Design, synthesis and in vitro antitumor activity of 4-aminoquinoline and 4-aminoquinazoline derivatives targeting EGFR tyrosine kinase

Article abstract of DOI:10.1016/j.bmc.2008.07.038

Two series of new 6-alkoxy-4-substituted-aminoquinazolines (2-4f) and their bioisoteric quinoline congeners (5-7c) were designed and synthesized. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors. The newly synthesized compounds were tested in vitro on human breast carcinoma cell line (MCF-7) in which EGFR is highly expressed. Most of the tested compounds exploited potent antitumor activity with IC₅₀ values in the nanomolar range in particular compound 3b which displayed the highest activity among the tested compounds with IC₅₀ equal to 0.13 nmol.

Full text of DOI:10.1016/j.bmc.2008.07.038

Bioorganic & Medicinal Chemistry 16 (2008) 7543–7551
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and in vitro antitumor activity of 4-aminoquinoline
and 4-aminoquinazoline derivatives targeting EGFR tyrosine kinase
b
Khaled Abouzid a, , Samia Shouman
*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbasia, Cairo 11566, Egypt
b Department of Cancer Biology, National Cancer Institute, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series of new 6-alkoxy-4-substituted-aminoquinazolines (2–4f) and their bioisoteric quinoline cong-
eners (5–7c) were designed and synthesized. Virtual screening was carried out through docking the
designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if
these compounds have analogous binding mode to the EGFR inhibitors.
The newly synthesized compounds were tested in vitro on human breast carcinoma cell line (MCF-7) in
which EGFR is highly expressed. Most of the tested compounds exploited potent antitumor activity with
IC50 values in the nanomolar range in particular compound 3b which displayed the highest activity
among the tested compounds with IC50 equal to 0.13 nmol.
Received 15 March 2008
Revised 10 July 2008
Accepted 16 July 2008
Available online 20 July 2008
Keywords:
Aminoquinazoline
Aminoquinoline
EGFR tyrosine kinase inhibitor
Antitumor activity
Docking study
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
efforts have targeted this aberrant kinase activity in cancer, asth-
ma, psoriasis, and inflammation.9 Recent advances in the identifi-
Protein tyrosine kinases are enzymes involved in many cellular
processes such as cell proliferation, metabolism, survival, and
apoptosis. Several protein tyrosine kinases are known to be acti-
vated in cancer cells and to drive tumor growth and progression.
Blocking tyrosine kinase activity therefore represents a rational ap-
proach to cancer therapy. Protein kinases (PTKs) catalyze the phos-
phorylation of tyrosine and serine/threonine residues in various
proteins involved in the regulation of all functions.1 They can be
broadly classified as receptor such as EGFR, or non-receptor ki-
nases. Inappropriate or uncontrolled activation of many of these ki-
nases, by over-expression, constitutive activation, or mutation, has
been shown to result in uncontrolled cell growth.2 The epidermal
growth factor receptor belongs to the family of transmembrane
growth factor receptor PTKs. The EGFR erbB1 and erbB2 PTKs have
been identified as interesting targets for medicinal chemistry pro-
grams especially in cancer therapy. Excellent descriptions of the
involvement of erbB family proteins in cell physiology and disease
applications have been reported and reviewed.3–6
cation of erbB family kinase inhibitors have created hope for the
modulation of uncontrolled cell growth in cancer therapy for solid
tumors.10 This strongly suggests that these targets represent drug
intervention opportunities due to pivotal role in governing cellular
proliferation, survival, and metastasis.
A great number of different structural classes of tyrosine kinase
inhibitors have been reported and reviewed.3–5 The most promising
small molecule selective EGFR-TK inhibitors include 4-anilinoqui-
nazolines, anilinoquinolines, and pyrrolopyrimidines. Figure 1 in-
cludes some examples that are currently approved drugs or in
clinical trials.8
In May 2003, the FDA approved gefitinib (ZD1839, IressaÒ) as
monotherapy for the treatment of patients with locally advanced
or metastatic non-small cell lung cancer after chemotherapies
had failed.11
Consequently, various approaches were adopted to enhance the
potency and selectivity of these inhibitors. These efforts led to dis-
covery of lapatinib, a dual EGFR and erbB2 inhibitor,12 which is
currently in phase III clinical trials, while EKB-569 is a potent,
selective, and irreversible inhibitor of epidermal growth factor
receptor (EGFR) that is being developed as an anticancer agent.13,14
Later, it has been reported that somatic mutations in the tyro-
sine kinase domain of the EGFR gene occur in a subset of patients
with lung cancer who showed a dramatic response to the EGFR
tyrosine kinase inhibitors gefitinib and erlotinib.15–17
Overexpression of these receptors was found in a number of
cancers (e.g., breast, ovarian, colon, and prostate), their expression
levels often correlate with vascularity, and is associated with poor
prognosis in patients.7,8 Inhibitors of the EGFR PTK are therefore
expected to have great therapeutic potential in the treatment of
malignant and nonmalignant epithelial diseases. Drug discovery
Intensive research in the area of tyrosine kinase inhibitors led to
* Corresponding author. Tel.: +202 25080848; fax: +202 2508 0728.
E-mail address: abouzid@yahoo.com (K. Abouzid).
development of enormous number of active compounds.18–25
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.07.038

7544
K. Abouzid, S. Shouman / Bioorg. Med. Chem. 16 (2008) 7543–7551
NH
Br
NH
N
N
O
O
OH
N
N
H
N
PKI 166
PD153035
F
NH
O
O
Cl
NH
N
O
N
O
O
O
O
N
N
N
Gefitinib (Iressa)
Erlotinib (Tarceva))
F
F
Cl
NH
N
H
N
O
O
S
O
NC
N
HN
O
Cl
NH
N
O
O
N
EKB-569
Lapatinib
Figure 1. EGFR TK inhibitors.
In the same direction, and in continuing effort to find more po-
tent selective lead compound, herein, we describe the design and
synthesis of two series of 4-aminoquinoline and aminoquinazoline
derivatives as possible antitumor agents that may act through
EGFR inhibition.
differentially selective molecules. The design of our ligands was
done based on previous structure–activity relationship (SAR) of
4-anilinoquinazolines and earlier work with quinazoline-based
inhibitors of EGFR which established that 6,7-dialkoxy substitution
is compatible with good activity, and pivotal interactions between
the receptor and the inhibitors.
Inmorerecentapproach, itwasfoundthatdualinhibitionofEGFR
and ErbB-2 may offer increased activity over agents which target
only one of these receptor kinases.12,30 After discovery of lapatinib,
it was claimed that 4 position of the aniline can tolerate a lot of bulky
substituents; this leads to fundamental change in the pharmaco-
phore and claims moderate ErbB-2 activity with little or no EGFR
activity.
In this direction and in an approach to enhance the selectivity to-
ward ErbB-2, we introduced larger moiety at 4 position of the aniline
such as heterocyclylsulfonamido moiety in a fashion similar to
lapatinib which binds in the ATP-binding cleft, so that the bulky
group could be oriented deep in the back of the ATP binding site
and makes predominantly hydrophobic interactions with the pro-
tein mimicking the 30-chloro-40-[(3-fluorobenzyl)oxy]aniline group
of lapatinib. Moreover, in two compounds we replaced the aniline
moiety with substituted piperazine fragment to assess if such dra-
matic change in the pharmacophoric model of anilinoquinolines or
quinazoline will have appreciable effect on the activity.
2. Rational and design
In recent years, 4-anilinoquinazolines have emerged as a versa-
tile template for inhibition of a diverse range of receptor tyrosine
kinases. The most widely studied of these is the epidermal growth
factor receptor (EGFR), with the small-molecule inhibitor gefitinib
being the first agent from this class to be approved for the treat-
ment of non-small cell lung cancer refractory to prior chemother-
apeutic intervention.26,27
Subsequent research aimed at further exploration of the SAR of
this novel template has led to discovery of highly selective com-
pounds that target EGFR. These compounds act via competing with
ATP for binding at the catalytic domain of tyrosine kinase. Later on,
a great structural variety of compounds of structurally diverse clas-
ses have proved to be highly potent and selective ATP-competitive
inhibitors. Among them, 4-anilinoquinoline-3-carbonitriles and
others provide the necessary binding properties for inhibition of
the ErbB family of tyrosine as they mimic the adenine portion of
ATP.28,29
In this study, we present a new sub-family of compounds con-
taining 4-aminoquinazoline, and quinoline core as promising po-
tent and selective EGFR inhibitors. Our strategy is directed
toward designing a variety of ligands with diverse chemical prop-
erties hypothesizing that the potency of these molecules might be
enhanced by adding alternative binding group such as sulfonamide
and carboxylic group in the aniline moiety.
The binding mode and docking energy of the designed com-
pounds in EGFR homology model could be helpful tool for predict-
ing their mechanism of antitumor activity of the target
compounds.
3. Chemistry
General syntheses for target compounds are depicted in
Schemes 1 and 2 starting from the central scaffold 2,4-quinazolin-
dione or 4-quinolinone.
In this way, such substitution pattern could target different re-
gions of the ATP-binding site of the protein kinase domain to create

K. Abouzid, S. Shouman / Bioorg. Med. Chem. 16 (2008) 7543–7551
7545
CH3
O
S
N
N
O
H3CO
H3CO
COOH
NH2
1a
(c)
H3CO
H3CO
N
(a)
N
Cl
O
H3CO
H3CO
2
NH
O
NHR
N
O
S
H
1b
O
HN
(b)
Cl
N
H3CO
H3CO
(d)
N
H3CO
H3CO
N
N
Cl
Cl
3a,b
3a:R= 5-Methylisoxazol-3-yl
1c
3b
: R= Thiazol-2-yl
R1
R2
HN
R3
H3CO
H3CO
N
(e)
N
Cl
4a-f
4a; R1,R2=Cl, R3= H
4b: R1,R3= H, R2= COOH
4c
: R1= CONH2, R2,R3=H
4d; R1,R3=H,R2=CH3CH2CH2OCO
4e: R1= CH3OCO, R2,R3=OCH3
4f: R1= COOH, R2,R3=OCH3
Scheme 1. Reagents and conditions: (a) KCNO, AcOH then NaOH; (b) POCl3, N,N-dimethylaniline; (c) p-toluenesulfonylpiperazine THF, rt 24 h; (d) sulfamethoxazole or
sulfathiazole, 2-propanol, reflux; (e) substituted-anilines, ethanol, reflux.
In the first scheme, the synthesis of final 4-quinazolin-4-amines
(2–4) was described. Accordingly, the quinazolinedione (1b) was
synthesized from 4,5-dimethoxyanthranilic acid (1a) and potas-
sium cyanate in acetic acid followed by NaOH and acidification
according to reported method.31a Chlorination of the dione with
phosphoryl chloride in the presence N,N-dimethylaniline gave
the key starting material, 2,4-dichloro-6,7-dimethoxyquinazoline
(1c).31b The 4-substituted-aminoquinazoline compounds were
synthesized via the reaction of (1c) with different nucleophilic
amine derivatives under carefully controlled conditions to prevent
disubstitution. The piperazine derivative (2) was obtained by
reacting the N1-p-toluenesulfonylpiperazine at room temperature
overnight in THF followed by liberation of the free base with so-
dium carbonate. The sulfonamide derivatives 3a,b were smoothly
obtained as their hydrochloride salt via nucleophilic substitution
of the more reactive chlorine at the 4 position of the dichloroqui-
nazoline 1c with the respective sulfonamide under reflux in 2-pro-
panol for 2 h. Furthermore, anilinoquinazoline derivatives (4a–f)
were obtained by reaction between different aniline derivatives
and the dichloroquinazoline derivative 1c under careful reaction
condition.
and ethyl acetoacetate to give the condensation product which was
cyclized in diphenyl ether affording 6-ethoxy-4-hydroxy-2-meth-
ylquinoline (1e).32,33 The latter compound was treated with phos-
phorus oxychloride to afford the desired 4-chloro derivative 1f.
Furoylpiperazinylquinoline 5 was obtained by coupling 4-chloro-
quinoline derivative 1f with N-furoylpiperazine in ethanol under
reflux, while the reaction between 1f and either sulfonamide or
the requisite aniline derivatives proceeds preferably in presence
of catalytic amount of HCl. The structures of all the newly synthe-
sized compounds were elucidated with H1 NMR, EIMs, and ele-
mental analyses.
4. Experimental
Melting points were determined using a Stuart Scientific appa-
ratus and were uncorrected. IR spectra were recorded on a Perkin-
Elmer FT-IR series using KBr cell. 1H NMR spectra were recorded on
Brücker 300 MHz. in d scale. All the spectra were obtained on solu-
tions in DMSO-d6 with TMS as internal standard; the values of the
chemical shifts (d) are given in ppm, and coupling constants (J) are
given in Hz. The electron impact (EI) mass spectra were recorded
on Finnigan Mat SSQ 7000 (70 ev) mass spectrometer. Analytical
thin layer chromatography (TLC) on silica gel plates containing
UV indicator was employed routinely to follow the course of
On the other hand, Scheme 2 describs the synthetic pathway of
various quinolinamine compounds 5–7. The key intermediate 1f
was synthesized by standard methods starting from p-phenetidine

7546
K. Abouzid, S. Shouman / Bioorg. Med. Chem. 16 (2008) 7543–7551
O
O
N
N
(c)
O
O
NH2
N
CH3
1d
(a)
5
O
S
NHR
O
HN
N
Cl
O
O
(d)
(b)
O
O
CH3
N
CH3
N
H
CH3
6a-e
1e
6a: R= 5-Methylisoxazol-3-yl
6b: R= Thiazol-2-yl
1f
6c: R = Pyrimidin-2-yl
NH
6d: R = H
6e: R =
NH2
R1
R2
R3
HN
O
(e)
N
CH3
7a-c
7a; R1,R2=Cl, R3= H
7b
: R1= CH3OCO, R2,R3=OCH3
7c: R1,R2=H, R3= OH
Scheme 2. Reagents and conditions: (a) Ethyl acetoacetate, reflux then diphenyl ether reflux, Dean stark; (b) POCl3, reflux; (c) 2-furoylpiperazine reflux; (d) sulfonamides,
2-propanol, reflux; (e) substituted-anilines, ethanol, reflux, few drops HCl.
reactions and to check the purity of products. All reagents and sol-
vents were purified and dried by standard techniques. Elemental
microanalyses were performed at Microanalytical Center, Cairo
University, and were within 0.4% unless otherwise stated. The
chemicals used in the synthesis are purchased from Aldrich and
Merck and are of analytical grades. p-Toluenesulfonylpiperazine
was not commercially available and was synthesized according
to reported method.34
4.2.
4-(2-Chloro-6,7-dimethoxyquinazolin-4-ylamino)-N-(5-
methylisoxazol-3-yl)benzenesulfonamide hydrochloride (3a)
A
mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (1c)
(0.181 g, 0.7 mmol) and 4-amino-N-(5-methylisoxazol-3-yl)ben-
zenesulfonamide (sulfamethoxazole) (0.177 g, 0.7 mmol) in iso-
propanol (20 mL) was heated at reflux and stirred for 2 h. The
white solid formed was filtered while hot and recrystallized from
methanol/DMF to give 3a. Yield: 0.28 g, 88%; mp 310–312 °C, 1H
NMR (DMSO-d6) (300 MHz) d: 2.30 (s, 3H, CH3), 3.93 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 6.16 (s, 1H, isoxazole), 7.20 (s, 1H, qui-
nazoline), 7.8–8.06 (m, 5H, ArH), 10.16 (s, 1H, NH, D2O exchange-
able), 11.36 (s, 1H, NH, D2O exchangeable).
4.1. 2-Chloro-6,7-dimethoxy-4-(4-tosylpiperazin-1-yl)quinazoline
hydrochloride (2)
A mixture of equimolar amounts of 2,4-dichloro-6,7-dimeth-
oxyquinazoline (1c) (0.181 g, 0.7 mmol) and 1-tosylpiperazine
(0.168 g, 0.7 mmol) in THF (15 mL) was stirred at ambient temper-
ature overnight. The white solid formed was filtered, washed with
diethyl ether, and recrystallized from methanol to give 2 as buff so-
lid. Yield: 0.234 g, 67%; mp 196–198 C; 1H NMR (DMSO-d6)
(300 MHz) d: 2.4 (s, 3H, CH3), 3.13 (m, 4H, CH2, piperazine), 3.76
(m, 4H, CH2, piperazine), 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3),
7.05–7.66 (m, 6H, Ar H).
IR (KBr) cmꢀ1. 3275 (NH), 1625, 1514, 1428, 1336, 3293; MS m/z
478 (M+3, 100%). Anal. Calcd for C22H22N4O4SꢁHCl: C, 46.88; H,
3.74; N, 13.67. Found: C, 46.48; H, 3.91; N, 13.89.
4.3. 4-(2-Chloro-6,7-dimethoxyquinazolin-4-ylamino)-N-(thiazol-
2-yl)benzene-sulfonamide hydrochloride (3b)
Compound 3b was prepared as described for 3a from 1c and 4-
amino-N-(thiazol-2-yl)benzenesulfonamide (sulfathiazole) and
recrystallized from Methanol/DMF. Yield: 91%; mp 290–292 °C
(decomp), 1H NMR (DMSO-d6) (300 MHz) d: 3.39 (s, 3H, OCH3),
IR (KBr) cmꢀ1 1570, 1484, 1347 (S@O). MS m/z 462 (M+, 2.9%),
464 (M+2, 0.8%). Anal. Calcd for C21H23ClN4O4SꢁHCl: C, 50.50; H,
4.84; N, 11.22. Found: C, 50.95; H, 5.29; N, 11.10.

K. Abouzid, S. Shouman / Bioorg. Med. Chem. 16 (2008) 7543–7551
7547
3.97 (s, 3H, OCH3), 6.82–7.97 (m, 8H, Ar H), 10.19 (s, 1H, NH, D2O
exchangeable), 11.24 (s, 1H, NH, D2O exchangeable).
recrystallized from ethanol as faint yellow crystals. Yield: 67%;
mp 278–280 °C; 1H NMR (DMSO-d6) (300 MHz) d: 3.81 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.93 (s, 3H, OCH3),
3.95 (s, 3H, OCH3), 7.18–8.15 (m, 4H, Ar H), 11.08 (s, 1H, NH,
D2O exchangeable).
IR (KBr) cmꢀ1, 3286 (NH), 1631 (C@N), 1568, 1435, 1328 (S@O);
MS m/z 477 (M+, 22.4%). Anal. Calcd for C19H16ClN5O4S2ꢁHCl: C,
44.36; H, 3.33; N, 13.61. Found: C, 44.77; H, 3.55; N, 13.81.
IR (KBr) cmꢀ1 2950 (CH aliphatic), 1673 (C@O, ester). MS m/z 433
(M+, 56.8%), 435 (M+2, 18.9%), 374 (100%). Anal. Calcd for
4.4. 2-Chloro-4-[N-(2,4-dichlorophenyl)amino]-6,7-dimethoxy-
quinazoline hydrochloride (4a)
C20H20ClN3O6. C, 55.37; H, 4.65; N, 9.69. Found: 55.81; H, 4.70; N, 9.93.
Compound 4a was prepared as described for 3a from 1c and
2,4-dichloroaniline, and the product obtained was recrystallized
from methanol. Yield: 74%; mp 264–266 °C, 1H NMR (DMSO-d6)
(300 MHz) d: 3.93 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 7.16 (s, 1H,
Ar H), 7.50–7.59 (m, 2H, Ar H), 7.76 (s, 1H, Ar), 7.90 (s, 1H, ArH)
10.09 (s, 1H, NH, D2O exchangeable).
4.9. 2-(2-Chloro-6,7-dimethoxyquinazolin-4-ylamino)-4,5-dimeth-
oxybenzoic acid (4f)
Compound 4f was prepared as described for 3a from 1c and 4,5-
dimethoxyanthranilic acid, and the product was stirred in a solu-
tion of sodium acetate, filtered, and recrystallized from methanol
to give yellow solid. Yield: 52%; mp 296–298 °C; 1H NMR
(DMSO-d6) (300 MHz) d: 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3),
3.86 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.98 (s, 1H, Ar H), 7.05 (s,
1H, Ar H), 7.29 (s, 1H, Ar), 8.61 (s, 1H, Ar H), 11.98 (s, 1H, NH,
D2O exchangeable), 12.3 (br s, 1H, COOH, D2O exchangeable).
IR (KBr) cmꢀ1 3436 (NH), 2928 (CH aliphatic), 1732 (C@O, acid).
MS m/z 419 (M+, 45.2%), 421 (M+2, 21%), Anal. Calcd for
C19H18ClN3O6.0.25 H2O. C, 53.78; H, 4.39; N, 9.90. Found: C,
53.67; H, 4.89; N, 9.88.
IR (KBr) cmꢀ1 3430, 3230 (NH), 1627 (C@N), 1590. MS m/z 383
(M+, 19.4%), 385 (M+2, 7.6%). Anal. Calcd for C16H12Cl3N3O2ꢁHCl: C,
49.96; H, 3.14; N, 10.92. Found: C, 49.64; H, 3.44; N, 11.22.
4.5. 4-(2-Chloro-6,7-dimethoxyquinazolin-4-ylamino)benzoic
acid hydrochloride (4b)
Compound 4b was prepared as described for 3a from 1c and 4-
aminobenzoic acid and the product was recrystallized from DMF as
off-white solid. Yield: 79%; mp 322–324 °C (decomp), 1H NMR
(DMSO-d6) (300 MHz) d: 3.86 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
7.05 (s, 1H, Ar H), 7.70 (s, 1H, Ar H), 7.84 (d, 2H, Ar), 7.92 (d, 2H,
ArH), 10.10 (s, 1H, NH, D2O exchangeable), 11.3 (br s, 1H, COOH,
D2O exchangeable).
4.10. 6-Ethoxy-4-[4-(2-furoyl)piperazin-1-yl]-2-methylquino-
line hydrochloride monohydrate (5)
A mixture of equimolar amount of 4-chloro-6-ethoxy-2-meth-
ylquinoline (1f) and 1-(2-furoyl) piperazine (1 mmol) each in eth-
anol (15 mL) was heated at reflux and stirred for 6 h. The solution
was cooled, diluted with diethyl ether, and the solid formed was
filtered and crystallized from absolute ethanol to give buff solid.
Yield: 45%; mp 266–268 °C; 1H NMR (DMSO-d6) (300 MHz) d:
1.41 (t, 3 H, J = 6.9 Hz, OCH2CH3) 2.72 (s, 3H, CH3), 3.82 (m, 4H,
CH2, piperazine), 3.98 (m, 4H, CH2, piperazine), 4.21 (q, 2H,
J = 6.9 Hz, OCH2CH3), 6.61 (s, 1H, quinoline C-3), 7.08–7.11 (m,
2H, Ar H), 7.37 (s, 1H, Ar H), 7.6 (d, 1H, J = 9.3 Hz, Ar H), 7.88 (s,
1 H, Ar H), 8.08 (d, 1H, J = 9.3 Hz, furan).
IR (KBr) cmꢀ1 3425 (OH), 1694 (C@O), 1629. MS m/z 359 (M+,
100%), 361 (M+2, 52.1%). Anal. Calcd for C17H14ClN3O4ꢁHCl: C,
56.75; H, 3.92; N, 11.68. Found: C, 56.66; H, 4.11; N, 11.88.
4.6. 2-(2-Chloro-6,7-dimethoxyquinazolin-4-ylamino)benzamide
hydrochloride (4c)
Compound 4c was prepared as described for 3a from 1c and 2-
aminobenzamide, and the product was recrystallized from metha-
nol as buff solid. Yield: 65%; mp 214–216 °C, 1H NMR (DMSO-d6)
(300 MHz) d: 3.92 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.18 (s, 1H,
Ar H), 7.42 (s, 1H, Ar H), 7.60–8.80 (m, 4H, Ar), 11.6 (s, 1H, NH,
D2O exchangeable), 13.08 (s, 2H, CONH2, D2O exchangeable).
IR (KBr) cmꢀ1 3386 (NH), 1625 (amide C@O), 1545. MS m/z 358
(M+, 52.8%), 360 (M+2, 21.5%). Anal. Calcd for C17H15ClN4O3ꢁHCl: C,
51.66; H, 4.08; N, 14.18. Found: C, 51.62; H, 4.98; N, 14.28.
IR (KBr) cmꢀ1627,1592. MS m/z 365 (M+, 67.6%,). Anal. Calcd for
C21H23N3O3ꢁHClꢁH2O: C, 60.07; H, 6.24; N, 10.01. Found: C, 59.81;
H, 6.14; N, 10.22.
4.11. 4-(6-Ethoxy-2-methylquinolin-4-ylamino)-N-(5-methyli-
soxazol-3-yl)benzene sulfonamide hydrochloride (6a)
4.7. Propyl 4-(2-chloro-6,7-dimethoxyquinazolin-4-ylamino)benzoate
hydrochloride(4d)
A mixture of equimolar amounts of 4-chloro-6-ethoxy-2-meth-
ylquinoline (1f) (0.7 mmol), and 4-amino-N-(5-methylisoxazol-3-
yl)benzenesulfonamide (sulfamethoxazole) in methoxyethanol
(15 mL) was heated at reflux and stirred for 6 h. A white solid
was formed, which was filtered and recrystallized from metha-
nol/DMF to give 6a as white powder. Yield: 87%; mp 298–300 °C,
1H NMR (DMSO-d6) (300 MHz) d: 1.41 (t, 3H, J = 6.9, Hz OCH2CH3),
2.31 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.26 (q, 2H, J = 6.9 Hz, OCH2CH3),
6.16 (s, 1H, isoxazole), 7.02 (s, 1H, quinoline C-3), 7.62–8.1 (m, 7H,
ArH), 10.69 (s, 1H, NH, D2O exchangeable), 11.39 (s, 1H, NH, D2O
exchangeable).
Compound 4d was prepared as described for 3a from 1c and
propyl 4-aminobenzoate, and the product was recrystallized from
methanol as beige solid. Yield: 74%; mp 258–260 °C, 1H NMR
(DMSO-d6) (300 MHz) d: 1.01 (t, 3H, CH3), 1.74 (m, 2H, CH2), 3.93
(s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.2 (t, 2H, OCH2), 7.18 (s, 1H, Ar
H), 7.97–7.99 (m, 5H, ArH), 10.17 (s, 1H, NH, D2O exchangeable).
IR (KBr) cmꢀ1; 3217 (NH), 2970 (CH aliphatic), 1720 (C@O, ester).
MS m/z 401 (M+, 100%), 403 (M+2, 33.8%). Anal. Calcd for
C
20H20ClN3O4ꢁHCl: C, 59.78; H, 5.02; N, 10.46. Found: C, 59.52; H,
IR (KBr) cmꢀ1 1608, 1585,1457, 1396 (S@O). MS m/z 438 (M+,
100%). Anal. Calcd for C22H22N4O4SꢁHCl: C, 55.63; H, 4.88; N,
11.80. Found: C, 55.53; H, 5.13; N, 11.77.
5.32; N, 10.71.
4.8. Methyl 2-(2-chloro-6,7-dimethoxyquinazolin-4-ylamino)-
4,5-dimethoxybenzoate (4e)
4.12. 4-(6-Ethoxy-2-methylquinolin-4-ylamino)-N-(thiazol-2-
yl)benzenesulfonamide hydrochloride (6b)
Compound 4e was prepared as described for 3a from 1c and
methyl 4,5-dimethoxyanthranilate, and the product was sus-
pended in saturated solution of Na2CO3 and stirred, filtered, and
Compound 6b was prepared as described for 6a from 1f and 4-
amino-N-(thiazol-2-yl)benzenesulfonamide (sulfathiazole), and

7548
K. Abouzid, S. Shouman / Bioorg. Med. Chem. 16 (2008) 7543–7551
recrystallized from Methanol/DMF. Yield: 86%; mp 320–322 °C
(decomp), 1H NMR (DMSO-d6) (300 MHz) d: 1.368 (t, 3H, J = 6.9,
Hz OCH2CH3) 2.54 (s, 3H, CH3), 4.26 (q, 2H, J = 6.9 Hz, OCH2CH3),
6.84 (d, 1H, J = 4.5 Hz, thiazole), 6.85 (s, 1H, ArH), 7.24 (d, 1H,
J = 4.5 Hz, thiazole), 7.56–7.94 (m, 7H, ArH), 8.17 (s, 1H, NH, D2O
exchangeable), 10.67 (s, 1H, NH, D2O exchangeable).
IR (KBr) cmꢀ1 3302 (NH), 1609 (C@N), 1578. MS m/z 346 (M+,
100%), 348 (M+2, 56%), 350 (M+4, 13.3%). Anal. Calcd for
18H16Cl2N2O.0.5 H2O. C, 60.69; H, 4.81, N, 7.86. Found: C, 60.49;
H, 5.12, N, 7.77.
C
4.17. Methyl 2-(6-ethoxy-2-methylquinolin-4-ylamino)-4,5-dim-
ethoxybenzoate hydrochloride (7b)
IR (KBr) cmꢀ1, 1606, 1557,1457, 1396 (S@O) MS m/z 440 (58.6%
M+). Anal. Calcd for C21H20N4O3S2ꢁHCl: C, 51.89; H, 4.14; N, 12.10.
Found: C, 51.62; H, 4.29; N, 12.02.
A mixture of equimolar quantities of 1f (0.22 g, 1 mmol) and
methyl 4,5-dimethoxyanthranilate (0.21 g, 1 mmol) and 3 drops
conc. HCl in n-pentanol (12 mL) was heated under reflux and stir-
ring for 6 h, and the mixture was left at room temperature over-
night. The yellow solid formed was filtered washed with diethyl
ether and recrystallized from ethanol/DMF. Yield: 0.2 g, 47:%; mp
252–254 °C; 1H NMR (DMSO-d6) (300 MHz) d: 1.43 (t, 3H, J = 6.9,
Hz OCH2CH3), 2.56 (s, 3H, CH3), 3.66 (s, 3H, OCH3), 3.86 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 4.25 (q, 2H, J = 6.9 Hz, OCH2CH3), 6.43
(s, 1H, Ar H), 7.15 (s, 1H, Ar H), 7.45 (s, 1H, Ar H), 7.6 (d, 1H,
ArH), 8.04–8.07 (m, 2H, ArH), 10.40 (s, 1H, NH, D2O exchangeable).
IR (KBr) cmꢀ1 3442, 2945 (CH aliphatic), 1697(C@O, ester),
1609,1457, 1396. MS m/z 396 (M+, 100%). Anal. Calcd for
4.13. 4-(6-Ethoxy-2-methylquinolin-4-ylamino)-N-(pyrimidin-
2-yl)benzenesulfonamide hydrochloride (6c)
Compound 6c was prepared as described for 6a from 1f and 4-
amino-N-(pyrimidin-2-yl) benzenesulfonamide (sulfadiazine), and
recrystallized from methanol/DMF. Yield: 78%; mp 316–318 °C
(decomp), 1H NMR (DMSO-d6) (300 MHz) d: 1.39 (t, 3H, J = 6.9,
Hz OCH2CH3) 2.62 (s, 3H, CH3), 4.25 (q, 2H, J = 6.9 Hz, OCH2CH3),
7.0 (s, 1H, ArH), 7.07 (t, 1H, J = 2 Hz, pyrimidine), 7.65–8.1 (m,
7H, ArH), 8.53 (d, 2H, J = 2 Hz, pyrimidine), 10.64 (s, 1H, NH, D2O
exchangeable), 11.55 (s, 1H, NH, D2O exchangeable).
IR (KBr) cmꢀ1, 1611, 1586,1458, 1399 (S@O) MS m/z 435 (M+,
31.2%). Anal. Calcd for C22H21N5O3SꢁHCl. C, 55.99; H, 4.70; N,
14.84. Found: C, 55.76; H, 4.68; N, 14.64.
C
22H24N2O5ꢁHCl: C, 61.04; H, 5.82; N, 6.47. Found: C, 60.49; H,
5.55; N, 6.37.
4.18. 6-Ethoxy-4-[N-(3-hydroxyphenyl)amino]-2-methylquin-
oline hydrochloride (7c)
4.14. 4-(6-Ethoxy-2-methylquinolin-4-ylamino)benzenesulfon-
amide hydrochloride (6d)
Compound 7c was prepared as described for 7b from 1f and 3-
aminophenol, and crystallized from ethanol. Yield: 68%; mp 324–
326 °C; 1H NMR (DMSO-d6) (300 MHz) d: 1.42 (t, 3H, J = 6.9, Hz
OCH2CH3), 2.58 (s, 3H, CH3), 4.25 (q, 2H, J = 6.9 Hz, OCH2CH3),
6.67 (s, 1H, Ar H), 6.80–6.88 (m, 3H, Ar H), 7.34 (t, 1H, Ar H),
7.61 (d, 1H, ArH), 8.0 (d, 1H, ArH), 8.12 (s, 1H, ArH), 9.94 (s, 1H,
phenolic OH, D2O exchangeable), 10.47 (s, 1H, NH, D2O
exchangeable).
Compound 6d was prepared as described for 6a from 1f and 4-
aminobenzenesulfonamide (sulfanilamide) and recrystallized from
methanol/DMF. Yield: 66%; mp 314-316 °C (decomp), 1H NMR
(DMSO-d6) (200 MHz) d: 1.42 (t, 3H, J = 6.9, Hz OCH2CH3), 2.64 (s,
3H, CH3), 3.07 (s, 2H, SO2NH2), 4.25 (q, 2H, J = 6.9 Hz, OCH2CH3),
6.61 (s, 1H, quinoline at C3), 7.49–8.25 (m, 7H, ArH), 10.87 (s,
1H, NH).
IR (KBr) cmꢀ1, 3320 (NH), 1611, 1588, 1458, 1390 (S@O), Anal.
Calcd for C18H19N3O3SꢁHCl: C, 53.75; H, 4.78; N, 11.06. Found:
53.67; H, 4.98; N, 11.22.
IR (KBr) cmꢀ1, 3368 (OH), 3234 (NH), 2944 (CH aliphatic), 1613,
1591, 1457, 1396. MS m/z 294 (M+, 100%). Anal. Calcd for
C
18H18N2O2ꢁHCl: C, 65.35; H, 5.79; N, 8.47. Found: C, 65.75; H,
5.82; N, 8.33.
4.15. 6-Ethoxy-4-[N-(4-guanidosulfonylphenyl)amino]-2-meth-
ylquinoline hydrochloride (6e)
5. Molecular modeling study
Compound 6e was prepared as described for 6a from 1f and sul-
faguanidine, and crystallized from methanol. Yield: 83%; mp 302–
304 °C, 1H NMR (DMSO-d6) (300 MHz) d: 1.42 (t, 3H, J = 6.9, Hz
OCH2CH3), 2.63 (s, 3H, CH3), 4.25 (q, 2H, J = 6.9 Hz, OCH2CH3),
6.83–6.86 (m, 4H, 2 NH, NH2 guanido, D2O exchangeable), 6.92
(s, 1H, quinoline C-3), 7.60–8.17 (m, 7H, ArH), 10.68 (s, 1H, NH,
D2O exchangeable).
Docking study was carried out for the target compounds into
EGFR using SYBYL version 7.3, Tripos Inc and Molegro virtual dock-
er version 2007. The crystal structure of the enzyme with lapatinib
(1XKK) was obtained from protein data bank PDB.35
Since it was found that gefitinib mimic ATP and bind to the ATP
binding region of the kinase active site. The binding of ATP itself in-
volves two important hydrogen bonding interactions between the
purine base of ATP and the protein backbone between amino acids
Gln-767 and Met-769 and have two nitrogen atoms in the quinaz-
oline ring which both act as hydrogen bond acceptors. One of these
interactions involves the purine group acting as a hydrogen bond
donor, while the other involves purine acting as hydrogen bond
acceptor.
IR (KBr) cmꢀ1 3436, 3340, (NH, NH2) 1612, 1585, 1459, 1397
(S@O). MS m/z 399 (M+, 100%). Anal. Calcd for C19H21N5O3SꢁHCl:
C, 52.35; H, 5.09, N, 16.07. Found: C, 52.39; H, 5.14, N, 16.21.
4.16. 4-[N-(2,4-Dichlorophenyl)amino]-6-ethoxy-2-methylquin-
oline (7a)
Our compounds were modeled by positioning them in the
lapatinib binding site in accordance with the published crystal
structures of quinazoline derivatives bound to kinase.36 The entire
complex was then subjected to alternate cycles of minimization
and dynamics. The intent was to get a satisfactory structure for
the complex that was consistent with the published crystal
structure.37,38
From the comparative docking study of our compounds with
many structurally related lead compounds such as lapatinib and
gefitinib we could observe how our compounds might bind to the
A mixture of equimolar quantities of 1f and 2,4-dichloroaniline
(0.7 mmol for each) and 3 drops of conc. HCl in n-butanol (15 mL)
was heated under reflux and stirring for 8 h, and the mixture was
left at room temperature overnight where a fluffy solid is formed.
The solid was triturated in Na2CO3 solution, stirred, filtered, and
crystallized from ethanol. Yield: 48%; mp 248–250 °C. 1H NMR
(DMSO-d6) (300 MHz) d: 1.43 (t, 3H, J = 6.9, Hz OCH2CH3), 2.58 (s,
3H, CH3), 4.26 (q, 2H, J = 6.9 Hz, OCH2CH3), 6.29 (s, 1H, Ar H),
7.6–8.0 (m, 5H, ArH), 8.12 (s, 1H, ArH), 10.57 (s, 1H, NH, D2O
exchangeable).

K. Abouzid, S. Shouman / Bioorg. Med. Chem. 16 (2008) 7543–7551
7549
Figure 2. Overlying of 3b and Lapatinib in the ATP binding site of EGFR-TK shows amino acids in contact in the same position. This picture was created with SYBYL
version 7.3.
kinase binding site, based on the knowledge of the structure of sim-
ilar active sites. We redocked lapatinib into the active site of the en-
zyme (Fig. 2), then we replaced with our compounds in order to
compare the binding mode of both ligand and the test compound.
These docking studies have revealed that the quinazoline ring binds
to a narrow hydrophobic pocket in the N-terminal domain of EGFR
TK where N-1 of the quinazoline ring interacts with the backbone
NH of Met-769 via a hydrogen bond, and similarly, a water mole-
cule-mediated hydrogen bonding interaction is observed between
the N-3 of the quinazoline ring and the Thr-830 side chain. These
interactions underscore the importance of both nitrogen atoms for
binding and the subsequent inhibitory capacity. The aniline moiety
lies in a deep and hydrophobic pocket. The bulky sulfamoyl group
at the C-4 of aniline moiety lies at the same position of the 30-
chloro-40-(3-fluorobenzyl)oxy moiety of lapatinib.
binding site. In each case, the N-1 atom of the quinazoline is hydro-
gen bonded to the backbone nitrogen of Met 769, while the N-3 atom
is hydrogen bonded to the side chain hydroxyl of Thr 830 via a water
molecule, and in case of compound 3b we noticed that an additional
H bond is formed between thiazole N and water molecule. On the
other hand, in the quinoline counterparts, the N-1 atom is similarly
hydrogen bonded to Met 769 as shown in Figure 5.
6. Biological testing
6.1. Materials and methods
The human tumor cell lines (MCF-7) were obtained as a gift
from NCI, MD, USA.
All chemicals and solvents were purchased from Sigma–Aldrich.
The results of this virtual screening could support the postulation
that our active compounds may act on the same enzyme target
where EGFR inhibitor acts.Figure 2 shows optimum overlay of lapat-
inib with 3b with amino acids in vicinity kept in place, while Figures
3 and 4 demonstrate binding models of quinazoline in the ATP
6.1.1. Measurement of potential cytotoxicity
The cytotoxic activity was measured in vitro for the newly
synthesized compounds using the Sulfo-Rhodamine-B stain (SRB)
assay using the method of Skehan.39
Figure 3. Binding mode of compound 3b in the ATP binding site of EGFR-TK showing two H bonds between N-1 and Met 769 and another H-bonds between N-3 of the
quinazoline and N of thiazole ring to Thr 830 through water bridge.

7550
K. Abouzid, S. Shouman / Bioorg. Med. Chem. 16 (2008) 7543–7551
Figure 4. Binding model of compound 2 in the ATP binding site of EGFR showing H bonding between N-1 of the quinazoline and Met 769 and the water-bridged H-bond to
Thr 830. The hydrogen bonds are indicated as green dashed lines. This picture was created with Molegro, virtual docker program.
Figure 5. Binding of 6-Ethoxy-4-[N-(3-hydroxyphenyl)amino]-2-methylquinoline (7c) to ATP binding site of EGFR showing H bonding between N-1 of the quinazoline and
Met 769. This picture was created with Molegro, virtual docker program.
Cells were plated in 96-multiwell microtiter plate (104 cells/
well) for 24 h before treatment with the compound(s) to allow
Table 1
In vitro cytotoxic activities of the synthesized compounds against human breast
attachment of cell to the wall of the plate. Test compounds were
dissolved in DMSO and diluted with saline to the appropriate vol-
ume. Different concentrations of the compound under test (0.1, 2.5,
5, and 10 nmol/ml) were added to the cell monolayer. Triplicate
wells were prepared for each individual dose. Monolayer cells were
incubated with the compound(s) for 48 h at 37 °C and in atmo-
sphere of 5% CO2. After 48 h, cells were fixed, washed, and stained
for 30 min with 0.4% (wt/vol) with SRB dissolved in 1% acetic acid.
Unbound dye was removed by four washes with 1% acetic acid, and
attached stain was recovered with Tris-EDTA buffer. Color intensity
was measured in an ELISA reader. The relation between surviving
fraction and drug concentration is plotted to get the survival curve
for breast tumor cell line after the specified time. The concentra-
tion required for 50% inhibition of cell viability (IC50) was calcu-
lated and the results are given in Table 1. The inhibition curve
for the most potent compound (3b) is presented in Figure 6.
cancer cell (MCF-7)
a,b
Compound
Cytotoxicity (IC50
)
(nmol)
2
1.08
1.98
0.13
4.31
13.85
NA
3.96
19.25
4.38
1.67
2.84
3a
3b
5
6a
6b
6c
6e
7a
7b
7c
NA, means the IC50 not achieved at 20 nmol.
a
IC50, compound concentration required to inhibit tumor cell proliferation by
50%.
b
Values are means of three experiments.

K. Abouzid, S. Shouman / Bioorg. Med. Chem. 16 (2008) 7543–7551
7551
9. Cohen, P. Nat. Rev. Drug Disc. 2002, 1, 309.
10. Gschwind, A.; Fischer, O. M.; Ullrich, A. Nat. Rev. Cancer 2004, 4, 361.
11. Wakeling, A. E.; Guy, S. P.; Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Barker, A. J.
Cancer Res. 2002, 62, 5746.
12. Wood, E. R.; Truesdale, A. T.; McDonald, O. B.; Yuan, D.; Hassell, A.; Dickerson,
S. H.; Ellis, B.; Pennisi, C.; Horne, E.; Lackey, K.; Alligood, K. J.; Rusnak, D. W.;
Gilmer, T. M.; Shewchuk, L. Cancer Res. 2004, 64, 6652.
13. Yoshimuraa, N.; Kudoha, S.; Kimuraa, T.; Mitsuokaa, S.; Matsuuraa, K.; Hirataa,
K.; Matsuib, K.; Negoroc, S.; Nakagawad, K.; Fukuokad, M. Lung Cancer 2006, 51,
363.
14. Wissner, A.; Overbeek, E.; Reich, M. F.; Floyd, M. B.; Johnson, B. D.; Mamuya, N.;
Rosfjord, E. C.; Discafani, C.; Davis, R.; Shi, X.; Rabindran, S. K.; Gruber, B. C.; Ye,
F.; Hallett, W. A.; Nilakantan, R.; Shen, R.; Wang, Y. F.; Greenberger, L. M.; Tsou,
H. R. J. Med. Chem. 2003, 46, 49.
15. Paez, J. G.; Janne, P. A.; Lee, J. C.; Tracy, S.; Greulich, H.; Gabriel, S. Science 2004,
304, 149.
MCF7
1.20
1.00
0.80
0.60
0.40
0.20
0.00
0.00
5.00
10.00
15.00
20.00
25.00
16. Lynch, T. J.; Bell, D. W.; Sordella, R.; Gurubhagavatula, S.; Okimoto, R. A.;
Brannigan, B. W. N. Engl. J. Med. 2004, 350, 2129.
Concentrations of 3b in nmole
17. Pao, W.; Miller, V.; Zakowski, M.; Doherty, J.; Politi, K.; Sarkaria, I. Proc. Natl.
Acad. Sci. U.S.A 2004, 101, 13306.
Figure 6. Effect of different concentrations of 3b on the viability of MCF-7 cell line.
18. Lu, A.; Th, W.; We, L. Eur. J. Med. Chem. in press, doi:10.1016/
j.ejmech.2007.09.018.
7. Conclusions
19. Klutchko, S. R.; Zhou, H.; Winters, R. T.; Tran, T. P.; Bridges, A. J.; Althaus, I. W.;
Amato, D. M.; Elliott, W. L.; Ellis, P. A.; Meade, M. A.; Roberts, B. J.; Fry, D. W.;
Gonzales, A. J.; Harvey, P. J.; Nelson, J. M.; Sherwood, V.; Han, H. K.; Pace, G.;
Smaill, J. B.; Denny, W. A.; Showalter, H. D. J. Med. Chem. 2006, 49, 1475.
20. Yue-Mei, Z.; Stuart, C.; Stephen, B. G.; David, R.; Kathryn, S.; Dana, V.; Edgar,
W.; Karen, L. Bioorg. Med. Chem. Lett. 2004, 14, 111.
21. Hennequin, L. F. A.; Ballard, P.; Boyle, F. T.; Delouvrie, B.; Ellston, R. P. A.;
Halsall, C. T.; Craig, H. S.; Kevin, H.; Jane, K.; Elizabeth, P.; Ross, H. S.; Smithb, P.;
Vincentb, J. L. Bioorg. Med. Chem. Lett. 2006, 16, 2672.
22. Peter, B.; Bradbury, R. H.; Craig, S. H.; Laurent, F. A. H.; Mark, H.; Paul, D. J.;
Jason, G. K.; Teresa, K.; Andrew, G. L.; Remy, M.; Martin, P.; Donald, J. O.; Annie,
O.; Nicolas, W.; Emma, J. W. Bioorg. Med. Chem. Lett. 2006, 16, 1633.
23. Alessandra, A.; Andrea, T.; Fabiana, M.; Andrea, C.; Michela, R.; Patrizia, H.;
Maria, L. B.; Carlo, M. J. Med. Chem. 2006, 49, 6642.
24. Madhavi, P.; Sunil, K.; Norma, W.; John, G.; Shao-Hui, Z.; Alexei, B.; Guang, Y.;
Phoebe, Y.; Frank, G.; Naoki, S.; Miguel, B.; Jie-Fei, C. Bioorg. Med. Chem. Lett.
2007, 17, 5978.
Since breast cells are known to overexpress EGFR, which leads
to continuous activation of the EGFR pathway involved in cell pro-
liferation, therefore, we measured antitumor activity of the com-
pounds in vitro on human breast carcinoma cell line (MCF-7).
Most of the tested compounds exhibited potent inhibitory activity
against MCF-7 cell line.
In the quinazoline series, compounds 2, 3a, and 3b displayed
the most potent cytotoxic activity with IC50 equal to 1.08, 1.98,
and 0.13 nmol, respectively. On the other hand, in the quinoline
series, compounds 7b and 7c are the most potent ones with IC50
equal to 1.67 and 2.84, respectively. From the biological testing re-
sults, we concluded that the quinazoline derivatives with five-
membered hetrocyclysulfonamido moiety at C-4 of anilino group
are more active than their quinoline analogues. It was also noticed
that the activity is retained or enhanced in compounds 2 and 5
which have piperazine moiety in place of aniline.
25. Yi, J.; Hui-Yuan, L.; Li-Ping, L.; Jinzhi, T.; Jian, D.; Xiaomin, L.; Ya-Qiu, L. Bioorg.
Med. Chem. 2005, 13, 5613.
26. Peter, B.; Robert, H. B.; Craig, S. H.; Laurent, F. A. H.; Mark, H.; Jason, G. K.; Jane,
K.; Teresa, K.; Donald, J. O.; Stuart, E. P.; Emma, J. W.; Ingrid, W. Bioorg. Med.
Chem. Lett. 2006, 16, 4908.
27. Ranson, M. Br. J. Cancer 2004, 90, 2250.
28. Allan, W.; Brawner, F.; Sridhar, K.; Rabindran, R.; Nilakantan, L. M.;
Greenberger, R.; Yu-Fen, W.; Hwei-Ru, T. Bioorg. Med. Chem Lett. 2002, 12, 2893.
29. Palmer, B. D.; Trumpp-Kallmeyer, S.; Fry, D. W.; Nelson, J. M.; Showalter, H. D.
H.; Denny, W. A. J. Med. Chem. 1997, 40, 1519.
30. Michael, J. A.; Elizabeth, P. A.; Karen, E.; Lackeya, O. B.; McDonalda, E. R.;
Wooda, F. P.; Geoffrey, J. C.; Laurie, K.; Wei, L.; David, K. J. Bioorg. Med. Chem.
Lett. 2005, 15, 3778.
These preliminary encouraging results of biological screening of
the tested compounds could offer an excellent framework in this
field that may lead to discovery of potent antitumor agent.
Acknowledgments
31. (a) Heindel, N. D.; Brodof, T. A.; Kogelschatz, J. E. J. Heterocycl. Chem. 1966, 3,
222; (b) Althuis, T. H.; Hess, H.-J. J. Med. Chem. 1977, 20, 146.
32. Magnus, P.; Eisenbeis, S. A.; Fairhurst, R. A.; Iliadis, T.; Magnus, N. A.; Parry, D. J.
Am. Chem. Soc. 1997, 119, 5591.
33. Lauer, W. M.; Kaslow, C. E. Org. Synth. Coll. Vol. Ill, 580.
34. Quan, H.; Quan, Z.; Yuan, M.; Piao, H. Yanbian Daxue Xuebao, Ziran Kexueban
2000, 26, 194. through Chem Abstr. 135:76848.
35. website:.http://www.rcsb.org/pdb/explore.do?structureId=1XKK.
36. Shewchuk, L.; Hassell, A.; Wisely, B.; Rocque, W.; Holmes, W.; Veal, J.; Kuyper,
L. F. J. Med. Chem. 2000, 43, 133.
37. Edgar, R. W.; Anne, T. T.; Octerloney, B. M.; Derek, Y.; Anne, H.; Scott, H. D.;
Byron, E.; Christopher, P.; Earnes, T. H. ; Karen, L.; Krystal, J. A.; David, W. R.;
Tona, M. G.; Lisa, S. Cancer Res. 2004, 64, 6652.
Authors thank all the members of the pharmacology unit at the
National Cancer Institute, Cairo University, for performing the
cytotoxicity testing.
References and notes
1. Jordan, J. D.; Landau, E. M.; Iyengar, R. Cell 2000, 103, 193.
2. Blume-Jensen, P.; Hunter, T. Nature 2001, 411, 355.
3. Adams, J. A. Chem. Rev. 2001, 101, 2271.
4. Yarden, Y.; Sliwkowski, M. X. Nat. Rev. 2001, 2, 127.
5. Dumas, J. Curr. Opin. Drug Discov. Develop. 2001, 4, 378.
6. Bridges, A. J. Chem. Rev. 2001, 101, 2541.
7. Slichenmeyer, W. J.; Elliott, W. L.; Fry, D. W. Semin. Oncol. 2001, 28(Suppl. 16),
67.
8. Rowinsky, E. K. Horizons in Cancer Therapeutics: From Bench to Bedside 2001, 2, 2.
38. Assefa, H.; Kamath, S.; Buolamwini, John K.J. Comput.-Aided Mol. Des. 2003, 17,
475.
39. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.;
Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82,
1107.