Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity

Article abstract of DOI:10.1016/j.ejmech.2012.08.039

Novel quinoline-2-one based chalcones were synthesized from a Claisen-Schmidt condensation by using the couple KOH/1,4-dioxane as reaction medium. A relatively stable aldol was isolated and identified as the intermediate species in the formation of the target chalcones. Nine of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines. Products 16c, 16d, 16h and 27 exhibited the highest activity, being compound 27 the most active, displaying remarkable activity against 50 human tumor cell lines, thirteen of them with GI₅₀ values ≤1.0 μM, being the HCT-116 (Colon, GI₅₀ = 0.131 μM) and LOX IMVI (Melanoma, GI₅₀ = 0.134 μM) the most sensitive strains. Compound 27 was referred to in vivo acute toxicity and hollow fiber assay by the Biological Evaluation Committee of the NCI. The acute toxicity study indicated that compound 27 was well tolerated intraperitoneally (150 mg/kg/dose) by athymic nude mice. This compound may possibly be used as lead compound for developing new anticancer agents.

Full text of DOI:10.1016/j.ejmech.2012.08.039

European Journal of Medicinal Chemistry 57 (2012) 29e40
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor
activity
,
a
a
a
a
b
Rodrigo Abonia a , Daniel Insuasty , Juan Castillo , Braulio Insuasty , Jairo Quiroga , Manuel Nogueras ,
*
Justo Cobo b
a Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A.A. 25360 Cali, Colombia
b Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel quinoline-2-one based chalcones were synthesized from a ClaiseneSchmidt condensation by using
the couple KOH/1,4-dioxane as reaction medium. A relatively stable aldol was isolated and identified as
the intermediate species in the formation of the target chalcones. Nine of the obtained compounds were
in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human
tumor cell lines. Products 16c, 16d, 16h and 27 exhibited the highest activity, being compound 27 the
most active, displaying remarkable activity against 50 human tumor cell lines, thirteen of them with GI50
Received 15 June 2012
Received in revised form
27 August 2012
Accepted 28 August 2012
Available online 6 September 2012
values ꢀ1.0
m
M, being the HCT-116 (Colon, GI50 ¼ 0.131
m
M) and LOX IMVI (Melanoma, GI50 ¼ 0.134
mM)
Keywords:
Quinoline-2-one derivatives
Acetophenones
ClaiseneSchmidt condensation
Chalcones
the most sensitive strains. Compound 27 was referred to in vivo acute toxicity and hollow fiber assay by
the Biological Evaluation Committee of the NCI. The acute toxicity study indicated that compound 27 was
well tolerated intraperitoneally (150 mg/kg/dose) by athymic nude mice. This compound may possibly be
used as lead compound for developing new anticancer agents.
Anti-tumor agents
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
[8]. It has been found that their biological activities may be
enhanced by the insertion of heterocyclic rings in their structures
Cancer represents one of the most serious clinical problems in
the world and its incidence is rising in developing as well as
developed countries. Apart from the utility of surgical operations
and irradiation, chemotherapy still remains an important option for
the management of cancer [1]. Among the wide range of
compounds tested as potential anticancer agents, derivatives
[9]. The presence of the indole ring in chalcones 2 (R, R1, R2 ¼ OMe;
R, R2 ¼ H, R1 ¼ N(Me)2) increased significantly their anti-tumor
activities [10]. Recently we found that the presence of the pyr-
azole ring in chalcones 3 was convenient for their anti-tumor
activities displayed. Particularly substituents R ¼ NO2 and R1 ¼ Cl
showed the highest activity [11] (Fig. 1).
comprising functionalities as
a,
b-unsaturated Michael acceptor
Curcumin 4 is a naturally occurring b-diketonic yelloweorange
have attracted reasonable attention. Previous evidences suggest
that anticancer compounds such as alkylating agents bind directly
to various cellular nucleophiles, thus lacking selectivity. Mean-
while, Michael acceptors can be structurally modified, so that they
can react selectively with target nucleophiles [2]. A group of
representative natural and synthetic cytotoxic compounds con-
taining Michael acceptors are conjugated enones or enone-like
compounds such as chalcones and bis-chalcones.
dye isolated from the root of the Curcuma longa Linn (zingiberaceae).
Its versatile biological properties as anti-inflammatory [12], anti-
oxidant [13], antiviral [14] but mainly its chemopreventive and
anti-carcinogenic activities [15], have inspired a growing number of
scientist pursuing for the design, synthesis and anti-tumor studies
of novel symmetric and unsymmetric curcumin mimic derivatives,
based mainly in bis-arylideneketones. Structures 5e9 represent
some of such examples [16] (Fig. 2). It has been postulated that the
broad spectrum of anti-carcinogenic activity of curcumin and its
curcuminoid relatives may be due in part to an angiogenesis inhi-
bition mechanism [17], probably associated with their Michael
acceptor character
Chalcones 1 are synthetic or naturally occurring a,b-unsaturated
diaryl ketones which have shown a wide spectra of biological
activities, as antibacterial [3], antifungal [4], anti-tubercular [5],
anti-inflammatory [6], antimalarial [7], and mainly as antitumor
Quinolines and their oxo-derivatives have attracted consider-
able interest for many years due to their presence in the skeleton of
a large number of bioactive compounds and natural products [18].
Particularly the 3-substituted quinolin-2-one is an important
* Corresponding author. Fax: þ57 2 3393248.
E-mail address: rodrigo.abonia@correounivalle.edu.co (R. Abonia).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.08.039

30
R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
Fig. 1. Some chalcone derivatives of biological interest.
Fig. 3. Some quinoline-2-one based compounds with anti-tumor properties.
moiety which is found in a number of compounds with interesting
anti-tumor activities. Tyrosine kinases are a class of enzymes that
catalyze the transfer of the terminal phosphate of adenosine
triphosphate to tyrosine residues in protein substrates. They have
been shown to be important contributing factors in cell prolifera-
tion, carcinogenesis and cell differentiation. In this sense, several
types of compounds have been developed as inhibitor of tyrosine
kinase KDR receptors and currently are in clinical stage [19].
Between them, quinoline-2-one based compounds have recently
merged as promising and effective leader structures for KDR kinase
inhibition mechanism. Compounds 10e13 represent some exam-
ples of these quinoline-2-one based anti-tumor agents [20],
including a series of benzimidazoloquinolin-2-ones 13 recently
reported by us [20c,d] (Fig. 3).
Continuing with our current studies directed toward the
synthesis of potential anti-tumor agents [11,20c,d], herein we visu-
alized the possibility of combine the synergic anti-carcinogenic
effects of the Michael acceptors and the quinoline-2-one moiety
whiting a same structure, through the synthesis of the novel quin-
oline-2-one based chalcones 16, pursuing for an improvement of
their possibilities as anti-tumor agents, for such new compounds.
2. Results and discussion
2.1. Chemistry
The typical procedure for the synthesis of chalcones consists on
a ClaiseneSchmidt condensation of acetophenones and benzalde-
hydes in alcoholic solutions using alkali as catalyst [21]. Applying
this procedure to 4-bromoacetophenone 14a and 3-formylquinolin-
2-one 15 as our model reaction, Table 1, initially, the stirring of an
equimolar mixture of both compounds in ethanol, at ambient
temperature, in the presence of 10% aq NaOH afforded, after 5 h of
stirring, a white solid along with part of unreacted aldehyde 15. This
reaction proceeded in heterogeneous phase all time, being the low
solubility of aldehyde 15 in ethanol the main limiting to allow the
reaction reaches the completion. Nevertheless, the white solid was
isolated and purified after several washes with warm ethanol.
Surprisingly, after a complete spectroscopic analysis the structure of
this solid corresponded to the respective aldol intermediate 17a but
not to the expected chalcone 16a. Repeating this reaction with 4-
nitroacetophenone 14b also afforded to its corresponding aldol
intermediate 17b in similar manner, as a paled yellow solid.
Fig. 2. Curcumin 4 and some curcumin mimic derivatives with anti-tumor properties.

R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
31
Table 1
In all cases reactions proceeded with the same behavior, affording
the expected chalcones 16bej in excellent yields (Table 2).
According to the scheme depicted in the Table 1, aldols 17 are
proposed as intermediate for the formation of products 16. The
main 1H NMR signal of aldols 17a,b corresponded to a broad singlet
at 5.43[5.23] ppm assigned to the OH functionality and the CH and
CH2 aliphatic protons appearing as a AMX system at 3.07[3.19] ppm
(dd, Jgem ¼ 15.3[15.1] Hz, Jvic ¼ 9.3[9.5] Hz, 1H), 3.42[3.53] ppm
(dd, Jgem ¼ 15.3[15.2] Hz, Jvic ¼ 2.8[1.5] Hz, 1H) and 5.24
[5.55] ppm (dd, Jvic ¼ 9.2[9.5] Hz, Jvic ¼ 2.6[1.2] Hz, 1H), respec-
tively. Signals in brackets correspond to aldol 17b. In order to
confirm such intermediacy, after run the NMR spectra at ambient
temperature and confirm the structures 17a,b, subsequently, the
probe of the NMR machine was heated at 80 ꢁC with the samples
17a,b inside, and after cooling the NMR experiments were repeated
for the same two samples, to try to induce, in situ, the dehydration
of 17a,b. After three consecutive (heatingecooling) run the OH and
the aliphatic CH and CH2 signals disappeared completely in both
samples, and the new 1H , 13C NMR spectra unambiguously
matched with the structure of their corresponding chalcones 16a
and 16b. The increasing of the intensity of the water signal in
spectrum (b), Fig. 4, supports the dehydration process. The new AX
system in the 1H NMR spectra with two signals at 7.80[7.81] (d,
J ¼ 15.6[16.1] Hz, 1H) and 8.24[8.30] (d, J ¼ 15.6[15.6] Hz, 1H)
assigned to the new vinylic protons agrees with the proposed
structure for 16a,b. Signals in brackets correspond to chalcone 16b.
Fig. 4 shows the comparison of the 1H NMR spectra of aldol 17a
before (a) and after (b) heating into the probe of the NMR machine.
Furthermore, the melting points of aldols 17a and 17b were the
same than those of chalcones 16a and 16b respectively, indicating
their chemical transformations by thermal dehydration into the
melting point apparatus. These finding also agree with the inter-
mediate character of aldols 17a,b in the ClaiseneSchmidt conden-
sation process.
Optimization of reaction conditions for the synthesis of quinolinic chalcones 16a,b.
Entry Acetophenone Reaction conditions
Time Product Yield (%)
(h)
1
2
14a
14b
10% NaOH, EtOH, rt
10% NaOH, EtOH, rt
5
5
17a
17b
76/white
68/pale
yellow
3
4
14a
14a
20% NaOH, EtOH, 70 ꢁC
20% w/w A-15, AcOH,
110 ꢁC
KOH (1.6 mmol), 1,4-
dioxane, rt
60
30
16a
16a
64/yellow
69/yellow
5
6
14a
14a
4
16a
92/yellow
NaOH (1.6 mmol), 1,4-
dioxane, rt
120
ea
e
a
A complex mixture of aldol 17a, unreacted aldehyde 15, small amount of 16a
and unknown products was obtained.
Trying to overcome the above drawback our model reaction was
repeated in harder reaction conditions, by heating the solution at
70 ꢁC and using 20% aq NaOH. The expected product 16a was iso-
lated in 64% yield just until 60 h of heating, along with some of
unreacted aldehyde 15. Although product 16a was obtained directly
without isolation of the aldol intermediate 17a, the main limitation
of this approach was the long reaction time. Aimed to improve the
reaction yields of compound 16a and trying to avoid the limitation
of the low solubility of aldehyde 15 in ethanol, our model reaction
was carried out in acidic media [22,23]. Thus, an equimolar mixture
of acetophenone 14a and aldehyde 15, dissolved in AcOH, was
heated at 110 ꢁC in the presence of Amberlyst-15Ò (A-15) [23]. All
starting aldehyde 15 and ketone 14a dissolved and the reaction was
completed after 30 h of heating (TLC control). After cooling product
16a precipitated difficulting its separation from the Amberlyst-15Ò.
Finally product 16a could be mechanically isolated in 69% yield
from the Amberlyst-15Ò. This time-consuming approach encour-
ages us to continue exploring for a more efficient approach. Finally,
the mixture of compounds 14a and 15 was completely dissolved in
1,4-dioxane at ambient temperature, solid KOH (1.6 mmol) was
added and the solution was stirred for 4 h until completion, (TLC)
control. Then, solvent was removed under reduced pressure and
the crude resultant was washed with water (2 ꢂ 3 mL), then with
ethanol (2 ꢂ 3 mL) and dried under vacuum to afford the expected
product 16a in 92% isolated yield. This last approach turned optimal
for our goals because of softer reaction conditions, easier work-up
and higher reaction yields than the above. Repeating the same
reaction but switching KOH by NaOH (entry 6), afforded to
a complex mixture of products. Table 1 resumes all experiment
carried out for finding the optimal reaction conditions for the
synthesis of chalcone 16a.
Table 2
Synthesis and analytical data of the new quinoline-2-one based chalcones 16.
Entry
Product 16
Ar
p-BrC6H4
p-NO2C6H4
p-ClC6H4
p-CH3OC6H4
C6H5
Yield (%)a
Mp (ꢁC)
1
2
3
4
5
6
7
a
b
c
d
e
f
93
95
91
93
93
85
85
279e280
304e305
277e278
260e261
273e274
294e295
269e270
p-FC6H4
g
8
9
h
i
p-HOC6H4
p-CH3C6H4
87
91
329e330
266e267
10
j
95
316e317
In order to explore the generality and scope of the approach
described in entry 5, (Table 1), ClaiseneSchmidt condensations of
aldehyde 15 with various acetophenones 14bej were tested under
the conditions found to be optimal for 4-bromoacetophenone 14a.
a
Isolated yield.

32
R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
DMSO
CH2
CH
a
OH
12
11
10
9
8
7
6
5
4
3
2
1
0
ppm
H2O
DMSO
b
12
11
10
9
8
7
6
5
4
3
2
1
0
ppm
Fig. 4. Comparison of the 1H NMR spectra of aldol 17a (a) before heating into the probe of the NMR machine and (b) after heating.
A particularity of aldols 17 was their marked stabilities in solid
In order to expand the scope of our optimized protocol, the
state at ambient temperature. This fact should be explained in
terms of their abilities to form intra-molecular hydrogen bonding,
as shown in Fig. 5. Although some aldols 19, originated from aldol
condensations, have been isolated and identified [24]; certainly this
fact is usually rare because of their low chemical stabilities. Both
species 17 and 19 could form intra-molecular hydrogen bonding
through their ketonic carbonyl functionalities, but probably aldols
17 are more stable than 19 due to their capabilities to form a second
hydrogen bonding by the presence of the quinoline-amidic
carbonyl group in their structures, through species 18.
synthesis of indandione-chalcone 24 and the bis-arylideneketones
26 and 27 was planned. All three products were readily obtained in
82%, 87% and 91% yields, from the reaction of one and two equiv-
alents of aldehyde 15 with indandione 20, 1,4-diacetylbenzene 22
and acetone 23 respectively. In the case of compound 25, two
equivalents of dimedone 21 reacted with one of aldehyde 15
affording the 1:2 adduct 25 even when the reaction was performed
with an equimolar mixture of 15 and 21. In this experiment adduct
25 was obtained along with unreacted aldehyde 15. The impossi-
bility of isolate the 1:1 adduct indicates that a second molecule of
dimedone 21 rapidly effected a Michael addition over the 1:1
adduct as soon as it was formed. The optimized 1:2 ratio of 15 and
21 afforded compound 25 in 88% yield (Scheme 1).
Products 16aej and 24e27, also were characterized by analytical
and spectroscopic methods (elemental analyses, FT-IR, 1H , 13C 1D
and 2D NMR and EIMS) as summarized in experimental section.
The most relevant feature in the MS spectra of compounds 16aej
and 24e27 corresponded to a common base peak of 170 u.m.a,
assigned to the particularly stable furanic species 28 depicted in
Scheme 2.
3. Pharmacology
3.1. In vitro anticancer activity
The two-stage screening process started with a primary in vitro
evaluation of nine of the obtained compounds (i.e. 16c (NSC:
752191), 16d (NSC: 752192), 16g (NSC: 755788), 16h (NSC: 755790),
16j (NSC: 755789), 24 (NSC: 759499), 25 (NSC: 756788), 26 (NSC:
755791) and 27 (NSC: 752193)) selected by the Drug Evaluation
Branch of National Cancer Institute (NCI), Bethesda, MD, against 60
Fig. 5. Structure of aldol 17 showing its ketonic carbonyl and quinoline-amidic
carbonyl intramolecular hydrogen bonds.

R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
33
Scheme 1. Synthesis of novel quinoline-2-one derivatives 24e27 following the same procedure developed for chalcones 16.
human tumor cell lines at a single dose of 10
m
M. The 60 cell panel is
plates were incubated at 37 ꢁC, 5% CO2, 95% air and 100% relative
humidity for 24 h prior to addition of experimental drugs. After
24 h, two plates of each cell line are fixed in situ with TCA, to
represent a measurement of the cell population for each cell line at
the time of drug addition (Tz). Experimental drug was solubilized in
dimethyl sulfoxide at 400-fold the desired final maximum test
concentration and stored frozen prior to use. At the time of drug
addition, an aliquot of frozen concentrate is thawed and diluted to
twice the desired final maximum test concentration with complete
derived from nine different cancer types: Leukemia, lung, mela-
noma, colon, CNS, ovary, renal, breast and prostate cancers. The
output from the single dose screen was reported as a mean graph
available for analysis by the COMPARE program [25]. Results of this
primary assay, after a threshold inhibition criteria, suggested that
compounds 16c, 16d, 16h and 27 (Table 2 and Scheme 1), were
declared as active.
Subsequently, due to compounds 16c, 16d, 16h and 27 displayed
considerable antiproliferative activity, they were selected for an
advanced assay against the full 60 cell panel at five concentrations
at 10-fold dilution (i.e. 100, 10, 1.0, 0.1 and 0.001
tumor cell lines of the cancer screening panel were grown in RPMI
1640 medium containing 5% fetal bovine serum and 2 mM
glutamine. For a typical screening experiment, cells were inocu-
lated into 96 well microtiter plates in 100 L at plating densities
medium containing 50
or ½ log serial dilutions are made to provide a total of five drug
concentrations plus control. Aliquots of 100 L of these different
drug dilutions are added to the appropriate microtiter wells already
containing 100 L of medium, resulting in the required final drug
mg/mL gentamicin. Additional four, 10-fold
mM). The human
m
L-
m
concentrations. More details of this evaluation method and the
complementary information which is encoded by the activity
pattern over all cell lines have been published elsewhere [26].
The testing results were expressed according to the following
three dose response parameters: Growth inhibition of 50% (GI50),
which is the molar drug concentration resulting in a 50% reduction
in the net protein increase (as measured by SRB staining) in control
cells during the drug incubation, the molar drug concentration
resulting in total growth inhibition (TGI), and the molar concen-
tration of drug resulting in a 50% reduction in the measured protein
(LC50), at the end of the drug treatment as compared to that at the
beginning [27]. Furthermore, a mean graph midpoint (MG_MID) is
calculated for each of the mentioned parameters, giving an aver-
aged activity parameter over all cell lines. For the calculation of the
m
ranging from 5,000 to 40,000 cells/well depending on the doubling
time of individual cell lines. After cell inoculation, the microtiter
Scheme 2. Main fragmentation pattern of chalcones 16 and their analogs 24e27
observed from their mass spectra.

34
R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
MG_MID, insensitive cell lines are included with the highest
concentration tested. Selectivity of the compounds with respect to
one or more cell lines of the screen is characterized by a high
being utilized as the initial in vivo experience for agents found to
have reproducible activity in the in vitro anticancer drug screen.
deviation (D) of the particular cell line parameter compared to the
3.2.3. Methodology of the hollow fiber assay
MG_MID value.
A standard panel of 12 tumor cell lines is used for the routine
hollow fiber screening of the in vitro active compounds. These
include NCI-H23, NCI-H522, MDA-MB-231, MDA-MB-435, SW-620,
COLO 205, LOX, UACC-62, OVCAR-3, OVCAR-5, U251 and SF-295. In
addition, alternate lines can be used for specialized testing of
compounds on a nonroutine basis. The cell lines are cultivated in
RPMI-1640 containing 10% FBS and 2 mM glutamine. On the day
preceeding hollow fiber preparation, the cells are given a supple-
mentation of fresh medium to maintain log phase growth. For fiber
preparation, the cells are harvested by standard trypsinization
technique and resuspended at the desired cell density (2e10 ꢂ 106
cells/mL). The cell suspension is flushed into 1 mm (internal diam-
eter) polyvinylidene fluoride hollow fibers with a molecular weight
exclusion of 500,000 Da. The hollow fibers are heat-sealed at 2 cm
intervals and the samples generated from these seals are placed into
tissue culture medium and incubated at 37 ꢁC in 5% CO2 for 24e48 h
prior to implantation. A total of 3 different tumor lines are prepared
for each experiment so that each mouse receives 3 intraperitoneal
implants (1 of each tumor line) and 3 subcutaneous implants (1 of
each tumor line). On the day of implantation, samples of each
tumor cell line preparation are quantitated for viable cell mass by
a stable endpoint MTT assay so that the time zero cell mass is
known. Mice are treated with experimental agents starting on day
3 or 4 following fiber implantation and continuing daily for 4 days.
Each agent is administered by intraperitoneal injection at 2 dose
levels. The doses are based on the maximum tolerated dose (MTD)
determined during prior acute toxicity testing. The fibers are
collected from the mice on the day following the fourth compound
treatment and subjected to the stable endpoint MTT assay. The
optical density of each sample is determined spectropho-
tometrically at 540 nm and the mean of each treatment group is
calculated. The percent net growth for each cell line in each
treatment group is calculated and compared to the percent net
growth in the vehicle treated controls. A 50% or greater reduction
in percent net growth in the treated samples compared to the
vehicle control samples is considered a positive result. Each
positive result is given a score of 2 and all of the scores are totaled
for a given compound. The maximum possible score for an agent is
96 (12 cell lines ꢂ 2 sites ꢂ 2 dose levels ꢂ 2 [score]). A compound
is considered for xenograft testing if it has a combined ip þ sc
score of 20 or greater, a sc score of 8 or greater, or produces cell
kill of any cell line at either dose level evaluated. Then, compound
27 was tested against the following disease types and cell lines as
shown in Table 5.
Table 3 shows that compound 16c displayed good activity
against 57 human tumor cell lines, being SR (Leukemia,
GI50 ¼ 1.71
(Renal, GI50 ¼ 1.60
16d displayed good activity against 53 human tumor cell lines,
being LOX IMVI (Melanoma, GI50 ¼ 1.85 M) and CAKI-1 (Renal,
GI50 ¼ 1.78 M) the most sensitive strains. Table 4 shows that
compound 16h displayed good activity against 57 human tumor
cell lines, being SR (Leukemia, GI50 ¼ 1.66 M), NCI-H522 (Non-small
cell lung cancer, GI50 ¼ 1.70 M); HCT-116, KM12 and SW-620
(Colon, GI50 ¼ 1.94, 1.89 and 1.89 M, respectively), RXF 393
M) the most
mM), OVCAR-4 (Ovarian, GI50 ¼ 1.67
mM) and CAKI-1
M) the most sensitive strains, and compound
m
m
m
m
m
m
(Renal, GI50 ¼ 1.65
m
M) and BT-549 (Breast, GI50 ¼ 1.95
m
sensitive strains. Likewise, compound 27 displayed the most
remarkable activity against 50 human tumor cell lines, thirteen of
them with GI50 values ꢀ1.0
m
M. The HCT-116 (Colon,
GI50 ¼ 0.131
m
M) and LOX IMVI (Melanoma, GI50 ¼ 0.134
mM) were
the most sensitive strains. The cytotoxic effects associated with
compounds 16c, 16d, 16h and 27 were measured as LC50 displaying
values greater than 100 mM for most of the cell lines evaluated,
indicating a low toxicity of these compounds for normal human cell
lines, as required for development of potential antitumor agents.
3.2. In vivo evaluations
Owing to the remarkable activity displayed by compound 27, it
was subjected to two repetition tests and after that it was referred
to the Biological Evaluation Committee of the NCI, for in vivo acute
toxicity and hollow fiber assays.
3.2.1. Acute toxicity description
Generally, MTD determinations are done in a way that conserves
compound and limits the number of animals used to the barest
minimum possible. Thus, a single athymic nude mouse is given
a single injection intraperitoneally (IP) of 400 mg/kg; a second
mouse receives a dose of 200 mg/kg and a third mouse receives
a single dose of 100 mg/kg. Dose volumes are generally 0.1 mL/10 g
body weight and the mice are allowed ad libitum feed and water.
The mice are observed for a period of 2 weeks. They are sacrificed if
they lose more than 20% of their body weight or if there are other
signs of significant toxicity. If all 3 mice must be sacrificed, then the
next 3 dose levels (50, 25, 12.5 mg/kg) are tested in a similar way.
This process is repeated until a tolerated dose is found. This dose is
then designated the maximum tolerated dose (MTD) and is used to
calculate the amount of material given to experimental mice during
anti-tumor testing. Assays showed that the highest dose resulted in
no body weight loss or lethality, indicating that compound 27 was
well tolerated.
Although not further in vivo assays were programmed by the
Biological Committee of the NCI, it is worth mentioning that the
remarkable in vitro antitumor activity displayed by the bis-aryli-
deneketone 27 could be related to its closely structural relationship
with its curcumin mimic analogs depicted in Fig. 2. An angiogenesis
inhibition mechanism associated with its Michael acceptor char-
acter, probably is the responsible of such activity [17].
3.2.2. Hollow fiber assay
Advancement of potential anticancer agents from identification
in the in vitro screen to preclinical development is enhanced with
demonstration of in vivo efficacy in one or more animal models of
neoplastic disease. Most such models require considerable mate-
rials in terms of laboratory animals and test compound as well as
substantial amounts of time and cost to determine whether a given
experimental agent or series of agents have even minimal anti-
tumor activity. The hollow fiber assay has demonstrated the
ability to provide quantitative indices of drug efficacy with
minimum expenditures of time and materials and is currently
According to literature [28], pyrazolic derivatives of chalcones
have also displayed high anticancer activity. For that reason we
decided to obtain the pyrazolo-derivatives 29c,d by treatment of
the active chalcones 16c,d with thiosemicarbazide, following
a previously reported procedure [29] (Scheme 3), aimed to increase
their activities through their pyrazolic derivatives 29. Both
compounds 29c (NSC: 755793) and 29d (NSC: 755792) were eval-
uated in vitro by the NCI. After assays activities of compounds 29c,d
were lower than their starting chalcones 16c,d and were declared
inactives. Probably the presence of the a,b-unsaturated moiety is

R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
35
Table 3
In vitro testing expressed as growth inhibition of cancer cells by compounds 16c and 16d.
Panel/cell line
Compoundsa
16c
16d
b
c
b
c
GI50
(
m
M)
TGI (
m
M)
LC50
(
mM)
GI50
(
m
M)
TGI (
m
M)
LC50 (mM)
Leukemia
RPMI-8226
SR
CCRF-CEM
HL-60 (TB)
MOLT-4
Non-small cell lung cancer
EKVX
2.23
1.71
3.50
2.47
3.11
16.1
19.1
>100
>100
>100
>100
>100
>100
>100
>100
2.79
2.83
4.04
3.36
3.39
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
4.92
7.43
11.6
5.37
3.99
2.23
5.74
13.4
7.24
>100
44.2
38.9
93.3
18.9
6.58
50.5
79.0
>100
>100
>100
>100
>100
>100
47.2
>100
>100
>100
4.40
3.68
5.57
2.90
2.75
2.12
2.97
e
83.8
11.6
>100
14.9
8.34
6.13
8.76
e
>100
59.0
>100
>100
66.8
>100
80.9
e
HOP-62
NCI-H226
NCI-H23
NCI-H460
NCI-H522
HOP-92
NCI-H322M
A549/ATCC
Colon
3.21
>100
>100
COLO 205
HCT-116
HCT-15
HT29
KM12
SW-620
HCC-2998
CNS
10.1
3.26
3.18
3.84
3.23
3.38
6.55
51.3
14.8
20.2
22.5
16.3
12.1
22.3
>100
66.5
>100
>100
98.9
3.66
2.31
3.18
3.67
2.85
3.41
2.5
13.4
5.70
21.1
>100
7.81
8.89
6.49
77.6
31.6
>100
>100
26.9
40.2
29.0
56.6
59.6
SF-295
SF-539
U251
SF-268
SNB-19
SNB-75
4.57
2.07
2.52
7.15
5.11
6.21
38.3
8.02
11.4
63.1
>100
48.8
>100
74.2
39.7
>100
>100
>100
3.98
2.76
2.70
2.85
4.20
2.29
18.6
7.49
10.9
9.77
19.1
10.1
80.8
45.5
>100
40.7
75.8
47.2
Melanoma
LOX IMVI
MALME-3M
MDA-MB-435
SK-MEL-5
UACC-257
UACC-62
SK-MEL-2
M14
3.26
9.42
2.83
18.9
7.78
5.71
8.55
7.54
17.7
22.1
35.3
13.1
>100
46.9
54.3
25.7
39.7
72.5
>100
>100
>100
>100
>100
>100
72.6
1.85
e
5.54
e
33.3
e
3.92
5.73
4.90
4.38
3.91
4.06
7.59
17.4
18.1
18.0
19.3
40.1
22.5
30.6
91.6
45.0
65.5
60.2
>100
>100
>100
>100
>100
SK-MEL-28
Ovarian
IGROV1
3.71
5.90
1.67
4.00
4.93
12.7
19.7
14.7
30.9
>100
23.6
21.2
97.0
>100
50.7
e
e
e
OVCAR-3
OVCAR-4
NCI/ADR-RES
OVCAR-8
OVCAR-5
SK-OV-3
Renal
>100
>100
>100
88.4
>100
>100
2.49
2.94
2.63
3.57
3.60
4.44
6.72
>100
8.44
>100
18.4
>100
29.8
>100
>100
>100
>100
>100
ACHN
CAKI-1
RXF 393
SN12C
TK-10
7.27
1.60
4.32
8.16
5.05
5.27
13.8
27.4
3.3
90.6
6.8
3.93
1.78
3.41
3.17
3.54
e
16.7
3.51
8.53
>100
55.8
e
57.0
6.90
33.5
>100
>100
e
29.9
>100
20.8
>100
>100
>100
>100
75.8
>100
>100
UO-31
786-0
3.52
>100
>100
Prostate
DU-145
4.08
48.9
>100
3.14
11.2
35.8
Breast
MCF7
MDA-MB-231/ATCC
BT-549
T-47D
MDA-MB-468
HS 578T
2.41
6.16
3.86
7.31
2.96
11.1
>100
28.3
17.1
>100
9.88
>100
>100
>100
97.6
>100
53.2
2.86
3.29
2.70
3.55
2.38
3.30
88.7
17.9
7.90
>100
5.98
>100
>100
>100
46.3
>100
39.8
>100
>100
a
Data obtained from NCI’s in vitro disease-oriented human tumor cell lines screen [27].
b
GI50 was the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation,
determined at five concentration levels (100, 10, 1.0, 0.1 and 0.001 M).
LC50 is a parameter of cytotoxicity and reflects the molar concentration needed to kill 50% of the cells.
m
c

Table 4
In vitro testing expressed as growth inhibition of cancer cells by compounds 16h and 27.
Panel/cell line
Compoundsa
16h
27
b
c
b
c
GI50
(
mM)
TGI (
mM)
LC50
(
mM)
GI50
(
m
M)
TGI (
m
M)
LC50 (mM)
Leukemia
RPMI-8226
SR
CCRF-CEM
HL-60 (TB)
K-562
MOLT-4
Non-small cell lung cancer
EKVX
HOP-62
NCI-H226
NCI-H23
NCI-H460
NCI-H522
HOP-92
NCI-H322M
A549/ATCC
Colon
3.20
1.66
2.38
2.66
3.89
3.04
24.8
e
>100
>100
>100
>100
>100
>100
0.341
1.14
0.697
3.38
e
>100
>100
>100
>100
e
>100
>100
>100
>100
e
>100
6.86
>100
9.91
2.27
>100
>100
13.4
2.62
3.29
3.18
2.39
1.70
3.26
3.98
2.73
27.2
8.17
10.9
20.0
6.87
3.29
23.2
16.8
11.8
55.2
85.2
34.5
>100
>100
6.36
>100
55.5
89.9
2.61
3.65
2.77
2.42
4.63
2.52
>100
e
>100
>100
8.01
87.7
>100
e
>100
>100
>100
>100
>100
>100
>100
e
>100
e
0.764
e
>100
COLO 205
HCT-116
HCT-15
HT29
KM12
SW-620
HCC-2998
CNS
4.05
1.94
2.71
3.61
1.89
1.89
4.13
19.7
4.38
12.8
12.1
4.50
4.45
22.3
76.8
9.91
>100
41.4
15.4
>100
59.6
2.89
0.131
2.02
0.483
0.494
1.00
>100
0.299
>100
1.78
1.83
3.92
>100
>100
>100
e
5.12
>100
5.25
0.839
2.22
SF-295
SF-539
U251
SF-268
SNB-19
SNB-75
7.04
2.55
2.60
3.76
4.59
9.30
44.0
8.64
10.9
23.3
18.0
23.0
>100
61.674.2
45.3
>100
50.6
55.0
2.64
2.13
0.372
3.75
5.12
e
e
>100
>100
>100
>100
>100
e
>100
2.10
>100
>100
e
Melanoma
LOX IMVI
MALME-3M
MDA-MB-435
SK-MEL-5
UACC-257
UACC-62
SK-MEL-2
M14
2.47
10.4
2.94
3.98
3.87
2.88
4.13
2.60
5.11
12.7
33.6
16.8
13.3
16.0
8.73
13.6
6.57
19.5
>100
>100
>100
37.3
47.9
39.6
48.3
>100
66.3
0.134
e
0.352
e
e
e
0.258
5.63
1.98
4.61
>100
0.393
4.96
0.81
>100
4.79
>100
>100
e
e
>100
>100
>100
>100
>100
>100
SK-MEL-28
Ovarian
>100
IGROV1
4.35
3.22
e
45.1
11.8
e
>100
35.0
e
e
e
e
OVCAR-3
OVCAR-4
NCI/ADR-RES
OVCAR-8
OVCAR-5
SK-OV-3
Renal
4.20
2.06
>100
2.60
e
>100
>100
>100
>100
e
>100
>100
>100
>100
e
2.90
3.23
3.20
e
>100
21.1
12.8
e
>100
>100
44.4
e
18.1
>100
>100
A498
ACHN
CAKI-1
RXF 393
SN12C
TK-10
UO-31
786-0
8.44
2.67
4.71
1.65
3.48
3.81
4.38
e
21.3
8.86
>100
3.23
16.0
11.8
26.6
e
47.8
34.0
>100
6.33
>100
34.6
>100
e
e
e
e
2.49
2.36
1.79
2.66
4.60
e
>100
>100
3.73
>100
>100
e
>100
>100
7.73
>100
>100
e
2.75
6.82
>100
Prostate
DU-145
PC-3
4.02
5.39
14.3
55.3
38.0
>100
4.18
e
>100
e
>100
e
Breast
MCF7
MDA-MB-231/ATCC
BT-549
T-47D
MDA-MB-468
HS 578T
3.49
2.31
1.95
4.19
2.12
6.15
16.8
15.0
5.35
20.4
5.30
>100
82.9
0.327
3.49
1.90
3.27
1.58
e
>100
>100
6.15
>100
4.39
e
>100
>100
>100
>100
>100
e
>100
>100
79.6
19.8
>100
a
Data obtained from NCI’s in vitro disease-oriented human tumor cell lines screen [27].
b
GI50 was the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation.
Determined at five concentration levels (100, 10, 1.0, 0.1 and 0.001 M).
LC50 is a parameter of cytotoxicity and reflects the molar concentration needed to kill 50% of the cells.
m
c

R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
37
Table 5
values are within ꢃ0.4% of the theoretical values. Silica gel
aluminum plates (Merck 60 F254) were used for analytical TLC. All
chemicals including the starting acetophenones 14aej and ketones
20e23 were purchased from Aldrich, Fluka and Acros (analytical
reagent grades) and were used without further purification. The
key precursor 3-formylquinoline-2-one 15 was obtained from 2-
chloroquinoline 3-carbaldehyde according to a procedure previ-
ously described by us [20d].
In vivo hollow fiber testing expressed as growth inhibition of cancer cells by
compound 27.a
Panel name
Cell line
name
Panel name
Cell line
name
Experiment 1
Breast cancer
Experiment 3
Non-small cell lung
cancer
MDA-MB-
231
NCI-H23
NCI-H522
U251
Non-small cell lung
cancer
CNS cancer
Colon cancer
Experiment 2
Colon cancer
SW-620
Melanoma
Experiment 4
Melanoma
UACC-62
5.1. Synthesis of aldols (16a,b)
COLO 205
MDA-MB-
435
OVCAR-5
SF-295
To a mixture of equimolar amounts of acetophenones 14a (or b)
(1 mmol) and 3-formylquinolin-2-one 15 was added ethanol
(10 mL). Then aq 10% NaOH (10 drops) was added and the mixture
was stirred for 5 h. The solid formed was filtered under reduced
pressure, washed repeatedly with warm ethanol and finally
recrystallized from ethanol.
Melanoma
Ovarian cancer
LOX IMVI
OVCAR-3
Ovarian cancer
CNS cancer
a
Conditions for each experiment: schedule (QD ꢂ 4), route (IP), high dose
(150 mg/kg/dose).
indispensable for the activity of these type of compounds in
agreement with the angiogenesis inhibition mechanism as
mentioned previously [17].
5.1.1. 3-(3-(4-Bromophenyl)-1-hydroxy-3-oxopropyl)quinolin-
2(1H)-one (17a)
White solid. Mp 279e280 ꢁC; FTIR (KBr)
n
(cmꢄ1): 3265, 3237
4. Conclusion
(OH, NH), 3058, 2902, 1681 (C]O), 1648 (C]O), 1611, 1575 (C]C),
1183 (CeO); 1H NMR (DMSO-d6)
d
3.07 (dd, Jgem ¼ 15.3 Hz,
The synthesis of novel quinoline-2-one based chalcones 16aej
and 24e27 was performed. The best reaction condition for this
goal was achieved by using the couple KOH/1,4-dioxane as reaction
media. Results showed that the formation of such compounds is
mediated by a particularly stable aldol intermediate type 17. All
obtained compounds were completely characterized by spectro-
scopic data and elemental analyses. The in vitro antitumor assays
showed that, among the eleven samples selected and evaluated by
the NCI, compounds 16c, 16d, 16h and 27 exhibited the higher
activity. Particularly compound 27 displayed the most remarkable
activity against 50 human tumor cell lines, thirteen of them with
Jvic ¼ 9.3 Hz, 1H), 3.42 (dd, Jgem ¼ 15.3 Hz, Jvic ¼ 2.8 Hz, 1H), 5.24
(dd, Jvic ¼ 9.2 Hz, Jvic ¼ 2.6 Hz, 1H), 5.43 (bs, 1H, OH), 7.19 (t,
J ¼ 7.0 Hz, 1H), 7.35 (d, J ¼ 8.3 Hz, 1H), 7.48 (t, J ¼ 8.5 Hz, 1H), 7.71 (d,
J ¼ 7.0 Hz,1H), 7.74 (d, J ¼ 8.5 Hz, 2H), 7.98 (s, 1H), 7.98 (d, J ¼ 8.5 Hz,
2H), 11.85 (bs, 1H, NH) ppm; 13C NMR (DMSO-d6)
d 45.9 (CH2), 65.4
(CH), 115.3, 119.7 (Cq), 122.3, 127.6 (Cq), 128.2, 130.1, 130.7, 132.2,
134.7, 136.4 (Cq), 136.9 (Cq), 138.3 (Cq), 161.5 (HNC]O), 198.1 (C]
O) ppm. Anal. Calcd. for C18H14BrNO3: C, 58.08; H, 3.79; N, 3.76.
Found: C, 57.95; H, 3.85; N, 3.59.
5.1.2. 3-[(3-(4-Nitrophenyl)-1-hydroxy-3-oxopropyl)]quinolin-
GI50 values ꢀ1.0
m
M, being the HCT-116 (Colon, GI50 ¼ 0.131
m
M)
2(1H)-one (17b)
and LOX IMVI (Melanoma, GI50 ¼ 0.134
m
M) the most sensitive
Pale yellow solid. Mp 304e305 ꢁC; FTIR (KBr) (cmꢄ1): 3274,
n
strains. For that reason compound 27 was subjected to in vivo acute
toxicity and hollow fiber assay by the Biological Evaluation
Committee of the NCI. It is presumable that the remarkable in vitro
antitumor activity displayed by the bis-arylideneketone 27 could be
related to its closely structural relationship with the naturally
occurring curcumin.
3243 (OH, NH), 1685 (C]O), 1647 (C]O), 1607, 1575 (C]C), 1523,
1344 (NO2), 1190 (CeO); 1H NMR (DMSO-d6)
d
3.19 (dd,
Jgem ¼ 15.1 Hz, Jvic ¼ 9.5 Hz, 1H), 3.53 (dd, Jgem ¼ 15.2 Hz,
Jvic ¼ 1.5 Hz, 1H), 5.55 (dd, Jvic ¼ 9.5 Hz, Jvic ¼ 1.2 Hz, 1H), 7.19 (t,
J ¼ 7.8 Hz, 1H), 7.33 (d, J ¼ 7.9 Hz, 1H), 7.47 (t, J ¼ 8.0 Hz, 1H), 7.73 (d,
J ¼ 7.9 Hz,1H), 7.97 (s,1H), 8.26 (d, J ¼ 8.4 Hz, 2H), 8.36 (d, J ¼ 8.4 Hz,
2H), 11.89 (bs, 1H, NH) ppm; 13C NMR (DMSO-d6)
d 46.5 (CH2), 65.3
(CH), 115.3, 119.7 (Cq), 122.4, 124.3, 128.5, 129.3, 130.1, 134.8, 136.7
(Cq), 138.3 (Cq), 142.1 (Cq), 150.3 (Cq), 161.5 (HNC]O), 198.2 (C]O)
ppm. Anal. Calcd. for C18H14N2O5: C, 63.90; H, 4.17; N, 8.28. Found: C,
64.00; H, 4.02; N, 8.35.
5. Experimental
Melting points were determined on a Büchi melting point
apparatus and are uncorrected. IR spectra were recorded on a Shi-
madzu FTIR 8400 spectrophotometer in KBr disks. 1H and 13C NMR
spectra were recorded on a Bruker Avance 400 spectrophotometer
operating at 400 MHz and 100 MHz respectively, using DMSO-d6 as
solvent and tetramethylsilane as internal standard. Mass spectra
were run on a SHIMADZU-GCMS 2010-DI-2010 spectrometer
(equipped with a direct inlet probe) operating at 70 eV. Micro-
analyses were performed on an Agilent elemental analyzer and the
5.2. General procedure for the synthesis of oxo-quinoline chalcones
(16) and (24e27)
A mixture of 3-formylquinolin-2-one 15 (1 mmol), the corre-
sponding acetophenone 14 (1.2 mmol),1,4-dioxane (5 mL) and solid
KOH (1.6 mmol) was stirred at ambient temperature for 4e8 h. The
Scheme 3. Synthesis of the pyrazolo derivatives 29c,d from chalcones 16c,d.

38
R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
reaction progress was monitored by TLC and after complete
disappearance of the starting aldehyde 15 the solvent was removed
under reduced pressure and the solid formed was washed with
water (2 ꢂ 3 mL), then with ethanol (2 ꢂ 3 mL) and dried under
reduced pressure to afford compounds 16. The same procedure was
followed for the synthesis of compounds 24e27. In the case of
compound 24 indandione 20 was used as ketone. For the synthesis
of compound 25, 2 eq of dimedone 21 was necessary. For the
synthesis of bis-arylideneketones 26 and 27, 0.5 eq of 1,4-
diacetylbenzene 22 and acetone 23 were used respectively, for
each mmol of aldehyde 15.
5.2.5. (E)-3-(3-Oxo-3-phenylprop-1-en-1-yl)quinolin-2(1H)-one
(16e)
Yellow solid. FTIR
n
(cmꢄ1): 3110 (NH) w, 1672 (C]O) br, 1584,
7.26 (t, J ¼ 7.3 Hz, 1H, H-6), 7.36
1554 (C]C); 1H NMR (DMSO-d6)
d
(d, J ¼ 8.3 Hz, 1H, H-8), 7.58 (t, J ¼ 8.3 Hz, 1H, AreH), 7.61 (d,
J ¼ 7.9 Hz, 2H, AreH), 7.69 (t, J ¼ 7.3 Hz, 1H, H-7), 7.73 (d, J ¼ 8.5 Hz,
1H, H-5), 7.82 (d, J ¼ 15.6 Hz, 1H, H-9), 8.07 (d, J ¼ 7.5, 2H, AreH),
8.32 (d, J ¼ 15.6 Hz, 1H, H-10), 8.61 (s, 1H, H-4), 12.06 (bs, 1H,
NH) ppm; 13C NMR (DMSO-d6)
d 115.7, 119.7 (Cq),122.8, 124.5,126.4
(Cq), 128.8, 129.2, 129.4, 132.3, 133.6, 138.2 (Cq), 139.5 (Cq), 139.6,
141.8, 161.4 (HNC]O), 189.8 (C]O) ppm. MS (EI) m/z (%): 275 (Mþ,
1.70), 170 (100). Anal. Calcd. for C18H13NO2: C, 78.53; H, 4.76; N,
5.09. Found: C, 78.62; H, 4.55; N, 5.00.
5.2.1. (E)-3-(3-(4-Bromophenyl)-3-oxoprop-1-en-1-yl)quinolin-
2(1H)-one (16a)
Yellowsolid. FTIR
n
(cmꢄ1):3154(NH)w,1668 br(C]O),1586(C]
5.2.6. (E)-3-(3-(4-Fluorophenyl)-3-oxoprop-1-en-1-yl)quinolin-
C); 1H NMR (DMSO-d6)
d
7.24 (t, J ¼ 7.8 Hz,1H, H-6), 7.38 (d, J ¼ 8.3 Hz,
2(1H)-one (16f)
1H, H-8), 7.57 (t, J ¼ 8.3 Hz,1H, H-7), 7.73 (d, J ¼ 7.0 Hz,1H, H-5), 7.79
(d, J ¼ 8.5 Hz, 2H, AreH), 7.80 (d, J ¼ 15.6 Hz, 1H, H-9), 7.98 (d,
J ¼ 8.5 Hz, 2H, AreH), 8.24 (d, J ¼ 15.6 Hz,1H, H-10), 8.53 (s,1H, H-4),
Yellow solid. FTIR
n
(cmꢄ1): 3125 (NH) w, 1667 (C]O) br, 1591,
1554 (C]C); 1H NMR (DMSO-d6)
d
7.24 (t, J ¼ 7.5 Hz, 1H, H-6), 7.36
(d, J ¼ 8.3 Hz, 1H, H-8), 7.43 (bt, J ¼ 8.8 Hz, 2H, AreH), 7.58 (t,
J ¼ 7.6 Hz, 1H, H-7), 7.72 (d, J ¼ 7.8 Hz, 1H, H-5), 7.83 (d, J ¼ 15.6 Hz,
1H, H-9), 8.17 (dd, J ¼ 8.7 Hz, J ¼ 5.5 Hz, 2H, AreH), 8.32 (d,
11.88 (s, 1H, NH) ppm; 13C NMR (DMSO-d6)
d 115.6, 119.6 (Cq), 122.7,
124.6,126.5 (Cq),127.5(Cq),129.2,132.4,132.2,133.4,137.4(Cq),139.6
(Cq),140.0,141.9,161.3 (HNC]O),189.6 (C]O) ppm; MS (EI) m/z (%):
353/355 (Mþ, 0.70/0.65), 170 (100). Anal. Calcd. for C18H12BrNO2: C,
61.04; H, 3.41; N, 3.95. Found: C, 60.88; H, 3.53; N, 4.06.
J ¼ 15.6 Hz, 1H, H-10), 8.62 (s, 1H, H-4), 12.04 (bs, 1H, NH) ppm; 13
C
NMR (DMSO-d6)
d
115.6, 115.9 (d, JCeF ¼ 22.0 Hz), 119.7 (Cq), 122.7,
125.6, 125.2 (Cq), 129.2, 129.1, 131.6 (d, JCeF ¼ 9.5 Hz), 132.6 (d, JCe
¼ 3.7 Hz, Cq), 139.6, 141.6, 146.4 (Cq), 146.0 (d, JCeF ¼ 195.0 Hz,
F
5.2.2. (E)-3-(3-(4-Nitrophenyl)-3-oxoprop-1-en-1-yl)quinolin-
Cq-F), 161.3 (HNC]O), 185.8 (C]O) ppm. MS (EI) m/z (%): 293
(Mþ,1.3), 170 (100). Anal. Calcd. for C18H12FNO2: C, 73.71; H, 4.12; N,
4.78. Found: C, 73.85; H, 4.00; N, 4.65.
2(1H)-one (16b)
Yellow solid. FTIR
n
(cmꢄ1): 3121 (NH) w, 1671 (C]O) br, 1583,
7.25 (t,
1548 (C]C), 1520, 1346 (NO2); 1H NMR (DMSO-d6)
d
J ¼ 8.0 Hz, 1H, H-6), 7.36 (d, J ¼ 8.3 Hz, 1H, H-8), 7.59 (t, J ¼ 8.3 Hz,
1H, H-7), 7.73 (d, J ¼ 7.0 Hz, 1H, H-5), 7.81 (d, J ¼ 8.5 Hz, 2H, AreH),
7.83 (d, J ¼ 16.1 Hz, 1H, H-9), 8.01 (d, J ¼ 8.5 Hz, 2H, AreH), 8.28 (d,
5.2.7. (E)-3-(3-(Benzo[d][1,3]dioxol-5-yl)-3-oxoprop-1-en-1-yl)
quinolin-2(1H)-one (16g)
Yellow solid. FTIR
n
(cmꢄ1): 3120 (NH) w, 1676 (C]O) br, 1589,
6.18 (s, 2H,
J ¼ 15.6 Hz, 1H, H-10), 8.62 (s, 1H, H-4), 12.08 (s, 1H, NH) ppm; 13
C
1557 (C]C), 1262, 1029 (CeO); 1H NMR (DMSO-d6)
d
NMR (DMSO-d6)
d
115.6, 119.7 (Cq), 122.7, 125.0, 126.7 (Cq), 127.3
CH2), 7.13 (d, J ¼ 8.3 Hz, 1H, AreH), 7.23 (t, J ¼ 7.0 Hz, 1H, H-6), 7.35
(d, J ¼ 8.3 Hz,1H, H-8), 7.56 (t, J ¼ 8.5 Hz,1H, H-7), 7.57 (d, J ¼ 1.8 Hz,
1H, AreH), 7.71 (d, J ¼ 7.4 Hz, 1H, H-5), 7.77 (dd, J ¼ 8.3 Hz,
J ¼ 1.8 Hz, 1H, AreH), 7.81 (d, J ¼ 15.6 Hz, 1H, H-9), 8.29 (d,
(Cq), 129.1, 130.6, 132.1, 132.3, 137.6 (Cq), 139.7 (Cq), 140.0, 141.7,
161.3 (HNC]O), 189.8 (C]O) ppm; MS (EI) m/z (%): 320 (Mþ, 1), 170
(100). Anal. Calcd. for C18H12N2O4: C, 67.50; H, 3.78; N, 8.75. Found:
C, 67.66; H, 3.84; N, 8.68.
J ¼ 15.6 Hz, 1H, H-10), 8.61 (s, 1H, H-4), 12.01 (bs, 1H, NH) ppm; 13
C
NMR (DMSO-d6)
d 102.4 (CH2), 108.2, 108.6, 115.1, 119.8 (Cq), 121.8,
5.2.3. (E)-3-(3-(4-Chlorophenyl)-3-oxoprop-1-en-1-yl)quinolin-
125.1, 126.9 (Cq), 127.7, 129.0, 129.7, 131.8 (Cq), 137.2, 138.9 (Cq),
140.9, 148.6 (Cq), 151.6 (Cq), 162.0 (HNC]O), 188.4 (C]O) ppm. MS
(EI) m/z (%): 319 (Mþ, 1.98), 170 (100). Anal. Calcd. for C19H13NO4: C,
71.47; H, 4.10; N, 4.39. Found: C, 71.56; H, 3.98; N, 4.60.
2(1H)-one (16c)
Yellow solid. FTIR
n
(cmꢄ1): 3150 (NH) w, 1683 (C]O) br, 1621,
1552 (C]C); 1H NMR (DMSO-d6)
d
7.25 (t, J ¼ 7.3 Hz,1H, H-6), 7.36 (d,
J ¼ 8.3 Hz,1H, H-8), 7.58 (t, J ¼ 8.0 Hz,1H, H-7), 7.67 (d, J ¼ 8.5 Hz, 2H,
AreH), 7.72 (d, J ¼ 7.8 Hz,1H, H-5), 7.83 (d, J ¼ 15.6 Hz,1H, H-9), 8.05
(d, J ¼ 8.3 Hz, 2H, AreH), 8.31 (d, J ¼ 15.6 Hz,1H, H-10), 8.62 (s,1H, H-
5.2.8. (E)-3-(3-(4-Hydroxyphenyl)-3-oxoprop-1-en-1-yl)quinolin-
2(1H)-one (16h)
4), 12.10 (bs, 1H, NH) ppm; 13C NMR (DMSO-d6)
d
115.7, 119.6 (Cq),
Yellow solid. FTIR
n
(cmꢄ1): 3143 (OH, NH) br, 1664 (C]O) br,
6.93 (d,
122.7, 124.8, 126.6 (Cq), 129.1, 129.4, 130.6, 132.1, 137.1 (Cq), 138.4
(Cq), 139.7 (Cq), 140.0, 141.8, 161.3 (HNC]O), 189.4 (C]O) ppm; MS
(EI) m/z (%): (Mþ) is missing,170 (100). Anal. Calcd. for C18H12ClNO2:
C, 69.80; H, 3.90; N, 4.52. Found: C, 69.91; H, 3.83; N, 4.42.
1605, 1574, 1554 (C]C), 1254 (CeO); 1H NMR (DMSO-d6)
d
J ¼ 8.5 Hz, 2H, AreH), 7.25 (t, J ¼ 7.5 Hz, 1H, H-6), 7.36 (d, J ¼ 8.3 Hz,
1H, H-8), 7.57 (t, J ¼ 8.0 Hz, 1H, H-7), 7.72 (d, J ¼ 7.8 Hz, 1H, H-5),
7.76 (d, J ¼ 15.6 Hz, 1H, H-9), 8.00 (d, J ¼ 8.8 Hz, 2H, AreH), 8.31 (d,
J ¼ 15.6 Hz, 1H, H-10), 8.58 (s, 1H, H-4), 10.43 (bs, 1H, OH), 12.06 (s,
5.2.4. (E)-3-(3-(4-Methoxyphenyl)-3-oxoprop-1-en-1-yl)quinolin-
1H, NH) ppm; 13C NMR (DMSO-d6)
d 115.6, 116.0, 119.6 (Cq), 122.8,
2(1H)-one (16d)
124.6, 126.6 (Cq), 129.1, 129.7 (Cq), 131.4, 132.1, 138.2, 139.4 (Cq),
141.2,161.5 (HNC]O),162.7 (Cq),187.9 (C]O) ppm. MS (EI) m/z (%):
291 (Mþ, 1.2), 170 (100). Anal. Calcd. for C18H13NO3: C, 74.22; H,
4.50; N, 4.81. Found: C, 74.10; H, 4.68; N, 4.94.
Yellow solid. FTIR
n
(cmꢄ1): 3143 (NH) w, 1666 (C]O) br, 1592,
3.89 (s, 3H,
1552 (C]C), 1258, 1161 (CeO); 1H NMR (DMSO-d6)
d
OCH3), 7.09 (d, J ¼ 8.8 Hz, 2H, AreH), 7.22 (t, J ¼ 7.0 Hz, 1H, H-6),
7.38 (d, J ¼ 8.0 Hz, 1H, H-8), 7.54 (t, J ¼ 7.3 Hz, 1H, H-7), 7.71 (d,
J ¼ 8.5 Hz, 1H, H-5), 7.74 (d, J ¼ 15.6 Hz, 1H, H-9), 8.04 (d, J ¼ 8.8 Hz,
2H, AreH), 8.23 (d, J ¼ 15.6 Hz, 1H, H-10), 8.43 (s, 1H, H-4), 11.67 (bs,
5.2.9. (E)-3-(3-Oxo-3-(p-tolyl)prop-1-en-1-yl)quinolin-2(1H)-one
(16i)
1H, NH) ppm; 13C NMR (DMSO-d6)
d
56.1 (OCH3), 114.7, 115.6, 119.7
Yellow solid. FTIR
n
(cmꢄ1): 3110 (NH) w, 1663 (C]O) br, 1585,
2.42 (s, 3H, CH3), 7.24 (t,
(Cq), 122.6, 125.4, 127.0 (Cq), 129.0, 131.0, 131.5 (Cq), 131.8, 138.5,
139.5 (Cq), 141.1, 161.4 (HNC]O), 163.81 (Cq),188.8 (C]O) ppm. MS
(EI) m/z (%): 305 (Mþ, 0.89), 170 (100). Anal. Calcd. for C19H15NO3: C,
74.74; H, 4.95; N, 4.59. Found: C, 74.80; H, 5.00; N, 4.47.
1553 (C]C); 1H NMR (DMSO-d6)
d
J ¼ 7.3 Hz, 1H, H-6), 7.36 (d, J ¼ 8.0 Hz, 1H, H-8), 7.40 (d, J ¼ 8.0 Hz,
2H, AreH), 7.57 (t, J ¼ 7.9 Hz, 1H, H-7), 7.72 (d, J ¼ 7.8 Hz, 1H, H-5),
7.81 (d, J ¼ 15.8 Hz, 1H, H-9), 8.00 (d, J ¼ 8.3 Hz, 2H, AreH), 8.32 (d,

R. Abonia et al. / European Journal of Medicinal Chemistry 57 (2012) 29e40
39
J ¼ 15.6 Hz, 1H, H-10), 8.61 (s, 1H, H-4), 12.06 (bs, 1H, NH) ppm; 13
C
(d, J ¼ 8.3 Hz, 2H, H-8), 7.58 (t, J ¼ 7.3 Hz, 2H, H-7), 7.74 (d, J ¼ 8.0 Hz,
2H, H-5), 7.77 (d, J ¼ 15.6 Hz, 2H, H-9), 7.80 (d, J ¼ 15.6 Hz, 2H, H-
10), 8.52 (s, 2H, H-4), 12.10 (s, 2H, NH) ppm; 13C NMR (DMSO-d6)
NMR (DMSO-d6)
d 21.7 (CH3), 115.8, 119.8 (Cq), 122.7, 124.4, 125.6
(Cq), 127.8 (Cq), 128.9, 129.2, 129.9, 132.2, 137.4 (Cq), 139.0 (Cq),
139.3,141.6, 161.8 (HNC]O),188.5 (C]O) ppm. MS (EI) m/z (%): 289
(Mþ, 1.6), 170 (100). Anal. Calcd. for C19H15NO2: C, 78.87; H, 5.23; N,
4.84. Found: C, 79.01; H, 5.12; N, 4.98.
d
115.6, 119.7 (Cq), 122.6, 126.9 (Cq), 128.8, 129.1, 131.9, 138.0, 139.6
(Cq), 141.2, 161.3 (HNC]O), 189.8 (C]O) ppm. MS (EI) m/z (%): Mþ
is missing, 170 (100). Anal. Calcd. for C23H16N2O3: C, 74.99; H, 4.38;
N, 7.60. Found: C, 75.11; H, 4.23; N, 7.77.
5.2.10. (E)-3-(3-([1,10-Biphenyl]-4-yl)-3-oxoprop-1-en-1-yl)
quinolin-2(1H)-one (16j)
5.3. Synthesis of carbothioamides (29c,d)
Yellow solid. FTIR
n
(cmꢄ1): 3131 (NH) w, 1667 (C]O) br, 1585,
7.24 (t, J ¼ 7.8 Hz,1H, H-6), 7.39 (d,
1552 (C]C); 1H NMR (DMSO-d6)
d
A mixture of chalcone 16c (or d) (1.0 mmol), thiosemicarbazide
(1.2 mmol), solid NaOH (1.5 mmol) and ethanol (5 mL) was stirred
to reflux for 5 h (TLC control). After cooling the solid formed was
filtered under reduced pressure and purified by washings with
ethanol (3 ꢂ 1 mL).
J ¼ 8.3 Hz,1H, AreH), 7.44 (t, J ¼ 7.5 Hz,1H, H-8), 7.52 (t, J ¼ 8.3 Hz, 2H,
AreH), 7.56 (t, J ¼ 8.0 Hz, 1H, H-7), 7.73e7.80 (m, 3H), 7.82 (d,
J ¼ 15.6 Hz,1H, H-9), 7.86 (d, J ¼ 8.3 Hz, 2H, AreH), 8.13 (d, J ¼ 8.3 Hz,
2H, AreH), 8.30 (d, J ¼ 15.6 Hz, 1H, H-10), 8.50 (s, 1H, H-4), 11.78 (s,
1H, NH) ppm; 13C NMR (DMSO-d6)
d 115.6, 119.7 (Cq), 122.7, 125.3,
126.8 (Cq), 127.4, 127.5 (ꢂ2), 128.7, 129.1, 129.4, 129.5, 132.0, 137.3
(Cq),139.4,139.6 (Cq),141.5,145.0 (Cq),161.4 (HNC]O),190.0 (C]O)
ppm. MS (EI) m/z (%): 351 (Mþ, 1.3), 170 (100). Anal. Calcd. for
5.3.1. 3-(4-Chlorophenyl)-5-(2-oxo-1,2-dihydroquinolin-3-yl)-4,5-
dihydropyrazolo-1-carbothioamide (29b)
White solid. 75% yield, mp 299e300 ꢁC, FTIR (KBr) (cmꢄ1): 3428,
n
3267 (NH2), 166O (C]O), 1572 (C]C, C]N); 1H NMR (DMSO-d6)
C
24H17NO2: C, 82.03; H, 4.88; N, 3.99. Found: C, 81.85; H, 5.01; N, 4.12.
d
3.48(dd,Jgem ¼ 18.1Hz, Jvic¼ 11.5Hz,1H), 3.84(dd,Jgem ¼ 18.1Hz,
5.2.11. 2-(2-Oxo-1,2-dihydroquinolin-3-ylmethylene)-indan-1,3-
Jvic ¼ 4.5 Hz, 1H), 5.98 (dd, Jvic ¼ 11.5 Hz, Jvic ¼ 4.3 Hz, 1H), 7.11 (t,
J ¼ 7.3 Hz,1H), 7.22 (bs, 1H, NH2), 7.34 (d, J ¼ 8.0 Hz,1H), 7.41 (s,1H),
7.43 (t, J ¼ 7.3 Hz,1H), 7. 48 (d, J ¼ 8.3 Hz, 2H), 7.56 (d, J ¼ 7.8 Hz,1H),
7.66 (bs, 1H, NH2), 7.86 (d, J ¼ 8.3 Hz, 2H) ppm; 13C NMR (DMSO-d6)
dione (24)
Orange solid. 82% yield, mp 339e340 ꢁC, FTIR (KBr)
n
d
(cmꢄ1):
7.29 (t,
1726, 1689 (C]O), 1543 (C]C); 1H NMR (DMSO-d6)
J ¼ 7.0 Hz, 1H), 7.37 (d, J ¼ 8.0 Hz, 1H), 7.67 (t, J ¼ 7.7 Hz, 1H), 7.82 (d,
d
40.8 (CH2), 60.2 (CH), 115.5, 119.5 (Cq), 122.2, 128.2, 129.1 (ꢂ2),
J ¼ 7.0 Hz, 1H), 7.97e8.03 (m, 4H), 8.22 (s, 1H), 9.79 (s, 1H), 12.25 (s,
129.2, 130.2, 130.6 (Cq), 132.8 (Cq), 134.5 (Cq), 138.8 (Cq), 155.3 (Cq),
161.3 (C]O), 177.6 (C]S) ppm. Anal. Calcd. for C19H15ClN4OS: C,
59.60; H, 3.95; N, 14.63. Found: C, 59.82; H, 4.06; N, 14.48.
1H, NH) ppm; 13C NMR (DMSO-d6)
d 116.0, 119.2 (Cq), 123.2, 123.5,
123.6, 124.7 (Cq), 130.4, 130.9 (Cq), 133.8, 136.3, 136.4, 139.3, 140.2
(Cq), 141.4 (Cq), 142.5 (Cq), 146.2. 161.3 (HNC]O), 189.3 (C]O),
189.4 (C]O) ppm. MS (EI) m/z (%): 301 (Mþ,100), 245 (88), 216 (50),
189 (15). Anal. Calcd. for C19H11NO3: C, 75.74; H, 3.68; N, 4.65.
Found: C, 75.63; H, 3.81; N, 4.80.
5.3.2. 3-(4-Methoxyphenyl)-5-(2-oxo-1,2-dihydroquinolin-3-yl)-
4,5-dihydropyrazolo-1-carbothioamide (29d)
White solid. 84% yield, mp 289e290 ꢁC, FTIR (KBr) (cmꢄ1): 3435,
n
3273 (NH2), 1664 (C]O), 1584 (C]C, C]N), 1280, 1150 (OCH3); 1H
NMR(DMSO-d6)
5.2.12. 2,20-((2-Oxo-1,2-dihydroquinolin-3-yl)methylene)bis(3-
d
3.13 (dd, Jgem¼18.0 Hz, Jvic ¼ 11.8Hz,1H), 3.80 (s,
hydroxy-5,5-dimethylcyclohex-2-enone) (25)
1H, OCH3), 3.81 (dd, Jgem ¼ 17.8 Hz, Jvic ¼ 3.6 Hz, 1H), 5.90 (dd,
Jvic ¼ 11.4 Hz, Jvic ¼ 3.5 Hz, 1H), 6.99 (d, J ¼ 8.5 Hz, 2H), 7.14 (t,
J ¼ 7.3 Hz, 1H), 7.33 (d, J ¼ 8.7 Hz, 1H), 7.34 (s, 1H), 7.46 (t, J ¼ 7.5 Hz,
1H), 7.63 (d, J ¼ 7.8 Hz,1H), 7.81 (d, J ¼ 8.5 Hz, 2H), 7.87 (bs,1H, NH2),
White solid. 88% yield, mp >350 ꢁC, FTIR (KBr) (cmꢄ1): 3448 br
n
(OH, NH), 2961, 2873, 1662 br (C]O), 1627, 1569 (C]C), 1362, 1199
(CeO); 1H NMR (DMSO-d6)
d
0.97 (s, 6H, CH3), 1.06 (s, 6H, CH3), 2.07
8.01 (bs, 1H, NH2) ppm; 13C NMR (DMSO-d6)
d 40.8 (CH2), 55.8
(d, J ¼ 16.1 Hz, 2H), 2.25 (d, J ¼ 16.1 Hz, 2H), 2.43 (d, J ¼ 17.56 Hz,
2H), 2.53 (d, J ¼ 17.6 Hz, 2H), 4.61 (s, 1H), 7.12 (t, J ¼ 7.0 Hz, 1H), 7.24
(d, J ¼ 8.3 Hz, 1H), 7.39 (t, J ¼ 8.0 Hz,1H), 7.62 (d, J ¼ 7.5 Hz, 1H), 7.76
(s,1H), 11.10 (s, 1H, NH) ppm, OH signals are missing; 13C NMR
(OCH3), 59.3 (CH), 114.6, 115.4, 119.3 (Cq), 122.4, 123.8 (Cq), 128.3,
129.4,130.3,133.0 (Cq),133.6,138.5 (Cq),155.2 (Cq),161.2 (Cq),161.6
(C]O), 176.1 (C]S) ppm. Anal. Calcd. for C20H18N4O2S: C, 63.47; H,
4.79; N, 14.80. Found: C, 63.55; H, 4.56; N, 14.93.
(DMSO-d6)
d 27.0 (CH3) 29.3 (CH3), 30.8 (CH), 32.1 (Cq), 40.8 (CH2),
51.1 (CH2),112.0 (Cq),114.9,119.8 (Cq),121.8, 128.0,129.7,132.8 (Cq),
138.8 (Cq), 139.2, 161.0 (HNC]O), 164.5 (]CeOH), 196.4 (C]O)
ppm. Anal. Calcd. for C26H29NO5: C, 71.70; H, 6.71; N, 3.22. Found: C,
71.85; H, 6.50; N, 3.41.
Acknowledgments
The authors wish to credit The Developmental Therapeutics
Program (DTP) of the National Cancer Institute of the United States
(U.S.) for performing the screening of compounds. This work was
supported financially by Colciencias, Universidad del Valle, Con-
sejería de Innovación, Ciencia y Empresa (Junta de Andalucía,
Spain) and The Universidad de Jaén. Authors thank “Servicios
Técnicos de Investigación de la Universidad de Jaén” and the staff
for data collection.
5.2.13. 3,30-(1E,10E)-1,4-Phenylenebis(3-oxoprop-1-ene-3,1-diyl)
bis(quinolin-2-(1H)-one) (26)
Yellow solid. FTIR
n
(cmꢄ1): 3110 (NH) w,1662 (C]O) br,1584 (C]
C); 1H NMR (DMSO-d6)
d
7.25 (t, J ¼ 7.0, 2H, H-6), 7.40 (d, J ¼ 8.5 Hz,
2H, H-8), 7.58 (t, J ¼ 8.5 Hz, 2H, H-7), 7.74 (d, J ¼ 7.8 Hz, 2H, H-5), 7.84
(d, J ¼ 15.6 Hz, 2H, H-9), 8.20 (s, 4H, AreH). 8.30 (d, J ¼ 15.6, 2H, H-10),
8.55 (s, 2H, H-4), 11.85 (s, 2H, NH) ppm; 13C NMR (DMSO-d6)
d 115.7.
119.7 (Cq), 122.7, 125.3, 126.6 (Cq), 129.0, 129.2, 132.2, 139.7 (Cq),
140.3, 141.6 (Cq), 142.0, 161.3 (HNC]O), 190.5 (C]O), ppm. MS (EI)
m/z (%): Mþ is missing, 170 (100). Anal. Calcd. for C30H20N2O4: C,
76.26; H, 4.27; N, 5.93. Found: C, 76.11; H, 4.46; N, 6.05.
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Yellow solid. FTIR
n
(cmꢄ1): 3151 (NH), 1655 (C]O) br, 1548,
7.24 (t, J ¼ 7.8 Hz, 2H, H-6), 7.36
1522 (C]C); 1H NMR (DMSO-d6)
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