Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase

Article abstract of DOI:10.1016/j.bmcl.2015.10.006

A series of hybrids derived from 4-anilinoquinazoline and hydroxamic acid were designed, synthesized, and evaluated as dual inhibitors of vascular endothelia growth factor receptor-2 (VEGFR-2) tyrosine kinase and histone deacetylase (HDAC). Most of these compounds exhibited potent HDAC inhibition and moderate VEGFR-2 inhibition. Among them, compound 6l exhibited the most potent inhibitory activities against VEGFR-2 (IC₅₀ = 84 nM) and HDAC (IC₅₀ = 2.8 nM). It also showed the most potent antiproliferative ability against MCF-7, a human breast cancer line, with IC₅₀ of 1.2 μM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction of compound 6l at the active binding sites of VEGFR-2 and HDAC.

Full text of DOI:10.1016/j.bmcl.2015.10.006

Accepted Manuscript
Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of
vascular endothelial growth factor receptor-2 and histone deacetylase
Fan-Wei Peng, Ting-Ting Wu, Zi-Wei Zeng, Jia-Yu Xue, Lei Shi
PII:
S0960-894X(15)30114-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.10.006
BMCL 23162
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
1 September 2015
29 September 2015
3 October 2015
Please cite this article as: Peng, F-W., Wu, T-T., Zeng, Z-W., Xue, J-Y., Shi, L., Hybrids from 4-anilinoquinazoline
and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase,
Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.10.006
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Bioorganic & Medicinal Chemistry Letters
Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of
vascular endothelial growth factor receptor-2 and histone deacetylase
a
a
a
b
a
Fan-Wei Peng , Ting-Ting Wu , Zi-Wei Zeng , Jia-Yu Xue , Lei Shi *
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
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of hybrids derived from 4-anilinoquinazoline and hydroxamic acid were designed,
synthesized, and evaluated as dual inhibitors of vascular endothelia growth factor receptor-2
(VEGFR-2) tyrosine kinase and histone deacetylase (HDAC). Most of these compounds
exhibited potent HDAC inhibition and moderate VEGFR-2 inhibition. Among them, compound
6l exhibited the most potent inhibitory activities against VEGFR-2 (IC50 = 84 nM ) and HDAC
(
IC50 = 2.8 nM). It also showed the most potent antiproliferative ability against MCF-7, a human
Keywords:
Hybrid
breast cancer line, with IC50 of 1.2 µM. Docking simulation supported the initial
pharmacophoric hypothesis and suggested a common mode of interaction of compound 6l at the
active binding sites of VEGFR-2 and HDAC.
4
-Anilinoquinazoline
Hydroxamic acid
VEGFR-2
HDAC
Angiogenesis plays a pivotal role in the growth of most solid
tumors and also contributes to the progression of tumor
Histone deacetylases (HDACs) are a class of enzymes which
catalyze the removal of acetyl groups from lysine residues in
histone amino termini, leading to chromatin condensation and
[1,2]
metastasis
. Vascular endothelial growth factor (VEGF) and
[27,28]
its receptor tyrosine kinases VEGFR-2 or kinase insert domain
transcriptional repression
. The eighteen HDACs identified
[3-5]
receptor (KDR) are key regulators of angiogenesis
. Upon
in humans are classified in four classes depending on their
sequence homology to yeast HDACs, their subcellular
binding to VEGF, VEGFR-2 undergoes ligand-induced
dimerization and autophosphorylation and initiates downstream
signaling, ultimately leading to angiogenesis, tumor survival,
[28]
localization and their enzymatic activities
. Among them,
Classes I (HDAC1, HDAC2, HDAC3, and HDAC8), II (HDAC4,
HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10) and IV
[6-8]
proliferation, and migration
[
29]
become a valuable approach in the
(HDAC11) are zinc dependent metalloproteins . It has been
widely recognized that HDACs are diversely implied in cancer
progression. HDAC inhibitors (HDACI) can affect tumour cell
growth and survival by blocking the deacetylation of histone or
nonhistone proteins (such as α-tubulin, Hsp90, and transcription
factors p53 and NF-κB), inducing cell cycle arrest, angiogenesis
suppression, tumor cell antigenicity enhancement, and apoptosis
treatment of cancers. This is evident from the approval of the
anti-VEGF monoclonal antibody Bevacizumab for the treatment
of non-small-cell lung, colorectal, breast, kidney, and brain
[
9,10]
cancer by FDA
. Additionally, the small-molecule VEGFR-2
[11] [12]
tyrosine kinase inhibitors such as sorafenib
vandetanib , and pazopanib
, sunitinib
,
[13]
[14]
have been approved by FDA
[
30]
for treatment of diverse cancers. Recently, many researchers
including us have been pursuing VEGFR-2 kinase domain
. Recently immense efforts have been made to develop novel
[31-38]
HDAC inhibitors
.
[15-19]
inhibitors to discover novel anti-angiogenic drugs
.
Although HDACI show promise as single-agent anticancer
drugs, given the range of molecular and biological responses that
these agents can elicit and minimal toxicity to normal cells, their
use in combination with other anticancer agents could prove to be
their most useful application. Indeed, HDACI have been already
Unfortunately, a large number of patients do not respond to
VEGF/VEGFR-2 targeted therapy. In addition, the duration of
benefit from VEGF/VEGFR-2 targeted therapy can be relatively
short. Ultimately, the majority of patients who initially respond
[20-22]
to therapy will develop acquired resistance
. In order to
shown to function synergistically with a host of structurally and
overcome the acquired drug resistance to tyrosine kinase
inhibitors (TKIs), including VEGFR-2 TKIs, a number of
strategies have been tested, such as development of multi-
[30]
functionally diverse chemical compounds
. For example,
HDACI can function synergistically with imatinib, an ABL
kinase inhibitor which can kill BCR-ABL positive chronic
myeloid leukemia (CML) cells, to enhance apoptosis in BCR-
[23-26]
targeted inhibitors and combination therapies
.

[
39, 40]
ABL expressing CML cells
. More importantly, HDACI in
The preparation of target compounds followed the general
[41]
combination with imatinib was effective against imatinib-
refractory CML, and both wild-type BCR-ABL and the T315I
mutant form of BCR-ABL, which is resistant to imatinib, were
reaction route outlined in Scheme 1 . Compounds 3a-3d were
prepared through the coupling of 4-chloro-7-methoxyquinazolin-
6-yl acetate (1) with substituted anilines (2a-2d). Hydrolysis of
the acetyl group on compounds 3a-3d using lithium hydroxide
gave corresponding phenol intermediates 4a-4d. Alkylation of
the hydroxyl group on compounds 4a-4d with various chain
lengths of ethyl bromoalkanoate gave ethyl ester intermediates
[39, 40]
equivalently degraded following combination treatment
.
Unlike combinations of TKI and HDACI, a single agent with
VEGFR-2 and HDAC inhibitory activities offers some
advantages, such as concurrent pharmacokinetics, decreasing
drug-drug interactions caused by multiple drugs and off-target
adverse effects, increasing patient compliance, and reducing drug
cost. Recently, multi-acting inhibitors against HDAC and RTK
5
a-5p. Conversion of ethyl esters 5a-5p to hydroxamic acids
using freshly prepared hydroxylamine furnished target hybrids
a-6p. The structures of all the synthesized intermediates and
6
1
[41-44]
target compounds were confirmed by H-NMR, ESI-MS and
elemental analyses.
have been reported as potent anticancer agent
. In this paper,
a series of hybrids with 4-anilinoquinazoline and hydroxamic
acid motifs were discovered as novel VEGFR-2/HDAC dual
inhibitors.
Scheme 1. Synthesis of compounds 6a-6p. Reagents and conditions: (a) isopropanol, refiux; (b) LiOH.H
bromoalkanoate, K CO , DMF, 40 C; (d) NH OH, CH OH, 0 C.
2 3 2 3
2 3 2
O, CH OH, H O; (c) ethyl
o
o
The in vitro inhibitory activities of the target compounds
against VEGFR-2 and HDAC were evaluated. VEGFR-2 kinase
inhibitory activity was measured using HTScan VEGF Receptor
the Fluor de Lys HDAC fluorometric activity assay kit (Enzo
[45]
Life Sciences, Inc.)
. Besides, the in vitro antiproliferative
activities of the targeted hybrids against MCF-7 (a human breast
[17]
2
Kinase Assay Kit (Cell Signaling Technology, Inc.) by
adenocarcinoma cell line) were also evaluated by MTT assay
The biological results were summarized in Table 1.
.
colorimetric ELISA assay according to the manufacturer’s
[17]
instructions . HDAC inhibitory activity was measured using
Table 1. In vitro enzyme inhibitory activities and antiproliferative activities of target compounds.
1
2
3
4
Compouds
R
R
R
R
n
IC50
VEGFR-2 (nM)
HDAC (nM)
MCF-7 (µM)
>100
65.2
6
6
6
6
6
6
6
6
a
b
c
d
e
f
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
3
4
5
2
3
4
5
476
352
613
501
625
434
415
462
645
121
17
8.6
5.4
531
97
3.2
>100
68.4
g
h
15
8.5
4.5
2.8

6
6
6
6
6
6
6
6
i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
-
H
H
H
H
H
H
H
H
-
Cl
Cl
Cl
Cl
H
H
H
H
-
H
H
H
H
Cl
Cl
Cl
Cl
-
2
3
4
5
2
3
4
5
-
370
215
86
95.0
56.8
6.4
j
138
k
l
115
14
84
2.8
348
57
1.2
m
n
o
p
1260
2140
5200
2450
62
>100
44.5
13.7
4.0
21
8.4
>10000
12
Vandetanib
Vorinostat
18.5
4.5
-
-
-
-
-
>10000
As shown in Table 1, the synthesized hybrids 6a-6p showed
moderate VEGFR-2 inhibitory activities. Among them,
compound 6l exhibited the most potent inhibitory activity against
VEGFR-2 kinase with IC50 of 84 nM, which was comparable to
the reference VEGFR-2 TKI Vandetanib (IC50 = 62 nM).
Comparison of the VEGFR-2 inhibition of compounds 6i-6l with
the same substituents on the phenyl ring indicated that increasing
the length of the hydroxamic acid side chain increases VEGFR-2
inhibitory activity. However, this rule did not exist in other
compounds with the same substituents on the phenyl ring but
different hydroxamic acid chains. On the other hand, the type,
number and position of halogen substituent on the phenyl ring
play key roles in the VEGFR-2 inhibition. Comparison of
VEGFR-2 inhibition of compounds 6d (IC50 = 501 nM), 6h (IC50
line) by MTT assay. The results were summarized in Table 1.
Among these compounds, compound 6l with the most potent
VEGFR-2 and HDAC inhibitory activity also exhibited the most
potent anticancer activities with the IC50 of 1.2 μM against MCF-
7, which showed greater potency than the reference compounds
Vandetanib (IC50 = 18.5 μM) and Vorinostat (IC50 = 4.5 μM). It
seemed that the SARs analysis result of antiproliferation
activities of the target hybrids were more consistent with their
HDAC inhibitory activities, probably due to their potent
inhibitory activities against HDAC but moderate inhibitory
activities against VEGFR-2.
To investigate the HDAC isoform selectivity, representative
compound 6l with the most potent HDAC inhibitory activity and
highest antiproliferative activity against MCF-7 was chosen to
conduct enzyme inhibitory assays against HDAC1, HDAC2,
HDAC6 and HDAC8. Results in Table 2 showed that compound
=
462 nM), 6l (IC50 = 84 nM) and 6p (IC50 = 2450 nM) with the
same length of hydroxamic acid side chain demonstrated that
introduction of 2,4-dichloro substituents on the phenyl ring is
preferred for the VEGFR-2 inhibition.
6l exhibited potent inhibition against HDAC1, HDAC2, HDAC6
and HDAC8, with IC50 of 3.5 nM, 6.8 nM, 25.5 nM and 5.2 nM,
respectively. The most potent compound 6l was also selected to
further test their antiproliferative activity against four types of
human cancer cell lines, including a human breast cancer cell line
MCF-7, a human liver cancer cell line HepG2, a human lung
cancer cell line A549, and a human colon cancer cell line HCT-
116 (Table 2). Results showed that 6l exhibited potent
antiproliferative activities in the tested cancer cell lines.
The well accepted pharmacophore for HDACI, comprising the
zinc binding group chelating the zinc atom in the active site (such
as hydroxamic acid moiety), a linker that accommodate the
tubular access of the active site, and a cap group for interactions
with the external surface. Data in Table 1 illustrated that most of
the target hybrids 6a-6p exhibited potent HDAC inhibitory
activities, which suggested that the quinazolin-4-aniline motif is
a suitable cap group for HDAC inhibitor. It is noteworthy that,
compound 6l with the most potent VEGFR-2 inhibitory activity
also exhibited the most potent HDAC inhibitory activity with
IC50 of 2.8 nM, which promoted the potency significantly by
nearly 5-fold compared to that of reference HDACI Vorinostat
Table 2. In vitro inhibition of HDAC isoenzymes and inhibition
of proliferation in selected human cancer cell lines by
compound 6l.
HDAC isoenzyme
HDAC1
IC50 (nM)
3.5
Cell line
MCF-7
HepG2
A549
IC50 (µM)
1.2
(IC50 = 12 nM). Increasing the length of the hydroxamic acid side
chain increases HDAC inhibitory activity by comparing the
HDAC inhibitory activity of compounds 6i-6l with the same
substituent on the phenyl ring. Compoud 6i with the shortest
chain (n = 2) showed the weakest HDAC inhibitory activity with
IC50 of 215 nM. Moderate HDAC inhibition was observed when
the carbon chain length reached 4 carbons (n = 3, compound 6j,
IC50 = 86 nM). The HDAC inhibitory activity further increased
with the carbon chain length reached 5 carbons (n = 4, compound
HDAC2
6.8
2.7
HDAC6
25.5
5.2
5.4
HDAC8
HCT-116
1.8
Molecular docking of the most potent compound 6l into the
three dimensional X-ray structure of VEGFR-2 (PDB code:
[46]
[47]
6
(
k, IC50 = 14 nM). The optimal carbon chain length is 6 carbons
n = 5, compound 6l, IC50 = 2.8 nM). This discipline was also
found in other halogen substituted hybrids. Comparison of
HDAC inhibition of compounds 6d (IC50 = 5.4 nM), 6h (IC50
.5 nM), 6l (IC50 = 2.8 nM) and 6p (IC50 = 8.4 nM) with the same
2QU5) and HDLP (HDAC homologue, PDB code: 1C3S)
was carried out using the Discovery Studio 3.1 CDOCKER
protocol.The three-dimensional structure of the compound 6l was
constructed using ChemBio 3D Ultra 11.0 software [Chemical
Structure Drawing Standard; Cambridge Soft corporation, USA
(2008)], then it was energetically minimized by using MMFF94
with 5000 iterations and minimum RMS gradient of 0.10. The
crystal structures of VEGFR-2 kinase and HDLP were retrieved
=
4
hydroxamic acid side chain suggested that the the length of the
hydroxamic acid side chain rather than the halogen substituents
on the phenyl ring is the dominating factor for the HDAC
inhibition.
from
the
RCSB
Protein
Data
Bank
(
http://www.rcsb.org/pdb/home/home.-do). All bound waters and
To further explore the antitumor effect of these hybrids, all the
synthesized compounds 6a-6p were evaluated for their in vitro
anticancer activities against MCF-7 (a human breast cancer cell
ligands were eliminated and the polar hydrogen was added. The
whole 2QU5 or 1C3S was defined as a receptor and the site
sphere was selected based on the binding site of 2QU5 or 1C3S.

Compound 6lwere placed during the molecular docking
procedure. Types of interactions of the docked protein with
ligand were analyzed after the end of molecular docking.
hydrogen bond with the carbonyl oxygen atom of Asp1046
(O...H-N: 2.5 Å). In addition, the terminal hydroxyl oxygen atom
of compound 6l forms another hydrogen bond with the amino
hydrogen atom of Cys919 (O...H-N: 2.0 Å). Apart from that, the
phenyl ring of quinazoline moiety form a π-σ interaction with
Leu889 (distance: 2.8 Å).
Figure 1 shows the possible binding modes of compound 6l
into the ATP-binding cavity of VEGFR-2 kinase. In the binding
model, the imine hydrogen atom of compound 6l forms a
Figure 1. A) 2D molecular docking modeling of compound 6l into VEGFR-2 ATP-binding cavity. The hydrogen bonds are displayed
as green or blue dotted lines. The π-σ interactions are shown as yellow line. (B) 3D model of the interaction between compound 6l and
VEGFR-2 kinase ATP-binding site.
Figure 2 shows the possible binding modes of compound 6l
into the binding site of HDLP. In the binding model, the
hydrogen atom in amide group of compound 6l forms a hydrogen
bond with the two carboxylic oxygen atoms of Asp168 (O...H-N:
hydrogen atom of compound 6l forms a hydrogen bond with the
carbonyl oxygen atom of Gly295 (O...H-O: 2.4 Å) and also forms
another hydrogen bond with the carbonyl oxygen atom of Gln254
(O...H-O: 2.4 Å). The nice binding model of compound 6l with
VEGFR-2 and HDLP suggests that compound 6l might be a
potent dual inhibitor against VEGFR-2 and HDAC.
2.4 Å). Besides, the terminal hydroxyl oxygen atom of compound
6l forms a hydrogen bond with the amino hydrogen atom of
Gly295 (O...H-N: 2.3 Å). Additionally, the terminal hydroxyl
Figure 2. (A) 2D molecular docking modeling of compound 6l into the binding site of HDLP. The hydrogen bonds are displayed as
green or blue dotted lines. (B) 3D model of the interaction between compound 6l and the active site of HDLP.

In summary,
a
series of hybrids combined by 4-
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most potent inhibitory activity against VEGFR-2 and HDAC.
Besides, it showed excellent inhibition against HDAC1, HDAC2,
HDAC6 and HDAC8, which revealed its pan-HDAC inhibitory
activity. It also exhibited great inhibitory potency against human
cancer cell lines MCF-7, HepG2, A549, and HCT-116.
Molecular docking of the compound 6l into the active binding
sites of VEGFR-2 and HDLP was performed and the result
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This work was supported by National Natural Science
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Hybrids from 4-anilinoquinazoline and
hydroxamic acid as dual inhibitors of
vascular endothelial growth factor receptor-
Leave this area blank for abstract info.
2
and histone deacetylase
a
a
a
b
a
Fan-Wei Peng , Ting-Ting Wu , Zi-Wei Zeng , Jia-Yu Xue , Lei Shi *
A series of hybrids from 4-anilinoquinazoline and hydroxamic acid were discovered as potent dual inhibitors
of VEGFR-2 and HDAC. Compound 6l exhibited the most potent inhibitory activities with IC50 value of 84 nM
and 2.8 nM against VEGFR-2 and HDAC, respectively.