Simple C-2-substituted quinolines and their anticancer activity

Article abstract of DOI:10.2174/157018012801319544

Sixteen C-2-substituted quinolines were tested in both human cancer cell lines (MCF-7, H-460 and SF-268) and normal cell lines (Vero and THP-1). Preliminary results indicate that 2-α-furyl- and 2-γ-pyridinyl quinoline derivatives 1, 13 and 14 are active against three human cancer cell lines and, at the same time, were devoid of cytotoxic effect on normal cells. Biological activity and SAR results were compared with different molecular descriptors determined in silico using online available software, in an attempt to show a relationship with the possible mode of action of these quinoline derivatives.

Full text of DOI:10.2174/157018012801319544

680
Letters in Drug Design & Discovery, 2012, 9, 680-686
Simple C-2-Substituted Quinolines and their Anticancer Activity
Vladimir V. Kouznetsov*,a, Fernando A. Rojas Ruíza, Leonor Y. Vargas Méndeza and
Mahabir P. Guptab
aLaboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, A.A. 678
Bucaramanga, Colombia; bCentro de Investigaciones Farmacognósticas de la Flora Panameña (CIFLORPAN),
Facultad de Farmacia, Universidad de Panamá, Panamá, R. De P.
Received April 22, 2012: Revised May 16, 2012: Accepted May 18, 2012
Abstract: Sixteen C-2-substituted quinolines were tested in both human cancer cell lines (MCF-7, H-460 and SF-268) and
normal cell lines (Vero and THP-1). Preliminary results indicate that 2-ꢀ-furyl- and 2-ꢁ-pyridinyl quinoline derivatives 1,
13 and 14 are active against three human cancer cell lines and, at the same time, were devoid of cytotoxic effect on normal
cells. Biological activity and SAR results were compared with different molecular descriptors determined in silico using
online available software, in an attempt to show a relationship with the possible mode of action of these quinoline
derivatives.
Keywords: C-2-aryl quinoline derivatives, Synthesis, Anticancer activity, Cytotoxicity on normal cells, Toxic effects in silico.
INTRODUCTION
Quinoline ring plays an important role in new anti-cancer
agents development as their derivatives have shown
excellent results through different mechanism of action such
as growth inhibitors by cell cycle arrest, apoptosis, inhibition
of angiogenesis, disruption of cell migration, and modulation
of nuclear receptor responsiveness [8]. The anti-cancer
potential of several of these derivatives have been
demonstrated on various cancer cells including those of
leukemia and other cancer cells of breast, ovary, liver, lung,
pancreas and colon [9]. Although different researchers have
demonstrated that some plant-based anticancer quinolines
have a DNA-quinoline ring binding power, and perform a
DNA topoisomerase I inhibition [10].
Cancer, rapid unregulated pathological proliferation of
abnormal cells, is the second leading cause of death in
humans after cardiovascular diseases. According to data
from the World Health Organization, of the 58 million
deaths occurred worldwide in 2008, 7.6 million (13%) were
due to cancer. The pathologies that contribute most to
mortality are lung (1.3 million annual deaths), stomach
(740.000 deaths per year), liver (662.000 deaths annually),
colon (655.000 deaths annually), and breast cancer (502.000
deaths per year). It is expected that the global number of
cancer deaths will continue to rise around the world and will
reach 9 million by the year 2015 and 11.4 million by 2030.
The most common cancers in the world are, in order of
mortality in men - lung, stomach, liver, colon and rectum,
esophagus and prostate and in women - breast, lung,
stomach, colon and rectum, and cervix [1].
The drugs listed in Fig. (1) are expensive and have
pronounced side effects. The main problem with these agents
is the toxicity associated with them due to their lack of
specificity, as these agents also kill healthy cells. In addition,
drug resistance constitutes another problem that arises after
some time. Even though, it is possible to affirm that although
a good number of anticancer agents have been developed
from plants or their semi-synthetic and synthetic derivatives,
there is still a need to develop new anticancer drugs.
Lung cancer is a more common type of cancer in both
men and women. The treatment of lung adenocarcinomas is
very unsatisfactory, as this type of tumor is rarely curable by
surgery; and radiation therapy is used mainly as a palliative
to reduce pain and bleeding. In this case, chemotherapy can
be effective and seems to be the only feasible approach.
Among the available chemotherapeutic agents in clinical use
are adriamycin® (doxorubicin, anthracycline antibiotic) [2],
the alkaloid vinblastine (in combination with cisplatin, a
platinum coordination complex) [3] and topotecan [4,5].
Topotecan, an active second line chemotherapeutic drug
used to treat patients with relapsed ovarian carcinoma, and
It is known that diverse polyfunctionalized quinoline
molecules are used as potential anticancer agents [11]. As a
part of our medicinal chemistry program devoted to the
search of new anticancer compounds [12,13] we addressed
our attention to diverse quinoline derivatives that could serve
as models for the development of new antitumor drugs. Now
we report here the biological evaluations of three series of 2-
aryl substituted quinolines, in which C-2 function has a
different chemical moiety: ꢀ-furyl, ꢀ-thienyl, ꢁ-pyridinyl or
aryl fragments (Fig. 2)
irinotecan,
a
drug
employed
against
colorectal
adenocarcinoma [6,7], are both derivatives of the quinoline
alkaloid camptothecin (Fig. 1).
We expected at the outset that these chemical functions at
C-2 would alter the biological activity of the new quinoline
compounds obtained, and may help in developing structure–
activity relationships (SARs). The introduction of an hetaryl
*Address correspondence to this author at the Laboratorio de Química
Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de
Santander, A.A. 678 Bucaramanga, Colombia; E-mail: kouznet@uis.edu.co
1875-628X/12 $58.00+.00
© 2012 Bentham Science Publishers

Simple C-2-Substituted Quinolines and their Anticancer Activity
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 7 681
OH
O
O
Me
OH
O
O
Me
OH
O
O
N
Me
N
N
N
N
O
O
N
HO
Me
N
Quinoline
ring
O
N
Camptothecin
N
Topotecan (Hycamtin)
O
Me
O
N
Me
Irinotecan (Camptosar)
Fig. (1). Polycyclic chemotherapeutic agents bearing the quinoline ring.
R2
X
R1
N
R2
N
N
N
R1
I
II
R1
III
R2
CH3
Fig. (2). Evaluated C-2 functionalized quinoline series.
moiety in the C-2 position of quinoline ring would maybe
enhance the lipophilicity and DNA-quinoline binding
properties of the prepared compounds.
Selected Spectral Data
6-Methoxy-2-(thiophen-2-yl)quinoline (1) obtained in
96% yield, mp 144-144.5 °C. 1H NMR (CDCl3, 400 MHz), ꢀ
(ppm): 3.93 (s, 3H, OCH3), 6.57 (dd, J = 3.4, 1.8 Hz, 1H,
Harom.), 7.05 (d, J = 2.8 Hz, 1H, Harom.), 7.14 (dd, J = 3.4, 0.7
Hz, 1H, Harom.), 7.36 (dd, J = 9.2, 2.8 Hz, 1H, Harom.), 7.60
(dd, J = 1.7, 0.7 Hz, 1H, Harom.), 7.77 (d, J = 8.6 Hz, 1H,
Harom.), 8.03 (d, J = 9.0 Hz, 1H, Harom.), 8.05 (d, J = 8.3 Hz,
1H, Harom.). 13C NMR (CDCl3, 100 MHz,): ꢀ 55.5, 105.3,
109.1, 112.1, 117.8, 122.4, 128.1, 130.8, 135.3, 143.6, 144.1,
146.9, 153.8, 157.6. GC-MS: tR 30.72 min., m/z: 225 (M+).
Anal. Calcd. for C14H11NOS: C, 69.68; H, 4.59; N, 5.80.
Found: C, 69.52; H, 4.73; N, 5.64.
MATERIALS AND METHODS
Chemistry
IR spectra were recorded on a Lumex Infralum FT-02
1
spectrophotometer. H and 13C NMR spectra were measured
1
on a Bruker AM-400 spectrometer (400 MHz H NMR and
100 MHz 13C NMR), using CDCl3 as the solvent. TMS was
used as an internal standard. Chemical shifts (ꢀ) and J values
are reported in ppm and Hz, respectively. A Hewlett Packard
5890a Series II Gas Chromatograph interfaced to an HP
5972 Mass Selective Detector with an HP MS ChemStation
Data system was used for MS identification at 70 eV using a
6,8-Dimethoxy-2-(thiophen-2-yl)quinoline (2) obtained
in 95% yield, mp 119-119.5°C. 1H NMR (CDCl3, 400 MHz),
ꢀ (ppm): 3.89 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 6.62 (d, J
= 2.5 Hz, 1H, Harom.), 6.69 (d, J = 2.5 Hz, 1H, Harom.), 7.11 (dd,
J = 5.0, 3.7 Hz, 1H, Harom.), 7.40 (dd, J = 5.0, 1.1 Hz, 1H,
Harom.), 7.65 (dd, J = 3.7, 1.1 Hz, 1H, Harom.), 7.74 (d, J = 8.6
Hz, 1H, Harom.), 7.96 (d, J = 8.6 Hz, 1H, Harom.). 13C NMR
(CDCl3, 100 MHz), ꢀ (ppm): 55.4, 56.2, 97.0, 101.6, 118.6,
124.9, 127.5, 127.8, 128.8, 135.3, 136.4, 145.5, 149.1, 156.1,
158.0. GC-MS: tR 36.51 min., m/z: 271 (M+). Anal. Calcd.
for C15H13NO2S: C, 66.40; H, 4.83; N, 5.16. Found: C,
66.56; H, 4.77; N, 5.25.
60
m
capillary column coated with HP-5 [5%
Melting points were
phenylpoly(dimethylsiloxane)].
measured on a Fisher Johns melting point apparatus. The
reaction progress was monitored using thin layer
chromatography on a Silufol UV 254 TLC aluminum sheets.
Column chromatography was carried out using silica gel
(230-400 mesh). All reagents were purchased from Sigma
and Aldrich Chemical Co and used without further
purification.
6-Ethyl-2-phenylquinoline (8) obtained in 51% yield, mp
63-66 °C. IR (KBr): 2960, 2895, 1493, 1443 cm-1. H NMR
1
Syntheses of sixteen polyfunctionalized quinolines tested
in this work were easily carried out using diverse aldehydes
and anilines as starting materials following known synthetic
procedures [14-16].
(CDCl3, 400 MHz), ꢀ (ppm): 1.36 (3H, t, J = 7.6 Hz, CH3-
CH2-), 2.85 (2H, q, J = 7.6 Hz, CH3-CH2-), 7.46 (1H, t, J =
7.3 Hz, 4'-HPh), 7.53 (2H, t, J = 7.1 Hz, 3'-HPh and 5'-HPh),
7.61-7.59 (2H, m, 5-HQu and 7-HQu), 7.84 (1H, d, J = 8.6 Hz,

682 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 7
Kouznetsov et al.
4-HQu), 8.11 (1H, d, J = 9.3 Hz, 8-HQu), 8.15-8.13 (1H, m, 3-
HQu), 8.17-8.13 (2H, m, 2'-HPh and 6'-HPh). 13C NMR
(CDCl3, 100 MHz), ꢀ (ppm): 15.3, 28.8, 118.9, 124.9, 127.2,
127.4 (2C), 128.7 (2C), 129.0, 129.5, 130.8, 136.2, 139.8,
142.3, 147.1, 156.5. MS, m/z (EI) 233 (M+). Anal. Calcd. for
C17H15N: C, 87.52; H, 6.48; N, 6.00. Found: C, 87.41; H,
6.33; N, 6.25.
formed with PMA (phorbol myristate acetate) using the
Mosmann’s method based on the use of MTT (tetrazolium 3-
[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide)
[19,20].
RESULTS AND DISCUSSION
Chemistry
8-Ethyl-4-methyl-2-(pyridin-4-yl)quinoline (13) obtained
1
in 30 % yield, mp 72-74°C. H NMR (CDCl3, 400 MHz), ꢀ
(ppm): 1.48 (t, 3H, J = 7.6 Hz, 8-CH2-CH3), 2.83 (d, 3H, J =
0.8 Hz, 4-CH3), 3.46 (c, 2H, J = 7.6, 7.3 Hz, 8-CH2-CH3),
7.57 (dd, 1H, J = 8.3, 7.1 Hz, 6-HQu), 7.66 (d, 1H, J = 7.1 Hz,
7-HQu), 7.83 (d, 1H, J = 0.8 Hz, 3-HQu), 7.92 (dd, 1H, J = 8.3,
1.5 Hz, 5-HQu), 8.25 (dd, 2H, J = 4.8, 1.7 Hz, Hꢁ,ꢁ’-Py), 8.82
(dd, 2H, J = 4.8, 1.8 Hz, Hꢂ,ꢂ’-Py). GC-MS: tR 34.97 min.,
m/z: 248 (M+). Anal. Calcd. for C17H16N2: C, 82.22; H, 6.49;
N, 11.28. Found: C, 82.12; H, 6.79; N, 11.07.
In the present work, three small series of sixteen
polyfunctionalized quinoline derivatives I, II and III (Table
1) were easily prepared from diverse aldehydes and anilines
[14-16] as shown in Scheme 1. The routes a and b involve
two-step synthesis of 2-(2-furyl)- or 2-(2-thienyl) quinolines
1-6 (type I) and 2-arylquinolines 7-10 (type II), respectively.
Based on our experience on Diels-Alder reactions, this
synthesis was built on BiCl3-catalyzed three component
imino Diels-Alder between respective anilines and
8-Propyl-4-methyl-2-(pyridin-4-yl)quinoline (14) obtai-
1
ned in 26 % yield, red oil. IR: 2960, 2926, 1596 cm-1. H
aldehydes,
and
N-vinylpyrrolidin-4-one
and
high
temperature oxidation process of Diels-Alder adducts with
elemental sulfur that allows to synthesize target quinolines in
good to excellent yields [14,15].
NMR (CDCl3, 400 MHz), ꢀ (ppm): 1.44 (d, 6 H, J = 7.0 Hz,
8-CH(CH3)2), 2.78 (d, 3H, J = 0.8 Hz, 4-CH3), 4.50 (sept,
1H, J = 7.0 Hz, 8-CH(CH3)2), 7.55 (dd, 1H, J = 7.0, 1.0 Hz,
6-HQu), 7.64 (dd, 1H, J = 7.0, 1.0 Hz, 7-HQu), 7.77 (s, 1H, 3-
HQu), 7.88 (dd, 1H, J = 8.0, 1.0 Hz, 5-HQu ), 8.13 (dd, 2H, J =
4.0, 1.0 Hz, Hꢁ,ꢁ’-Py), 8.77 (dd, 2H, J = 5.0, 2.0, Hz, Hꢂ,ꢂ’-Py).
GC-MS: tR 27.48 min., m/z: 262 (M+). Anal. Calcd. for
C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.45; H,
6.57; N, 10.89.
The route c consists also in two-step synthesis toward 2-
(4-pyridinyl)quinolines 11-16 (type III). However, the
synthesis is based on simple Schiff reaction and a Kametani
reaction between respective aldimines and 2,2-
dimethoxypropane that offers the 4-methyl-2-alkyl-(4-
pyridinyl)quinolines in moderate yields [16].
All target compounds were obtained in good to moderate
yields and were fully characterized by spectroscopic
techniques.
Biological Assays
The antitumor activity was determined according to the
method of Monks et al. [17,18]. The three human cells lines
[breast (MCF-7), non-small cell lung (H-460) and central
nervous system (SF-268), obtained from U.S. National
Cancer Institute] were counted, diluted with fresh medium
and added to 96-well microtiter plates (100 mL/well)
containing test materials (1 mg in 100 mL in DMSO). Test
plates were incubated for 2 days at 37 °C in a 5% CO2
incubator. All treatments were performed in duplicate. After
the incubation periods, cells were fixed by addition of 50 mL
of cold 50% aqueous TCA solution (4°C for 60 min.),
washed 4-5 times with tap water, and air-dried. The fixed
cells were stained with 100 mL sulforhodamine B (SRB)
(0.4 % wt/vol. in 1% acetic acid ) for 15 min. Free SRB
solution was then removed by rinsing with 1% acetic acid (x
5). The plates were then air-dried, the bound dye was
solubilized with 100 mL of 10 mM tris-base, and absorbance
was determined at 515 nm using an ELISA plate reader (Bio-
Tek Instruments, Inc. Model ELX-800). Finally, the
absorbance values obtained with each of the treatment
procedures were averaged, and the averaged value obtained
with the zero day control was substracted measuring in this
way the relative cell growth or inviability in treated and
untreated cells. From the curves, growth inhibition (or
growth stimulation) and 50% inhibition of growth (GI50) was
calculated. Adriamycin was used as the reference compound.
Table
1 reports some physicochemical properties
calculated, employing free available software Molinspiration
[21], for all our prepared and tested small quinoline
molecules, e.g. acid-ionization constant pKa, calculated
based on the ionization of the quinoline nitrogen atom,
solubility in water expressed as Log S, hydrogen bound
acceptors, hydrogen bound donors, lipophilicity Log P and
finally, equilibrium binding constant Keq.
These pharmacokinetic properties could be useful in
developing SARs, the cornerstone of drug discovery during
the lead optimization stage. These results demonstrated that
all prepared small quinoline molecules have a good
absorption and permeability profiles and similar Log Keq
values of reference anticancer drugs.
Biological Activity
Therefore, sixteen substituted quinolines 1-16 of the
series I-III were tested in cancer (MCF-7, H-460 and SF-
268) as well as in normal (Vero and THP-1) cell lines.
Antitumor activity was tested in human cancer cell lines:
MCF-7 (mammary glands), H-460 (non-small cell lung) and
SF-268 (CNS cancer) [17,18]. All compounds 1-16 were
tested in duplicate, thus the reported IC50 values are an
average of these two measurements. The compounds that
showed a growth rate of cancer cells (% G) < 50% in any of
the three cell lines were tested again at 5 concentrations to
The mammalian cell cytotoxicity was assessed in Vero
cell line (ATCC), derived from African green monkey
kidney and monocyte macrophage THP-1 (ATCC) trans-

Simple C-2-Substituted Quinolines and their Anticancer Activity
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 7 683
route a
X
R2
R2
X
R2
X
O
H
N
NH2
+
N
i
H
O
ii
40-80%
75-96%
R1
R1
R1
N
1-6
I
N
O
route b
R2
R2
R2
O
H
NH2
N
N
+
ii
H
i
50-80%
40-80%
R1
R1
R1
7-10
N
O
II
N
O
route c
R1
N
R1
N
R1
N
N
N
NH2
+
O
iv
20-30%
iii
H
70-90%
11-16
R2
R2
CH3
R2
III
Scheme 1. Reagents and conditions i) 20 mol% BiCl3, CH3CN, r.t., 10-14 h; ii) excess S8, ꢂ = mp. of THQ, 10 min. iii) CH3CH2OH, ꢂ; iv)
.
CH3-C(OMe)2-CH3, BF3 OEt2, CH2Cl2, reflux, 14 h.
determine finally the concentration that inhibits 50% of the
growth of cancer cells (IC50).
tumour cell lines MCF-7, H-460 and SF-268 and four
molecules were active against one and / or two lines (IC50
ꢀ
10 ꢁg/mL). Thus, indicating that these simple quinolines are
interesting models in the development of new antitumor
agents with possible noncovalent intercalation mode of
action in which the drug is held rigidly perpendicular to a
DNA helix axis. The current anti-cancer drugs - irinotecan
(CPT-11), adriamycin etc. can destroy the DNA regular
helical structure and thus, interfere with the action of DNA-
binding enzymes such as DNA topoisomerases [5,6,22].
Being flat, heteroaromatic molecules, the active quinolines
could bind also to DNA by intercalating and stacking
between the base pairs of the DNA double helix.
Biological results are shown in Table 2. These results
confirmed that in general, biological activity against cancer
cells depends on the chemical nature of the substituents R1,
R2 and the C-2 quinoline position of the ring. Comparing the
IC50 data for the compounds of series I, it could be noted that
the 2-(2-thienyl)quinoline molecules with strong electron
donating groups (MeO) (comp. 1,2) were more active, than
compound 5 with a weaker electron donating groups (Me).
When the same quinoline skeletons have an electron
withdrawing group (Cl), molecule becomes inactive (comp.
4). The same trend is preserved in series II where the
thiophene (or furan) ring was replaced by the benzene ring.
The compounds 7 and 8 with electron donating groups (Me
and Et) were active against all three cancer cell lines. While
the compounds 9,10 with chlorine and fluorine atoms (strong
electron withdrawing groups) lost anticancer activity.
The strength of reversible binding to DNA could be
quantified for any drug by means of its equilibrium binding
constant (Keq). Although, according to the work developed
by Portugal [23], exploring molecular descriptors such as
molecular weight and the number of hydrogen bond
donor/acceptor for drugs binding noncovalently to DNA, it is
possible to obtain important information about their DNA-
binding affinity and help in the design of new anticancer
agents with higher activity. This drug-DNA interaction can
be predicted with moderate accuracy from other known
physicochemical properties. Employing the equation
developed by Portugal [23], we decided to calculate the Log
Keq of our quinoline compounds in an attempt to correlate
their activity and possible mode of action (see table 1).
Despite the low hydrogen bond donor/acceptor number of
compounds 1-16, the calculated Log Keq were above those
values reported for different active compounds currently
used in chemotherapy (4.30 to 6.89) [23], indicating a major
Analyzing data from the quinoline molecules of series
III, the relationship between anticancer activity and
chemical nature of the substituents R1, R2 was clearly
observed. The compound 11, a pattern of this family, exerted
activity only on one cancer line, MCF-7. When the quinoline
skeleton possesses electron donating substituents (Me, Et, i-
Pr), anticancer activity becomes noticeable against the three
selected lines (comp. 12-14). However, this activity is lost by
introducing a strong electron withdrawing group (NO2) in
the aromatic quinoline system (comp. 15,16).
Among 16 tested quinoline derivatives, six molecules
(1,2,8,12-14) were found to be active against all three

684 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 7
Kouznetsov et al.
Table 1. In Silico Physico-Chemical Properties of the C-2 Aryl Substituted Quinoline Derivatives (1-16) and Reference Anticancer
Drugs
Mol
Compound
R1
R2
X
Type
MW
pKaa
Log Sb
nONc
nOHNHd
Log P
Log Keq
formula
1
MeO
MeO
MeO
Cl
H
MeO
MeO
H
S
S
O
S
S
O
-
I
I
C14H11NOS
C15H13NO2S
C15H13NO3
C13H8ClNS
C14H11NS
C14H11NO
C16H13N
241.3
271.3
255.2
245.7
225.3
209.2
219.2
233.3
239.7
223.2
220.2
234.3
248.3
262.3
279.3
307.3
543.5
348.3
5.16
5.16
5.16
5.16
5.16
5.16
4.99
4.99
3.80
3.80
4.00
5.06
5.06
5.06
2.66
2.66
11.0
2.33
-4.38
-4.06
-3.49
-4.76
-4.36
-3.79
-4.44
-4.60
-4.84
-4.41
-3.31
-3.99
-4.15
-4.52
-4.63
-5.16
-2.67
-2.83
3
4
4
2
2
2
1
1
1
1
2
2
2
2
2
2
12
9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
7
4
4.07
3.95
2.58
4.76
4.69
3.32
4.70
5.12
4.77
4.37
3.37
3.85
4.27
4.60
3.71
4.37
0.48
1.48
7.56
7.37
7.20
7.83
7.82
7.65
8.00
8.05
8.01
7.96
7.65
7.71
7.77
7.81
7.70
7.78
6.71
6.87
2
3
I
4
I
5
Me
Me
Me
Et
H
I
6
H
I
7
H
II
II
II
II
III
III
III
III
III
III
--
8
H
-
C17H15N
9
Cl
H
-
C15H10ClN
C15H10FN
C15H12N2
10
F
H
-
11
H
H
-
12
Me
Et
H
-
C16H14N2
13
H
-
C17H16N2
14
15
i-Pr
Me
i-Pr
---
H
-
C18H18N2
NO2
NO2
---
---
-
C16H13N3O2
C18H17N3O2
C27H29NO11
C20H16N2O4
16
-
Adriamycin
-
Camptothecin
---
-
--
aCalculated based on the quinoline nitrogen atom ionization. bSolubility in water. cHydrogen bound acceptors. dHydrogen bound donors.
affinity for DNA base pairs. Although some studies consider
that large and complex molecules are more potent antitumor
agents [24], it is worth noting that these drugs, as well as the
quinoline derivatives prepared here, have in common that
they are small noncovalent DNA binding molecules.
200 ꢁg/mL) (Table 2). In order to assess the possible
pharmacological properties of quinoline molecules 1-16, a
toxicity profile evaluation was performed employing the
OSIRIS software [25,26], as it may point to the presence of
some fragments generally responsible for the irritant (I),
mutagenic (M), tumorigenic (T), or reproductive (R) effects
in these molecules [27]. As shown in Table 2 all synthesized
products represented no biological risks in contrast to
camptothecin structure. Moreover, these molecules present
lower molecular weights and improved Log P values in
comparison to adriamycin as reference. These theoretical
data are a clear evidence of the biological potential of the
designed series and support the observed cytotoxicity results,
pointing these derivatives as lead compounds with a low
toxicity risk profile.
According to the activity results, among the three groups
of compounds it was observed that molecules with higher
Log Keq values and without electron withdrawing groups on
their structures tend to be more active against the tree cancer
cell lines evaluated (compare Log Keq for compounds 1, 8
and 14 with their families). This can be explained as a
stronger DNA-quinoline binding that provides a higher cell
growth inhibition. Moreover, in an attempt to relate the
bioassay results and the bioavailability expressed through the
calculated partition coefficient (Log P), it can be seen that :
1. all molecules have log P values lower than five according
to Lipinsky’s rule; 2. reference drugs have much more
pronounced lipophilic character than the analyzed quinolines
and 3. within the group of active molecules there are not
much differences between this parameter.
CONCLUSION
In conclusion, six of 16 quinoline derivatives showed
good anticancer activity. Three 2-ꢂ-furyl- and 2-ꢃ-pyridinyl
quinoline molecules 1,13 and 14 were active against three
human cancer cell lines (MCF-7, H-460 and SF-268) and, at
the same time, were devoid of cytotoxic effect on normal
cells (Vero and THP-1). This preliminary work builds a basis
Commenting on the nonspecific cytotoxicity against
VERO cells and THP-1 macrophages, it may be noted that at
least three active molecules (comp. 1, 13 and 14) exhibit
very low general cytotoxicity (LC50 from 167.9 ± 2.1 to ꢀ

Simple C-2-Substituted Quinolines and their Anticancer Activity
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 7 685
Table 2. Biological Activities of the Prepared Quinolines
Cytotoxicity
Unspecific cytotoxicity12
Toxic effects
in silico***
Comp.
Structure
IC50 (ꢀg/mL)
LC50 (ꢀg/mL)
MCF-7
2.5
H-460
SF-268
4.1
Vero
THP-1
M
T
I
R
S
N
1
2
3
4
3.3
4.1
167.9 ± 2.1
>200
H3CO
OCH3
S
N
4.3
5.4
99.8 ± 12.1
>200
172.8 ± 13.6
203.4 ± 3.4
>200
H3CO
OCH3
O
N
55.1
21.4
64.6
35.0
72.5
38.8
H3CO
S
N
103.2 ± 3.4
Cl
S
N
5
6
5.9
7.8
12.0
51.2
5.8
26.3
60.8
58.2
6.5
>200
>200
nd*
nd
>200
>200
nd
H3
C
O
N
H3
C
N
7
5.9
H3
C
N
8
4.0
4.8
nd
H3CH2
C
N
9
56.5
24.9
57.8
49.4
71.5
48.1
nd
nd
Cl
N
10
nd
nd
F
N
N
11
12
13
9.0
4.1
3.6
10.0
4.2
10.0
5.9
nd
nd
nd
nd
CH3
CH3
N
N
CH3
CH3
N
N
3.4
4.1
>200
>200
CH3
H3C
CH3
N
N
14
15
16
3.3
3.8
3.7
>200
>200
>200
>200
>200
>200
CH3
CH3
N
N
74.8
81.8
53.3
98.2
72.3
NO2 CH3
H3
C
CH3
N
N
56.4
NO2 CH3
Adriamycin
0.16 ± 0.1
0.18 ± 0.2
0.065**
0.14 ± 0.1
nd
6.50 ± 2.80**
nd
nd
nd
0.69
(ng/mL)
Camptothecin
* Not determined; ** The data are from the literature; *** Calculated by OSIRIS software; Non risk associated;
Medium risk;
High risk.
for the design and development of new chemotherapeutic
ACKNOWLEDGEMENTS
agents bearing the quinoline skeleton, whose representatives
are easy to prepare by means of controlling its synthetic
route. Bioassay analysis and computational study showed
promising drug-like properties. Additionally, these
compounds were easy and inexpensive to prepare.
This research was financed by Universidad Industrial de
Santander (VIE-UIS, project 5176) and the National
Secretariat of Science, Technology and Innovation of
Panama (SENACYT). LYMV thanks COLCIENCIAS for
the fellowship. Thanks are due to SENACYT of Panama for
Supporting National System of Investigators.
CONFLICT OF INTEREST
Declared none.

686 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 7
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