Facile and efficient synthesis and biological evaluation of 4-anilinoquinazoline derivatives as EGFR inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.04.032

Series of 4-anilinoquinazoline derivatives were conveniently and efficiently synthesized and their antitumor activities were evaluated by MTT assay in three human cancer cell lines: H1975, HepG2 and SMMC-7721. New compounds 19a-19h were designed and synthesized to seek for powerful EGFR inhibitors and to explore whether methyl group at C-2 position of quinazoline ring has a positive effect on EGFR inhibition. All the compounds of 19a-19h were found potent against all three cell lines and five compounds (19c, 19d, and 19f-19h) were found more potent against H1975 than gefitinib. SAR studies revealed that methyl group at C-2 position of quinazoline ring could significantly improve the antitumor potency of 4-anilinoquinazolines. The same conclusion was also drawn according to the results of Western blotting analysis. Among all the tested compounds, 19g exhibited extremely potent against H1975 with an IC₅₀ value of 0.11 μM, remarkably lower than that of gefitinib (1.23 μM). The results of western blotting analysis showed that compounds 19c and 19g could notably inhibit the expression of phosphorylated EGFR, especially 19g, almost inhibited completely.

Full text of DOI:10.1016/j.bmcl.2016.04.032

Accepted Manuscript
Facile and efficient synthesis and biological evaluation of 4-anilinoquinazoline
derivatives as EGFR inhibitors
Zheng Wang, Xue Wu, Li Wang, Jiao Zhang, Jianli Liu, Zhongxing Song,
Zhishu Tang
PII:
S0960-894X(16)30405-X
http://dx.doi.org/10.1016/j.bmcl.2016.04.032
BMCL 23794
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 November 2015
11 April 2016
13 April 2016
Please cite this article as: Wang, Z., Wu, X., Wang, L., Zhang, J., Liu, J., Song, Z., Tang, Z., Facile and efficient
synthesis and biological evaluation of 4-anilinoquinazoline derivatives as EGFR inhibitors, Bioorganic & Medicinal
Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.04.032
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Bioorganic & Medicinal Chemistry Letters
Facile and efficient synthesis and biological evaluation of 4-anilinoquinazoline
derivatives as EGFR inhibitors
Zheng Wang,a Xue Wu,c Li Wang,a Jiao Zhang,a Jianli Liu,b Zhongxing Song,a Zhishu Tanga
a Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi Province Key Laboratory of New Drugs and Chinese
Medicine Foundation Research, Shaanxi Rheumatism and Tumor Center of TCM Engineering Technology Research,Shaanxi University of Chinese Medicine,
Xian Yang 712083, China
bKey Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi’an 710069,
China
cDepartment of Burns and Cutaneous Surgery, Xijing Hospital, Xi’an, 710032,China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Series of 4-anilinoquinazoline derivatives were conveniently and efficiently synthesized and
their antitumor activities were evaluated by MTT assay in three human cancer cell lines: H1975,
HepG2 and SMMC-7721. New compounds 19a-19h were designed and synthesized to seek for
powerful EGFR inhibitors and to explore whether methyl group at C-2 position of quinazoline
ring has a positive effect on EGFR inhibition. All the compounds of 19a-19h were found potent
against all three cell lines and five compounds (19c, 19d, and 19f-19h) were found more potent
against H1975 than gefitinib. SAR studies revealed that methyl group at C-2 position of
quinazoline ring could significantly improve the antitumor potency of 4-anilinoquinazolines.
The same conclusion was also drawn according to the results of Western blotting analysis.
Among all the tested compounds, 19g exhibited extremely potent against H1975 with an IC50
value of 0.11µM, remarkably lower than that of gefitinib (1.23µM). The results of western
blotting analysis showed that compounds 19c and 19g could notably inhibit the expression of
phosphorylated EGFR, especially 19g, almost inhibited completely.
Keywords:
4-anilinoquinazoline,
synthesis,
MTT assay,
Western blotting analysis
2009 Elsevier Ltd. All rights reserved.
1The epidermal growth factor receptor (EGFR, erbB1) is a
member of the erbB family of receptors including erbB2/HER2,
erbB3/HER3, and erbB4/HER4.1, 2 It is over-expressed in a large
number of human solid tumors, and is associated with cancer cell
proliferation, apoptosis, angiogenesis, and metastasis.3,4
Therefore, EGFR as a target of anticancer drugs has received
much attention in the past decade. A series of EGFR inhibitors
with different molecular scaffolds have been discovered. Among
them, 4-anilinoquinazolines play a key role and have been
extensively studied. As shown in Figure 1, PD153035, named 6,
7-dimethoxy-4-anilinoquinazoline, was the first EGFR inhibitor
reported in 1994.[5] Though finally it was abandoned due to the
depressing water solubility, the chemical structure of PD153035
was reserved to do structure modification. Gefitinib and erlotinib
have been used to treat non-small-cell lung cancer (NSCLC).[6-11]
Canertinib is the first irreversible kinase inhibitor to enter clinical
trial. [12]
of Met-769 via a hydrogen bond, and water mediated hydrogen
bonding is observed between the N-3 of the quinazoline ring and
the Thr-766 side chain, (3) the aniline moiety lies in a deep and
hydrophobic pocket, and (4) the substitution at C-6 or C-7 of the
quinazoline ring conveys a more favorable pharmacokinetic
profile and improves the physical properties.
These agents all belong to the 4-anilinoquinazoline class of
inhibitors and the key features between the receptor and this
template have been revealed as follows [13,14], (1) the quinazoline
moiety fits into the ATP binding pocket of the kinase domain, (2)
the N-1 of the quinazoline ring interacts with the backbone NH
Figure1. Chemical structure of tyrosine kinase inhibitors
It was reported that 4-substitution was assumed to be optimal
as aniline, with other linkers being less effective. However, the
structure activity relationship (SAR) of 4-arylamino was reported
barely. Therefore, nine 4-anilinoquinazolines with different
anilines substituted at 4-position were synthesized and the SAR
was discussed. In our ongoing to seek for more potential
substituent to enhance the antitumor activity of 4-
———
1 *Corresponding author: Tel.: +86 (0)29 38182201; e-mail
address: zst6565@126.com

anilinoquinazolines, we focus on Carmi’s work which reported 3-
aminopropanamide at C-6 position of 4-anilinoquinazoline can
covalently interact with a conserved cysteine residue in the
kinase domain of EGFR.[15] In addition, it was reported methyl
group at C-2 position of quinazoline ring could improve the
antitumor activity according to the SAR of AZixa (MPC-6827),
which was discovered as proapoptotic molecules and mitotic
inhibitor with potency at low concentration in multiple tumor cell
lines.[16] Therefore, novel 4-anilinoquinazoline derivatives 19a-
19h were synthesized with methyl group at C-2 position and 3-
aminopropanamide at C-6 position. And fortunately, compound
19g was found the most potent against H1975 with an IC50 value
of 0.11µM, greatly lower than that of gefitinib with an IC50 value
of 1.23µM.
Compounds 9a-9j were prepared via a convenient and
efficient way using isatoic anhydride as starting material. As
shown in Scheme 1, quinazolin-4(3H)-one 7 was prepared via
heating isatoic anhydride in formamide at 135~140 °C for 10h.
Chlorination of 7 using thionyl chloride yielded the desired
intermediated 8. The coupling of 8 with anilines generated the
corresponding target compounds 9a-9j.
R3
R2
O
Cl
O
N
HN
R1
O
O
N
a
NH
N
b
c
+
O
H
NH2
N
H
N
N
9a-9j
6
5
7
8
9a: R1=H, R2=H, R3=H;
9d: R1=H, R2=MeO, R3=H; 9e: R1=H, R2=Br, R3=H; 9f: R1=H, R2=Cl, R3=H;
9b: R1=H, R2=Cl, R3=F; 9c: R1=H, R2=NO2, R3=H;
9g: R1=H, R2=F, R3=H;
9j: R1=Cl, R2=H, R3=Cl
9h: R1=F, R2=H, R3=H; 9i: R1=H, R2=H, R3=F;
Scheme1. Reagents and conditions: (a) 135~140°C, 10h; (b) SOCl2, DMF, 70°C, 5h; (c) aniline derivatives, isopropanol, reflux, 6h
O
N OH
O
O2N
CN
O2N
O2N
a
b
c
+
O
O
O
N
N
H
N
N
N
H
H
12
11
10
13
F
F
HN
Cl
e
HN
Cl
F
O
O2N
H2N
N
N
d
+
Br
Cl
Cl
NH2
N
N
14
15
16
17
F
F
R1
N
HN
N
Cl
HN
Cl
H
H
N
N
Br
R2
N
g
f
N
O
O
N
18
19a-d
19a: R1R2NH=morpholine
19c: R1R2NH=dimethylamine
19b: R1R2NH=piperidine
19d: R1R2NH=methanamine
Scheme2. Reagents and conditions: (a) 95% H2SO4, NaNO3, 5°C, 3h; (b) HONH3Cl, H2O, sodium acetate, reflux, 30min; (c) POCl3, DMF, Na2CO3, H2O, 0°C –
rt-70°C, 4h; (d) acetic acid, reflux, 3h; (e) ethyl acetate, SnCl2, 75°C, 2h; (f) THF, 0°C – rt, TEA, 2h; (g) amine, KI, ethanol, reflux.
N
OH
O
F
O2N
CN
O2N
O2N
CN
a
+
b
O
N
O
+
Cl
NH2
N
N
N
NH2
H
22
14
21
20
12
F
F
HN
N
Cl
HN
Cl
O
O2N
H2N
N
e
N
+
c
d
Br
Cl
17
N
24
23
F
F
R1
HN
Cl
HN
N
Cl
H
H
N
N
N
Br
R2
N
f
N
O
O
N
19e-h
25
19e: R1R2NH=morpholine
19f: R1R2NH=piperidine
19h: R1R2NH=methanamine
19g: R1R2NH=dimethylamine
Scheme3. Reagents and conditions: (a) DMF, Na2CO3, 140°C, 1h; (b) toluene, acetic acid, 105°C, 1h; (c) acetic acid, reflux, 3.5h; (d) ethyl acetate, SnCl2, 75°C,
3h; (e) THF, 0°C –rt, TEA, 3h; (f) amine, KI, ethanol, reflux.
The target compounds 19a-19d were prepared as shown in
Scheme 2. It was a facile, novel and efficient strategy to
synthesize 4-anilinoquinazolines using isatin 10 as starting
material. Nitration of 10 using sodium nitrate in concentrated

sulfuric acid at 5°C gave 11. Compound 11 underwent
condensation with hydroxylamine hydrochloride followed by
heating in the solution of DMF and POCl3 to form 13.[17]
Compound 13 reacted with 3-chloro-4-fluoro-benzenamin to
generate 15. The nitro group of 15 was reduced by SnCl2•2H2O
in ethyl acetate to produce 16. Acylation of compound 16 with 3-
bromopropanoyl chloride gave the corresponding intermediated
18. Finally, reaction of compound 18 with different secondary
amines in the presence of KI generated the target compounds
19a-19d. [18-20]
was prepared by heating compound 12 in the presence of Na2CO3
in DMF at 140°C for 1h. Reaction of compound 20 with N, N-
dimethylacetamide dimethyl acetal generated the key
intermediate 22. The following steps to synthesize the final
compounds 19e-19h was similar to the preparation of compounds
19a-19d from compound 13.
The effect of the target compounds on cell proliferation was
evaluated by MTT assay in three human cancer cell lines, H1975
[21], HepG2 [22] and SMMC7721 [23], which over expresses EGFR.
The marketed drug gefitinib, an EGFR inhibitor, was used as a
positive control for the assay. The biologic results are shown in
Table 1.
The synthesis of target compounds 19e-19h was shown in
Scheme 3. The starting material was the intermediate 12
synthesized in Scheme 2. The 2-amino-5-nitrobenzonitrile 20
Table1. Inhibitory effect of target compounds 9a-9j and 19a-19h on the growth of the three tumor cell lines
R3
F
R1
HN
Cl
R2
HN
H
R1
N
N
R2
N
N
O
N
R3
N
19a-19h
9a-9i
Structure
IC50(µmol/L)a
HepG2c
Compd.
R1
H
H
H
H
H
H
H
F
R2
H
R3
H
H1975b
SMMC7721d
35.62±1.21
50.1±3.30
58.98±2.77
15.62±1.64
24.65±1.06
22.04±2.21
14.98±1.52
93.9±4.79
22.04±1.97
9.86±1.52
19.55±1.98
12.57±1.08
9.54±1.05
20.87±1.19
3.26±0.63
2.84±0.66
1.04±0.07
1.98±0.41
4.16±0.77
9a[17]
9b[17]
9c[24]
9d[17]
9e[17]
9f[25]
9g[25]
9h[17]
9i[17]
9j[17]
19a
35.62±1.36
4.51±1.22
61.25±2.72
31.32±1.66
10.56±1.44
10.38±1.22
7.58±1.07
10.64±1.36
23.51±1.89
7.12±1.26
3.01±0.50
1.85±0.15
0.36±0.08
0.68±0.09
1.14±0.06
0.87±0.09
0.11±0.03
0.48±0.09
1.23±0.30
65.81±4.82
>100
Cl
F
51.41±3.08
24.18±1.79
78.62±3.85
23.47±1.24
13.23±1.82
69.34±1.94
28.96±2.27
32.51±2.15
16.33±1.35
8.59±1.39
9.36±1.05
14.78±1.69
1.98±0.21
3.21±0.58
1.86±0.12
1.13±0.11
7.52±0.95
NO2
MeO
Br
Cl
H
H
H
H
F
H
H
H
H
Cl
H
F
H
Cl
H
R1R2NH=morpholine
19b
R1R2NH =piperidine
R1R2NH =dimethylamine
R1R2NH =methanamine
R1R2NH =morpholine
R1R2NH =piperidine
H
19c
H
19d
H
19e
Me
Me
Me
Me
19f
19g
R1R2NH =dimethylamine
R1R2NH =methanamine
19h
Gefitinib
aIC50, compound concentration required to inhibit tumor cell proliferation by 50%; bHuman lung cancer cell line (H1975); cHuman hematoma carcinoma cell
line (HepG2); dHuman hematoma carcinoma cell line (SMMC7721).
biologic results of compounds 9e-9g with different halogen
atoms at the same position, indicated fluorine was more suitable
than chlorine and bromine to improve the antitumor activity of 4-
anilinoquinazolines. The IC50 values of compounds 9g-9i with
The results indicated that most compounds showed moderate
to good activity with IC50 values in the µM range, except
compound 9b against HepG2 with an IC50 value more than
100µM. Eight compounds of 19a-19h were found more potent
fluorine at different positions of aniline ring, demonstrated that
against all three tumor cell lines than compounds of 9a-9j. It was
substituent at C-3 aniline position exhibited more potent than
indicated that 3-aminopropanamide at C-6 position significantly
substituent at C-2 and C-4 aniline positions. There was a slight
improved the potency of 4-anilinoquinazoline.
increase in inhibitor potency for 2, 4-dichlorobenzyl compound
We designed compounds 9a-9j in order to identify a suitable
9j. It was found that larger groups such as methoxyl group (9d)
4-arylamino group of 4-anilinoquinazolines. Though all the
and nitro group (9c) at C-3 aniline position exhibited reduced
compounds exhibited moderate potent against all three cell lines,
potency against tumor cell proliferation.
compound 9b was found more potent against H1975. The

ring had a positive effect on phosphorylated EGFR inhibition.
Furthermore, compound 19g showed encouraging inhibitory
potency against EGFR at 1µM which almost could completely
inhibit the expression of phosphorylated EGFR.
Compounds 19a-19h were synthesized to seek for more
potent EGFR inhibitors and to investigate whether methyl group
at C-2 position of quinazoline ring can improve the antitumor
activity of 4-anilinoquinazoline. By comparing the biological
results of compounds 19a-19h with the inhibitor potency of
compound 9b, it was concluded that 3-aminopropanamide at C-6
position could greatly improve the antitumor potency of 4-
anilinoquinazolines. Replacing the morpholine of 19a with other
amines, including piperazine (19b), dimethyllamine (19c), and
methanamine (19d), caused increase of the inhibitor potency,
especially of compounds 19c and 19d against H1975. A similar
trend was also reported in the series 19e-19h with methyl group
appending at C-2 position of quinazoline ring. Comparing the
antitumor potency of compounds 19a-19d with compounds 19e-
19h, it was revealed that methyl group at C-2 position of
quinazoline ring could significantly improve the antitumor
potency. All the compounds of 19a-19h showed excellent
inhibitor potency that was comparable or even better than that of
positive control gefitinib, especially compound 19c (0.36µM)
and 19g (0.11µM).
In conclusion, series of 4-anilinoquinazoline derivatives were
facilely and efficiently synthesized and their EGFR inhibitor
activity was evaluated by MTT assay in three human tumor cell
lines. Compounds 9a-9j were synthesized to elucidate the
structure activity relationship of 4-arylamino. Novel compounds
19a-19h were synthesized to seek for more powerful EGFR
inhibitors and to explore whether methyl group at C-2 position of
quinazoline ring could improve the inhibitor potency of 4-
anilinoquinazolines. Fortunately, compound 19g was found
extremely potent against H1975 cells with an IC50 value of
0.11µM according to the MTT assay. By comparing the IC50
values of compounds 19a-19h, it was concluded that methyl
group at C-2 position of quinazoline ring had a positive effect on
tumor cell proliferation. And the same conclusion was also drawn
according to the results of Western blotting analysis.
Acknoledgements
The present work was supported by the Program for Chang
Jiang Scholars and Innovative Research Team in University (No.
IRT1174), the National Natural Science Foundation of China (No.
20872118, 30070905), the Foundation of the Technology
Department of Shaanxi Province (2015SF074).
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Graphical Abstract
Facile and efficient synthesis and biological
evaluation of 4-anilinoquinazoline
derivatives as EGFR inhibitors
Leave this area blank for abstract info.
Zheng Wang,a Xue Wu,c Li Wang,a Jiao Zhang,a Jianli Liu,b Zhongxing Song,a Zhishu Tanga
a Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi Province
Key Laboratory of New Drugs and Chinese Medicine Foundation Research, Shaanxi Rheumatism and Tumor
Center of TCM Engineering Technology Research,Shaanxi University of Chinese Medicine, Xian Yang 712083,
China
bKey Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of
Life Science, Northwest University, Xi’an 710069, China
cDepartment of Burns and Cutaneous Surgery, Xijing Hospital, Xi’an, 710032,China