Synthesis of some quinolinyl chalcone analogues and investigation of their anticancer and synergistic anticancer effect with doxorubicin1

Article abstract of DOI:10.1134/S1068162012030119

Two derivatives of 2-(4-acetylanilino)quinolines (IIIa, b) were synthesized as scaffolds for synthesis of open chalcone analogues (Va-f) through Claisen-Schmidt condensation with a set of aromatic aldehydes (IVa-d). Derivatives (Va, b) were further manipulated into cyclic α,β- unsaturated ketones by Michael-addition of acetylac-etone and ethylacetoacetate affording derivatives (VI-VII). Deethoxycarboxylation of derivatives (VIIa, b) afforded cyclohexenons (VIIIa, b) allowing formation of a mini library of α,β-unsaturated ketones for screening their anticancer and synergistic anticancer effect with doxorubicin using colon cancer cell line (Caco-2). Two open enones, (Vb) and (Ve), showed significant anticancer activity with IC50 of 5.0 and 2.5 μM respectively. Only one cyclic enone, (VIa) showed synergistic anticancer activity with doxorubicin at 10 μM. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1068162012030119

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2012, Vol. 38, No. 4, pp. 428–434. © Pleiades Publishing, Ltd., 2012.
Synthesis of Some Quinolinyl Chalcone Analogues
and Investigation of Their Anticancer
and Synergistic Anticancer Effect with Doxorubicin1
, 2
Mohamed R. E. Alya , ElꢀSayed I. Ibrahimb, Fakher A. El Shahedb, Hamdy A. Solimanb,
Zein S. Ibrahimc, and Samir A. M. ElꢀShazlyd
aChemistry Department, Faculty of Science, Taif University, 888 AlhawyahꢀTaif, Kingdom of Saudi Arabia;
Chemistry Department, Faculty of Applied Science, Port Said University, Port SaidꢀEgypt
bChemistry Department, Faculty of Science, Suez Canal University, IsmailiaꢀEgypt
cPhysiology Department, Faculty of Medicine, Taif University, TaifꢀKSA; Department of Physiology,
Faculty of Veterinary Medicine, KaferelSheikh University, Egypt
dBiotechnology Department, Faculty of Science, Taif University, TaifꢀKSA; Department of Biochemistry,
Faculty of Veterinary Medicine, KaferelSheikh University, Egypt
Received May 18, 2011; in final form, July 27, 2011
Abstract—Two derivatives of 2ꢀ(4ꢀacetylanilino)quinolines (IIIa
open chalcone analogues (Va ) through Claisen–Schmidt condensation with a set of aromatic aldehydes (IVa
Derivatives (Va ) were further manipulated into cyclic ꢀunsaturated ketones by Michaelꢀaddition of acetylacꢀ
etone and ethylacetoacetate affording derivatives (VI VII). Deethoxycarboxylation of derivatives (VIIa
afforded cyclohexenons (VIIIa ) allowing formation of a mini library of ꢀunsaturated ketones for screening
their anticancer and synergistic anticancer effect with doxorubicin using colon cancer cell line (Cacoꢀ2). Two open
enones, (Vb) and (Ve), showed significant anticancer activity with IC50 of 5.0 and 2.5 M respectively. Only one
cyclic enone, (VIa) showed synergistic anticancer activity with doxorubicin at 10 M.
,
b
) were synthesized as scaffolds for synthesis of
–f
–d).
,
b
α,β
–
, b)
,
b
α,β
μ
μ
Keywords: quinoline, chalcones, doxorubicin, antiproliferative effect, synergistic effect
DOI: 10.1134/S1068162012030119
2 1
INTRODUCTION
i.e. 1,3ꢀdiarylꢀ2ꢀpropenꢀ1ꢀones
involved as thiolꢀspecific carbohydrate reagents utiꢀ
lized in affinity separation of proteinꢀtype toxins as
well as posttranslation of freeꢀcysteine containing proꢀ
teins [15]. The enone core was reported to be responꢀ
sible for eliciting the biological activity of chalcones
through targeting specific host enzymes if the periphꢀ
ery of this core is optimum for the recognition event
[1a, 16].
Chalcones,
(Fig. 1) are important class of natural products
belonging to the flavonoid and isoflavonoid families
[1]. They are easily accessible via Claisen–Schmidt
condensation of acetylated aryls with aldehydes,
therefore, an endless number of chalcone derivatives is
continually reported.
One of the emerging discoveries in the role of chalꢀ
cones in cancer therapy, even if they have no own cytoꢀ
The wide diversity of the periphery around the
enone core (Fig. 1) gave the chalcones the potency to
have a reported broad spectrum of biological activities
as anticancer [2], antioxidant [2], antiꢀinflammatoryꢀ
analgesicꢀantipyretic [3], antimicrobial [4], antiparaꢀ
sitic [5], antihepatotoxic [3], antiallergic [6], antihyꢀ
perglycemic [7], NOꢀsynthase inhibitors [8], antiferꢀ
tility [9], antinociceptive [10], as immunomodulators
[11], anticonvulsant [12], antiangial [3b], anticataꢀ
Enone
Core
O
R'
R
racts [13] and as probes for in vivo imaging of ꢀamyꢀ
β
loid plaques in Alzheimer’s disease [14], In bioorganic
chemistry, they served as tags for glycoconjugates
Diverse Perifery
1
The article is published in the original.
Corresponding author: phone: 00966562694753; eꢀmail:
2
Fig. 1. Chemical structure of chalcones.
mrea34@hotmail.com.
428

SYNTHESIS OF SOME QUINOLINYL CHALCONE ANALOGUES
Side chain variations and yields of compounds (
429
)–(VIII
I
)
toxicity, is their synergistic effect with the anticancer
natural product doxorubicin. Thus, chalcones with
specific basic periphery were reported to enhance the
curative potency of this drug through inhibition of the
drugꢀefflux protein Pgps characteristic for cancer cells
and responsible for their drug resistance response [17].
Compd
R
R'
R"
Yield (%)
(
(
Ia
Ib
)
)
H
CH3
H
CH3
–
–
–
–
H
H
CH3
H
CH3
–
–
–
–
H
–
–
–
–
H
OMe
NMe2
Cl
H
Cl
–
–
83
98
–
–
–
–
85
85
86
80
77
47
65
66
75
70
50
96
(
(
IIIa
IIIb
)
)
Therefore, we initiated a program to trace this
encouraging discovery, at this stage, to synthesize a set
of quinolineꢀcontaing chalcone analogues to investiꢀ
gate their own anticancer activity as well as their synꢀ
ergistic anticancer potency with doxorubicin taking
colonꢀcancer cell line (Cacoꢀ2) as cancer module.
Quinoline was elected both for its basic nature and its
known pharmacophore activities [18], besides, the
(
IVa)
(
IVb
)
(
IVc)
(IVd
)
(
Va )
(Vb)
H
H
(
Vc)
CH3
CH3
CH3
CH3
H
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
H
H
H
designed series sustains a pꢀimino group relative to the
enone moiety which is necessary for protonation
under physiological pH to ensue the potential activity.
(
(
(
Vd
Ve
Vf
)
)
)
OMe
NMe2
Cl
H
Cl
H
Cl
H
Cl
(
(
VIa
VIb
)
)
RESULTS AND DISCUSSION
(
(
VIIa
VIIb
)
)
Chemistry
2ꢀ(
thesized from the relevant 2ꢀchloroquinolines (Ia
and ꢀacetylaniline II in refluxing EtOH containing
drops of cone. HCl as described by Ashour et al. for
pꢀAcetylanilino)quinolines (IIIa, b) were synꢀ
(
(
VIIIa
VIIIb
)
)
, b)
H
H
p
( )
(
IIIa
)
[19]. Compound
(IIIb) showed a broad band for
oxycarbonyl,
the IRꢀspectra of these compounds, clear NH stretchꢀ
ing vibration bands appeared at
3333 cm–1 as for
derivatives Va ). Furthermore, a second C=O band
arose at the ordinary frequency
1720 cm–1 due to
the acetyl and ester side chains besides the enone’s
(VIIa, b) side chains in good yields. In
the
N
H+2 at 3375 cm–1, IR spectrum, as well as a
bathochromic shifted band at 1660 cm–1 for the aroꢀ
≈
(
–f
1
matic C=O group. In the H NMR spectrum, the
≈
N
H+2 signal was downfield shifted out of scale at
C=O stretching vibration band at
≈
1650 cm–1. In the
VIa, b a signal at
δ
10.87 ppm due to the quaternary nature of the nitroꢀ
gen atom. Claisen–Schmidt condensation of quinoꢀ
lines IIIa, b with a set of aldehydes IVa (scheme
and table), afforded the required first set of cinꢀ
namoylquinolines Va in very good yields, most of
1H NMR spectra of compounds
(
)
(
)
(
–d)
δ
6.48 ppm was observed in both compounds which
might refer to the single olefinic proton of the cycloꢀ
hexene ring. This proton appeared as doublet with
(
–f)
the case. IRꢀspectra showed clearly the existence of
the characteristic stretching vibration bands of the
coupling constant less than 1.0 Hz in enone
(VIa)
and 1.8 Hz for enone VIb). This coupling is due to
(
enone moiety at
ν
1652–1642 cm–1 for the C=O and
the allylicꢀlike coupling with H4 protons. For the
cyclohexenone protons at C4, C5 and C6 atoms, the
1609–1599 cm–1 for the olefinic groups. The expected
bathochromicꢀshift of the carbonyl groups refers to
their conjugation with the olefinic double bond. The
1H NMR of compound
(
VIb
VIa), thus, the common coupling of
1.8 Hz for the fourꢀdoublet signal at 2.94 ppm
) was much clear than for
compound
(
1
last group, i.e. the olefinic protons in the H NMR
δ
spectra could not be assigned due to overlap of its proꢀ
tons with aromatic protons at δ ≈ 8.20–6.90 ppm while
the NH signal appeared clearly downfield as broad sinꢀ
glet at δ ≈ 9.80 ppm. In all next derivatives, the N–H
signal was observed at nearly the same value and it was
D2O exchangeable. In 13C NMR, the C=O signal was
assigned it to be one of the diastereotopic protons of
C4 methylene protons. Other common coupling of
17.4 Hz in the previous signal with the doubletꢀofꢀ
doublet at
other diastereotopic proton of the same methylene
group. The multiplet at 3.44 ppm, which was
δ
3.07 ppm assigned the later to be the
δ
observed in compound
(Ve)
at
δ
186.67 ppm.
deoverlaped from the H2O signal of DMSO by D2O
labeling, was assigned for the cyclohexenone’s H5
Chalcone analogues
(
Va , b
)
were further manipuꢀ
while the doubletꢀofꢀdoublet at 2.76 is for H6 of the
δ
lated to be converted into cyclic enones with side
chain diversity to have a mini library of the required
class. To this endeavor, Michaelꢀaddition of acetyꢀ
lacetone and ethylacetoacetate with compounds
Va , b ) in refluxing EtOH containing NaOMe
afforded cyclic enones with acetyl, VIa, b)
same ring. A multiplicity of doubletꢀofꢀdoublet
rather than a doublet for H6 might be attributed to
the racemic nature of this compound. Both comꢀ
pounds showed one signal for both carbonyl groups at
(
(
and ethylꢀ δ ≈ 198.4 ppm in the 13C NMR.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 4
2012

430
MOHAMED R. E. ALY et al.
O
R
R'
+
H2N
N
Cl
(Ia, b)
(II)
a
R
O
R'
N
N
H.HCl
(IIIa, b)
R''
b
OHC
(IVa–d)
R
O
R'
N
N
H
R''
(Va–f)
d
O
Oc
O
O
O
N
N
H
R''
N
N
H
R''
(VIa, b)
(VIIa, b)
e
O
N
N
H
R''
(VIIIa, b)
Scheme.Reagents and conditions: (a) EtOH, HCl, rfx; (b) NaOH, EtOH–H2O, rt; (c) (Va ) or (Vb), acetylacetone,
NaOMe, MeOH, rfx; (d) (Va ) or (Vb), ethylacetoacetate, NaOMe, MeOH, rfx; (e) NaOH, aq. EtOH, rfx.
In the 1H NMR spectra of compounds
ethyl group’s signals appeared normally as triplet for tons signals in the H NMR spectra were good eviꢀ
the –CH3 and a quartet for the –CH2– groups at dences for this elimination. Compound VIIIb
δ ≈ 0.90 and 3.90 ppm respectively. The cyclohexꢀ showed a smooth spectrum as compound VIb). Massꢀ
(
VIIa, b
)
the
≈
1720 cm–1, while, disappearance of the ethyl proꢀ
1
(
)
(
enone ring showed the diastereotopic C6 methylene spectra as well as elemental analysis were in good
protons as doubletꢀofꢀdoublet for each one at δ ≈ 4.11 agreement with the molecular formulas of all comꢀ
and 2.78 ppm. Proton H5 appeared as multiplet at pounds.
δ ≈ 3.60 ppm, while, the methine proton, i.e. H4,
appeared as doublet at δ ≈ 3.00 ppm.
The antiꢀproliferative effect of 10 of the syntheꢀ
sized enones (Fig. 2) was examined using Cacoꢀ2
The labile ethyloxycarbonyl side chains of derivaꢀ colon cancer cells and MTT assay [20]. Moreover the
tives VIIa, b could be easily removed by treatment synergetic effects of these derivatives in combination
with NaOH in refluxing aqueous EtOH to afford a with the drug Doxorubicin were also examined. The
third variety of cyclic enones VIIIa, b). The IR specꢀ results revealed that highly significant, < 0.001, antiꢀ
tra revealed disappearance of the C=O band at proliferative effect were observed with compounds
(
)
(
p
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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2012

SYNTHESIS OF SOME QUINOLINYL CHALCONE ANALOGUES
140
431
120
100
80
60
40
20
0
Fig. 2. Antiproliferative response of Cacoꢀ2 Colon cancer cell line to compounds (Va
–
e
), (VIa
,
b
), (VIIb) and (VIIIb) at 10 M
µ
with and without doxorubicin (Dox), 10 µM, for 48 h.
having open enone moieties including compounds kinꢀElmer 1430 spectrophotometer using KBr disks
Vb and Ve with inhibition potency of 54% and 58% technique in the toxicology Center, Faculty of Sciꢀ
and IC50 at 5.0
results, might roughly, exhibiting the relevance of the 13C spectra were recorded on Varian Gemini 200 MHz
ꢀchloro substitution on ring B in nonmethylated spectrometer in the micro analytical center of the Facꢀ
quinolyl derivatives and the basic ꢀNMe2 group on ulty of Science, Cairo University and Bruker 600 MHz
ring B in the methylated analogous. Although, comꢀ spectrometer, central laboratory, King Abd El Aziz
pounds Va, Vc, Vd, Vf, VIa, VIIb and VIIId showed University, Gedah, KSA, DMSOꢀd6 was used as solꢀ
(
)
( )
1
μ
M
and 2.5 M respectively. These ence, Suez Canal University, Egypt. H NMR and
μ
p
p
(
)
variable antiproliferative activities, their effects were vent using Trimethylsilane (TMS) as internal standard
statistically nonsignificant. On the other hand, i.e. the and D2O was used to locate the N–H signal. Mass
synergistic effect with doxorubicin, derivatives
showed a statistically nonsignificant synergistic effect spectrometer (Japan) in the micro analytical Center of
and only compound VIa having a cyclic enone moiꢀ the Faculty of Science, Cairo University. Elemental
(Vc–f)
spectra were recorded on Shimadzu Qpꢀ2010 Puls
(
)
ety with an acetyl side chain among the tested related analysis was performed in the micro analytical Center,
cyclic derivatives showed a significant synergistic Faculty of Science, Cairo University.
effect. Thus, the antiproliferative effect of doxorubicin
alone, 74%, was elevated to 84% inhibition upon mixꢀ
ing with (VIb) which corresponds to an increased
General Procedure for the Synthesis of (IIIa
A mixture of chloroquinoline Ia, b (0.1 mol) and
ꢀacetylaniline II (0.1 mol) in absolute EtOH (40 mL)
containing cone HCl (50 ) was refluxed for 8 h then
left to reach ambient temperature. The crystalline preꢀ
cipitate formed was filtered and dried at the pump.
, b)
(
)
potency of 10%. The non significant anticancer activꢀ
ity of this compound along with its statistically signifiꢀ
cant effect on the antiproliferative efficacy of doxoruꢀ
bicin encourages that this compound is synergistic and
its activity might be referred to its probable inhibition
of cancer cells drug efflux proteins Pgp due to the simꢀ
ilarities of the active core with the series reported by
Go et al. [17].
p
( )
μL
1ꢀ[4ꢀ(4,6ꢀDimethylquinolinꢀ2ꢀylamino)phenyl]ethaꢀ
none hydrochloride (IIIb). Lemon yellow crystals in
98% yield from EtOH–H2O. Mp 174–177°C. IR
(KBr): 3375 (N–Hstr), 1660 (C=Ostr). Found, %: C
69.70, H 6.00, N 8.90. C19H19ClN2O. Calcd., %: C
69.83, H 5.86, N 8.57. 1H NMR (200 MHz, DMSO):
EXPERIMENTAL
δ
10.89 (2 H, br.s, –NH2+), 8.06–7.19 (8 H, m, Ar),
All chemicals and solvents were purchased from the
local Egyptian productions and Merck chemical
industries and were directly used without purification.
Melting points were uncorrected and measured on
MelꢀTempII laboratory devices USA using open capꢀ
illary tubes. TLC Monitoring tests were carried out
2.64 (3 H, s, –COCH3), 2.58, 2.48 (6 H, 2s, 2CH3).
General Procedure for the Synthesis of Chalcones (Va
A mixture of the acetyl derivative IIIa, b
IVa
–
f
)
(
)
f
using plastic sheets precoated with silica gel 60F245 (3.0 mmol), the appropriate aldehyde
(
–
)
(layer thickness 0.2 mm) purchased from Merck. Mixꢀ (7.0 mmol) and NaOH (7.0 mmol) in EtOH–H2O
ture benzene–MeOH, 9 : 1 was commonly used as (10.0 : 0.5 mL) was stirred overnight. The precipitate
mobile phase. Spots were visualized by their fluoresꢀ formed was filtered at the pump, washed with a little
cence under UVꢀlamp (
λ
245 and 366 nm) and stainꢀ cold EtOH, dried well and recrystallized from the relꢀ
ing with iodine. IR spectra were recorded on USA Perꢀ evant solvent.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 4
2012

432
MOHAMED R. E. ALY et al.
(
E
)ꢀ3ꢀPhenylꢀ1ꢀ[4ꢀ(quinolinꢀ2ꢀylamino)phenyl]propꢀ
2ꢀenꢀ1ꢀone (Va). Yellow crystals in 85% yield from 143.81, 132.38, 131.34, 130.58, 130.46, 129.92,
MeOH. Mp 203–204 . IR (KBr): 3318 ( Hstr), 129.77, 129.71, 127.00, 124.08, 123.16, 122.34,
1649 (C=Ostr), 1606 (C=Cstr). Found, %: C 82.10, 122.34, 117.14, 116.27, 114.08, 114.01, 112.00, 111.82
H 5.30, N 7.90. C24H18N2O. Calcd., %: C 82.26, (CAr), 39.78 (–NMe2), 21.17, 18.50 [2 (CH3)quin
H 5.18, N 7.99. 1H NMR (600 MHz, DMSO): (%): 421 (100, M+), 406 (85.0), 289
9.98 EI MS,
(1 H, s, NHD2O exch.), 8.20 (4 H, m, Ar), 8.15 (1 H, d, (23.8), 195 (36.7).
JA,B 9.0, Ar), 8.00 (1 H, d, 15.6, Ar), 7.90 (2 H, m,
δ
181.67 (C=O), 152.96, 151.81, 145.89, 144.42,
°C
N⎯
].
δ
m/z
J
(E)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀ[4ꢀ(4,6ꢀdimethylquinoꢀ
Ar), 7.79 (2 H, m, Ar), 7.71 (1 H, d, JA,B 15.6, Ar),
7.64 (1 H, m, Ar), 7.46 (3 H, m, Ar), 7.36 (1 H, m,
linꢀ2ꢀylamino)phenyl]propꢀ2ꢀenꢀ1ꢀone (Vf). Yellow
crystals in 47% yield from benzene: EtOH. Mp 260–
Ar), 7.14 (1 H, d, JA,B 9.0, Ar). EI MS, m/z (%): 350
262
(C=Cstr), 793 (C–Clstr). Found, %: C 75.30, H 4.90,
6.80. C26H21ClN2O. Calcd., %: C 75.63, H 5.13, N
°C. IR (KBr): 3333 (N–Hstr), 1652 (C=Ostr), 1599
(100, M+), 333 (9.0), 247 (29.9), 218 (43.3), 174
(32.8), 128 (61.2).
N
1
(E
)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀ[4ꢀ(quinolinꢀ2ꢀylamino)
phenyl]propꢀ2ꢀenꢀ1ꢀone (Vb). Yellow crystals in 85%
yield from EtOH. Mp 221–223 . IR (KBr): 3314
6.78. H NMR (600 MHz, DMSO):
δ
9.47 (1 H, s,
A,B 15.6
⎯
NHD2O exch), 8.17 (4 H, m, Ar), 8.02 (1 H, d,
J
,
°
C
Ar), 7.94 (2 H, m, Ar), 7.70–7.66 (3 H, m, Ar), 7.53–
7.46 (3 H, m, Ar), 6.95 (1 H, m, –CO–CH=CH–),
(N–Hstr), 1652 (C=Ostr), 1604 (C=Cstr), 809 (C–Clstr)
Found, %: C 74.60, H 4.30, N 7.60. C24H17ClN2O
Calcd., %: C 74.90, H 4.45, N 7.28. H NMR
(200 MHz, DMSO):
(15 H, m, Ar, –CO–CH=CH–), 7.15 (1 H, d, JA,B
9.0, Ar). EI MS,
(%): 384 (100, M+), 355 (26.6),
247 (21.2), 218 (46.4), 174 (36.9).
.
.
2.58, 2.46 (6 H, 2s, (CH3)quin). EI MS,
m/z (%): 414 (24),
1
412 (70.7, M+), 384 (38.7), 247 (48).
δ
9.98 (1 H, s, NH), 8.21–7.11
General Procedure for Synthesis of Compounds (VIa, b)
m/z
A mixture of acetylacetone (3.0 mL, 29.0 mmol)
and NaOMe (1%, 10 mL) was kept for an hour at ambiꢀ
ent temperature then added to the appropriate chalcone
(E
)ꢀ1ꢀ[4ꢀ(4,6ꢀDimethylquinolinꢀ2ꢀylamino)phenyl]ꢀ
3ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (Vc). Yellow crystals in 86%
yield from EtOH/H2O. Mp 193–195 . IR (KBr):
°
C
derivative (Va , b ) (2.0 mmol) and the mixture was
3342 (N–Hstr), 1652 (C=Ostr), 1609 (C=Cstr). Found, %:
C 82.30, H 5.60, N 7.40. C26H22N2O. Calcd., %:
C 82.51, H 5.86, N 7.40. H NMR (200 MHz,
DMSO):
–CO–CH=CH–), 6.98 (1 H, s, –CO–CH=CH–)
2.60, 2.49 (6 H, 2 s, 2CH3). EI MS, (%): 378
(87.0, M+), 377 (100), 349 (28), 24.7 (25).
refluxed for 15 h then left to reach ambient temperature.
The precipitate formed was filtered at the pump, dried
well then recrystallized from the proper solvent.
1
δ
9.82 (1 H, s, NH), 8.19–7.00 (14 H, m, Ar,
6ꢀAcetylꢀ5ꢀphenylꢀ3ꢀ[4ꢀ(quinolinꢀ2ꢀylamino)phenyl]
cyclohexꢀ2ꢀenꢀ1ꢀone (VIa). Yellow crystals from
m/z
EtOH : benzene in 65% yield. Mp 248–251°C. IR
(KBr): 3333 (N–Hstr), 1718 (C=Oacetyl), 1641
(C=Oenone), 1586 (C=Cstr). Found, %: C 80.50,
5.30. C29H24N2O2. Calcd., %: C 80.53, H 5.59.
1H NMR (600 MHz, DMSO):
9.82 (1 H, s,
NHD2O exch), 8.08–7.09 (15 H, 3m, Ar), 6.48 (1 H, d,
Jallylic < 1.0, H2cyclohex), 3.45 (1 H, d, H5cyclohex, overlapped),
.50–2.77 (3 H, m, H4, H4', H6cyclohex), 2.49 (3 H s,
(E)ꢀ1ꢀ[4ꢀ(4,6ꢀDimethylquinolinꢀ2ꢀylamino)phenyl]ꢀ
3ꢀ(4ꢀmethoxyphenyl)propꢀ2ꢀenꢀ1ꢀone (Vd). Orange
H
crystals in 80% yield from benzene: petroleum ether.
δ
Mp 224–226
(C=Ostr), 1599 (C=Cstr), 1257, 1226 (C–O–Caryl),
1034 (C–O–Calkyl . Found, %: C 79.50, H 6.10,
7.10. C27H24N2O2. Calcd., %: C 79.39, H 5.92,
6.86.1H NMR (200 MHz, DMSO):
9.78 (1 H, s,
°C. IR (KBr): 3345 (N–Hstr), 1648
⎯
)
3
13
N
N
COCH3). C NMR (150 MHz, DMSO):
δ
198.43
δ
(2C=O), 158.24, 153.90, 146.83, 144.06, 143.65,
137.31, 129.77, 129.57, 129.12, 128.65, 127.70,
127.40, 127.24, 126.77, 126.58, 123.87, 123.27,
121.78, 118.04, 114.45 (CAr, C23olef), 43.72–34.97
–NH), 8.18–6.98 (14 H, m, 4Ar, –CH=CH–), 3.84
(3 H, s, –OCH3), 2.60, 2.48 (6 H, 2s, 2 –CH3). EI
MS, m/z
(%): 408 (100, M+), 407 (80), 393 (53.3), 392
(C4aliph). EI MS, m/z
(%): 432 (20.5, M+), 390 (100),
(46.7), 391 (40), 317 (33.3), 309 (40), 308 (40), 307
(26.7), 279 (40), 278 (40), 246 (66.7).
285 (74.8), 257 (33.1), 218 (20.5).
(
E
)ꢀ3ꢀ[4ꢀ(Dimethylaminophenyl)]ꢀ1ꢀ[4ꢀ(quinolinꢀ
2ꢀylamino)phenyl]propꢀ2ꢀenꢀ1ꢀone (Ve). Red crystals
in 77% yield from benzene : EtOH. Mp 248–250
6ꢀAcetylꢀ5ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ[4ꢀ(quinoIinꢀ2ꢀylamino)
phenyl]cyclohexꢀ2ꢀenꢀ1ꢀone (VIb). Yellow crystals
°C.
from EtOH : benzene in 66% yield. Mp 252–254°C.
IR (KBr): 3338 (N–Hstr), 1646 (C=Ostr), 1585
(C=Cstr), 819 (C–Clstr). Found, %: C 75.00, H 5.10,
IR (KBr): 3340 (N–Hstr), 1642 (C=Ostr), 1599
(C=Cstr). Found, %: C 79.60, H 6.60, N 10.10.
C28H27N3O. Calcd., %: C 79.78, H 6.46, N 9.97.
N
N
5.80. C29H23ClN2O2. Calcd., %: C 74.59, H 4.96,
1H NMR (600 MHz, DMSO):
δ
9.47 (1 H, s,
NHD2O exch), 8.13 (2 H, m, Ar), 7.70 (2 H, d,
JA,B 9.0, Ar), 7.68–7.62 (6 H, m, Ar), 7.46 (1 H, dd,
1.2, 8.4, Ar), 6.94 (1 H, s, –CO–CH=CH–), 6.74
(2 H, d, A,B 9.0, Ar), 3.00 (6 H, s, –NMe2), 2.60, 2.46
(6 H, 2 s, 2(CH3)quin). C NMR (150 MHz, DMSO):
5.99. 1H NMR (600 MHz, DMSO):
δ
9.76 (1 H, s,
⎯
NHD2O exch), 8.10 (5 H, m, Ar), 7.76–7.70 (6 H, m,
Ar), 7.61–7.59 (2 H, m, Ar), 7.08 (1 H, d, 9.0, Ar),
6.48 (1 H, d, allylic1.8, H2cyclohex), 3.44 (1 H, m,
H5cyclohex), 3.07 (1 H, dd, 4.2, Jgem 17.4, H4cyclohex),
J
J
J
J
13
J
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 4
2012

SYNTHESIS OF SOME QUINOLINYL CHALCONE ANALOGUES
433
'
J4,510.8, Jgem 17.4, H4cyclohex),
2.94 (1 H, 4d,
J
J
allylic 1.8,
13.2, 16.2, H6cyclohex), 2.50 (3 H, s,
COCH3). C NMR (150 MHz, DMSO): 198.03
reach ambient temperature. The precipitate formed
was filtered in vacuo and recrystallized from the releꢀ
vant solvent(s).
2.76 (1 H, dd,
13
δ
5ꢀPhenylꢀ3ꢀ[4ꢀ(quinolinꢀ2ꢀylamino)phenyl]cyclohexꢀ
(2C=O), 157.98, 153.76, 146.76, 143.59, 143.48,
143.02, 137.26, 131.21, 129.70, 129.43, 129.15,
128.45, 128.39, 127.65, 127.36, 126.51, 123.79,
123.21, 121.68, 117.94, 117.87, 114.36, 114.31
2ꢀenꢀ1ꢀone (VIIIa). Yellow crystals from benzene:
EtOH in 50% yield. Mp 258
(N
). EI C 82.80, H 5.90, N 7.30. C27H22N2O. Calcd., %:
°C. IR (KBr): 3332
Hstr), 1650 (C=Ostr), 1585 (C=Cstr). Found, %:
⎯
(CAr, olef), 43.42 (C6cyclohex), 39.64, 34.64 (3Caliph
MS,
(%): 424 (100, M+), 285 (63), 257 (37.5), 218 C 83.05, H 5.68, N 7.17. H NMR (200 MHz,
(12.5).
DMSO): 9.73 (1 H, br. s, –NH), 8.12–7.07 (15 H,
m, Ar), 6.49 (1 H, s, –CO–CH=CH), 3.20–2.53
1
m/z
δ
'
(5 H, m, H6cyclohex
,
H6cyclohex , H5cyclohex, H4cyclohex
,
General Procedure for Synthesis of Compounds (VIIa, b)
'
H4cyclohex ). EMS,
m
/
z
(%): 390 (100, M+), 361 (12.8),
285 (84.6), 257 (43.6), 218 (38.5).
Ethylacetoacetate (3.09 g, 0.02 mol) was stirred
with NaOMe solution (1%, 10 mL) at rt for 1 h then
refluxed for 10 h with the appropriate chalcone derivꢀ
5ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ[4ꢀ(quinolinꢀ2ꢀylamino)phenyl]
ative (Va , b ) (1.0 g, 0.002 mol) and left to reach ambiꢀ
cyclohexꢀ2ꢀenꢀ1ꢀone (VIIIb). Yellow crystals from
ent temperature. The precipitate formed was filtered at
the pump, dried then recrystallized from the relevant
solvent.
benzene : EtOH in 96% yield. Mp 242–245°C. IR
(KBr): 3338 (N–Hstr), 1642 (C=Ostr), 1584 (C=Cstr),
820 (C–Clstr). Found, %: C 76.20, H 5.10, N 6.70.
C27H21ClN2O. Calcd., %: C 67.32, H 4.98, N 6.59.
Ethyl
ylamino)phenyl]cyclohexꢀ3ꢀenecarboxylate
Yellow crystals in 75% yield from benzene : petroleum
ether. Mp 232 . IR (KBr): 3335 (N–Hstr), 1744
2ꢀoxoꢀ6ꢀphenylꢀ4ꢀ[4ꢀ(quinolinꢀ2ꢀ
1H NMR (600 MHz, DMSO):
δ
9.77 (1 H, s,
NHD2O exch), 8.10–8.08 (4 H, m, Ar), 7.73 (3 H, m,
Ar), 7.60 (1 H, m, Ar), 7.46 (2 H, m, Ar), 7.40 (2 H,
m, Ar), 7.32 (1 H, m, Ar), 7.08 (1 H, d, A,B 9.0, Ar),
6.48 (1 H, d, Jallylic 1.8, H2cyclohex), 3.40 (1 H, m,
H5cyclohex), 3.05 (1 H, dd, 4.2, 17.4, H4cyclohex), 2.94
(VIIa).
⎯
°C
(C=Oester), 1645 (C=Oenone), 1586 (C=Cstr). Found, %:
C 77.70, H 5.60, N 6.20. C30H26N2O3. Calcd., %:
J
1
C 77.90, H 5.67, N 6.06. H NMR (200 MHz,
J
DMSO):
Ar), 7.78–7.26 (13 H, m, Ar), 7.11 (1 H, d,
Ar), 6.53 (1 H, d,
H6cyclohex), 3.91 (2 H, q,
m, H5cyclohex), 3.07 (1 H, d,
(1 H, dd, H1cyclohex), 0.92 (3 H, t,
δ
9.78 (1 H, br. s, NH), 8.11 (1 H, d,
J
A,B 8.4
,
,
'
(1 H, 4 d, allylic 1.8, gem 17.4, J 10.8, H4cyclohex ), 2.76
(1 H, dd, 13.2, 16.2, H6cyclohex), 2.52 (1 H, m,
J
J
JA,B 9.1
J
16.4, H3cyclohex), 4.11 (1 H, dd,
7.08, CH2 ethyl), 3.65 (1 H,
7.26, H5'cyclohex), 2.78
7.08, –CH3).
J
J
13
'
H6cyclohex). C NMR (150 MHz, DMSO):
δ
198.10
J
(C=O), 158.04, 153.83, 146.78, 143.62, 143.03,
137.29, 131.23, 129.73, 129.46, 129.18, 128.47,
128.42, 127.67, 127.38, 126.53, 123.82, 123.24,
J
Ethyl 6ꢀ(4ꢀchlorophenyl)ꢀ2ꢀoxoꢀ4ꢀ[4ꢀ(quinolinꢀ2ꢀ
ylamino)phenyI]cyclohexꢀ3ꢀenecarboxylate (VIIb).
Yellow crystals in 70% yield from EtOH : H2O : ether.
121.71, 117.98, 114.38 (23CAr,
), 43.44, 39.50, 34.66
olef
(3Caliph).
Mp 229–230°C. IR (KBr): 3334 (N–Hstr), 1744
(C=Oester), 1645 (C=Oenone), 1587 (C=Cstr), 784
(C–Clstr). Found, %: C 72.30, H 4.80, N 5.50.
C30H25ClN2O3. Calcd., %: C 72.50, H 5.07, N 5.64.
Cell Proliferation Studies
The proliferation inhibition ability of 10 comꢀ
1H NMR (200 MHz, DMSO):
δ
9.79 (1 H, br. s, NH),
8.11 (1 H, d, JA,B 7.6, Ar), 7.78–7.43 (12 H, m, Ar),
7.10 (1 H, d, A,B 9.0, Ar), 6.53 (1 H, d, 16.0,
H3cyclohex), 4.12 (1 H, dd, 12.0, H6cyclohex), 3.93 (2 H,
q, 7.08, –CH2 ethyl–), 3.63 (1 H, m, H5cyclohex), 3.06
pounds of the prepared ꢀunsaturated ketones was
α
,
β
determined by MTT assay method described by Mosꢀ
mann, 1983 using colon cancer cell line (Cacoꢀ2)
obtained from VACSERA, the holding company for
biological products and vaccines, Cairo, Egypt.
Briefly, Colon cancer cell line (Cacoꢀ2) was seeded at
20000 cells/well in 96 well tissue culture plates, volꢀ
J
J
≈
J
J
'
J 8.34, H5cyclohex ), 2.57 (1 H, m, H1cyclohex),
(1 H, d,
0.95 (3 H, t,
J
7.08, –CH3). EI MS, m/z (%): 496 (5.1,
ume 100
5% CO2. The cells, except the control, were treated
with DMSO, Doxorubicin at 10 , derivatives Va – f,
VIa, b, VIIb and VIIIb at 10 , combination
between these derivatives at 10 and Doxorubicin
at 10 . After incubation for 48 h, 25 of
μL/well and incubated for 24 h at 37°C and
M+), 467 (6.1), 449 (32.7), 423 (41.8), 395 (21.4), 339
(17.3), 322 (50.0), 285 (56.1).
μ
M
μM
)
μ
M
General Procedure for the Synthesis
μM
μL
of Compounds (VIIIa
, b)
(0.5 mg/mL) MTT stain was added to each well and
the plates were incubated at 37oC for 4 h, then, a stop
solution was added to each well and mixed thoroughly
by repeated pipetting with a multichannel pipette. The
A mixture of the appropriate ethylester
(VIIa, b)
(0.002 mol) and NaOH (1.5 g, 0.037 mol) in EtOH :
H2O, 1.5 : 1 (25 mL) was refluxed for 6 h then left to
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 4
2012

434
MOHAMED R. E. ALY et al.
2001, vol. 9, pp. 1999–2013; (c) Ninomiya, Y.,
Shimma, N., and Ishitsuka, H., Antiviral Res., 1990,
vol. 13, pp. 61–74.
plates were then shacked at room temperature for an
hour. The developed color was measured at 570 nm
using ELIZA micro plate reader. Cell viability was calꢀ
culated according to the following equation
5. (a) Nielsen, S.F., Christensen, S.B., Cruciani, G.,
Kharazmi, A., and Liljefors, T., J. Med. Chem., 1998,
vol. 41, pp. 4819–4832; (b) Liu, M., Wilairat, P., and
Go, M.L., J. Med. Chem., 2001, vol. 44, pp. 4443–
4452.
Viability % = (test reading/control reading) × 100.
The obtained data were statically analyzed using
STATE view using postꢀHock ANOVA.
6. (a) Claesson, H.E. and Dahlen, S.E., J. Int. Med.
,
1999, vol. 245, p. 205; (b) Lieberman, P., Allergy Asthma
Proc., 2009, vol. 30, pp. 345–348.
CONCLUSIONS
7. Raju, B.C., Yiwari, A.K., Kumar, J.A., Ali, A.Z.,
Agwane, S.B., Saidachary, G., and Madhusudana, K.,
Bioorg. Med. Chem., 2010, vol. 18, pp. 358–365.
A set of quinoline derivatives having a enone moiꢀ
ety can be easily synthesized via Claisen–Schmidt
condensation and Michaelꢀaddition reactions affordꢀ
ing a series of
α
, ꢀunsaturated ketones bearing the
β
8. Carrion, M.D., Luisa, C., Lopez, L.C., Camacho, M.E.,
Tapias, V.G., Escames Castroviejo, D.A., Espinosa, A.,
basic quinolyl grafts for investigation of their anticanꢀ
cer and synergistic anticancer potency with doxorubiꢀ
cin. Both anticancer and synergistic anticancer activiꢀ
ties were observed which supports synthesis of more
derivatives of this series.
Gallo, M.A., and Entrena, A., Eur. J. Med. Chem.
2008, vol. 43, pp. 2579–2591.
,
9. Moersch, G.W., Morrow, D.F., and Neuklis, W.A.,
J. Med. Chem., 1967, vol. 10, pp. 154–158.
10. Milano, J., Oliveira, S.M., Rossato, M.F., Sauzem, P.D.,
Machado, P., Beck, P., Zanatta, N., Martins, M.A.P.,
Mello, C.F., Rubin, M., Ferreira, J., and Bonacorso, H.G.,
Eur. J. Pharmacol., 2008, vol. 581, pp. 86–96.
ACKNOWLEDGMENTS
The supports of Taif University/Kingdom Saudi
Arabia, Grant number 1ꢀ431ꢀ768 and Suez Canal 11. Pergola, C. and Werz, O., Expert Opin. Ther. Patents,
2010, vol. 20, pp. 355–375.
12. Ozdemir, Z., Kandilci, H.B., Gumusel, B.H., Cal
and Bilgin, A.A., Eur. J. Med. Chem., 2007, vol. 42,
pp. 373–379.
University/Egypt are gratefully acknowledged.
ι
s, U.,
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