Synthesis and anticancer activity of novel tetrahydroquinoline and tetrahydropyrimidoquinoline derivatives

Article abstract of DOI:10.1007/s00044-015-1388-7

A series of new tetrahydroquinolines with different substituents at C-2 and C-4 positions in addition to several tetrahydropyrimidoquinolin-4-amines and tetrahydropyrimidoquinoline-2,4-diamines were synthesized. The in vitro anticancer activity of all new

Full text of DOI:10.1007/s00044-015-1388-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1388-7
ORIGINAL RESEARCH
Synthesis and anticancer activity of novel tetrahydroquinoline
and tetrahydropyrimidoquinoline derivatives
Ehab M. Gedawy1 Asmaa E. Kassab1 Afaf A. El-Malah1
•
•
Received: 22 November 2014 / Accepted: 22 June 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of new tetrahydroquinolines with dif-
ferent substituents at C-2 and C-4 positions in addition to
several tetrahydropyrimidoquinolin-4-amines and tetrahy-
dropyrimidoquinoline-2,4-diamines were synthesized. The
in vitro anticancer activity of all newly synthesized com-
pounds was tested against human colon carcinoma
(HCT116) and human breast adenocarcinoma (MCF7) cell
lines. Seven compounds 1a, 5a, 5b, 6a, 6b, 7a and 7b
showed potent anticancer activity against both HCT116
and MCF7 cell lines with IC50 between 16.33 and
34.28 lM. All these compounds were more potent than
Introduction
The discovery of new leads with anticancer potential is still
a great interest of medicinal chemists, hoping that they may
design more selective and safer anticancer agents. The
quinoline core is naturally occurring in many alkaloids
with potent antitumor activity, for example, camptothecin
(Fig. 1) (Wall et al., 1966). It was reported also that a large
number of quinolines and their derivatives possessed potent
anticancer activity (Chen et al., 2005a, b, 2006; Zhao et al.,
2005; Li et al., 2006; Tseng et al., 2008, 2012; Al-Said
et al., 2011; Luniewski et al. 2012; Karthikeyan et al.,
2015). Several studies supported that the pyrimidine
nucleus is an important pharmacophore in various antitu-
mor agents (Ghorab et al., 1996, 2006a, b; Ghorab, 2000;
Abou El Ella et al., 2008; Liu et al., 2014; Shao et al.,
2014; Kandeel et al., 2015; Ma et al., 2015). Moreover, it is
present in potent marketed anticancer drugs, for example,
gefitinib (IressaTM) (Wakeling et al., 2002) and erlotinib
(TarcevaTM) (Moyer et al., 1997), and thus, it is considered
as attractive target for the design of new anticancer agents.
Recently, several tetrahydroquinolines and their pyrimidine
derivatives were synthesized and evaluated for their anti-
cancer activity, and it was found that the tetrahydropy-
rimidoquinolines I and II exhibited potent anticancer
activity (Faidallah and Rostomb, 2013; Alqasoumi et al.,
2010) (Fig. 2).
imatinib
(IC50 = 34.40 lM)
and
tamoxifen
(IC50 = 34.30 lM). Compound 7b was the most active
against HCT116 cell line with 2.1-fold more potent anti-
tumor activity than imatinib. Also, compounds 1a, 5b and
6a exhibited the highest anticancer activity against MCF7
cell line, having two- to 1.79-fold more potent anticancer
activity than tamoxifen.
Keywords Tetrahydroquinolines Á
Tetrahydropyrimidoquinolin-4-amines Á
Tetrahydropyrimidoquinoline-2,4-diamines Á Synthesis Á
Anticancer activity
Taking into consideration the above findings, and in an
effort to identify novel potent anticancer leads through the
combination of the two active anticancer moieties, we deci-
ded to prepare several tetrahydroquinolines with different
groups at C-2 and C-4 positions, several tetrahydropyrimi-
doquinolin-4-amines and tetrahydropyrimidoquinoline-2,4-
diamines with different aryl groups at position number 5 to
substantiate the possible effects of these substitutions on the
& Ehab M. Gedawy
ehab_gedawy@yahoo.com
1
Pharmaceutical Organic Chemistry Department, Faculty of
Pharmacy, Cairo University, 33 Kasr El-Aini Street,
Cairo 11562, Egypt
123

Med Chem Res
catalytic amount of potassium hydroxide according to the
reported procedure (Patai and Israeli, 1960).
O
N
N
General procedure for the preparation of compounds (1a–c)
O
A mixture of cyclohexanone (4.9 g, 0.05 mol), the appro-
priate pyridine carboxaldehyde (0.05 mol), ethyl cyanoac-
etate (5.65 g, 0.05 mol) and ammonium acetate (30.8 g,
0.4 mol) in n-butanol (150 mL) was heated under reflux for
8 h. After cooling, the separated solid was filtered, washed
with ethanol, dried and crystallized from ethanol.
O
O
H
Fig. 1 Structure of camptothecin
anticancer activity against both human colon carcinoma
(HCT116) and human breast adenocarcinoma (MCF7) cell
lines.
2-Oxo-4-(pyridin-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-car-
bonitrile (1a) Brown solid (ethanol); this compound was
prepared from heating under reflux a mixture of cyclo-
hexanone (4.9 g, 0.05 mol), 2-pyridine carboxaldehyde
(5.35 g, 0.05 mol), ethyl cyanoacetate (5.65 g, 0.05 mol)
and ammonium acetate (30.8 g, 0.4 mol) in n-butanol
(150 mL) for 8 h. After cooling, the separated solid was
filtered and washed with ethanol. It was obtained 7.53 g of
1a (yield 60 %), brown solid; mp [ 300 °C; IR (KBr)
Materials and methods
Chemistry
Melting points were obtained on a Griffin apparatus and
were uncorrected. Microanalyses for C, H and N were
carried out at the microanalytical center, Al-Azhar
University. IR spectra were recorded on a Shimadzu 435
v
max: 3143, 2222, 1647 cm-1 1H NMR (DMSO-d6,
;
300 MHz,): d = 12.40 (1H, s, NH, D2O exchangeable),
8.71–8.60 (1H, m, J = 6.0 Hz, H-60), 7.98–7.87 (1H, m,
J = 6.0 Hz, H-40), 7.54–7.48 (1H, m, J = 6.0 Hz, H-30),
7.46–7.42 (1H, m, J = 6.0 Hz, H-50), 2.64–2.59 (2H, m,
H-8), 2.11–2.03 (2H, m, H-5), 1.69–1.66 (2H, m, H-7),
1.59–1.54 (2H, m, H-6); 13C NMR (DMSO-d6, 300 MHz,):
d = 159.58 (C, C-4), 158.32 (C, C=O), 150.73 (C, C-20),
150.08 (CH, C-60), 147.68 (CH, C-40), 135.54 (C, C-8a),
131.46 (CH, C-50), 123.46 (C, C-3), 115.90 (C, C:N),
112.43 (CH, C-30), 100.72 (C, C-4a), 27.21 (CH2, C-8),
24.77 (CH2, C-5), 21.67 (CH2, C-7), 20.44 (CH2, C-6);
EIMS m/z 251 [M]? (41.51), 78 (100); Anal. Calcd. for
1
spectrometer, using KBr disks. H NMR and 13C NMR
spectra were performed on JOEL NMR FXQ-300 MHz
and JOEL NMR FXQ-400 MHz using TMS, as the internal
standard. Mass spectra were recorded on a GCMP-QP1000
EX Mass spectrometer. Progress of the reactions was
monitored by TLC, using precoated aluminum sheet silica
gel MERCK 60F 254, and was visualized by UV lamp. The
substituted benzylidenmalononitriles 4a and b were syn-
thesized from the condensation of the appropriate ben-
zaldehyde with malononitrile in ethanol, in the presence of
O
Ar
N
NH2
Cl
N
N
H
O
NH2
N
N
N
S
SO2NH2
O
I
II
Ar = 2,4-C6H3Cl2
Fig. 2 Structure of potent anticancer tetrahydropyrimidoquinolines
123

Med Chem Res
C15H13N3O (251.28): C, 71.70; H, 5.21; N, 16.72. Found:
C, 71.79; H, 5.24; N, 16.89.
General procedure for the preparation of compounds (2a–c)
mixture of the corresponding quinolones 1a–
A
2-Oxo-4-(pyridin-3-yl)-1,2,5,6,7,8-hexahydroquinoline-3-car-
bonitrile (1b) Yellow crystals (ethanol); this compound
was prepared from heating under reflux a mixture of
cyclohexanone (4.9 g, 0.05 mol), 3-pyridine carboxalde-
hyde (5.35 g, 0.05 mol), ethyl cyanoacetate (5.65 g,
0.05 mol) and ammonium acetate (30.8 g, 0.4 mol) in
n-butanol (150 mL) for 8 h. After cooling, the separated
solid was filtered and washed with ethanol. It was
obtained 7.9 g of 1b (yield 63 %), yellow crystals; mp
c (0.0075 mol), N,N-dimethylaniline (10 mL) and phos-
phorous oxychloride (10 mL) was heated under reflux for
10 h. The reaction mixture was cooled and poured into
crushed ice. The formed solid was filtered off, dried and
crystallized from ethanol.
2-Chloro-4-(pyridin-2-yl)-5,6,7,8-tetrahydroquinoline-3-car-
bonitrile (2a) Brown solid (ethanol); this compound was
prepared from heating under reflux a mixture of compound
1a (1.88 g, 0.0075 mol), N,N-dimethylaniline (10 mL) and
phosphorous oxychloride (10 mL) for 10 h. The reaction
mixture was cooled and poured into crushed ice. The
formed solid was filtered off and dried. It was obtained
1.3 g of 2a (yield 65 %), brown solid; mp 141–143 °C; IR
1
248–250 °C; IR (KBr) vmax: 3147, 2218, 1658 cm-1; H
NMR (DMSO-d6, 300 MHz,): d = 12.48 (1H, s, NH,
D2O exchangeable), 8.69 (1H, d, J = 4.8 Hz, H-20), 8.55
(1H, s, H-60), 7.84 (1H, d, J = 4.8 Hz, H-40), 7.58–7.53
(1H, m, J = 4.8 Hz, H-50), 2.66–2.62 (2H, t, J = 6.3 Hz,
H-8), 2.06–2.02 (2H, t, J = 6.3 Hz, H-5), 1.71–1.67 (2H,
m, H-7), 1.60–1.55 (2H, m, H-6); 13C NMR (DMSO-d6,
400 MHz,): d = 160.07 (C, C-4), 158.91 (C, C=O),
151.22 (CH, C-20), 150.67 (CH, C-60), 148.23 (C, C-8a),
136.05 (CH, C-40), 131.99 (C, C-30), 124.02 (CH, C-50),
116.46 (C, C-3), 112.89 (C, C-4a), 101.29 (C, C:N),
27.71 (CH2, C-8), 25.29 (CH2, C-5), 22.22 (CH2, C-7),
20.98 (CH2, C-6); EIMS m/z 251 [M]? (100); Anal.
Calcd. for C15H13N3O (251.28): C, 71.70; H, 5.21; N,
16.72. Found: C, 71.81; H, 5.25; N, 16.85.
(KBr) vmax: 2280, 1600 cm-1
;
1H NMR (DMSO-d6,
300 MHz,): d = 8.86–8.82 (1H, m, H-60), 7.49–7.12 (1H,
m, H-40), 6.87–6.54 (2H, m, H-50, H-30), 3.00–2.95 (2H, m,
H-8), 1.95–1.51 (4H, m, H-7, H-5), 1.33–1.22 (2H, m,
?
H-6); EIMS m/z 271 [M?2] (20.26), 269 [M]? (59.10),
268 (100); Anal. Calcd. for C15H12ClN3 (269.73): C, 66.79;
H, 4.48; N, 15.58. Found: C, 66.83; H, 4.51; N, 15.46.
2-Chloro-4-(pyridin-3-yl)-5,6,7,8-tetrahydroquinoline-3-car-
bonitrile (2b) Blue solid (ethanol); this compound was
prepared from heating under reflux a mixture of compound
1b (1.88 g, 0.0075 mol), N,N-dimethylaniline (10 mL) and
phosphorous oxychloride (10 mL) for 10 h. The reaction
mixture was cooled and poured into crushed ice. The
formed solid was filtered off and dried. It was obtained
1.37 g of 2b (yield 68 %), blue solid; mp 232–234 °C; IR
2-Oxo-4-(pyridin-4-yl)-1,2,5,6,7,8-hexahydroquinoline-3-car-
bonitrile (1c) Orange solid (ethanol); this compound was
prepared from heating under reflux a mixture of cyclo-
hexanone (4.9 g, 0.05 mol), 4-pyridine carboxaldehyde
(5.35 g, 0.05 mol), ethyl cyanoacetate (5.65 g, 0.05 mol)
and ammonium acetate (30.8 g, 0.4 mol) in n-butanol
(150 mL) for 8 h. After cooling, the separated solid was
filtered and washed with ethanol. It was obtained 8.8 g
of 1c (yield 70 %), orange solid; mp [ 300 °C; IR (KBr)
(KBr) vmax: 2229, 1600 cm-1
;
1H NMR (DMSO-d6,
300 MHz,): d = 8.73 (1H, d, J = 4.2 Hz, H-20), 8.64 (1H,
s, H-60), 7.92 (1H, d, J = 7.8 Hz, H-40), 7.62–7.58 (1H, t,
J = 7.8 Hz, H-50), 2.98–2.94 (2H, t, J = 6.3 Hz, H-8),
2.43–2.39 (2H, t, J = 6.3 Hz, H-5), 1.85–1.80 (2H, m,
H-7), 1.71–1.65 (2H, m, H-6); 13C NMR (DMSO-d6,
400 MHz,): d = 163.53 (C, C-8a), 153.33 (C, C-2), 150.72
(CH, C-20), 148.37 (C, C-4), 142.93 (CH, C-60), 130.56 (C,
C-4a), 130.33 (CH, C-40), 129.43 (C, C-30), 123.36 (CH,
C-50), 114.89 (C, C-3), 113.13 (C, C:N), 33.18 (CH2,
C-8), 26.71 (CH2, C-5), 21.86 (CH2, C-7), 21.78 (CH2,
v
max: 3115, 2216, 1674 cm-1 1H NMR (DMSO-d6,
;
300 MHz,): d = 12.51 (1H, s, NH, D2O exchangeable),
7.46 (2H, d, J = 4.5 Hz, H-20, H-60), 7.38 (2H, d,
J = 4.5 Hz, H-30, H-50), 2.66–2.62 (2H, t, J = 6.0 Hz,
H-8), 2.03–1.99 (2H, t, J = 6.0 Hz, H-5), 1.70–1.65 (2H,
m, H-7), 1.60–1.55 (2H, m, H-6),; 13C NMR (DMSO-d6,
300 MHz,): d = 159.98 (C, C-4), 158.50 (C, C=O),
151.38 (C, C-40), 151.23 (CH, C-20, C-60), 149.08 (C,
C-8a), 148.76 (C, C-3), 143.43 (CH, C-30, C-50), 123.31
(C, C-4a), 115.86 (C, C:N), 27.48 (CH2, C-8), 24.57
(CH2, C-5), 21.65 (CH2, C-7), 20.51 (CH2, C-6); EIMS
m/z 251 [M]? (100); Anal. Calcd. for C15H13N3O
(251.28): C, 71.70; H, 5.21; N, 16.72. Found: C, 71.83;
H, 5.24; N, 16.87.
?
C-6); EIMS m/z 271 [M?2] (20.58), 269 [M]? (65.38),
268 (100); Anal. Calcd. for C15H12ClN3 (269.73): C, 66.79;
H, 4.48; N, 15.58. Found: C, 66.86; H, 4.51; N, 15.67.
2-Ch loro -4-(pyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-
carbonitrile (2c) Gray solid (ethanol); this compound
was prepared from heating under reflux a mixture of
compound 1c (1.88 g, 0.0075 mol), N,N-dimethylaniline
123

Med Chem Res
(10 mL) and phosphorous oxychloride (10 mL) for 10 h.
The reaction mixture was cooled and poured into crushed
ice. The formed solid was filtered off and dried. It was
obtained 1.47 g of 2c (yield 73 %), gray solid; mp
5-(Pyridin-3-yl)-6,7,8,9-tetrahydropyrimido[4,5-b]quino-
line-2,4-diamine (3b) Orange crystals (ethanol); to a cold
solution of sodium (0.506 g, 0.022 mol) in absolute etha-
nol (50 mL), guanidine hydrochloride (1.84 g, 0.022 mol)
was added. The formed sodium chloride was filtered and
washed with ethanol, and the filtrate was evaporated under
reduced pressure. The formed oily mass was diluted with
pyridine (5 mL), and finally, the corresponding 2-chloro-
quinoline-3-carbonitrile 2b (0.89 g, 0.0033 mol) was
added. The reaction mixture was heated under reflux for
5 h, cooled and finally poured on water (25 mL). The
formed precipitate was filtered and washed with ethanol. It
was obtained 0.82 g of 3b (yield 86 %), orange crystals;
1
190–192 °C; IR (KBr) vmax: 2233, 1597 cm-1; H NMR
(DMSO-d6, 300 MHz,): d = 8.78 (2H, d, J = 5.7 Hz,
H-20, H-60), 7.48 (2H, d, J = 5.7 Hz, H-30, H-50),
2.97–2.93 (2H, t, J = 6.0 Hz, H-8), 2.40–2.36 (2H, t,
J = 6.0 Hz, H-5), 1.83–1.77 (2H, m, H-7), 1.70–1.64 (2H,
m, H-6),; 13C NMR (DMSO-d6, 400 MHz,): d = 167.99
(C, C-8a), 159.81 (C, C-2), 158.84 (C, C-4), 151.00 (CH,
C-20, C-60), 148.84 (C, C-40), 132.20 (C, C-30, C-50), 130.42
(C, C-4a), 111.54 (C, C-3), 111.42 (C, C:N), 27.28 (CH2,
C-8), 27.21 (CH2, C-5), 22.84 (CH2, C-7), 22.17 (CH2,
mp 174–176 °C; IR (KBr) vmax: 3367–3167, 1597 cm-1
;
?
C-6); EIMS m/z 271 [M?2] (36.93), 269 [M]? (90.31),
1H NMR (DMSO-d6, 300 MHz,): d = 8.75 (1H, s, H-20),
8.55 (1H, d, H-60), 8.45–8.40 (1H, m, H-40), 7.85–7.80 (1H,
m, H-50),7.38 (2H, s, C-4 NH2, D2O exchangeable), 6.58
(2H, s, C-2 NH2, D2O exchangeable), 2.60–2.55 (2H, m,
H-8), 2.20–2.14 (2H, m, H-5),1.80–1.75 (2H, m, H-7),
1.70–1.60 (2H, m, H-6); EIMS m/z 293 [M?1]? (0.02), 78
(100); Anal. Calcd. for C16H16N6 (292.34): C, 65.74; H,
5.52; N, 28.75. Found: C, 65.88; H, 5.50; N, 28.92.
268 (100); Anal. Calcd. for C15H12ClN3 (269.73): C, 66.79;
H, 4.48; N, 15.58. Found: C, 66.87; H, 4.52; N, 15.65.
General procedure for the preparation of compounds (3a–c)
To a cold solution of sodium (0.506 g, 0.022 mol) in
absolute ethanol (50 mL), guanidine hydrochloride
(1.84 g, 0.022 mol) was added. The formed sodium chlo-
ride was filtered and washed with ethanol, and the filtrate
was evaporated under reduced pressure. The formed oily
mass was diluted with pyridine (5 mL), and finally, the
5-(Pyridin-4-yl)-6,7,8,9-tetrahydropyrimido[4,5-b]quinoline-
2,4-diamine (3c) Brown solid (ethanol); to a cold solution
of sodium (0.506 g, 0.022 mol) in absolute ethanol
(50 mL), guanidine hydrochloride (1.84 g, 0.022 mol) was
added. The formed sodium chloride was filtered and
washed with ethanol, and the filtrate was evaporated under
reduced pressure. The formed oily mass was diluted with
pyridine (5 mL), and finally, the corresponding 2-chloro-
quinoline-3-carbonitrile 2c (0.89 g, 0.0033 mol) was
added. The reaction mixture was heated under reflux for
5 h, cooled and finally poured on water (25 mL). The
formed precipitate was filtered and washed with ethanol. It
was obtained 0.74 g of 3c (yield 77 %), brown solid;
corresponding
2-chloroquinoline-3-carbonitrile
2a–
c (0.0033 mol) was added. The reaction mixture was
heated under reflux for 5 h, cooled and finally poured on
water (25 mL). The formed precipitate was filtered and
crystallized from ethanol.
5-(Pyridin-2-yl)-6,7,8,9-tetrahydropyrimido[4,5-b]quinoline-
2,4-diamine (3a) Brown solid (ethanol); to a cold solution
of sodium (0.506 g, 0.022 mol) in absolute ethanol
(50 mL), guanidine hydrochloride (1.84 g, 0.022 mol) was
added. The formed sodium chloride was filtered and
washed with ethanol, and the filtrate was evaporated under
reduced pressure. The formed oily mass was diluted with
pyridine (5 mL), and finally, the corresponding 2-chloro-
quinoline-3-carbonitrile 2a (0.89 g, 0.0033 mol) was
added. The reaction mixture was heated under reflux for
5 h, cooled and finally poured on water (25 mL). The
formed precipitate was filtered and washed with ethanol. It
was obtained 0.78 g of 3a (yield 81 %), brown solid;
1
mp [ 300 °C; IR (KBr) vmax: 3369–3134, 1597 cm-1; H
NMR (DMSO-d6, 300 MHz,): d = 8.70 (2H, d, H-20,
H-60), 7.62 (2H, d, H-30, H-50), 7.39 (2H, s, C-4 NH2, D2O
exchangeable), 6.50 (2H, s, C-2 NH2, D2O exchangeable),
2.65–2.60 (2H, m, H-8), 2.15–2.10 (2H, m, H-5), 1.80–1.75
(2H, m, H-7), 1.65–1.60 (2H, m, H-6); EIMS m/z
291[M-1]? (3.58), 269 (100); Anal. Calcd. for C16H16N6
(292.34): C, 65.74; H, 5.52; N, 28.75. Found: C, 65.84; H,
5.55; N, 28.90.
1
mp [ 300 °C; IR (KBr) vmax: 3417–3240, 1604 cm-1; H
NMR (DMSO-d6, 300 MHz,); d = 8.00–6.40 (8H, m,
H-30, H-40, H-50, H-60 and 2NH2), 2.85–2.80 (2H, m, H-8),
1.90–1.75 (2H, m, H-5), 1.30–1.15 (4H, m, H-6, H-7);
EIMS m/z 292 [M]? (2.42), 63 (100); Anal. Calcd. for
C16H16N6 (292.34): C, 65.74; H, 5.52; N, 28.75. Found: C,
65.83; H, 5.55; N, 28.88.
General procedure for the preparation of compounds (5a
and b)
To a solution of menthone (1.54 g, 0.01 mol) in absolute
ethanol (30 mL), the appropriate arylidenemalononitrile 4a
b (0.01 mol) and ammonium acetate (6.08 g,
and
123

Med Chem Res
20.21 (CH3, C-5 CH3), 16.33 (CH3, –CHCH3 isopropyl),
15.88 (CH3, –CHCH3 isopropyl); EIMS m/z 323 [M]?
(1.27), 43 (100); Anal. Calcd. for C20H22FN3 (323.41): C,
74.28; H, 6.86; N, 12.99. Found: C, 74.35; H, 6.90; N,
13.01.
0.08 mol) were added. The mixture was heated under
reflux for 5 h. The separated solid was collected by filtra-
tion, dried and crystallized from ethanol.
2-Amino-4-(4-chlorophenyl)-8-isopropyl-5-methyl-5,6,7,8-
tetrahydro-quinoline-3-carbonitrile (5a) Buff solid (etha-
nol); to a solution of menthone (1.54 g, 0.01 mol) in absolute
ethanol (30 mL), arylidenemalononitrile 4a (1.88 g, 0.01 mol)
and ammonium acetate (6.08 g, 0.08 mol) were added. The
mixture was heated under reflux for 5 h. The separated solid
was collected by filtration, dried and washed with ethanol. It
was obtained 2.75 g of 5a (yield 81 %), buff solid; mp
162–164 °C; IR (KBr) vmax: 3421,3344, 2210, 1616 cm-1; 1H
NMR (DMSO-d6, 300 MHz,): d = 7.60–7.52 (2H, dd,
J = 6.0 Hz, H-20, H-60), 7.44–7.29 (2H, dd, J = 6.0 Hz, H-30,
H-50), 6.53 (2H, s, NH2, D2O exchangeable), 2.95–2.90 (1H, m,
H-8), 2.66–2.58 (2H, m, CH(CH3)2 isopropyl, H-5), 1.66–1.57
(4H, m, H-6, H-7), 0.99 (3H, d, J = 6.6 Hz, C-5 CH3), 0.71
(3H, d, J = 7.5 Hz, –CHCH3 isopropyl), 0.65 (3H, d,
J = 7.2 Hz, –CHCH3 isopropyl); 13C NMR (DMSO-d6,
400 MHz,): d = 164.32 (C, C-2), 156.85 (C, C-8a), 152.84 (C,
C-4), 134.90 (C–Cl, C-40), 130.18 (C, C-10), 129.45 (CH, C-30,
C-50), 128.96 (CH, C-20, C-60), 128.86 (C, C-4a), 127.14 (C,
C-3), 116.48 (C, C:N), 46.91 (CH, C-8), 32.22 (CH, –CHCH3
isopropyl), 29.83 (CH, C-5), 28.30 (CH2, C-6), 21.56 (CH2,
C-7), 20.62 (CH3, C-5 CH3), 16.55 (CH3, –CHCH3 isopropyl),
16.35 (CH3, –CHCH3 isopropyl); EIMS m/z 341 [M?2]?
(4.28), 339 [M]? (12.58), 297 (100); Anal. Calcd. for C20H22-
ClN3 (339.86): C, 70.68; H, 6.52; N, 12.36. Found: C, 70.84; H,
6.58; N, 12.45.
General procedure for the preparation of compounds (6a
and b)
A mixture of the appropriate 2-aminoquinoline-3-carboni-
triles 5a and b (0.01 mol) and excess formamide (15 mL)
was refluxed on an oil bath for 15 h at 210 °C. The mixture
was cooled. The separated solid was filtered, dried and
crystallized from ethanol.
5-(4-Chlorophenyl)-9-isopropyl-6-methyl-6,7,8,9-tetrahydropy-
rimido-[4,5-b]quinolin-4-amine (6a) Brown solid (ethanol);
A mixture of 2-aminoquinoline-3-carbonitrile 5a (3.4 g,
0.01 mol) and excess formamide (15 mL) was refluxed on
an oil bath for 15 h at 210 °C. The mixture was cooled.
The separated solid was filtered and dried. It was obtained
2.5 g of 6a (yield 68 %), brown solid; mp 155–157 °C IR
1
(KBr) vmax: 3468,3305, 1600 cm-1; H NMR (DMSO-d6,
300 MHz,): d = 7.81 (1H, s, H-2), 7.40 (2H, d,
J = 9.0 Hz, H-20, H-60), 7.24 (2H, d, J = 9.0 Hz, H-30,
H-50), 6.19 (2H, s, NH2, D2O exchangeable), 2.41–2.34
(1H, m, H-9), 2.24–2.22 (2H, m, –CHCH3 isopropyl, H-6),
1.48–1.34 (4H, m, H-7, H-8), 0.94 (3H, d, C-6 CH3), 0.77
(3H, d, –CHCH3 isopropyl), 0.52 (3H, d, –CHCH3 iso-
propyl); 13C NMR (DMSO-d6, 300 MHz,): d = 162.87
(CH, C-9a), 160.57 (C, C-4), 155.79 (C, C-10a), 155.54
(CH, C-2), 145.18 (C, C-5), 131.56 (C–Cl, C-40), 130.76
(CH, C-30), 129.89 (CH, C-50), 129.19 (C, C-10), 127.84 (C,
C-5a), 120.77 (CH, C-20), 120.74 (CH, C-60), 112.81 (C,
C-4a), 47.23 (CH, C-9), 34.77 (CH, –CHCH3 isopropyl),
28.77 (CH, C-6), 27.16 (CH2, C-7), 20.33 (CH2, C-8),
20.11 (CH3, C-6 CH3), 17.63 (CH3, –CHCH3 isopropyl),
2-Amino-4-(4-fluorophenyl)-8-isopropyl-5-methyl-5,6,7,8-
tetrahydro-quinoline-3-carbonitrile (5b) Yellow crystals
(ethanol); to a solution of menthone (1.54 g, 0.01 mol) in
absolute ethanol (30 mL), arylidenemalononitrile 4b
(1.72 g, 0.01 mol) and ammonium acetate (6.08 g,
0.08 mol) were added. The mixture was heated under
reflux for 5 h. The separated solid was collected by filtra-
tion, dried and washed with ethanol. It was obtained 2.16 g
of 5b (yield 67 %), yellow crystals; mp 122–124 °C; IR
?
16.50 (CH3, –CHCH3 isopropyl); EIMS m/z 368 [M?2]
(15.59), 366 [M]? (0.35), 257 (100); Anal. Calcd. for
C21H23ClN4 (366.89): C, 68.75; H, 6.32; N, 15.27. Found:
C, 68.87; H, 6.29; N, 15.41.
(KBr) vmax: 3491,3352, 2210, 1612 cm-1
;
1H NMR
(DMSO-d6, 300 MHz,): d = 7.41 (2H, d, J = 7.8 Hz,
H-20, H-60), 7.36 (2H, d, J = 7.8 Hz, H-30, H-50), 6.52 (2H,
s, NH2, D2O exchangeable), 2.92–2.91 (1H, m, H-8),
2.70–2.63 (2H, m, –CHCH3 isopropyl, H-5), 1.66–1.57
(4H, m, H-6, H-7), 0.99 (3H, d, J = 6.9 Hz, C-5 CH3),
0.72 (3H, d, J = 7.2 Hz, –CHCH3 isopropyl), 0.63 (3H, d,
J = 7.2 Hz, –CHCH3 isopropyl); 13C NMR (DMSO-d6,
300 MHz,): d = 163.44 (C, C-2), 160.30 (C, C-8a), 157.55
(C–F, C-40), 152.81 (C, C-4), 132.76 (CH, C-30), 131.43
(CH, C-50), 130.87 (CH, C-20), 130.08 (CH, C-60), 124.87
(C, C-10), 115.50 (C, C-4a), 115.43 (C, C-3), 113.90 (C,
C:N), 46.16 (CH, C-8), 33.78(CH, –CHCH3 isopropyl),
28.97 (CH, C-5), 28.22 (CH2, C-6), 21.26 (CH2, C-7),
5-(4-Fluorophenyl)-9-isopropyl-6-methyl-6,7,8,9-tetrahy-
dropyrimido-[4,5-b]quinolin-4-amine (6b) Orange solid
(ethanol); A mixture of 2-aminoquinoline-3-carbonitrile 5b
(3.23 g, 0.01 mol) and excess formamide (15 mL) was refluxed
on an oil bath for 15 h at 210 °C. The mixture was cooled. The
separated solid was filtered and dried. It was obtained 2.94 g of
6b (yield 84 %), orange solid; mp 260–262 °C; IR (KBr) vmax
:
1
3500, 3321, 1595 cm-1; H NMR (DMSO-d6, 300 MHz,):
d = 8.43 (1H, s, H-2), 7.65–7.55 (4H, m, H-20, H-60 and NH2),
7.48 (2H, d, J = 7.5 Hz, H-30, H-50), 3.15–3.13 (1H, m, H-9),
2.93–2.91 (1H, m, H-6), 2.74–2.72 (1H, m, –CHCH3 isopropyl),
1.77–1.70 (4H, m, H-7, H-8), 1.06 (3H, d, J = 6.6 Hz, C-6
123

Med Chem Res
CH3), 0.85 (3H, d, J = 6.9 Hz, –CHCH3 isopropyl), 0.70 (3H,
d, J = 6.6 Hz, –CHCH3 isopropyl); 13C NMR (DMSO-d6,
400 MHz,): d = 166.85 (CH, C-9a), 163.96 (C, C-4), 162.69
(C, C-10a), 157.49 (CH, C-2), 157.49 (C–F, C-40), 145.47 (C,
C-5), 135.55 (C, C-10), 133.54 (CH, C-30), 132.54 (CH, C-50),
131.98 (C, C-5a), 131.09 (CH, C-20), 131.01 (CH, C-60), 117.17
(C, C-4a), 47.43 (CH, C-9), 29.97 (CH, –CHCH3 isopropyl),
29.37 (CH, C-6), 28.69 (CH2, C-7), 21.56 (CH2, C-8), 20.89
(CH3, C-6 CH3), 17.07 (CH3, –CHCH3 isopropyl), 16.24 (CH3,
–CHCH3 isopropyl); EIMS m/z 350 [M]? (8.72), 43 (100);
Anal. Calcd. for C21H23FN4 (350.43): C, 71.98; H, 6.62; N,
15.99. Found: C, 72.06; H, 6.59; N, 16.07.
(0.08), 315 (100); Anal. Calcd. for C21H24ClN5 (381.9): C,
66.04; H, 6.33; N, 18.34. Found: C, 66.13; H, 6.37; N,
18.47.
5-(4-Fluorophenyl)-9-isopropyl-6-methyl-6,7,8,9-tetrahydro-
pyrimido-[4,5-b]quinoline-2,4-diamine (7b) Buff solid
(ethanol); guanidine hydrochloride (2.1 g, 0.025 mol) was
added to a solution of sodium (2.6 g, 0.113 mol) in methanol
(95 mL), and the precipitated sodium chloride was filtered
off. The o-amino cyano derivative 5b (4.84 g, 0.015 mol)
was added to the filtrate. The reaction mixture was heated
under reflux for 6 h. The mixture was cooled, and the sepa-
rated solid was filtered, washed well with ethanol. It was
obtained 4.21 g of 7b (yield 77 %), buff solid; mp
General procedure for the preparation of compounds (7a
and b)
1
272–274 °C; IR (KBr) vmax: 3363–3194, 1662 cm-1; H
NMR (DMSO-d6, 300 MHz,): d = 7.41 (2H, d,
J = 12.0 Hz, H-20, H-60), 7.33 (2H, d, J = 12.0 Hz, H-30,
H-50), 7.03 (2H, s, C-4 NH2, D2O exchangeable), 6.52 (2H, s,
C-2 NH2, D2O exchangeable), 2.94–2.89 (1H, m, H-9),
2.67–2.63 (2H, m, –CHCH3 isopropyl, H-6), 1.66–1.58 (4H,
m, H-7, H-8), 1.00 (3H, d, J = 6.9 Hz, C-6 CH3), 0.72 (3H,
d, J = 6.9 Hz, –CHCH3 isopropyl), 0.65 (3H, d,
J = 6.9 Hz, –CHCH3 isopropyl); 13C NMR (DMSO-d6,
400 MHz,): d = 133.29 (C, C-2), 131.80 (C, C-9a), 131.58
(C, C-4), 130.66 (C, C-40), 130.58 (C, C-10a), 125.34 (C,
C-5), 116.94 (C, C-10), 116.03 (CH, C-30, C-50), 115.95 (C,
C-5a), 115.81 (CH, C-20, C-60), 115.74 (C, C-4a), 46.64 (CH,
C-9), 29.29 (CH, –CHCH3 isopropyl), 28.69 (CH, C-6),
28.23 (CH2, C-7), 21.45 (CH2, C-8), 20.93 (CH3, C-6 CH3),
16.90 (CH3, –CHCH3 isopropyl), 16.36 (CH3, –CHCH3
isopropyl); EIMS m/z 365 [M]? (18.26), 144 (100); Anal.
Calcd. for C21H24FN5 (365.45): C, 69.02; H, 6.62; N, 19.16.
Found: C, 69.09; H, 6.67; N, 19.24.
Guanidine hydrochloride (2.1 g, 0.025 mol) was added to a
solution of sodium (2.6 g, 0.113 mol) in methanol
(95 mL), and the precipitated sodium chloride was filtered
off. The o-amino cyano derivative 5a or 5b (0.015 mol)
was added to the filtrate. The reaction mixture was heated
under reflux for 6 h. The mixture was cooled, and the
separated solid was filtered, washed well with ethanol and
crystallized from ethanol.
5-(4-Chlorophenyl)-9-isopropyl-6-methyl-6,7,8,9-tetrahydro-
pyrimido-[4,5-b]quinoline-2,4-diamine (7a) White solid
(ethanol); guanidine hydrochloride (2.1 g, 0.025 mol) was
added to a solution of sodium (2.6 g, 0.113 mol) in
methanol (95 mL), and the precipitated sodium chloride
was filtered off. The o-amino cyano derivative 5a (5.09 g,
0.015 mol) was added to the filtrate. The reaction mixture
was heated under reflux for 6 h. The mixture was cooled,
and the separated solid was filtered, washed well with
ethanol. It was obtained 4.29 g of 7a (yield 75 %), white
solid; mp 284–286 °C; IR (KBr) vmax: 3360–3197,
Biological testing
1658 cm-1 1H NMR (DMSO-d6, 300 MHz,): d = 7.43
;
(2H, d, J = 6.9 Hz, H-20, H-60), 7.24 (2H, d, J = 6.9 Hz,
H-30, H-50), 7.08 (2H, s, C-4 NH2, D2O exchangeable),
5.36 (2H, s, C-2 NH2, D2O exchangeable), 2.90–2.85 (1H,
m, H-9), 2.62–2.57 (2H, m, –CHCH3 isopropyl, H-6),
1.65–1.61 (4H, m, H-7, H-8), 0.99 (3H, d, J = 6.9 Hz, C-6
CH3), 0.71 (3H, d, J = 6.9 Hz, –CHCH3 isopropyl), 0.65
(3H, d, J = 6.6 Hz, –CHCH3 isopropyl); 13C NMR
(DMSO-d6, 300 MHz,): d = 168.93 (C, C-2), 163.14 (C,
C-9a), 157.54 (C, C-4), 152.84 (C, C-10a), 145.56 (C, C-5),
135.31 (C, C-10), 131.94 (C, C-40), 129.57 (C, C-5a),
128.65 (CH, C-30), 127.42 (CH, C-50), 126.45 (C, C-4a),
116.46 (CH, C-20), 115.40 (CH, C-60), 46.40 (CH, C-9),
29.59 (CH, –CHCH3 isopropyl), 28.58 (CH, C-6), 28.14
(CH2, C-7), 22.11 (CH2, C-8), 20.50 (CH3, C-6 CH3),
Materials and methods
The human colon carcinoma (HCT116) and human breast
adenocarcinoma (MCF7) cell lines were obtained as a gift
from NCI, MD, USA.
All chemicals and solvents were purchased from Sigma-
Aldrich.
Measurement of anticancer activity
Anticancer screening of the newly synthesized compounds
was measured in vitro, on HCT116 and MCF7 cell lines,
using Sulforhodamine-B stain (SRB) assay, applying the
method of Skehan et al., (1990) as follows:
17.35 (CH3, –CHCH3 isopropyl), 15.87 (CH3, –CHCH3
(0.12), 381 [M]?
Cells were plated in 96-multi-well plates (104 cells/
well), for 24 h, before treatment with the compound to
?
isopropyl); EIMS m/z 383 [M?2]
123

Med Chem Res
calculated response parameter was IC50 (concentration of
the compound which causes 50 % inhibition of cell
viability).
Table 1 Concentrations required for 50 % inhibition of cell viability
(IC50)
Compound no.
IC50 in lMa
The synthesized compounds IC50, compared to Imatinib
and tamoxifen, are shown in Table 1, and the results are
represented graphically in Fig. 3.
HCT116
MCF7
17.13
1a
50.59
69.72
66.53
75.09
61.71
69.51
66.43
60.27
76.71
29.96
34.28
30.68
32.40
26.41
16.33
34.40
–
From the analysis of the in vitro observed data, it was
found, interestingly, that compounds 5a, 5b, 6a, 6b, 7a and
7b showed potent anticancer activity against both HCT116
and MCF7 cell lines, with IC50 between 16.33 and
34.28 lM. In addition, compound 1a (IC50 = 17.13 lM)
was the most potent compound against MCF7 cell line.
Thus, all these compounds are more potent than imatinib
(IC50 = 34.40 lM) and tamoxifen (IC50 = 34.30 lM).
Compound 7b was found to be the most active against
HCT116 cell line (IC50 = 16.33 lM), with 2.1-fold more
potent antitumor activity than imatinib. Compounds 1a, 5b
and 6a (IC50 : 17.13, 18.65 and 19.12 lM) exhibited, also,
the highest anticancer activity against MCF7 cell line,
having two- to 1.79-fold more potent anticancer activity
than tamoxifen.
1b
[100
[100
[100
[100
1c
2a
2b
2c
55.39
3a
37.67
83.90
54.79
30.43
18.65
19.12
24.09
27.55
27.26
3b
3c
5a
5b
6a
6b
7a
7b
Imatinib
Tamoxifen
a
–
It was found that Compound 3a (IC50 = 37.67 lM)
showed antitumor activity against MCF7 cell line, in
comparison with tamoxifen.
34.30
The values given are means of three experiments
Moreover, compounds 1a–c, 2a–c and 3a–c showed
moderate anticancer activity against HCT116 cell line,
while compounds 1b, 1c, 2a and 2b were inactive against
MCF7 cell line.
allow attachment to the wall of the plate. Different con-
centrations of the compounds (0, 1, 2.5, 5 and 10 lg/mL)
were added to the cell monolayer in triplicate, and wells
were prepared for each individual dose. Monolayer cells
were incubated with the compounds for 48 h at 37 °C, in
atmosphere of 5 % CO2. After 48 h, cells were fixed,
washed and stained with Sulforhodamine-B stain. Excess
stain was washed with acetic acid, and attached stain was
recovered with Tris EDTA buffer. Color intensity was
measured in an ELISA reader. The relation between sur-
viving fraction and compound concentration was plotted to
get the survival curve for each tumor cell line. For each
experimental agent, IC50 (concentration which caused
50 % inhibition of cell viability) was calculated and results
are given in Table 1.
It was observed that, among the quinoline derivatives
1a–c, only compound 1a, with 2-pyridyl moiety at C-4
position, showed potent anticancer activity. Replacement
of the carbonyl group at C-2 position with a chloro group in
compounds 2a–c resulted in a marked decrease in the
activity. Also the pyrimidoquinolines 3a–c exhibited weak
activity.
Introduction of branched cyclohexyl moiety in quinoline
derivatives 5a and b abolished the anticancer potency of
these derivatives. Interestingly, in the same manner, this
250
200
150
Results
HCT116
MCF7
100
50
0
In vitro anticancer screening
The in vitro anticancer activity of all newly synthesized
compounds was evaluated, using HCT116 and MCF7 cell
lines. Imatinib and tamoxifen, potent anticancer drugs,
were used, in this study, as reference standards.
Compound no
The relationship between surviving fraction and sample
concentration was plotted to obtain the survival curve. The
Fig. 3 Anticancer activity of the synthesized compounds against
HCT116 and MCF7 cell lines compared to imatinib and tamoxifen
123

Med Chem Res
Ar
CN
O
O
ArCHO
NCCH2COOC2H5
CH3COONH4
N
H
1a-c
POCl3
Ar
CN
Cl
N
2a-c
.HCl
NH
NH2
NH2
Ar
N
NH2
N
N
NH2
3a-c
N
,
,
Ar =
N
N
Scheme 1 The synthetic path and reagents for the preparation of target compounds 1–3
Compounds with 2-pyridyl, 4-chlorophenyl or 4-fluo-
rophenyl showed potent anticancer activity.
modification in the pyrimidoquinoline derivatives 6a and
b and 7a and b resulted in a marked increase in the anti-
cancer activity against both HCT116 and MCF7 cell lines.
In this study, we can conclude that:
3. In quinoline derivatives, it was clear that the substituents
at position 2 have a marked effect on the anticancer
activity, since compounds with carbonyl or amino
groups possessed potent anticancer activity, while those
with chloro group at C-2 position were inactive.
1. The anticancer activity of the synthesized quinoline
and pyrimidiquinoline compounds appeared to be
related to the cycloalkyl moiety fused to the pyridine
ring, since the best activity was obtained by com-
pounds bearing the branched cyclohexyl moiety.
4. The introduction of amino group at C-4 position or C-2
and C-4 positions in pyrimidoquinolines was tolerated,
and resulted in potent anticancer activity.
2. The aryl group at C-4 position in quinoline derivatives
and at position number 5 in pyrimidoquinolines
exhibited a considerable effect on the activity.
5. Tetrahydroquinolines and their fused pyrimidine
derivatives represent novel and promising class of
123

Med Chem Res
Ar1
N
CN
NC
NC
H
CH3COONH4
+
O
Ar1
NH2
4a&b
5a&b
.HCl
NH
HCONH2
NH2
NH2
Ar1
N
NH2
Ar1
NH2
N
N
N
N
N
NH2
7a&b
6a&b
Ar1 =
,
Cl
F
Scheme 2 The synthetic path and reagents for the preparation of target compounds 5–7
presence of absorption bands at 3147–3115 cm-1 corre-
sponding to NH group and absorption band at
2222–2216 cm-1 attributed to CN group, in addition to an
absorption band at 1674–1647 cm-1 corresponding to C=O
group. On the other hand, the 1H NMR spectra of these com-
anticancer agents, so further studies are required to
explore the mechanism of action and to optimize the
anticancer activity of these derivatives.
Discussion
pounds showed exchangeable singlet signals at
d
12.40–12.51 ppm, indicating the presence of NH proton. On
refluxing 1a–c with phosphorus oxychloride, the correspond-
ing 2-chloro derivatives 2a–c were obtained. The IR spectra of
these compounds revealed the disappearance of the absorption
bands corresponding to NH and C=O groups, whereas the 1H
NMR spectra disclosed the disappearance of NH signal, which
indicated thesuccessof chlorination. Reactingcompounds 2a–
c with guanidine base—after liberation from its hydrochloric
Chemistry
The synthesis of the target compounds is outlined in
Schemes 1 and 2. In this work, the desired 3-cyanoquinolines
1a–c were prepared via one pot reaction of cyclohexanone, the
appropriate pyridine carboxyaldehyde, ethyl cyanoacetate and
ammonium acetate. The IR spectra of 1a–c revealed the
123

Med Chem Res
of certain 4-anilino-8-methoxy-2-phenylquinoline and 4-anilino-
8-hydroxy-2-phenylquinoline derivatives. Bioorg Med Chem
14(9):3098–3105
salt—in pyridine afforded the pyrimidoquinoline-2,4-diami-
nes 3a–c. The IR spectra of 3a–c showed the presence of an
absorption band at 3417–3134 cm-1 attributed to NH2 groups
and indicated the disappearance of the absorption band cor-
responding to CN group. Besides, the 1H NMRspectra ofthese
compounds showed two exchangeable singlet signals at d
6.50–6.58 and 7.38–7.39 ppm, corresponding to two NH2
protons. The substituted benzylidenmalononitrile 4a and
b were synthesized from the condensation of the appropriate
benzaldehyde with malononitrile in ethanol, in the presence of
catalytic amount of potassium hydroxide [25]. The 2-amino-4-
arylquinoline-3-carbonitriles 5a and b were prepared via
refluxing menthone with the appropriate benzyliden-
malononitrile 4a and b, in the presence of ammonium acetate
Faidallah HM, Rostomb SAF (2013) Synthesis, in vitro antitumor
evaluation and DNA-binding study of novel tetrahydroquinoli-
nes and some derived tricyclic and tetracyclic ring systems. Eur J
Med Chem 63:133–143
Ghorab MM (2000) New biologically active n-(tetrahydrobenzoth-
ienopyrimidin-4-yl)-amino acids, thiourethane, sulfonamides
and related compounds. Phosphorus Sulfur Silicon 165:221–235
Ghorab MM, Abdel-Hamide SG, Abou Zeid MM (1996) Synthesis of
some new thiadiazole, selena, triazine, thiazole and cyanopy-
ridine derivatives with assay for their antitumor activity.
Phosphorus Sulfur Silicon 112:7–17
Ghorab MM, Osman AN, Noaman E, Heiba HI, Zaher NH (2006a)
The synthesis of some new sulfur heterocyclic compounds as
potential radioprotective and anticancer agents. Phosphorus
Sulfur Silicon 181:1935–1950
Ghorab MM, Osman AN, Noaman E, Heiba HI, Zaher NH (2006b)
The utility of isothiocyanato thiophenes in the synthesis of
thieno[2,3-d]pyrimidine derivatives as possible radioprotective
and anticancer agents. Phosphorus Sulfur Silicon 181:1983–1996
Kandeel MM, Refaat HM, Kassab AE, Shahin IG, Abdelghany TM
(2015) Synthesis, anticancer activity and effects on cell cycle
profile and apoptosis of novel thieno[2,3-d]pyrimidine and
thieno[3,2-e]triazolo[4,3-c]pyrimidine derivatives. Eur J Med
Chem 90:620–632
1
in ethanol. The H NMR spectra of 5a and 5b showed the
presence of exchangeable singlet signals at d 6.53 and
6.52 ppm, respectively, corresponding to NH2 protons. The
target 4-aminopyrimidoquinoline derivatives 6a and b were
obtained through heating 5a and b, under reflux with excess
formamide. The IR spectra of these compounds revealed the
disappearance of the absorption band belonging to CN group.
1
Moreover the H NMR spectra of 6a and 6b showed the
Karthikeyan C, Lee C, Moore J, Mittal R, Suswam EA, Abbott KL,
Pondugula SR, Manne U, Narayanan NK, Trivedi P, Tiwari AK
(2015) IND-2, a pyrimido[100,200:1,5]pyrazolo[3,4-b]quinoline
derivative, circumvents multi-drug resistance and causes apop-
tosis in colon cancer cells. Bioorg Med Chem 23:602–611
Li SY, Chen YL, Wang C, Tzeng CC (2006) Synthesis and
antiproliferative evaluation of certain pyrido[3,2-g]quinoline
derivatives. Bioorg Med Chem 14(22):7370–7376
presence of singlet signal at d 7.81and8.43 ppm, respectively,
corresponding to C2 proton. Reacting the 2-aminoquinoline-3-
carbonitriles 5a and b with guanidine base afforded the 2,4-
diaminopyrimidoquinolines 7a and b. The 1H NMR spectra of
7a and 7b showed two NH2 peaks as exchangeable singlet
signals, at d 5.36, 7.08 and d 6.52, 7.03 ppm, respectively.
Liu Z, Wu S, Wang Y, Li R, Wang J, Wang L, Zhao Y, Gong P
(2014) Design, synthesis and biological evaluation of novel
thieno[3,2-d]pyrimidine derivatives possessing diaryl semicar-
bazone scaffolds as potent antitumor agents. Eur J Med Chem
87:782–793
Acknowledgments We are grateful to all members of the depart-
ment of Cancer Biology, National Cancer Institute, Cairo, Egypt, for
carrying out the anticancer screening.
Luniewski W, Wietrzyk J, Godlewska J, Switalska M, Piskozub M,
Peczynska-Czoch W, Kaczmarek L (2012) New derivatives of
11-methyl-6-[2-(dimethylamino)ethyl]-6H-indolo[2,3-b]quino-
line as cytotoxic DNA topoisomerase II inhibitors. Bioorg Med
Chem Lett 22:6103–6107
Ma L, Wang B, Pang L, Zhang M, Wang S, Zheng Y, Shao K, Xue D,
Liu H (2015) Design and synthesis of novel 1,2,3-triazole–
pyrimidine–urea hybrids as potential anticancer agents. Bioorg
Med Chem Lett 25:1124–1128
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