Table 2). Among them, compound 8l potently inhibited
VEGFR-2 at low IC50 value of 0.29 μM. Moreover, compounds
8a and 8j possessed IC50 values of 0.87 and 0.53 μM,
respectively. The result of VEGFR-2 kinase assay was
corresponding with that of in vitro inhibitory activity on A549
and HepG2 cell lines, which might indicate the target
compounds acted as the VEGFR-2 kinase inhibitors.
Sorafenib
Axitinib
a Binding free energy (kcal/mol)
b Inhibition constant (μM)
Table 2 The VEGFR-2 inhibitory activity of target compounds
Entry
VEGFR-2 IC50 (μM)a
0.87 ± 0.06
8a
8j
0.53 ± 0.09
8l
0.29 ± 0.02
8u
1.22 ± 0.12
Sorafenib
0.95 ± 0.09
a
IC50 values are the mean
±
S.D. of three separate
experiments.
Molecular docking
Fig. 5 Comparison of the binding site between 8l (magenta),
Sorafenib (yellow) and Axitinib (blue)
To understand the SARs between inhibitors and VEGFR-2,
molecular docking simulations were performed using
AutoDock 4.2 software.17 The VEGFR-2 kinase domain crystal
structure of Sorafenib (PDB ID: 4ASD) was selected as the
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To further evaluate the SARs, compound 8l was chosen as The representative compound 8l showed a good binding mode
a representative compound and docked into the binding site of with VEGFR-2. The N1-nitrogen of pyridine and the NH group
VEGFR-2 in comparison to Sorafenib and Axitinib. As displayed of picolinamide formed two essential hydrogen bonds with
in Fig. 5 and Fig. 6, compound 8l almost totally overlapped Cys919. The central aryl moiety and the terminal pyridine ring
with Sorafenib and Axitinib, and showed a good binding mode were involved in hydrophobic interactions with residues. In
with VEGFR-2. On the moiety of pyridine core, there were two conclusion, these compounds have strong potential to be
important hydrogen bonds formed with Cys919. The N1- further developed as novel VEGFR-2 inhibitors. Further
nitrogen of pyridine core was hydrogen bonded to the structural optimization of the most active candidates may lead
backbone NH of hinge residue Cys919, and the NH group of to the discovery of better inhibitors, and the studies are
picolinamide was hydrogen bonded to the backbone carbonyl currently in progress.
of hinge residue Cys919. Furthermore, the pyridine core had
some hydrophobic interactions and Van der Waals contacts
Conflicts of interest
with Leu840, Leu1035, Ala866 and Glu917. The central aryl
moiety located in the linker region and contacted with Ala866,
Cys1045, Lys868, Val848, Val916 and Phe1047. The terminal
pyridine ring that connected the central aryl moiety via ethenyl
penetrated into the hydrophobic pocket created by the hinge
residues Asp1046, Glu885, Leu889, Leu1019 and Val914.
All authors declare that there is no conflict of interest.
Acknowledgements
This work was financially supported by the Key Projects in the
Beijing Municipal Natural Science Foundation (No.
KZ201510005007).
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In summary, a novel series of picolinamide-based derivatives
was designed and synthesized as potential VEGFR-2 inhibitors,
and their structures were characterized by H NMR, 13C NMR,
7.
8.
9.
1
HRMS and single crystal X-ray diffraction. The antiproliferative
activities were evaluated against A549 and HepG2 cell lines
with Sorafenib (IC50=19.3 μM and 29.0 μM) and Axitinib
(IC50=22.4 μM and 38.7 μM) as reference. Of these derivatives,
8j (IC50=12.5 μM and 20.6 μM) and 8l (IC50=13.2 μM and 18.2
μM) emerged as the most active members against both cell
lines. Also, 8d and 8k displayed good inhibitory activities
against A549 with IC50=16.2 μM and 15.6 μM, and 8a and 8u
exhibited effective inhibitory activities against HepG2 with
IC50=21.6 μM and 22.4 μM. The inhibitory activities of the most
10.
11.
12.
13.
active compounds 8a, 8j, 8l and 8u against VEGFR-2 were
further evaluated. Compound 8l was found to be the most
active counterpart against VEGFR-2 with IC50 value of 0.29 μM.
Molecular docking was performed to investigate the binding
capacity and binding mode with VEGFR-2. The docking results
14.
15.
indicated that 8j (Δ
G=-10.28 kcal/mol, Ki=0.029 μM) and 8l
(ΔG=-10.52 kcal/mol, Ki=0.019 μM) exhibited better binding
capacities, corresponding with their antiproliferative activities.
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