Novel brominated quinoline and pyrimidoquinoline derivatives as potential cytotoxic agents with synergistic effects of γ-radiation

Article abstract of DOI:10.1007/s12272-012-0803-6

New quinoline derivatives 6, 7 and 19, pyrimidoquinoline derivatives 8-16 and triazolopyrimidoquinoline derivatives 17 and 18 bearing a bromo-substituent were synthesized starting from 3-(4-Bromophenylamino)-5,5-dimethylcyclohex-2- enone 3. All the newly

Full text of DOI:10.1007/s12272-012-0803-6

Arch Pharm Res Vol 35, No 8, 1335-1346, 2012
DOI 10.1007/s12272-012-0803-6
Novel Brominated Quinoline and Pyrimidoquinoline Derivatives as
Potential Cytotoxic Agents with Synergistic Effects of γ-Radiation
Mostafa M. Ghorab1, Fatma A. Ragab2, Helmi I. Heiba3, Yassin M Nissan2, and Walid M. Ghorab3
1Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Riy-
2
adh 11451, Saudi Arabia, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt,
3
and Department of Drug Radiation Research, National Centre for Radiation Research and Technology, Atomic Energy
Authority, Cairo, Egypt
(Received August 16, 2011/Revised October 10, 2011/Accepted November 3, 2011)
New quinoline derivatives 6, 7 and 19, pyrimidoquinoline derivatives 8-16 and triazolopyrim-
idoquinoline derivatives 17 and 18 bearing a bromo-substituent were synthesized starting
from 3-(4-Bromophenylamino)-5,5-dimethylcyclohex-2-enone 3. All the newly synthesized com-
pounds were evaluated for their in vitro anticancer activity against human breast cancer cell
line (MCF7). Compounds
respectively) comparable to that of the reference drug doxorubicin (IC50 = 32.02
other hand, compound 14 and 19 exhibited better activity than doxorubicin with IC50 values
of 8.5, 23.5 and 23.7 M. Additionally, the most potent compounds 14 and 19 were evalu-
ated for their ability to enhance the cell killing effect of -radiation.
9
,
11
,
17 and 18 showed IC50 values (36.4, 39.7, 39.02 and 36.4
µM,
µ
M). On the
6
,
µ
6,
γ
Key words: Quinoline, Pyrimidoquinoline, Triazolopyrimidoquinoline, Brominated, γ-Radiation
et al., 2009), and the most common mechanism was
the inhibition of tyrosine kinase isozymes (Pannala et
INTRODUCTION
Quinoline derivatives posses a wide range of biologi- al., 2007; Mulvihill et al., 2008; Nishii et al., 2010; Ghorab
cal activities including anti-inflammatory (El-Sayed et et al., 2011).
al., 2004), antileishmanial (Palit et al., 2009), antifungal
The chemistry of pyrimidine and fused pyrimidine
(Kategaonkar et al., 2010), antituberculosis (Eswaran derivatives has been of increasing interest, since
et al., 2010) and antimalarial activities (Joshi et al., many of these compounds revealed several biological
2005; Milner et al., 2010). Also, several novel quinoline activities and useful applications as anticancer and
derivatives have been reported to show substantial antibacterial agents (Kamen et al., 2000; Chauhan et
anticancer activities (Ferlin et al., 2001; Gopal et al., al., 2005; Amr et al., 2006; Cocco et al., 2006; Kashyap
2007; Kim et al., 2005; Zhao et al., 2005; Behforouz et et al., 2011). Also, the therapeutic effects of 1,2,4-triazole
al., 2007; Abouzid et al., 2008; Kemnitzer et al., 2008; ring has been studied for a number of pathological
Alqasoumi et al., 2010; Heiniger et al., 2010; Al-Ghamdi conditions which include anti-inflammatory and anti-
et al., 2012).
cancer (Palaska et al., 2002; Dogan et al., 2005; Singhal
It has been known that quinoline derivatives may et al., 2011).
act as anticancer agents through a variety of mecha-
All the synthesized compounds were designed to
nisms such as cell cycle arrest in the G2 phase (Kim et carry a bromophenyl moiety, as it has been reported
al., 2005), topoisomerase inhibition (Cheng et al., 2008), that several 2-(bromophenyl)quinoline-carboxylic acid
and inhibition of tubulin polymerization (Alqasoumi derivatives showed activity as synthase inhibitor
AG337 in human colon, breast and ovarian cancers
(Mani et al., 2004). It is also found that several bromo-
Correspondence to: Mostafa M. Ghorab, Medicinal, Aromatic
phenylpyrimido[4,5-c]quinolin-1(2H)ones possessed in
vitro cytotoxic activity against cancer cells (Metwally
et al., 2010). On the other hand, it has been reported
that 9-bromonoscapine is 10-15 fold more potent than
and Poisonous Plants Research Center (MAPPRC), College of
Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Tel: 966-534292860, Fax: 966-01-4670560
E-mail: mmsghorab@yahoo.com
1335

1336
M. M. Ghorab et al.
its congener noscapine in hormone insensitive human
breast cancer. Noscapine is a natural antitumor iso-
quinoline derivative that triggered apoptosis in many
cancer types (Zhou et al., 2003; Mahmoudian, M. and
Rahimi-Moghaddam, 2009).
2-Amino-1-(4-bromophenyl)-7,7-dimethyl-5-oxo-
4-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-car-
bonitrile (6)
A mixture of compound
3
(2.9 g, 0.01 mol) and 2-(4-
(1.6 g, 0.01 mol) in
methylbenzylidene)malononitrile
4
We report here the synthesis of some new quinoline ethanol (20 mL) containing 3 drops of triethylamine
derivatives and 19, pyrimidoquinoline derivatives was refluxed for 6 h. The reaction mixture was filtered
8-16 and triazolopyrimidoquinoline derivatives 17 and while hot and the solid product was recrystallized
18. The anticancer screening was done against a from dioxane to give
. IR (KBr cm−1): 3311, 3203
human breast cancer cell line (MCF7). We also aimed (NH2), 3099 (CH arom.), 2978, 2838 (CH aliph.), 2179
to evaluate the ability of the cell killing effect of (C 0.6, 0.9 (2s,
N), 1656 (C=O). 1H-NMR (DMSO-d6):
radiation to sensitize the in vitro cytotoxic activity of 6H, 2CH3), 1.9-2.2 (m, 4H, 2CH2), 2.3 (s, 3H, CH3 tolyl),
6, 7
6
γ-
≡
δ
the most active compounds.
4.6 (s, 1H, CH), 5.4 (s, 2H, NH2 D2O-exchangeable),
7.1-8.0 (m, 8H, Ar-H). MS, m/z (%): 462 [M+] (20.36),
372 (100). Anal. Calcd. for C25H24BrN3O: C, 64.94; H,
5.23; N, 9.09. Found: C, 64.54; H, 5.53; N, 9.45.
MATERIALS AND METHODS
Chemistry
Melting points are uncorrected and were determined
on a Stuart melting point apparatus (Stuart Scienti-
fic). Elemental analyses (C, H, N) were performed on
Perkin Elmer 2400 analyser (Perkin-Elmer) at the
Ethyl N-1-(4-bromophenyl)-3-cyano-7,7-dime-
thyl-5-oxo-4-p-tolyl-1,4,5,6,7,8-hexahydroquino-
lin-2-ylformimidate (7)
A solution of compound
6 (4.6 g, 0.01 mol) in tri-
Microanalytical Laboratories of the Faculty of Science, ethylorthoformate (20 mL) was refluxed for 8 h. The
Cairo University. All compounds were within ± 0.4% reaction mixture was cooled and then poured onto ice
of the theoretical values. Infrared spectra (KBr) were water. The precipitated solid was filtered and recry-
determined using Shimadzu IR-110 spectrophotometer stallized from ethanol to give
7
. IR (KBr cm−1): 3099
N), 1638
0.6, 0.9 (2s, 6H, 2CH3),
1
(Shimadzu), H-NMR spectra were carried out using (CH arom.), 2959, 2890 (CH aliph.), 2199 (C
≡
BRUCKER proton NMR-Avance 300 (300, MHz) (C=O). 1H-NMR (DMSO-d6):
δ
(Bruker), in DMSO-d6 as a solvent, using tetramethyl- 1.1 (t, 3H, CH3 ethyl), 1.9-2.2 (m, 4H, 2CH2), 2.3 (s,
silane (TMS) as internal standard, mass spectra were 3H, CH3 tolyl), 3.9 (q, 2H, CH2 ethyl), 4.6 (s, 1H, CH),
recorded on a JEOL JMS AX-500 spectrometer (JEOL 7.1-7.8 (m, 8H, Ar-H), 8.1 (s, 1H, N=CH). Anal. Calcd.
JMS), in electronic impact (EI). All reactions were for C28H28BrN3O2: C, 64.48; H, 5.44; N, 8.11. Found: C,
monitored by thin layer chromatograph (TLC) using 64.44; H, 5.03; N, 8.55.
precoated Aluminium sheets Silica gel Merck 60 F254.
Ethyl acetate-cyclohexane (2.5:7.5 mL) mixture was
used as eluting solvent and TLC sheets were visualiz-
ed by UV lamp (Merck).
10-(4-Bromophenyl)-2-(4-chlorophenyl)-8,8-dim-
ethyl-5-p-tolyl-7,8,9,10-tetrahydropyrimido[4,5-
b]quinoline-4,6(3H,5H)-dione (8)
A mixture of compound
6 (4.6 g, 0.01 mol) and 4-
chlorobenzoyl chloride (1.7 g, 0.01 mol) in pyridine (20
mL) was refluxed for 8 h. The reaction mixture was
cooled then poured onto ice cold water. The solid
3-(4-Bromophenylamino)-5,5-dimethylcyclohex-
2-enone (3)
A mixture of 5,5-dimethylcyclohexane-1,3-dione
1
(1.4 g, 0.01 mol) and 4-bromoaniline
2 (1.7 g, 0.01 mol) obtained was crystallized from dioxane to give 8. IR
in ethanol (20 mL) was refluxed for 5 h. The reaction (KBr cm−1): 3310 (NH), 3017 (CH arom.), 2956, 2854
mixture was cooled then poured onto cold water. The (CH aliph.), 1731, 1654 (2C=O), 1580 (C=N). 1H-NMR
obtained solid was crystallized from dioxane to give
3
.
(DMSO-d6): δ 0.7, 0.9 (2s, 6H, 2CH3), 1.9-2.1 (m, 4H,
IR (KBr cm−1): 3203 (NH), 3099 (CH arom.), 2978, 2CH2), 2.3 (s, 3H, CH3 tolyl), 4.5 (s, 1H, CH), 7.1-7.9 (m,
1
2838 (CH aliph.), 1656 (C=O). H-NMR (DMSO-d6):
δ
12H, Ar-H), 8.0 (s, 1H, NH). MS, m/z (%): 600 [M+]
1.1 (s, 6H, 2CH3), 2.2, 2.4 (2s, 4H, 2CH2), 4.3 (s, 1H, (0.75), 143 (100). Anal. Calcd. for C32H27BrClN3O2: C,
NH), 5.5 (s, 1H, CH), 6.5 (d, 2H, 2CH, = 6 Hz, Ph), 63.96; H, 4.53; N, 6.99. Found: C, 63.54; H, 4.25; N, 6.66.
7.3 (d, 2H, 2CH, = 6 Hz, Ph). Anal. Calcd. for
J
J
C14H16BrNO: C, 57.16; H, 5.48; N, 4.76. Found: C,
57.56; H, 5.10; N, 4.36.
4-Amino-10-(4-bromophenyl)-8,8-dimethyl-5-p-
tolyl-7,8,9,10-tetrahydropyrimido[4,5-b]quino-
lin-6(5H)-one (9)
A solution of compound
6 (4.6 g, 0.01 mol) in for-

Novel Quinolines As Cytotoxic and Radiosensitizers
1337
mamide (20 mL) was refluxed for 5 h. The reaction (2 g) in dry acetone (20 mL) was refluxed for 24 h. The
mixture was cooled and poured onto ice cold water. reaction mixture was filtered and the filtrate was
The precipitated solid was filtered and crystallized poured onto ice cold water. The precipitated solid was
from ethanol to give
(NH2), 3017 (CH arom.), 2952, 2897 (CH aliph.), 1635 (KBr cm−1): 3091 (CH arom.), 2952, 2831 (CH aliph.),
(C=O), 1588 (C=N). 1H-NMR (DMSO-d6): 0.6, 0.9 (2s, 1711, 1658, 1627 (3C=O), 1590 (C=N). 1H-NMR (DMSO-
6H, 2CH3), 1.9-2.2 (m, 4H, 2CH2), 2.3 (s, 3H, CH3 tolyl), d6): 0.6, 0.7 (2s, 6H, 2CH3), 1.1 (t, 3H, CH3 ethyl),
9
. IR (KBr cm−1): 3310, 3230 filtered and crystallized from dioxane to give 12. IR
δ
δ
4.6 (s, 1H, CH), 6.5-7.4 (m, 9H, Ar-H + CH pyrimidine), 1.7-1.9 (m, 4H, 2CH2), 2.3 (s, 3H, CH3 tolyl), 3.8 (q, 2H,
7.7 (s, 2H, NH2). MS, m/z (%): 489 [M+] (20.36), 91 CH2 ethyl), 4.1 (s, 1H, CH), 4.6 (s, 2H, CH2CO), 6.8-7.2
(100). Anal. Calcd. for C26H25BrN4O: C, 63.81; H, 5.15; (m, 9H, Ar-H + CH pyrimidine). Anal. Calcd. for
N, 11.45. Found: C, 63.42; H, 5.50; N, 11.80.
C30H30BrN3O4: C, 62.50; H, 5.25; N, 7.29. Found: C,
62.90; H, 5.60; N, 7.60.
10-(4-Bromophenyl)-8,8-dimethyl-5-p-tolyl-7,8,9,
10-tetrahydropyrimido[4,5-b]quinoline-4,6(3H, 10-(4-Bromophenyl)-8,8-dimethyl-4-thioxo-5-p-
5H)-dione (10)
A solution of
mL) was refluxed for 5 h. The reaction mixture was
tolyl-3,4,7,8,9,10-hexahydropyrimido[4,5-b]quin-
olin-6(5H)-one (13)
A mixture of 10 (4.9 g, 0.01 mol) and phosphorus
6
(4.6 g, 0.01 mol) in formic acid (15
cooled and poured onto ice cold water. The solid pentasulphide (1.9 g, 0.01 mol) in xylene (20 mL) was
precipitate was filtered and crystallized from ethanol refluxed for 8 h. The reaction mixture was evaporated
to give 10. IR (KBr cm−1): 3210 (NH), 3085 (CH arom.), and the solid obtained was filtered off and recry-
2951, 2863 (CH aliph), 1710, 1633 (2C=O), 1583 (C=N). stallized from ethanol to give 13. IR (KBr cm−1): 3215
1H-NMR (DMSO-d6):
δ 0.6, 0.9 (2s, 6H, 2CH3), 1.9-2.2 (NH), 3036 (CH arom.), 2959, 2871 (CH aliph.), 1638
1
(m, 4H, 2CH2), 2.3 (s, 3H, CH3 tolyl), 4.6 (s, 1H, CH), (C=O), 1600 (C=N), 1239 (C=S). H-NMR (DMSO-d6):
7.3-7.6 (m, 9H, Ar-H + CH pyimidine), 7.9 (s, 1H, NH). 0.6, 0.9 (2s, 6H, 2CH3), 1.9-2.2 (m, 4H, 2CH2), 2.3 (s,
13C-NMR (DMSO-d6):
22.6, 26.7 (2), 33.1, 41.6, 42.9, 3H, CH3 tolyl), 4.6 (s, 1H, CH), 7.1-7.5 (m, 9H, Ar-H +
54.4, 102.3, 112.7, 114.3, 119.1 (2), 128.6 (2), 129.1 (2), CH pyimidine), 13.7 (s, 1H, NH). 13C-NMR (DMSO-
δ
δ
134.5 (2), 137.2, 141.7, 143.2, 152.6, 153.0, 156.1, 163.7, d6):
δ 22.6, 24.8 (2), 34.7, 41.8, 47.9, 53.0, 111.4, 113.6,
199.8. MS, m/z (%): 490 [M+] (11.11), 55 (100). Anal. 115.2, 119.3 (2), 128.7 (2), 129.3 (2), 133.8, 134.2, 135.9,
Calcd. for C26H24BrN3O2: C, 63.68; H, 4.93; N, 8.57. 140.8, 143.0, 153.4, 155.1, 157.7, 200.2, 203.6. MS, m/
Found: C, 63.41; H, 4.72; N, 8.33.
z
(%): 506 [M+] (8.09), 66 (100). Anal. Calcd. for
C26H24BrN3OS: C, 61.66; H, 4.78; N, 8.30. Found: C,
61.96; H, 4.48; N, 8.61.
10-(4-Bromophenyl)-2-(chloromethyl)-8,8-dim-
ethyl-5-p-tolyl-7,8,9,10-tetrahydropyrimido[4,5-
b]quinoline-4,6(3H,5H)-dione (11)
10-(4-Bromophenyl)-4-chloro-8,8-dimethyl-5-p-
tolyl-7,8,9,10-tetrahydropyrimido[4,5-b]quino-
lin-6(5H)-one (14)
A mixture of compound
6 (4.6 g, 0.01 mol) and chlo-
roacetyl chloride (1.3 g, 0.01 mol) in dimethylforma-
mide (20 mL) was refluxed for 10 h. The reaction mix-
A mixture of 10 (4.9 g, 0.01 mol) and thionyl chlorid
ture was cooled and then poured onto ice cold water (1.2 g, 0.01 mol) in dry benzene (20 mL) was refluxed
and the solid obtained was crystallized from dioxane for 10 h. The reaction mixture was concentrated and
to give 11. IR, (KBr cm−1): 3422 (NH), 3025 (CH arom.), the solid obtained was crystallized from dioxane to
2950, 2880 (CH aliph.), 1672, 1663 (2C=O). 1H-NMR give 14. IR (KBr cm−1): 3030 (CH arom.), 2970, 2857
1
(DMSO-d6):
δ
0.6, 0.9 (2s, 6H, 2CH3), 1.9-2.2 (m, 4H, (CH aliph.), 1678 (C=O), 1589 (C=N), 816 (C-Cl). H-
2CH2), 2.3 (s, 3H, CH3 tolyl), 4.6 (s, 1H, CH), 5.1 (s, NMR (DMSO-d6):
δ
0.6, 0.9 (2s, 6H, 2CH3), 1.9-2.2 (m,
2H, CH2Cl), 7.3-7.9 (m, 8H, Ar-H), 8.2 (s, 1H, NH). 4H, 2CH2), 2.3 (s, 3H, CH3 tolyl), 4.6 (s, 1H, CH), 6.5-
MS, m/z (%): 538 [M+] (1.05), 78 (100). Anal. Calcd. 8.3 (m, 9H, Ar-H + CH pyimidine). MS, m/z (%): 508
for C27H25BrClN3O2: C, 60.18; H, 4.68; N, 7.80. Found: [M+] (13.69), 65 (100). Anal. Calcd. for C26H23BrClN3O:
C, 60.43; H, 4.42; N, 7.67.
C, 61.37; H, 4.56; N, 8.26. Found: C, 61.70; H, 4.15; N,
8.60.
Ethyl 2-(10-(4-bromophenyl)-8,8-dimethyl-4,6-
dioxo-5-p-tolyl-6,7,8,9-tetrahydropyrimido[4,5- 10-(4-Bromophenyl)-4-isothiocyanato-8,8-dime-
b]quinolin-3(4H,5H,10H)-yl)acetate (12)
A mixture of 10 (4.9 g, 0.01 mol), ethyl bromoacetate
(1.6 g, 0.01 mol) and anhydrous potassium carbonate
thyl-5-p-tolyl-7,8,9,10-tetrahydropyrimido[4,5-b]
quinolin-6(5H)-one (15)
A mixture of 14 (5 g, 0.01 mol) and ammonium

1338
M. M. Ghorab et al.
thiocyanate (0.76 g, 0.01 mol) in dry acetone (20 mL)
was refluxed for 2 h. The reaction mixture was filtered
while hot and the filtrate was poured onto ice cold
water where a solid precipitate was formed. The
7-(4-Bromophenyl)-2,9,9-trimethyl-12-(4-methyl-
phenyl)-8,9,10,12-tetrahydro[1,2,4]triazolo[1',5':
1,6]pyrimido[4,5-b]quinolin-11(7H)-one (18)
A solution of 16 (0.5 g, 0.01 mol) in acetic anhydride
precipitate was filtered and crystallized from ethanol (20 mL) was refluxed for 5 h. The reaction mixture was
to give 15. IR (KBr cm−1): 3017 (CH arom.), 2969, 2861 then concentrated, the solid separated was recrystal-
(CH aliph.), 2028 (N=C=S), 1670 (C=O), 1590 (C=N). lized from ethanol to give 18. IR (KBr cm−1): 3056 (CH
1
1H-NMR (DMSO-d6):
δ
0.6, 0.9 (2s, 6H, 2CH3), 1.9- arom.), 2957, 2866 (CH aliph.), 1632 (C=O). H-NMR
2.2 (m, 4H, 2CH2), 2.3 (s, 3H, CH3 tolyl), 4.6 (s, 1H, (DMSO-d6):
CH), 6.5-8.2 (m, 9H, Ar-H + CH pyimidine). MS, m/ 2CH2), 2.3 (s, 3H, CH3 tolyl), 2.4 (s, 3H, CH3 triazole),
(%): 531 [M+] (1.01), 275 (100). Anal. Calcd. for 4.6 (s, 1H, CH), 6.5-8.2 (m, 9H, Ar-H + CH pyimidine).
C27H23BrN4OS: C, 61.02; H, 4.36; N, 10.54. Found: C, MS, m/z (%): 528 [M+] (7.67), 438 (100). Anal. Calcd.
δ 0.6, 0.9 (2s, 6H, 2CH3), 1.9-2.2 (m, 4H,
z
61.40; H, 4.70; N, 10.34.
for C28H26BrN5O: C, 63.64; H, 4.96; N, 13.25. Found:
C, 63.42; H, 4.67; N, 13.55.
3-Amino-10-(4-bromophenyl)-4-imino-8,8-dim-
ethyl-5-p-tolyl-3,4,7,8,9,10-hexahydropyrimido N'-(1-(4-bromophenyl)-3-cyano-7,7-dimethyl-5-
[4,5-b]quinolin-6(5H)-one (16)
A mixture of (5.1 g, 0.01 mol) and hydrazine hydrate
(0.5 g, 0.01 mol) in ethanol (20 mL) was stirred for 24
oxo-4-p-tolyl-1,4,5,6,7,8-hexahydroquinolin-2-yl)-
N-(4-sulfamoylphenyl)formimidamide (19)
7
A mixture of
7 (5.1 g, 0.01 mol) and sulfanilamide (1.7
h at room temperature. The reaction mixture was g, 0.01 mol) in ethanol (20 mL) was stirred at room
poured onto ice cold water. The solid precipitate was temperature for 3 h. The reaction mixture was poured
filtered and crystallized from dioxane to give 16. IR, onto ice cold water. The solid precipitate was filtered
(KBr cm−1): 3340, 3292, 3150 (NH, NH2), 3090 (CH and crystallized from ethanol to give 19. IR (KBr cm−1):
arom.), 2977, 2856 (CH aliph.), 1715 (C=O), 1596 (C=N). 3344, 3250, 3160 (NH, NH2), 3085 (CH arom.), 2951,
1H-NMR (DMSO-d6):
(m, 4H, 2CH2), 2.3 (s, 3H, CH3 tolyl), 2.5 (s, 1H, NH2 (DMSO-d6):
δ
0.6, 0.9 (2s, 6H, 2CH3), 1.9-2.2 2850 (CH aliph.), 2202 (C
0.7, 0.9 (2s, 6H, 2CH3), 2.1-2.2 (m, 4H,
≡
N), 1641 (C=O). 1H-NMR
δ
D2O-exchangeable), 4.6 (s, 1H, CH), 5.2 (s, 1H, NH), 7.1- 2CH2), 2.3 (s, 3H, CH3 tolyl), 3.8 (s, 1H, NH, D2O-ex-
8.1 (m, 9H, Ar-H + CH pyimidine). MS, m/z (%): 504 changeable), 4.5 (s, 1H, CH), 7.1-7.9 (m, 14H, Ar-
[M+] (2.94), 379 (100). Anal. Calcd. for C26H26BrN5O: C, H+SO2NH2), 8.1 (s, 1H, N=CH). Anal. Calcd. for
61.91; H, 5.20; N, 13.88. Found: C, 61.61; H, 5.55; N, C32H30BrN5O3S: C, 59.63; H, 4.69; N, 10.86. Found: C,
13.58.
59.93; H, 4.39; N, 10.56.
7-(4-Bromophenyl)-9,9-dimethyl-12-(4-methyl- In vitro anticancer screening
The in vitro anticancer screening was done by the
pharmacology unit at the National Cancer Institute,
phenyl)-8,9,10,12-tetrahydro[1,2,4]triazolo[1',5':
1,6]pyrimido[4,5-b]quinolin-11(7H)-one (17)
A solution of 16 (0.5 g, 0.01 mol) in formic acid (20 Cairo University using the human tumor breast cell
mL) was refluxed for 5 h. The reaction mixture was line (MCF7). Irradiation was performed in the Nation-
cooled and then poured onto ice cold water. The solid al Center for Radiation Research and Technology,
precipitate was filtered and crystallized from ethanol Atomic Energy Authority, Cairo, Egypt using the
to give 17. IR (KBr cm−1): 3053 (CH arom.), 2955, 2846 gamma cell-40 (60CO) source.
1
(CH aliph.), 1690 (C=O). H-NMR (DMSO-d6):
δ
0.6,
The cytotoxic activity was measured in vitro for the
0.9 (2s, 6H, 2CH3), 1.9-2.2 (m, 4H, 2CH2), 2.3 (s, 3H, newly synthesized compounds using the Sulfo-Rhoda-
CH3 tolyl), 4.6 (s, 1H, CH), 6.5-8.3 (m, 10H, Ar-H + mine-B stain (SRB) assay using the method of (Skehan
CH pyimidine + CH triazole). 13C-NMR (DMSO-d6):
δ
et al., 1990). Cells were plated in 96-multiwell microtiter
23.9, 25.4 (2), 33.0, 38.8, 43.6, 54.1, 109.7, 115.3, 116.7, plate (104 cells/well) for 24 h before treatment with the
119.2 (2), 119.9, 128.9 (2), 129.7 (2), 134.3, 135.9 (2), compound(s) to allow attachment of cell to the wall of
137.6, 140.0, 146.1, 149.6, 153.8, 171.4, 201.2. MS, m/ the plate. Test compounds were dissolved in DMSO
z
(%): 514 [M+] (28.13), 422 (100). Anal. Calcd. for and diluted with saline to the appropriate volume.
C27H24BrN5O: C, 63.04; H, 4.70; N, 13.61. Found: C, Different concentrations of the compound under test
63.44; H, 4.40; N, 13.31. (0, 1, 2.5, 5, and 10 M/mL) were added to the cell
µ
monolayer. Triplicate wells were prepared for each
individual dose. Monolayer cells were incubated with
the compound(s) for 48 h at 37oC and in atmosphere of

Novel Quinolines As Cytotoxic and Radiosensitizers
1339
5% CO2. After 48 h, cells were fixed, washed, and which includes:
stained for 30 min with 0.4% (wt/vol) SRB dissolved in
1% acetic acid. Excess unbounded 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 human breast tumor
cell line after the specified time. The molar concentra-
tion required for 50% inhibition of cell viability (IC50)
was calculated and compared to the reference drug
doxorubicin (CAS, 25316-40-9). The surviving fractions
1. 3D protonation of the structures.
2. Running conformational analysis using systemic
search.
3. Selecting the least energetic conformer.
4. Applying the same docking protocol used with co-
crystallized legand.
RESULTS AND DISCUSSION
Chemistry
From the literature survey, it was found that the brom-
were expressed as means ± S.E. and the results are ine containing compounds exhibited known broad
given in Table I.
spectrum biological activities especially anticancer
one (Zhou et al., 2003; Mahmoudian and Rahimi-
Moghaddam, 2009).
Radiosensitizing evaluation
The most potent compounds resulted from the in
Enaminone
5,5-dimethylcyclohexane-1,3-dione
the 4-chloro-pyrimidoquinoline derivative 14, and the line . The structure of compound
sulfamoylphenyl formimidamide derivative 19, were by elemental analysis and spectral data. IR spectrum
selected to be evaluated again for their in vitro anti- of compound showed the presence of bands at 3203
cancer activity alone and in combination with
-radia- cm−1 (NH), 3099 cm−1 (CH arom.), 2978 and 2838 cm−1
tion. This study was conducted to evaluate the ability (CH aliph.), 1656 cm−1 (C=O). Also, the 1H-NMR spec-
of the cell killing effect of -radiation to sensitize the trum in (DMSO-d6) indicated the presence of a singlet
in vitro cytotoxic activity of the most active compounds. at 4.3 ppm which could be assigned to NH of enaminone
Cells were subjected to a single dose of -radiation at . Treatment of enaminone with 2-(4-methylbenzyli-
a dose level of 8 Gy with a dose rate of 2 Gy/min. dene)malononitrile in ethanol containing a catalytic
Irradition was performed in the National Center for amount of triethylamine, as catalyst, yielded the cor-
Radiation Research and Technology, Atomic Energy responding hexahydroquinoline derivative via the
Authority, Cairo, Egypt, using Gamma cell-40 (60Co) formation of the intermediate Michael type product
source. The surviving fractions were expressed as followed by intramolecular cyclization. IR spectrum of
means ± S.E. The results were analyzed using 1-way compound
showed bands at 3311, 3203 cm−1 (NH2),
N), 1656 cm−1 (C=O). The mass spectrum
exhibited a molecular ion peak m/z at
462 (M+, 20.36%), with a base peak m/z at 372 (Scheme
3
was obtained from condensation of
with 4-bromoani-
was established
vitro anticancer screening; the quinoline derivative
6,
1
3
2
3
γ
γ
γ
3
3
4
6
5
6
ANOVA test (Figs. 1A-C).
2179 cm−1 (C
of compound
≡
6
Molecular docking study
The most biologically active compounds were docked 1).
using MOE software based on the protein data bank
file 1VR2 which contains crystal structure of the afforded the formimidate derivative
Treatment of compound
6
with triethylorthoformate
. The formation
of compound 7 was supported from its microanalytical
7
VEGFR2 kinase domain in complex with Vatalanib.
and spectral data. IR spectrum exhibited the absence
of the band corresponding to the (NH2) and the pre-
Validation of the docking protocol
To perform accurate validation of the docking proto- sence of band at 2199 cm−1 corresponding to the cyano
col docking of the co-crystallized ligand should be group. Also, the 1H-NMR spectrum for compound
7 in
carried out to study the scoring energy (s), root mean DMSO-d6 showed the presence of a triplet at 1.1 ppm
standard deviation (RMSD) and amino acid interac- for the CH3 and a quartet at 3.9 ppm of CH2 of the
tions. Docking was performed using London dG force ethyl group. Refluxing compound
6 with 4-chloro-
and refinement of the results was done using Force benzoyl chloride in pyridine yielded the corresponding
field energy.
2-(4-chlorophenyl)pyrimidoquinoline derivative
spectrum of compound showed absence of the (C
band and presence of (2C=O) bands at 1731, 1654 cm−1.
with formamide yielded the 4-
ing was achieved via their 3D structure built by MOE. aminopyrimidoquinoline derivative which exhibited
Certain procedures should be taken before docking the absence of (C N) band in IR spectrum to confirm
8
. IR
8
≡N)
Preparing compounds for docking
Preparation of the synthesized compounds for dock- Heating of compound
6
9
≡

1340
M. M. Ghorab et al.
Scheme 1. Formation of hexahydroquinolinecarbonitrile derivative 6.
cyclization. The pyrimidoquinoline derivative 10 was alysis and spectral data. IR spectrum showed absence
obtained by refluxing compound in formic acid. This of band corresponding to cyano group and presence of
reaction proceeded via condensation followed by elimi- bands at 1672, 1663 cm−1 for (2C=O) (Scheme 2).
nation of two moles of water. IR spectrum of compound Reaction of compound 10 with ethyl bromoacetate in
10 showed bands at 1710, 1633 cm−1 for (2C=O). Reac- dry acetone in the presence of anhydrous potassium
tion of compound with chloroacetyl chloride in DMF, carbonate yielded the corresponding ester derivative
6
6
intramolecular cyclization took place gaving the 2- 12. IR spectrum of compound 12 exhibited the presence
chloromethylpyrimidoquinoline derivative 11. Struc- of bands at 1711, 1658, 1627 cm−1 for (3C=O). Also, the
ture of compound 11 was supported by elemental an- 1H-NMR spectrum for compound 12 in (DMSO-d6
)
Scheme 2. Synthesis of quinoline and pyrimidoquinoline derivatives.

Novel Quinolines As Cytotoxic and Radiosensitizers
1341
showed the presence of significant triplet at 1.1 ppm trum showed absence of band corresponding to (C≡N)
for the CH3 and quartet at 3.8 ppm of CH2 of the ethyl and presence of bands at 3340, 3292, 3150 correspond-
group. Thionation of compound 10 with phosphorus ing to (NH, NH2). The mass spectrum of compound 16
penta-sulfide in xylene afforded the corresponding 4- exhibited a molecular ion peak m/z at 504 (M+, 2.94%),
thioxo-pyrimidoquinoline derivative 13. IR spectrum with a base peak m/z at 379. When compound 16 was
of compound 13 showed bands at 1638 cm−1 (C=O) and refluxed with formic acid the corresponding triazolo-
1239 cm−1 (C=S). While, treatment of compound 10 with pyrimidoquinoline derivative 17 was formed via intra-
thionyl chloride afforded the 4-chloro-pyrimidoquinoline molecular cyclization. IR spectrum of compound 17
derivative 14. The mass spectrum of compound 14 revealed the absence of bands corresponding to (NH,
exhibited a molecular ion peak m/z at 508 (M+, 13.69%), NH2). Similarly, the corresponding 2-methyl-triazolo-
with a base peak m/z at 65. Finally, the 4-isothiocya- pyrimidoquinoline derivative 18 was obtained when
natopyrimidoquinoline derivative 15 was obtained by compound 16 was refluxed with acetic anhydride.
refluxing compound 14 with ammonium thiocyanate Mass spectrum of compound 18 exhibited a molecular
in dry acetone. IR spectrum of compound 15 afforded ion peak m/z at 528 (M+, 7.67%), with a base peak m/z
the presence of band at 2028 cm−1 for (N=C=S) (Scheme at 438. Interaction of compound
7 with sulfanilamide
3).
Reaction of compound
at room temperature in ethanol, the N-(4-sulfamoyl-
with hydrazine hydrate in phenyl)formimidamide derivative 19 was obtained. IR
9
ethanol at room temperature yielded the correspond- spectrum of compound 16 exhibited bands at 3344,
ing N-aminopyrimidoquinoline derivative 16. IR spe- 3250, 3160 corresponding to (NH, NH2). 1H-NMR
Scheme 3. Formation of pyrimidoquinoline derivatives.

1342
M. M. Ghorab et al.
Scheme 4. Formation of triazolopyrimidoquinoline and sulfonamide derivatives.
spectrum for compound 19 in (DMSO-d6) showed the famoylphenyl formimidamide derivative 19 (IC50
absence of triplet and quartet corresponding to ethyl 23.7 M) exhibited better activity than the reference
group, and revealed presence of singlet at 3.8 of (NH) drug doxorubicin (IC50 = 32.02 M). While Compounds
11, 17 and 18 showed IC50 values (36.4, 39.7, 39.02
and 36.4 M, respectively) are nearly as active as
doxorubicin as positive control. While the other com-
=
µ
µ
exchangeable with D2O (Scheme 4).
9,
µ
In vitro anticancer screening
From results in Table I, it was observed that the pounds showed IC50 values lower than that of the
quinoline derivative (IC50 = 8.5 M), 4-chloro-pyri- reference drug doxorubicin ranging from 42.9-53 M.
midoquinoline derivative 14 (IC50 = 23.5 M) and sul-
6
µ
µ
µ
Table I. In vitro anticancer screening of the synthesized compounds against human breast cell line (MCF7)
Compound concentration ( M)
25 50
Surviving fraction (Means ± S.E.)#
µ
Compound
IC50 (µM)
10
100
Doxorubicin
0.451 ± 0.02
0.276 ± 0.01
0.904 ± 0.03
0.807 ± 0.08
0.792 ± 0.03
0.967 ± 0.01
0.659 ± 0.01
0.920 ± 0.02
0.851 ± 0.01
0.582 ± 0.01
0.584 ± 0.01
0.209 ± 0.01
0.780 ± 0.01
0.740 ± 0.06
0.514 ± 0.01
0.352 ± 0.02
0.130 ± 0.03
0.685 ± 0.01
0.723 ± 0.03
0.361 ± 0.01
0.515 ± 0.01
0.569 ± 0.01
0.417 ± 0.01
0.719 ± 0.01
0.161 ± 0.01
0.346 ± 0.03
0.119 ± 0.01
0.487 ± 0.09
0.442 ± 0.01
0.277 ± 0.01
0.290 ± 0.01
0.176 ± 0.01
0.355 ± 0.01
0.293 ± 0.01
0.145 ± 0.01
0.185 ± 0.02
0.137 ± 0.01
0.272 ± 0.02
0.340 ± 0.01
0.134 ± 0.01
0.083 ± 0.01
0.088 ± 0.01
0.112 ± 0.01
0.102 ± 0.01
0.092 ± 0.01
0.280 ± 0.03
0.143 ± 0.01
0.209 ± 0.01
0.133 ± 0.01
0.174 ± 0.01
0.123 ± 0.01
0.233 ± 0.01
0.146 ± 0.01
0.115 ± 0.01
0.206 ± 0.01
0.178 ± 0.02
0.078 ± 0.01
0.203 ± 0.01
0.203 ± 0.01
0.194 ± 0.01
32.02
8.5
53
6
7
8
47.3
36.4
43.1
39.7
42.9
48.8
23.5
28
27.19
39.02
36.4
23.7
9
10
11
12
13
14
15
16
17
18
19
#Each value is the mean of three values ± S.E.

Novel Quinolines As Cytotoxic and Radiosensitizers
1343
Table II. In vitro anticancer screening of compounds 6, 14, 15 and 19 against human breast cell line (MCF7) in
combination with -radiation
γ
Compound concentration (
10 25
Surviving fraction (Means ± S.E.)#
µ
M) + Irradiation (8 Gy)
Irradiated
(8 Gy)
Control
Compd.No.
50 100
IC50 (µM)
6
14
19
1.000
1.000
1.000
0.927 ± 0.02*
0.927 ± 0.02*
0.927 ± 0.02*
0.147 ± 0.01* 0.082 ± 0.04* 0.036 ± 0.01* 0.021 ± 0.01*
0.146 ± 0.01* 0.085 ± 0.01* 0.018 ± 0.01* 0.016 ± 0.01*
0.165 ± 0.02* 0.127 ± 0.01* 0.039 ± 0.01* 0.025 ± 0.01*
1.57
1.68
1.31
#Each value is the mean of three values ± S.E.; *Significant difference from control group at
p < 0.001.
Radiosensitizing evaluation
The rationale for combining chemotherapy and radio-
therapy is based mainly on two ideas, one being spa-
tial cooperation, which is effective if chemotherapy is
sufficiently active to eradicate subclinical metastases
and if the primary local tumor is effectively treated by
radiotherapy. In this regard, no interaction between
radiotherapy and chemotherapy is required. The other
idea is the enhancement of radiation effects by direct
enhancement of the initial radiation damage by incor-
porating drugs into DNA, inhibiting cellular repair,
accumulating cells in a radiosensitive phase or elimin-
ating radioresistant phase cells, eliminating hypoxic
cells, or inhibiting the accelerated repopulation of
tumor cells. Virtually, all chemotherapeutic agents
have the ability to sensitize cancer cells to the lethal
effects of ionizing radiation (Nishimura, 2004).
From the results obtained in Table I, compound
showed an in vitro cytotoxic activity with IC50 value of
8.5 M, when the cells were subjected to different
6
µ
concentrations of the compound alone. While when
the cells were subjected to the same concentrations of
compound
radiation at a dose level of 8 Gy. The IC50 value was
synergistically decreased to 1.57 M. Similarly, com-
pounds 14 and 19 showed IC50 values of 23.5 and 23.7
M respectively, when used alone. The IC50 values
6, and irradiated with a single dose of γ-
µ
µ
were decreased to 1.68 and 1.31
irradiation (Figs. 1A-C).
µM respectively after
Molecular docking study
Vatalnib which is a known VEGFR2 inhibitor was
the reference drug for docking on the active site of
VEGFR2. Vatalanib interacted with Cys A919 with
one hydrogen bond 2.7 Ao and with Lys A868 with
arene cation interaction as shown in Figs. 2(A-B).
Docking results for the most biologically active com-
pounds and Vatalnib were summarized in Table II.
From Table II we can conclude the following:
Fig. 1. Survival curve for MCF7 cell line for: (
alone and in combination with
compound 14 alone or in combination with
Gy), and ( ) compound 19 alone and in combination with
irradiation (8 Gy).
A
) compound
6
γ
-irradiation (8 Gy), (
B)
1. All compounds were fit in the active site of VGEFR2
with good to moderate scoring energy compared to
Vatalanib but Compound 19 was fit in the active
γ
-irradiation (8
C
γ-

1344
M. M. Ghorab et al.
Fig. 3. Compound 19 in the active site of VGEFR2, 2D (
A)
and 3D ( ).
B
3. The objective of the present study was to synthe-
size and investigate the anticancer activity of some
novel quinoline
triazolopyrimidoquinoline derivatives 17
human breast cancer cell line (MCF7). Quinoline
derivative , 4-chloro-pyrimidoquinoline 14 and sul-
famoylphenyl formimidamide 19 exhibited significant
anticancer activity, when compared to doxorubicin
as a reference drug. Additionally, pyrimidoquinolines
6
,
7
,
19, pyrimidoquinoline 8-16 and
Fig. 2. Vatalnib in the active site of VEGFR2, 2D (A) and
3D (B).
,
18 against
Table III. Results of docking of the most three
biologically active compounds and Vatalanib on the active
site of VEGFR2a
6
Compound No.
(S) in Kcal/mole
9
,
11 and triazolopyrimidoquinolines 17
, 18 showed
Vatalanib
17.2652
6.2635
13.1624
13.7245
IC50 values (36.4, 39.7 and 39.02, 36.4 M, respecti-
vely) comparable to that of the reference drug doxo-
rubicin. Moreover, the most three active compounds
µ
6
14
19
6, 14 and 19 showed the ability to sensitize cancer
cells to the lethal effects of ionizing radiation. Also,
compound 19 exhibited high cytotoxic activity and
a binding mode comparable to Vatalanib (reported
vascular endothelial growth factor receptor tyrosine
kinase inhibitor VEGFRTKI) and this may contribute
at least to its anticancer activity.
site of VGEFR2 with scoring energy comprable to
Vatalnib.
2. Since compound 19 showed scoring energy com-
prable to Vatalanib, it was interesting to study its
amino acid interaction in the active site of VGEFR2.
Compound 19 interact with two amino acids, Lys
A838 with one hydrogen bond 2.78 Ao, and Cys
A919 with one hydrogen bond 3.01 Ao as shown in
Figs. 3(A-B).
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