Synthesis and antitumor activity of novel 6,7,8-trimethoxy N-aryl-substituted-4-aminoquinazoline derivatives

Article abstract of DOI:10.1016/j.bmcl.2018.05.033

A series of 6,7,8-trimethoxy N-aryl-substituted-4-aminoquinazoline derivatives were synthesized as epidermal growth factor receptor (EGFR) inhibitors, and their antitumor activities were assessed in the gastric cancer cell line SGC7901 using MTT assay. All compounds of Tg1–14 were found to inhibit SGC7901 cell proliferation, and compound Tg11 (IC₅₀ = 0.434 μM) was found to be slightly more effective against SGC7901 cells than epirubicin (IC₅₀ = 5.16 μM). This suggests that compound Tg11 can be used as a new substitution structure to develop more efficacious antitumor agents. Western blot analysis showed that treatment with Tg11 (40 μM for 30 min) resulted in near complete inhibition of EGF-induced ERK1/2 phosphorylation, indicating that its anti-proliferative effect is largely associated with inhibition of ERK1/2 activation. These data imply that Tg11 is a potential anticancer agent capable of inhibiting cell proliferation.

Full text of DOI:10.1016/j.bmcl.2018.05.033

Accepted Manuscript
Synthesis and antitumor activity of novel 6, 7, 8-trimethoxy N-aryl substitu-
ted-4-aminoquinazoline derivatives
Fang Liu, Ziyou Huai, Guotai Xia, Liuping Song, Sha Li, Yulan Xu, Kangjun
Hong, Mingyue Yao, Gang Liu, Yinjiu Huang
PII:
S0960-894X(18)30434-7
https://doi.org/10.1016/j.bmcl.2018.05.033
BMCL 25850
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
2 February 2018
14 May 2018
15 May 2018
Please cite this article as: Liu, F., Huai, Z., Xia, G., Song, L., Li, S., Xu, Y., Hong, K., Yao, M., Liu, G., Huang, Y.,
Synthesis and antitumor activity of novel 6, 7, 8-trimethoxy N-aryl substituted-4-aminoquinazoline derivatives,
Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.05.033
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Synthesis and antitumor activity of novel 6, 7, 8-trimethoxy
N-aryl substituted-4-aminoquinazoline derivatives
a,¶
b,¶
a
b
a
a
a
Fang Liu , Ziyou Huai , Guotai, Xia , Liuping Song , Sha, Li , Yulan Xu , Kangjun Hong ,
b
c,*
b,＊
Mingyue Yao , Gang Liu and Yinjiu Huang
a
School of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center
of Biochemical Pharmaceuticals, Bengbu 233030, Anhui, PR China;
b
Department of Bioscience, Bengbu Medical College, Bengbu 233030, Anhui, PR China;
c
School of Chemistry and Materials Science, Ludong University, Yantai 264000, Shandong, PR
China.
Abstract: A series of 6, 7, 8-trimethoxy N-arylsubstituted-4-aminoquinazoline derivatives were
synthesized as epidermal growth factor receptor (EGFR) inhibitors, and their antitumor activities
were assessed in the gastric cancer cell line SGC7901 using MTT assay. All compounds of
Tg1–14 were found to inhibit SGC7901 cell proliferation, and compound Tg11 (IC50=0.434 μM)
was found to be slightly more effective against SGC7901 cells than epirubicin (IC50=5.16 μM).
This suggests that compound Tg11 can be used as a new substitution structure to develop more
efficacious antitumor agents. Western blot analysis showed that treatment with Tg11 (40 μM for
30 min) resulted in near complete inhibition of EGF-induced ERK1/2 phosphorylation, indicating
that its anti-proliferative effect is largely associated with inhibition of ERK1/2 activation. These
data imply that Tg11 is a potential anticancer agent capable of inhibiting cell proliferation.
Keywords: Synthesis; 4-anilinoquinazoline; antitumor; epidermal growth factor receptor (EGFR)
Cancer is one of the most serious diseases that currently threaten human health. Cancer
treatment and prevention has long been a major problem and is a challenge to the medical
1
profession as well. Epidermal growth factor receptor (EGFR) is one of the most widely expressed
members of the human epidermal growth factor receptor (HER) family in human cancers, and is
highly expressed in non-small cell lung cancer, prostate cancer, gastric cancer, and breast cancer
¶
These authors contributed equally.
*
Corresponding author.
E-mail address: gangliu1977@163.com (Gang Liu), yinjiuhuang1973@163.com (Yinjiu Huang).

cells. EGFR and its family members play an important role in carcinogenesis by regulating cell
proliferation, apoptosis, migration, and tumor angiogenesis. Therefore, EGFR has become the
2,3
focus of anticancer drug research.
In recent years, a large number of studies have shown that quinazoline derivatives have
4,5
6
anti-tumor, anti-viral, bactericidal, anti-mite, and other biological activities. Since 1994, when
Fry et al. first discovered that 4-aniline quinazoline (PD153035) acts as an EGFR tyrosine
kinase-specific inhibitor, quinazoline derivatives have become compounds of interest in
7,8
anti-cancer drugs research. Among all derivatives, 4-substituted aniline quinazoline compounds
are the most active compounds with tyrosine kinase inhibitory activity. Some of these compounds
have been commercialized due to their high efficiency, low toxicity, good selectivity, and
specificity; for instance, gefitinib, erlotinib, and lapatinib, have been authorized for cancer
9,10
treatment by the US Food and Drug Administration (FDA) (Fig. 1).
Use of gefitinib and
erlotinib as EGFR inhibitors has been highly effective in the treatment of lung-cancer patients
1
1,12
with activated EGFR mutations.
reported to develop resistance to these drugs.
EGFR and HER2, and was approved for the treatment of breast cancer in 2007.
black box warning was released in 2008 due to the hepatotoxicity of lapatinib in relevant clinical
Unfortunately, patients with mutated EGFR (T790M) were
1
3,14
Lapatinib has a dual role in the inhibition of
1
5,16
However, a
1
7
trials and post marketing surveillance.
Fig. 1. Chemical structure of commercialized tyrosine kinase inhibitors.
Nazartinib, osimertinib, and rociletinib were designed as third-generation EGFR inhibitors to
avoid steric the interference caused by Met790. However, the emergence of new resistance
mechanisms limits the effective treatment of patients with the EGFR-T790M drug resistance

1
8
mutation. This mutation blocks the formation of covalent bonds with third generation inhibitors
1
9
and reduces their efficacy. Therefore, there is an urgent need to explore new epidermal growth
factor receptor inhibitors for the effective treatment multifarious cancers.
Comprehensive analysis of literature, especially concerning the 4-anilinoquinazoline
compounds that have shown excellent inhibition of EGFR-TK (Representative compound
PD153035), showed that modifications for improving the EGFR inhibitory activity of
4
-anilinoquinazoline derivatives mainly focus on the C-4, C-6, and C-7 positions of the
quinazoline ring. Particularly, 6, 7-dialkoxy-4-anilinoquinazoline and
-amino-4-anilinoquinazoline show strong inhibitory effects on EGFR, and the activity of fluorine
6
atom in aniline is better. In order to discover new drugs for cancer treatment, and to guide their
development, fourteen novel 6, 7, 8-trimethoxy N-aryl substituted-4-aminoquinazoline derivatives
were designed and synthesized (Fig. 2 and Scheme 1); simultaneously, fluorine atoms were
introduced into the quinazoline matrix. The antitumor activities of the resulting compounds were
then evaluated in the gastric cancer cell line, SGC7901.
Fig. 2. Design idea for target compound.

Scheme 1. Design and synthesis of novel 6, 7, 8-trimethoxy N-arylsubstituted
-
4-aminoquinazoline derivatives. Reagents and conditions: (i) (CH
ii) CH OH, H SO , 5 h, 61.6%; (iii) HNO , CH COOH, 2.5 h; (iv) 0.8mol/L NaOH, 95%
CH OH, 1.5 h, 87.5 %; (v) Fe, AcOH, MeOH, 59.7 %; (vi) HCONH , 6 h, 28.6 %; (vii)
POCl , 3 h, 65.5 %; (viii) i-PrOH, reflux, 4-24 h, 35.9-69.5 %.
3 2 4
) SO , NaOH, r.t. 4 h, 86.3%;
(
3
2
4
3
3
CH
3
2
2
3
The synthetic route of the 6, 7, 8-trimethoxy N-arylsubstituted-4-aminoquinazoline
derivatives Tg1-14 is summarized in Scheme 1. Initial assumption, Gallic acid was used as the
starting material; after etherification, nitration, and reduction, 2-amino-3, 4, 5-trimethoxybenzoic
(
5) was obtained. But after etherification followed by nitration, a decarboxylation product was
obtained. Therefore, after esterification we choose to protect the carboxylate group and performed
nitration to avoid decarboxylation and obtained the desired product (4). The starting 3, 4,
5
-trimethoxybenzoic acid (1) was prepared with excellent yields by the reaction of Gallic acid
with dimethyl sulfate and sodium hydroxide solution refluxed for 3 h in the presence of nitrogen
20
for protection. By comparing various kinds of esterification and nitration reactions as shown in
Table 1, the yield of methyl esters was found to be higher, and therefore, methyl ester was selected
preliminarily. The 3, 4, 5-trimethoxybenzoic acid (1) was reacted with anhydrous methanol and
21,22
sulfuric acid at the reflux temperature for 5 h to yield methyl 3, 4, 5-trimethoxybenzoate (2).
By comparing among the three nitration methods, the method with higher yield was selected, and
2
5
-nitro-3, 4, 5-trimethoxybenzoic acid methyl ester (3) was then prepared from 3, 4,
23,24
-trimethoxybenzoic acid methyl ester (2), acetic acid, and nitric acid at 65°C for 2.5 h.
Table 1. Comparison of esterification and nitration
methyl ester ethyl ester
Product state of esterification solid
isobutyl ester
oily liquid
solid
Product state of nitration
Esterification yield
solid
solid
oily liquid
69.8%
56.2%
…………
Nitration yield
24.9%
11.2%
The product is more miscellaneous
Direct reduction of 2-nitro-3, 4, 5-trimethoxybenzoic acid methyl ester (3) did not yield the
desired product (5). Thus, many reduction methods involving Fe/CH COOH, SnCl /HCl, and
Fe/NH Cl were attempted but all these methods of post-processing failed to achieve the desired
3
2
4
product. In the end, the 2-nitro-3, 4, 5-trimethoxybenzoic acid methyl ester (3) was hydrolyzed to
carboxylic acid, and 2-nitro-3, 4, 5-trimethoxybenzoic acid (4) was prepared by the reaction of the
2
-nitro-3, 4, 5-trimethoxybenzoic acid methyl ester (3) with 0.8 mol/L sodium hydroxide solution
and 95 % ethyl alcohol, and the product was obtained in excellent yields. The 2-nitro-3, 4,

5
-trimethoxybenzoic acid (4) was then reduced using iron powder, acetic acid, methanol, and
proper post-processing, to obtain the expected product, 2-amino-3, 4, 5-trimethoxybenzoic acid
25
(
5).
The 6, 7, 8-trimethoxyquinazolin-4(3H)-one (6) was prepared by the reaction of the
-amino-3, 4, 5-trimethoxy benzoic acid (5) and formamide under the reported reaction
2
24
conditions. By comparing the experiments, we found that increasing the reaction temperature is
beneficial to the closed loop reaction of the quinazoline compounds, but the yield of quinazoline
compounds containing trimethoxy groups is low. This may be related to the electron withdrawal
and steric hindrance effects.
The 4-chloro-6, 7, 8-trimethoxyquinazoline (7) was prepared from 6, 7,
8
-trimethoxyquinazolin-4(3H)-one (6) and three phosphorus oxychloride using the reported
2
6,27
procedures.
At first, 4-chloro-6, 7, 8-trimethoxyquinazoline (7) was synthesized from 6, 7,
8
-trimethoxyquinazolin-4(3H)-one(6), three phosphorus oxychloride, and phosphorus
pentachloride. However, no prospective quinazoline chloride product was found and only a brown
mucus-like substance was obtained. Use of three phosphorus oxychloride as the chlorinating
reagent and solvent, with N, N-dimethylaniline used as the catalyst yielded a better result with a
higher yield (62.5%). Increasing the reaction temperature or the reaction time did not have much
effect on the yield for this reaction, presumably due to a balance that renders the reaction
incomplete.
The target 6, 7, 8- trimethoxyl-4-anilinoquinazoline derivatives (Tg1-14) were synthesized
by the reaction of 4-chloro-6, 7, 8-trimethoxyquinazoline (7) (0.4 mmol) and aromatic amines (0.4
mmol) in isopropyl alcohol (5 mL), stirred at the reflux temperature for about 4 to 24 h, and the
disappearance of 4-chloro-6, 7, 8-trimethoxyquinazoline (7) was monitored by TLC using ethyl
acetate and hexanes. After TLC tracking to no raw material points (expansion agent: petroleum
ether: ethyl acetate = 1: 1, V/V), the reaction was stopped; after cooling, solid precipitation,
2
8
filtration, and recrystallization, 6, 7, 8- trimethoxyl-4-anilinoquinazoline (Tg1-14) was obtained.
The gastric cancer cell line SGC7901, was used for the screening of anticancer drugs. The
preliminary bioassay results were compared with those for a commercial anticancer drug,
epirubicin. As shown in Table 2, compared with the epirubicin treatment group, most compounds
showed relatively low inhibitory effects on the tested cells at the corresponding concentration, but
treatment with compound Tg11 at 10 μM, and even at 1 μM for 72 h, showed high antitumor
activity against SGC7901 cells. These results suggested that the title compound Tg11 is a potential
anticancer agent.
Through analysis of structure-activity relationship, we found that when the 4-sites in the
aromatic ring link halogen atoms as with compounds Tg1 and Tg2, activity was only found at

high concentration whereas weak activity was observed at low concentrations. When the 4-sites in
the aromatic ring link boric acid as with Tg11, good bioactivity is found both at high and low
concentrations. Future studies will investigate the reasons for this along with the toxicity
mechanisms of the compound.
Table 2. Inhibitory effect of 6, 7, 8-trimethoxy N-arylsubstituted-4-aminoquinazoline derivatives
on the gastric cancer cell line SGC7901 in vitro
a
Sr. No.
Compound No.
X
IC50 (μM)
1
2
3
4
5
6
7
8
9
Tg1
Tg2
3`-chloro, 4`-fluorine
3`- acetylene
5.415
5.824
>30
Tg3
3`-fluorine, 4`-bromine
2`-fluorine, 3`-chloro
2`-fluorine, 3`-fluorine
4`-three fluoromethyl
2`-fluorine, 3`-chloro, 4`-fluorine
2`-fluorine, 5`-bromine
2`-fluorine, 5`-three fluoromethyl
3`- iodide
Tg4
>30
Tg5
>30
Tg6
>30
Tg7
>30
Tg8
18.367
10.326
8.641
0.434
14.963
>30
Tg9
1
0
1
Tg10
Tg11
Tg12
Tg13
Tg14
1
4`-boric acid
1
1
1
1
2
3
4
5
2`-fluorine, 3`-chloro, 4`-bromine
3`-three fluoromethyl
2`-fluorine, 3`-bromine
>30
b
epirubicin
5.16
a
Values are means of at least three experiments, standard deviations were within 20% of reported
values.
b
positive control
In order to study and evaluate the antitumor activity of compound Tg11, morphological
observations and determination of the preliminary mechanism of action were carried out in

SGC7901. Morphological observation revealed that epirubicin-treated cells were diminished and
eventually broken down. However, treatment with compound Tg11 showed no obvious
morphological effect on cells at a low concentration and in the early stage of action. However,
proliferation inhibition was observed in compound Tg11 treated cells with the increase in
concentration and prolongation of time, as the cells began shrinking and became smaller, with the
appearance of apoptotic bodies. Together, these results suggested that compound Tg11 showed
antitumor activity through an anti-proliferative pathway rather than cytotoxicity which was further
confirmed by inhibition of EGF-induced phosphorylation of ERK1/2 by Tg11. (Fig. 3)
Fig. 3. Effect of indicated concentrations of DMSO, epirubicin, and compound Tg11 on SGC7901
cells. Cells were plated into 96-well plates. After 24 h, the cells were treated with 0.1% (v/v)
DMSO, 1 and 10 μM of compound Tg11 or 1 and 10 μM of epirubicin for 24, 48, and 72 h.
Based on the data shown in Table 2 and Fig. 3, we determined whether the observed
inhibitory action of compound Tg11 on SGC7901 cells was due to its anti-proliferative effect. We
first determined the effect of compound Tg11 on MAPK activation, especially MAPK/ERK1/2.
The MAPK family comprises ERKs, JNK (stress-activated protein kinase), and p38, which are
functional units participating in three different signaling pathways. Several studies have found that
ERK and p38 signaling are associated with proliferation and differentiation, whereas the JNK
pathway is linked with apoptosis. The effect of compound Tg11 on ERK1/2 in SGC7901 cells was
assessed by western blotting. As shown in Fig. 4, compared with the DMSO control, treatment of
SGC7901 cells with compound Tg11 resulted in a moderate to almost complete inhibition of
EGF-induced ERK1/2 phosphorylation in a dose-dependent manner.

Fig. 4. Inhibitory effect of compound Tg11 on EGF-induced ERK1/2 phosphorylation in
SGC7901 cells. SGC7901 cells were cultured in RPMI 1640 with 10% serum and at 80%
confluency, they were treated with 0.1% (v/v) DMSO or 1, 10, 20, and 40 μM concentrations of 6,
7, 8-trimethoxy N-(phenylboronic)-4-aminoquinazoline (Tg11) after stimulation with 40 ng/ml
EGF for 10 min except in the DMSO control. Cell lysates were prepared and subjected to
SDS-PAGE, followed by western blotting. The membranes were probed with
anti-phospho-ERK1/2
and
anti-actin
antibodies,
followed
by
the
appropriate
peroxidase-conjugated secondary antibody. Proteins were visualized using the ECL detection
system. Actin was used as the loading control. The data shown are representative of three
independent experiments. *Compared with EGF control, the (Tg11+EGF) treatment showed no
statistically significant difference in ERK1/2 phosphorylation (P > 0.05). **Compared with EGF
control, the DMSO, (10+EGF), (20+EGF), (40+EGF) treatments showed a statistically significant
decrease in ERK1/2 phosphorylation (P < 0.05).
Compared with the DMSO control, the qualitative densitometric analysis indicated that EGF
treatment alone markedly induced ERK1/2 phosphorylation. Compared with the DMSO control
and EGF treatment alone, after 30 min of treatment with compound Tg11, the 1 μM and 10 μM
doses showed mild inhibition of ERK1/2 activation. However, a higher inhibition was observed at

both 20 μM and 40 μM doses, showing almost complete inhibition of EGF-stimulated ERK1/2
phosphorylation as shown in Fig. 4.
Taken together, these findings indicate that compound Tg11 demonstrates its antitumor
activity through an anti-proliferative pathway rather than via cytotoxicity. Moreover, the
inhibitory effect of compound Tg11 on SGC7901 cells is largely associated with its inhibition of
ERK1/2 phosphorylation. EGFR is known to be the primary target of quinazoline derivatives as
antitumor drugs. The EGFR family plays a vital role in promoting the development of human
cancer. The signal transduction pathway mediated by EGFR eventually activates MAPKs
followed by nuclear translocation and activation of transcription factors related to cell growth,
differentiation, and proliferation. It should be pointed out that this study focused on the inhibition
of ERK1/2 activation by compound Tg11 in SGC7901 cells. Whether this effect is direct or due to
the impairment of upstream signals such as tyrosine kinase receptor and cytosolic signaling, needs
further investigation.
In summary, we designed and synthesized a series of novel 4-anilinoquinazoline derivatives
with the 6, 7, 8- trimethoxyl groups substituted. Preliminary screening was performed by the MTT
assay, and all compounds, Tg1–14, were found inhibit the gastric cancer cells SGC7901;
compound Tg11 was found to show slightly more activity against gastric cancer cells SGC7901
compared to epirubicin. Furthermore, western blotting analysis showed that treatment of cells with
Tg11 resulted in near complete inhibition of EGF-induced ERK1/2 phosphorylation suggesting
that its anti-proliferative effect is largely associated with its inhibition of ERK1/2 activation. These
data suggest Tg11 as a potential anticancer agent with anti-proliferative activity.
Acknowledgements
This study was supported by the Natural Science Research Project of Colleges in Anhui
Province [KJ2017A230, KJ2015B001by]; the Natural Science Foundation of Anhui Province
[
[
1408085MH164]; and the National Innovative Training Program in Undergraduates of China
201710367013, 201710367003, 201610367048].
References
1.
Liu F, Tang BD, Liu H, et al. 4-Anilinoquinazoline derivatives with Epidermal Growth Factor
Receptor inhibitor activity. Anticancer Agents Med Chem. 2016; 12: 1652.
2.
Szymanska M, Fosdahl AM, Nikolaysen F, et al. A combination of two antibodies
recognizing non-overlapping epitopes of HER2 induces kinase activity-dependent
internalization of HER2. J Cell Mol Med. 2016; 20: 1999-2011.
3.
Kherrouche Z, Monte D, Werkmeister E, et al. PEA3 transcription factors are downstream

effectors of Met signaling involved in migration and invasiveness of Met-addicted tumor
cells. Mol Oncol. 2015; 9: 1852-1867.
4
5
.
.
Akhtar J, Khan AA, Ali Z, Haider R, Shahar YM. Structure-activity relationship (SAR) study
and design strategies of nitrogen-containing heterocyclic moieties for their anticancer
activities. Eur J Med Chem. 2016; 125: 143-189.
Sedenkova KN, Dueva EV, Averina EB, et al. Synthesis and assessment of
4-aminotetrahydroquinazoline derivatives as tick-borne encephalitis virus reproduction
inhibitors. Org Biomol Chem. 2015; 13: 3406-3415.
6
7
8
.
.
.
Fry DW, Kraker AJ, McMichael A, et al. A specific inhibitor of the epidermal growth factor
receptor tyrosine kinase. Science. 1994; 265: 1093-1095.
Zhang Y, Huang YJ, Xiang HM, et al. Synthesis and anti-cancer activities of 4-(4-substituted
piperazin)-5,6,7-trialkoxy quinazoline derivatives. Eur J Med Chem. 2014; 78: 23-34.
Garofalo, A, Goossens L, Six P, et al. Impact of aryloxy-linked quinazolines: a novel series of
selective VEGFR-2 receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2011; 21:
2106-2112.
9
1
.
Mowafy S, Galanis A, Doctor ZM, et al. Toward discovery of mutant EGFR inhibitors;
design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and
thioureido-quinazoline derivatives. Bioorg Med Chem. 2016; 24: 3501-3512.
0. Ryan Q, Ibrahim A, Cohen MH, et al. FDA drug approval summary: lapatinib in combination
with capecitabine for previously treated metastatic breast cancer that over expresses HER-2.
Oncologist. 2008; 13: 1114-1119.
1
1
1
1
1
1
1
1. Kuwano M, Sonoda K, Murakami Y, et al. Overcoming drug resistance to receptor tyrosine
kinase inhibitors: Learning from lung cancer. Pharmacol Ther. 2016; 161: 97-110.
2. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical
response to gefitinib therapy. Science. 2004; 304: 1497-1500.
3. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of
lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011; 3: 75ra26.
4. Jia Y, Yun CH, Park E, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with
mutant-selective allosteric inhibitors. Nature. 2016; 534: 129-132.
5. Medina PJ, Goodin S. Lapatinib: a dual inhibitor of human epidermal growth factor receptor
tyrosine kinases. Clin Ther. 2008; 30: 1426-1447.
6. Reid A, Vidal L, Shaw H, de Bono J. Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2
(
HER2/neu). Eur J Cancer. 2007; 43: 481-489.
7. Towles JK, Clark RN, Wahlin MD, Uttamsingh V, Rettie AE, Jackson KD. Cytochrome P450
A4 and CYP3A5-catalyzed bioactivation of Lapatinib. Drug Metab Dispos. 2016; 44:
3

1584-1597.
18. Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance
to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015; 21:
560-562.
1
2
9. Engel J, Becker C, Lategahn J, et al. Insight into the inhibition of drug-resistant mutants of
the receptor tyrosine kinase EGFR. Angew Chem Int Ed Engl. 2016; 55:10909-10912.
0. Mauthner F, Clarker HT, Gilman H. Organic Synthesis Collection. Wiley, New York. 1941; p.
537.
2
2
1. Kudryashova NI, DacidenKov LR, Khromovborison N. Zh. Obshch. Khim. 1959; 29: 1855.
2. Wang K, Ju CF, Xiao J, Chen Q. Methyl 4-(benzyloxy)-3-methoxybenzoate. Acta cryst Cryst.
2013; E69, o1562.
2
2
2
2
2
3. Tasler F, Muller O, Wieber T, et al. Substituted 2-arylbenzothiazoles as kinase inhibitors:
Hit-to-lead optimization. Bioorg Med Chem. 2009; 17: 6728-6737.
4. Li SL, Wang X, He Y, et al. Design and synthesis of novel quinazoline nitrogen mustard
derivatives as potential therapeutic agents for cancer. Eur J Med Chem. 2013; 67: 293-301.
5. Wu XQ, Li MD, Tang WH, et al. Design, synthesis, and in vitro antitumor activity evaluation
of novel 4-pyrrylamino quinazoline derivatives. Chem Biol Drug Des. 2011; 78: 932-940.
6. Furuta T, Sakai T, Senga T, et al. Identification of potent and selective inhibitors of PDGF
receptor autophosphorylation. J Med Chem. 2006; 49: 2186-2192.
7. Liu HB, Xu HJ, Lu P, Pan NN, Li SQ. Synthesis and in vitro antitumor activities of
6
2
,7-dimethoxy-4-piperazinquinazoline thiosemicarbazone derivatives. Acta chimica sinica,
012; 70: 674-678.
2
8. Wang Z, Wu X, Wang L, Zhang J, Song ZX, Tang ZS. Facile and efficient synthesis and
biological evaluation of 4-anilinoquinazoline derivatives as EGFR inhibitors. Bioorg Med
Chem Lett. 2016; 26: 2589-2593.

Inhibitory effect of 6, 7, 8-trimethoxy N-arylsubstituted-4-aminoquinazoline on ERK1/2
phosphorylation in SGC7901 cells induced by EGF. After treatment of SGC7901 cells with 6, 7,
8-trimethoxy N-(phenylboronic)-4-aminoquinazoline at the concentration of 20 and 40 μM for 30
min, ERK1/2 phosphorylation induced by EGF was inhibited, which is largely associated with its
antiproliferation effect.

Highlights:




Novel 6, 7, 8-trimethoxy N-arylsubstituted-4-aminoquinazoline derivatives were synthesized
Compound Tg11 was found to be more effective against SGC7901 cells than epirubicin
The anti-proliferative effect is largely associated with inhibition of ERK1/2 activation
Compound Tg11 is a potential anticancer agent capable of inhibiting cell proliferation