Synthesis and in vitro evaluation of N-Aryl pyrido-quinazolines derivatives as potent epidermal growth factor receptor inhibitors

Article abstract of DOI:10.1111/cbdd.12133

A series of pyrido-quinazolines have been synthesised, characterized, and tested for their in vitro epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. The compounds were prepared from Alkylideno/arylideno-bis-ureas. Their final structure of the compounds was elucidated on the basis of spectral studies (IR, ¹H NMR, FT-IR, and EI-MS). The cellular EGFR internalization response of selected compounds was evaluated using HeLa cells. Most of the synthesized compounds displayed potent EGFR-TK inhibitory activity and structurally halogenated derivatives had a pronounced effect in inhibiting EGFR internalization.

Full text of DOI:10.1111/cbdd.12133

Chem Biol Drug Des 2013; 82: 119–124
Research Letter
Synthesis and In Vitro Evaluation of N-Aryl Pyrido-
Quinazolines Derivatives as Potent Epidermal Growth
Factor Receptor Inhibitors
Vinay K. Singh1*, Himanshu Sharma2, Sanjay K.
direction due to some resemblance with folic acid
(21,22).
Singh3 and Lakshmi Gangwar3
1Department of Chemistry, DrKNMIET, Modinagar, Meerut
201204, India
Epidermal growth factor receptor (EGFR) a transmembrane
glycoprotein is composed of a glycosylated N-terminus,
having three binding regions an extracellular ligand binding
region, a hydrophobic transmembrane region and a C-ter-
minal intracellular regions. When epidermal growth factors
(EGF) bind to EGFR, the TK domain is activated, and this
triggers a chain of different signal transduction events
inside the cell that eventually leads to cell growth, prolifera-
tion, and differentiation. Elevated receptor tyrosine kinase
activity is often observed in malignant tumors. Tyrosine
kinases (TK) are enzymes that bind ATP and catalyze the
transfer of g-phosphate to tyrosine residues on proteins,
thereby regulating their activity and function. Several tyro-
sine kinases can be targets for cancer chemotherapy, the
most important being the receptor tyrosine kinases.
2Department of Applied Sciences, MIET, Meerut 250005,
India
3Department of Applied Sciences, IET, Lucknow 226021,
India
*Corresponding author: Vinay K. Singh,
vinayk2003@rediffmail.com
A series of pyrido-quinazolines have been synthesised,
characterized, and tested for their in vitro epidermal
growth factor receptor (EGFR) tyrosine kinase inhibi-
tory activity. The compounds were prepared from
Alkylideno/arylideno-bis-ureas. Their final structure of
the compounds was elucidated on the basis of spec-
tral studies (IR, 1H NMR, FT-IR, and EI-MS). The cellu-
lar EGFR internalization response of selected
compounds was evaluated using HeLa cells. Most of
the synthesized compounds displayed potent EGFR-
TK inhibitory activity and structurally halogenated
derivatives had a pronounced effect in inhibiting EGFR
internalization.
In continuation of our research straightly, we are designing
novel quinazolines analogues having more efficacy to inhi-
bit EGFR for treatment of various cancers.
Materials and Method
Key words: anticancerous, epidermal growth factor receptor,
HeLa, quinazolines, spectroscopy
All chemicals used in this study are of analytical grade pur-
chased from Sigma. All the solvents were used after distil-
lation. Thin layer chromatography (TLC) was run on the
silica get coated aluminum sheets (silica gel 60 F254, E
Merck, Germany) and visualized under UV light. FTIR
spectra were recorded on the FT-IR Perking Elmer Spec-
trum BX Spectrophotometer with KBr disks. NMR spectra
were measured in CDCl3 by Bruker 200 MHz apparatus
with Me4Si as an internal standard. EI-MS spectra were
recorded on a JEOL SX102/DA (KV 10 mA) instrument.
Elemental analysis was performed on elemental analyzer
Gmbh variable system. Radio complexation and radio
chemical purity was checked by instant strip chromatogra-
phy (silica gel impregnated paper chromatography) with
ITLC-SG (Gellman sciences, Ann arbar, MI, USA). The
gamma scintillation counting was performed at Electronic
Corporation of India Ltd. Gamma Ray Spectrometer K
2700 B. All the reaction steps were monitored by TLC
[chloroform/methanol/hexane: 4:3:1]. Distilled water is
used during whole of the procedure.
Received 16 November 2012, revised 16 February 2013 and
accepted for publication 26 February 2013
The quinazoline skeletons, present in a variety of biologi-
cally active compounds, are pharmacologically very
attractive as reflected by activity in various assays. They
are well known for a wide range of biological properties,
including hypnotic, sedative, analgesic, anticonvulsant,
antibacterial, antidiabetic, anti-inflammatory, and antitumor
(1–11). They also demonstrate several other useful and
interesting properties such as hypertensive adrenergic
blocker, selective phosphodiesterase inhibitor, against
prostate disorders, dihydrofolate reductase inhibitor (12–
20), etc. In addition, some derivatives are calcium
antagonists and share the common property of interfering
with the influx of extracellular calcium via the calcium L
channel. Recently, quinazoline chemistry has found new
ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12133
119

Singh et al.
Synthesis
Biological studies of N-Aryl pyrido-
quinazolines derivatives
Total synthesis of Aryl pyrido-quinazolines derivatives are
described in chemical Scheme 1, started with synthesis of
Alkylideno/arylideno-bis-ureas. A mixture of an aldehyde
(0.01 mol) and urea (0.2 mol) in ethanol was heated under
reflux 4 h. Subsequently, ethanol was distilled off and
residual thick oily material was cooled to 0 °C. It solidified
in about 1 h. After washing initially with 1% NaOH solution
and finally with cold water, the resultant solid was filtered.
The crude material was dried at 100 °C and recrystallized
from diluted ethanol.
In vitro serum stability assay
The Pharmacokinetics of the synthesized compounds
were determined by tracer methods through technetium
EtOH
+
R CHO NH CONH
H N CO NH
2
2
2
CHR
H N CO NH
2
(1)
Alkylideno/arylideno-bis-urea (0.06 mol) (1) and p-amino-
benzoic acid (0.06 mol) were mixed together and heated at
145–150 °C for 4 h. A clear liquid was obtained on heat-
ing, which on cooling to room temperature solidified. It was
treated with diluted HCl (50 mL) and stirred very well. After
filtering off the solid, it was washed with water several
times and treated with an aqueous solution of sodium
bicarbonate (10%). Vigorous effervescence as a result of
evolution of carbon dioxide occurred, which subsided on
adding more solution of sodium bicarbonate. When the
effervescence completely ceased, the solid was filtered off.
This solid was rejected, and the filtrate was acidified with
diluted hydrochloric acid. On complete neutralization, a
solid separated out which was filtered off and washed with
water. It was dried at 100 °C and recrystallized from glacial
acetic acid. The intermediate compound4-aryl-6-carboxyla-
to-1,2,3,4-tetrahydroquinazoline (2) of this category are
recorded in Table 1 along with their characterization data.
HOOC
NH
2
R
C
H
HOOC
NH
C O
N
H
(2)
P.P.A.
C H CH(OH)COC H
6
5
6
5
O
C
R
O
NH
H
C O
H C
N
H
5
6
C H
5
5
Synthesis of 4-Aryl-8,9-diphenyl-1,4-dihydro-3H-7-
oxa-1,3-diazaanthracene-2,6-dianes (3)
(3)
C H N
5
5
A mixture of 4-aryl-6-carboxylato-1,2,3,4-tetrahydroquinaz-
oline (0.02 mol) (2) and benzoin (desyl alcohol) (0.02 mol)
in polyphosphoric acid (10 mL) was heated at 100 °C for
5 h. During heating, the contents were occasionally stirred.
Subsequently, the reaction mixture was poured into ice-
cold water (100 mL) and left as such for 1 h. A solid sepa-
rated out, which was filtered off and washed initially with
10% aqueous sodium bicarbonate solution (50 mL) and
finally with water (2 9 25 mL). The solid thus obtained
was dried under vacuum and recrystallized from methanol.
R'
NH
2
O
C
R
R'
N
NH
H
C
O
H C
N
H
5
6
C H
6
5
(4)
Compd.
No.
R
R’
Molecular
formula
N-Aryl-8,9-diphenyl (-2-oxo-pyrido-[g]-4-aryl-2-
oxo-1,3-dihydro-quinazolines 4(A–G)
The titled compounds (4) were synthesized by heating under
reflux a mixture of 4-aryl-8,9-diphenyl-1,4-dihydro-3H-7-
oxa-1,3-diazanthracene-2,6-dione 3 (0.01 mol) and aro-
matic primary amine (0.02) in anhydrous pyridine (30 mL) for
6 h. The solution was cooled to room temperature and acid-
ified with dil. HCl (50 mL). A solid separated out which was
filtered off and washed with water successively
(4 9 25 mL). It was air-dried and recrystallized from diluted
ethanol. The final compounds of this category are present in
Table 1 along with their data for characterization.
4(A)
4(B)
4(C)
4(D)
4(E)
4(F)
4(G)
Phenyl
Phenyl
Phenyl
Phenyl
Hydrogen
Chloro
C35H25N3O2
C35H24N3O2Cl
C36H27N3O3
C36H27N3O2
C29H21N3O2
C29H20N3O2Cl
C30H23N3O3
Methoxy
Methyl
Hydrogen Hydogen
Hydrogen Chloro
Hydrogen Methoxy
Scheme 1: Synthesis of N-Aryl pyrido-quinazolines derivatives.
Chem Biol Drug Des 2013; 82: 119–124
120

Quinazolines Derivatives as Potent EGFR Inhibitors
Table 1: Characterization data of N-Aryl-pyrido [g] – quinazolines
Compound
no.
Yield Molecular
% N
Found(Calcd) I.R.
R
R’
M.P. °C (%)
formula
1H NMR
1a
Phenyl
–
178
65
C9H12N4O2
26.52 (26.92)
–
6.0 (s, 2H, –NH2)
6.98 (t, 1H, –CH)
7.09–7.20 (m, 5H, ArH)
6.01 (s, 2H, –NH2)
6.8 (t, 2H, –CH2)
6.0 (s, 1H, –NH)
1b
2a
Hydrogen
Phenyl
–
–
169
284
70
60
C3H8N4O2
42.15 (42.42)
10.20 (10.45)
–
–
C15H12N2O3
6.3 (d, 1H, –NH)
7.2–7.8 (m, 8H, Ar-H)
6.4 (d, 1H, –CH)
2b
3a
Hydrogen
Phenyl
–
–
249
145
67
53
C9H8N2O3
14.33 (14.58)
5.99 (6.31)
–
4.12 (d, 2H, –CH2)
6.13 (s, 1H, NH)
6.01 (t, 1H, NH)
7.30–7.80 (m, 3H, Ar-H)
4.40 (d, 2H, -CH2)
6.14 (s, 1H, -NH)
6.3 (d, 1H, NH)
C29H20N2O3
1740 (O-C=O d
lactones)
3032 (Aromatic
C-H str. H)
1125 (Cyclic ether
C-O-C)
7.10–7.9 (m, 11H, ArH)
1665 (C=O)
3465 (NH str.)
1742 (O-C=O d
lactones)
3036 (Aromatic
C-H)
3b
Hydrogen
–
136
59
C23H16N2O3
7.31 (7.61)
6.0 (d, 1H, -CH)
6.11 (s, 1H, -NH)
6.29 (d, 1H, –NH)
7.09–7.90 (m, 17H, ArH)
1125 (Cyclic ether
C-O-C)
1670 (C=O)
–
4a
4b
4c
Phenyl
Phenyl
Phenyl
Hydrogen 128
45
42
40
C
35H25N3O2
7.89 (8.09)
7.37 (7.59)
7.34 (7.65)
6.9–7.9 (m, 22H, ArH)
6.01 (s, 1H, -NH), 6.10
(d, 1H, -NH)
6.0 (s, 1H, NH), 6.09
(d, 1H, NH), 7.10–7.89
(m, 21H, ArH)
3.70 (s, 3H, -OCH3)
6.0 (S, 1H, -NH)
6.0 (s, 1H, -NH)
Chloro
140
170
C35H24N3O2Cl
–
Methoxy
C36H27N3O3
1360 (OCH3)
3470 (NH str.)
1565 (NH bend)
1695 (C=O
amide), 1640
(C=O d lactam)
3020 (Aromatic
C-H)
6.19 (d, 1H, -NH)
6.99–7.81 (m, 21H, ArH)
4d
Phenyl
Methyl
130
40
C36H27N3O2
7.39 (7.83)
2930 (C-H of CH3)
3465 (NH str.)
1660 (NH bend)
1700 (C=O sec
amide)
2.40 (s, 3H, -CH3)
5.98 (s, 1H, NH)
6.9 (d, 1H, -NH)
7.10–7.79 (m, 21H, Ar-H)
1635 (C=O d
lactum)
3035 (Aromatic
C-H)
4e
4f
Hydrogen Hydrogen 220
38
49
40
C29H21N3O2
C29H20N3O2Cl
C30H23N3O3
9.29 (9.48)
8.50 (8.79)
8.41 (8.88)
–
4.30 (d, -2H, -CH2)
6.03 (s, 1H, NH)
6.11 (d, 1H, NH)
7.11–7.67 (m, 17H, Ar-H)
4.38 (d, 2H, CH2)
6.03 (s, 1H, NH)
Hydrogen Chloro
194
186
–
6.09 (d, 1H, -NH)
7.11–7.70 (m, 16H, -ArH)
4g
Hydrogen Methoxy
Chem Biol Drug Des 2013; 82: 119–124
121

Singh et al.
Table 1: continued
Compound
no.
Yield Molecular
M.P. °C (%) formula
% N
R
R’
Found(Calcd) I.R.
1H NMR
1367 (OCH3)
3474 (NH str.)
1530 (NH bend)
1680 (C=O amide)
3.74 (s, 3H, –OCH3)
4.32 (d, 2H, -CH2)
6.6 (s, 1H, -NH)
6.9 (d, 1H, -NH)
1658 (C=O d lactum) 7.10–7.90 (m, 16H, ArH)
3030 (Aromatic C-H)
labeling (23–25). The fresh human serum was prepared by
allowing blood collected from healthy volunteers to clot for
1 h at 37o C in a humidified incubator maintained at 5%
carbon dioxide, 95% air. Then, the sample was centri-
fuged at 400 rpm and the serum was filtered through
0.22 micron syringe filter into sterile plastic culture tubes.
The above freshly prepared technetium radio complexes
were incubated in fresh human serum at physiological
conditions that is at 37 °C at a concentration of 100 nM/
mL and then analyzed by ITLC-SG at different time inter-
vals to detect any dissociation of complex. Percentage of
free pertechnetate at a particular time point that was esti-
mated using saline and acetone as mobile phase, repre-
sented percentage dissociation of the complex at that
particular time point in serum.
Anticaner activity
The synthesized compounds were tested against (HeLa)
cell line. Routine culture maintenance and experimental
studies were carried out at 37 °C in a cell incubator with
humid atmosphere at 5% CO2. Cell propagation was
achieved in Dubecco’s modified eagle minimal medium
(DMEM) with phenol red, 10% fetal bovine serum, L-gluta-
mine, penicillin, streptomycin, and gentamycin as
described in previous literature. Before any experiment,
the cells were transferred for 4 days to a defined medium,
containing phenol red free DMEM, supplemented with
10% charcoal-stripped. Estrogen (17 b-estrodiol) in con-
centration up to 100 lg added to defined medium. Doxo-
rubicin is taken as standard. The MTT assay with 3-(4, 5-
dimethylthiazole-2-yl)-2, 5-phenyltetrazolium bromide was
used to determine the number of viable cells. For assay,
HeLa cells (1 9 104 cells/well) were platted in a 96-well
tissue culture plate and exposed to the compounds under
investigation. Cells were processed with the MTT assay for
24, 48, and 72 h of incubation. In brief, 10 lL of MTT
(final concentration = 250 lg/mL) in phosphate-buffered
saline (PBS) was added to every well containing 100-lL
cell suspension in medium, and the cultures were allowed
to incubate at 37 °C for 5 h. The reaction mixture was
carefully taken out and 100 lL of DMSO was added to
each well and pipetted up and down several times unless it
became homogenic. After 10 minutes, the color was read
at 540 nm using spectrophotometer plate reader (Bio-Rad,
Tokyo, Japan). The inhibitory effect on cell proliferation was
determined after 72 h of treatment with various concentra-
tions (0.1–300 nM) of the tested compound.
Blood kinetic studies
The blood clearance study was performed in normal rab-
bit, weighing 2–2.5 kg. Five MBq of the 99mTc labeled
compounds (0.3 mL) was administered intravenously
through the dorsal ear vein. At different time intervals
about 0.5-mL blood samples were withdrawn from the
dorsal vein of other ear, and radioactivity was measured in
the gamma counter. The data from the experiment were
expressed as percentage of administered dose at each
time interval.
Biodistribution study in mice
Albino mice strain (A) (taken in triplicate set) was used for
the tissue distribution studies. Animal handling and experi-
mentation were carried out as per the guidelines of the
Institutional Animal Ethics Committee.
EGFR kinase activity assay
To study biological activity, compounds were evaluated
against EGFR kinase activity assays. Briefly, 96-well plates
were precoated with a synthetic substrate poly-Glu-Tyr
(Sigma, 0.25 mg/mL) overnight at 37 °C. Ten microliters of
EGFR-TK extract, reaction medium and tested compound
(20 lL) were added. The reaction mixtures were incubated
for 30 min at room temperature while being shaken.
Kinase reaction was quenched by removal of the reaction
mixture and then the wells were washed with washing buf-
fer for three times. Phosphorylated tyrosine substrate was
blocked in PBS containing 3% BSA for 30 min, washed
with washing buffer (PBS containing 0.1% Tween 20) for
An equal dose of 10 lCi of labeled test compound was
injected in mice through tail vein of each animal. At differ-
ent time intervals, mice were sacrificed, blood was col-
lected, and different tissue and organs were dissected and
analyzed. The radioactivity was measured in a gamma
counter. The actual amount of radioactivity administered to
each animal was calculated by subtracting the activity left
in the tail from the activity injected. Radioactivity accumu-
lated in each organ was expressed as percentage admin-
istered dose per gram of tissue. Total volume of the blood
was calculated as 7% of the body weight.
122
Chem Biol Drug Des 2013; 82: 119–124

Quinazolines Derivatives as Potent EGFR Inhibitors
Table 2: Effects of compounds 4[A]–4[G] on epidermal growth
factor receptor (EGFR)-TK activity and HeLa cell proliferation
three times, detected by adding antiphosphotyrosine anti-
body for 1 h. Then antibody was removed, and wells were
washed with washing buffer for three times. The optical
density was measured at 450 nm by an ELISA reader.
Experiment with triplicate data was performed. IC50 values
were calculated for test compounds using a regression
analysis of the concentration/inhibition data.
Compound
IC50 (lM) EGFR-TK
IC50 (nM) HeLa
4[A]
4[B]
4[C]
4[D]
4[E]
4[F]
4[G]
0.238 Æ 0.002
0.132 Æ 0.005
0.051 Æ 0.003
0.185 Æ 0.006
0.152 Æ 0.005
0.085 Æ 0.006
0.140 Æ 0.005
8.05 Æ 1.24
4.51 Æ 0.51
35.40 Æ 1.34
11.02 Æ 0.59
38.49 Æ 1.02
49.32 Æ 0.59
23.49 Æ 1.02
Result and Discussion
All intermediates as well as final quinazoline analogues
were analyzed by different spectroscopic technique such
as IR, NMR, mass spectroscopy, and by elemental analy-
sis. Comparing the TLC with the starting materials, which
resulted a single spot different from the starting materials,
checked the synthesized ligand. The spectral evidence
confirms the presence of different functionalities (IR at
3351, 1640, 1467/cm). Similarly, NMR multiplet in the
range of (6.2–8) p.p.m. of 5–15 hydrogen also confirms
the presence of aromatic rings. It also confirms the pro-
posed stoichiometry and structure for the pyrido-quinazo-
lone. Integral of NMR confirms the number of protons in
pyrido-quinazolones as well as coupling constant confirms
the nature of double bonds.
The values are the mean Æ SD of independent experiments. Con-
centration of compound resulting in 50% inhibition of EGFR-TK
activity.
activity in the stomach precludes the presence of free per-
technetate, which indicates in vivo stability of preparation.
The percentage distribution of drug in various organs of
mice is shown as percentage of injected dose per organ
or tissue at different time interval. The drug localized in the
liver and kidneys, with the passage of time the activity in
kidney amplified for most of the compounds, while in
intestine, there were negligible increase in activity. This
shows that the major route of excretion of activity is
through kidneys. With passage of time, there was an
increase in accumulation of activity in urinary bladder.
Besides this, there was retention of radioactivity in liver for
considerable period, indicating that metabolism of drugs
probably takes place in liver, but the excretion of drugs
and metabolites is mainly through kidney. Accumulation of
drugs in liver may also be because of protein binding nat-
ure of drugs. Very slight accumulation of activity was
observed in lungs, spleen, and stomach. Negligible accu-
mulation occurs in heart and brain.
Modern medicine demands progressively more sophisti-
cated methods for the accurate diagnosis of diseased
states, and there is a massive worldwide research effort
into developing and improving imaging techniques.
Preliminary Complexation of novel synthesized compounds
with 99mTc was found to give sufficiently stable complexes
under physiological conditions. The in vitro serum stability
of the radio complexes is necessary parameter meant to
measure the effectiveness of chelating moiety to co-ordi-
nate the radio metal. Generally, there is transchelation of
radio metal to serum proteins particularly albumin. In vitro
serum stability of the complexes clearly indicates that ini-
tially there was fall in the stability of the complex but fur-
ther showing a constant stability. Initial fall in the labeling
efficiency after addition of fresh serum could be attributed
to the trans-chelation that could have taken place in serum
due to high affinity of plasma proteins for metal ions.
The cell proliferation was measured by MTT assay, and
the results were expressed as IC50 values. The activity
data are given in Table 2. The inhibition of the EGFR
activity by 4[A] - 4[G] were evaluated in human breast can-
cer cell line, HeLa. These cells are also known to over
express EGFR, which leads to continuous activation of the
EGFR pathway involved in cell proliferation. The inhibitory
effects on HeLa cell proliferation were determined after
72 h of treatment with various concentrations (10À5
–
10À10 M) of the tested compound, and the results were
expressed as IC50 values ranging from (4.5–50 nM). It was
found that for these molecules cell-based numbers are
lower than the enzyme numbers, which may be due to
their interactive nature of diaza type of compounds and
further validates the need of investigation to increase the
insight for mechanistic aspect of these molecules.
The retention of drug in the blood of the animal depends
upon the pharmacological and physical properties of the
drugs. Nearly, all the pyrido-quinazolone shows a very
rapid clearance of radioactivity from the blood. Approxi-
mately 55–65% of activity was removed within 1 h and
more than 90% in 4 h. It shows rapid kinetics, which may
be attributed to the hydrophilic nature of the drug radio
metal complexes.
Conclusion
Biodistribution of the radio complexes is an important phe-
nomenon to study because it gives an idea about its
excretory metabolic pathway and in vivo distribution of the
radio complex drug. Accumulation of low amount of radio-
Here, we describe the synthesis of designed compounds,
which are able to irreversibly block epidermal growth factor
receptor (EGFR) that may effective for cancer treatment.
Chem Biol Drug Des 2013; 82: 119–124
123

Singh et al.
The synthetic way for the preparation of the pyrido-quinazo-
lone derivatives is easy and convenient. Additional investiga-
tion to increase their efficacy as anticancerous activity and
to improve the pharmacokinetics performance of these new
pyrido-quinazolone derivatives may result in potent drugs
becoming available for commercial exploitation and impor-
tance of molecule as multimodal application.
11. Veerachamy A., Murugananthan G., Ramachandran V.
(2003) Synthesis, analgesic, anti-inflammatory and anti-
bacterial activities of some novel 2-methyl-3-substi-
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diovascular agents. Pharm Chem J;16:734–741.
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Conflict of interest
This is also certified that there is no conflict of interest
between the authors.
14. Charpiot B., Brun J., Donze I., Naef R., Stefani M.,
Mueller T. (1998) Quinazolines: combined type 3 and 4
phosphodiesterase inhibitors. Bioorg Med Chem
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