Synthesis and antiproliferative activity of α-branched α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.ejmech.2013.10.041

A series of α-branched α,β-unsaturated ketones were prepared in a straightforward manner by the acid catalyzed coupling between arylalkynes and carbaldehydes. The method also allows producing as side product chalcone analogs bearing an additional α,β-unsaturated arylketone in the molecular scaffold. The evaluation of the antiproliferative activity in the human solid tumor cell lines HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon) provided a structure-activity relationship. Overall, the compounds presented active against the resistant cancer cells T-47D. The resulting lead, displaying an unprecedented chalcone scaffold, showed GI₅₀ values in the range 0.32-0.53 μM against all cell lines tested. The methoxy group present in the lead might play an important role in the activity.

Full text of DOI:10.1016/j.ejmech.2013.10.041

European Journal of Medicinal Chemistry 70 (2013) 568e578
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antiproliferative activity of
ketones
a-branched a,b-unsaturated
,
b,
*
Ieva Karpaviciene a, Inga Cikotiene a , José M. Padrón
**
a Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, Vilnius LT 03225, Lithuania
b BioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad
de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of
catalyzed coupling between arylalkynes and carbaldehydes. The method also allows producing as side
product chalcone analogs bearing an additional -unsaturated arylketone in the molecular scaffold. The
evaluation of the antiproliferative activity in the human solid tumor cell lines HBL-100 (breast), HeLa
(cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon) provided a structureeactivity
relationship. Overall, the compounds presented active against the resistant cancer cells T-47D. The
resulting lead, displaying an unprecedented chalcone scaffold, showed GI50 values in the range 0.32
a-branched a,b-unsaturated ketones were prepared in a straightforward manner by the acid
Received 30 May 2013
Received in revised form
27 August 2013
Accepted 13 October 2013
Available online 22 October 2013
a,b
Keywords:
Antitumor agents
e0.53
mM against all cell lines tested. The methoxy group present in the lead might play an important
role in the activity.
a
-Branched a,b-unsaturated ketones
Ó 2013 Elsevier Masson SAS. All rights reserved.
Chalcones
Lewis acids
Structureeactivity relationships
1. Introduction
acyloxy-
a
,b
-unsaturated ketones (III, Fig. 1) prepared via iron (III)
catalyzed tandem processes, show remarkable biological activity
towards human cancer cell lines, including cell cycle arrest and
apoptosis induction [8,9].
Chemically, chalcones are defined as open chain flavonoids
consisting of two aromatic rings joined by a three carbon a,b-un-
saturated carbonyl system (I, Fig. 1). Although chalcones may exist
in Z and E isomeric forms, the E form is thermodynamically favor-
able. A common synthetic approach toward the synthesis of a,b-
unsubstituted chalcones is via the ClaiseneSchmidt condensation
between acetophenones and benzaldehydes in basic media [10,11].
Moreover, some modern synthetic protocols have been reported,
such as the palladium-mediated Suzuki coupling between cinna-
moyl chloride and phenyl boronic acids [12], the carbonylative
Heck coupling with aryl halides and styrenes in the presence of
carbon monoxide [13] and MeyereSchuster rearrangement of
Chalcones (1,3-diaryl-2-propen-1-ones, I, Fig. 1) represent a
class of flavonoids that occur naturally in fruits and vegetables. This
class of natural products and their synthetic derivatives has shown
interesting biological properties [1,2], among which, anticancer
activity [3,4] is of particular interest to us. For the chalcones with
various antitumor activities reported in the literature in the last
decade, their mechanism of action could be organized into diverse
categories including induction of apoptosis, antiangiogenesis,
antimetastasis, antiinvasion, chemoprevention, cell signal trans-
duction, regulation of cell cycle, NF-kB pathway, and rediffer-
entiation [5]. In addition, some chalcone based compounds were
not toxic to normal cells, while have shown in clinical trials
reasonable plasma concentrations and did not cause toxicity [6].
Besides all these advantages, there is still room for exploding the
pharmacological potential of chalcones by modifications on the
molecular scaffold [7]. In this particular context, we have reported
propargylic alcohols [14] have been reported. For the synthesis of a-
substituted chalcones the Knoevenagel [15], Aldol-Grob [16] type
condensations as well as Horner-Wadsworth-Emmons olefination
[17] reactions can be applied. Another useful alternative for the
construction of the C]C bond is through an alkyne carbonyl
metathesis. This transformation represents a completely atom-
economical alternative to the use of stabilized Wittig reagents in
carbonyl olefination reactions [18]. The metathesis reaction
earlier that a-branched a,b -
-unsaturated ketones (II, Fig. 1) and b0
* Corresponding author. Tel.: þ34 922 316 502x6126; fax: þ34 922 318 571.
** Corresponding author. Tel.: þ370 52193195; fax: þ370 52330987.
E-mail addresses: inga.cikotiene@chf.vu.lt (I. Cikotiene), jmpadron@ull.es (J.
M. Padrón).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.10.041

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
569
generally proceeds via a formal [2 þ 2] cycloaddition and cyclo-
reversion pathway and produces conjugated carbonyl compounds
[19].
produced. After the work-up of the reaction mixture, 2:1 adduct 4dl
was isolated in poor yield as sole reaction product (entry 20).
Moreover, the formation of 2:1 adducts 4 was observed in the case
when plain benzaldehyde (entry 11) or halogenated benzaldehydes
(entries 12, 13, 16, 25) were used.
Having in mind that the chalcone scaffold and
unsaturated ketones are important pharmacophores, we explored
the possibility of -substituted chalcones as antitumor agents.
Herein we report on the synthesis and biological activity of a series
of functionalized -substituted chalcones and structural analogs.
a-substituted a,b-
a
3. Antiproliferative activity
a
The compounds were obtained by the Lewis acid catalyzed
coupling of alkynes and aldehydes. As a model system to study the
biological activity, the representative human solid tumor cells HBL-
100 (breast), HeLa (cervix), SW1573 (non-small cell lung cancer,
NSCLC), T-47D (breast) and WiDr (colon cancer) were selected. A
structureeactivity relationship (SAR) is also discussed.
From the set of 43 synthesized chalcone analogs, a total of 40
compounds were submitted for biological assays. The in vitro ac-
tivity was assessed in HBL-100, HeLa, SW1573, T-47D and WiDr
human solid tumor cells. The results expressed as GI50 were ob-
tained using the SRB assay [21], and the results are given in Table 2.
In addition, Fig. 2 shows the mean graph derived from the obtained
doseeresponse data. The standard anticancer drugs cisplatin and
etoposide were used as positive controls. Overall, the data on
antiproliferative activity show that all tested compounds exhibited
growth inhibition in at least two of the cell lines of the panel. For
the most active compound of the series 4dl the GI50 values were in
2. Chemistry
For the preparation of a-branched a,b-unsaturated ketones, we
utilized the reaction between arylalkynes and carbaldehydes. First
of all, we tested the reactivity of starting alkynes towards Lewis
acid-catalyzed coupling reaction with aldehydes. Several Lewis
acids such as BF3$Et2O, FeCl3, AgSbF6, SbF5, BBr3, TMSOTf, diverse
solvents (DCM, DCE, CH3CN, THF, CH3NO2) and different reaction
temperatures were examined. After this brief searching of the most
suitable reaction conditions we came to conclusion that 1 equiva-
lent of BF3$Et2O in dichloromethane at room temperature gave the
best results. It should be noted that using nitromethane as a solvent
resulted in smoother reactions; however side condensation of
benzaldehydes with solvent occurs. Moreover, we found that the
outcome of the reaction strongly depends on the structure of both
starting materials and, in some cases together with main E-
configuration enone 2, smaller amounts of Z-isomer 3 or 2:1 adduct
4 formed (Scheme 1). The data of reactions between alkynes 1aef
and various aldehydes under the optimal conditions are summa-
rized in Table 1.
Thus, when phenylacetylene 1a and (3-chloroprop-1-ynyl)
benzene 1b were used, in all cases a regioselective formation of
enones 2 took place (Table 1, entries 1e6). However, during the
reaction of 1,2-diphenylethyne 1c and cyclohexylcarbaldehyde, two
products e major E (2) and minor Z (3) were isolated (entry 7). On
the other hand, during the reaction between 1,2-diphenylethyne 1c
and 2,4-dichlorobenzencarbaldehyde, Z-enone (3) was isolated as
sole product (entry 8).
the range 0.32e0.53 mM.
The analysis of the GI50 values allowed us to establish some
SARs. A first comparison was done between E (2) and Z (3) isomers.
In most cases, E isomers (2ca, 2di, 2dj, 2dk, 2ec, 2fc) appear more
active than the corresponding Z isomer (3ca, 3di, 3dj, 3dk, 3ec, 3fc).
However, E compounds 2dg, 2eb and 2fb did not show a clear
enhanced activity when compared to the corresponding Z analogs
3dg, 3eb and 3fb, respectively. When considering the substituent at
the
b position of the unsaturated ketone, an alkyl side chain pro-
duces loss of activity (2db) when compared to cHex (2da, 2fa) or Ar
(2dc, 2dd, 2de, 2dg, 2dh, 2di, 2dj, 2dk, 2fb, 2fc). This result is
consistent with our past observations [8]. In the same context, the
presence of halogenated substituents on the aryl ring tend to
ameliorate the antiproliferative activity (2bd > 2bc > 2bb;
2dd > 2dc) if they are allocated at the para position. In contrast, a
substituent at the ortho position (2dc vs 2dg, 2dh) does not influ-
ence positively the antiproliferative effect. Next, the presence of
chloromethyl (2bb, 2bc, 2bd), acetoxymetyl (2dc, 2dd, 2di, 2fb,
2fc), benzyloxymethyl (2eb, 2ec) groups in a-position of chalcone
moiety enhances the antiproliferative activity. Finally, a chlorine
atom in para position of the phenyl ring next to the ketone does not
produce a significant effect on the activity (2da, 2dd, 2di vs 2fa, 2fb,
2fc; respectively). A direct comparison of the GI50 data of E (2)
chalcones with the previously reported data for analog II (Fig. 1) [9]
indicates that compounds 2dd, 2fb and 2fc show an improved
biological activity only in the most resistant cell line T-47D.
In addition to E (2) and Z (3) chalcones, our synthetic procedure
produces adduct 4 under certain conditions as described above.
From the five adducts obtained in our investigations, the best re-
sults of antiproliferative activity were obtained for adduct 4dl,
which showed as the most potent compound from the whole study.
Results of the reactions between 3-arylprop-2-inylcarboxylates
1def and carbaldehydes were much more intriguing. While in all
cases when aliphatic carbaldehydes were used (entries 9, 10, 21, 24)
the selective formation of E-configurated alkyneecarbonyl
metathesis products 2 took place in low or moderate yields. Low
overall yields can be explained by possible side self-condensation
reaction between two aliphatic aldehydes molecules. However,
the mixtures of E (2) and Z (3) isomers of the corresponding
a
,b
-
These adducts possess in their structure an additional a,b-unsatu-
unsaturated ketones were formed during reaction of 1def with
aromatic aldehydes, especially those having an ortho-substituent
(Table 1, entries 14, 15, 17e19, 22, 23, 26). The reaction of 1d with 4-
methoxybenzaldehyde was complicated and took longer times for
the full conversion of the alkyne; and also a lot of tars were
rated arylketone. When considering the GI50 data, adducts 4dc,
4dd, 4de, 4dh and 4fb do not improve the results of their corre-
sponding E (2) and Z (3) chalcones. However, analog 4dl, the only
compound of the series with a methoxy group in para position of
the phenyl ring at the
b position of the unsaturated ketone.
Fig. 1. General structure of chalcones (I) and previously described anticancer compounds II and III.

570
I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
Scheme 1. BF3$Et2O catalyzed reaction of arylalkynes and aldehydes: a) R2CHO, BF3$Et2O, CH2Cl2, r.t. See Table 1 for substituents.
Unfortunately, the corresponding E and Z chalcones of 4dl could not
be obtained by the reported methodology. Thus, it was not possible
to establish the role in the activity of methoxy group, although we
speculate that it should be favorable. Contrary to what holds for
compound II, a direct comparison of linear product III with those
branched analogs reported in this work is not possible due to the
differences in structure. Nevertheless, the lead 4dl is more potent in
all cell lines tested than the reference compound III (GI50 in the
5.1.1.1. (E)-3-Cyclohexyl-1-phenylprop-2-en-1-one
Yellow oil. Yield 16%. 1H NMR (300 MHz, CDCl3)
: 1.19e1.35 (5H, m,
cHex), 1.76e1.86 (5H, m, cHex), 2.20e2.30 (1H, m, cHex), 6.83 (1H,
(2aa)
[22].
d
3
4
dd, JH,H
¼
15.6 Hz, JH,H
¼
1.2 Hz, ]CH), 7.01 (1H, dd,
3JH,H ¼ 15.6 Hz, 3JH,H ¼ 6.6 Hz, ]CH),7.45 (2H, t, 3JH,H ¼ 7.5 Hz, ArH),
7.55 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.90e7.93 (2H, m, ArH) ppm.
5.1.1.2. (E)-3-(2,4-dichlorophenyl)-1-phenylprop-2-en-1-one (2ab)
[23]. Yellow solid; m. p. ¼ 69e70 ꢀC. Yield 42%. 1H NMR (300 MHz,
range 1.8e3.9
mM against the same cell lines).
CDCl3)
d
: 7.30 (1H, ddd, 3JH,H ¼ 8.4 Hz, 4JH,H ¼ 2.1 Hz, 5JH,H ¼ 0.6 Hz,
4. Conclusions
ArH), 7.45e7.54 (4H, m, ]CH, ArH), 7.60 (1H, t, 3JH,H ¼ 7.5 Hz, ArH),
7.68 (1H, d, 3JH,H ¼ 8.4 Hz, ArH), 7.99e8.03 (2H, m, ArH), 8.10 (1H, dt,
3JH,H ¼ 15.9 Hz, 5JH,H ¼ 0.6 Hz, ]CH) ppm.
In summary, we have described a straightforward synthetic
methodology to obtain a series of E and Z -substituted chalcones in
addition to unprecedented adducts bearing two -unsaturated
a
a
,b
5.1.1.3. (Z)-2-(Chloromethyl)-3-cyclohexyl-1-phenylprop-2-en-1-one
arylketone frameworks. We evaluated their ability to inhibit tumor
cell growth and from the results some structureeactivity re-
lationships have been derived. Although the experiments are pre-
liminary, these compounds show remarkable biological activity
towards human cancer cell lines. Overall, the compounds show
active against the resistant breast cancer cell line T-47D. In partic-
ular, the lead compound displays similar activity profile against
drug sensitive (HBL-100, HeLa and SW1573) and resistant (T-47D
and WiDr) cell lines. More experiments are needed to establish the
scope and limitations of the methoxy group present in the most
active compound of the series. This general methodology allows the
quick production of a variety of chalcones useful for the discovery of
novel bioactive compounds.
(2ba). Yellow oil. Yield 34%. IR (KBr): nmax ¼ 1651 (C]O) cmꢁ1. 1H
NMR (300 MHz, CDCl3) d: 1.13e1.38 (5H, m, cHex), 1.68e1.78 (5H,
m, cHex), 2.51e2.64 (1H, m, cHex), 4.50 (2H, s, CH2Cl), 6.24 (1H, d,
3
3JH,H ¼ 9.9 Hz, ]CH), 7.43 (2H, t, JH,H ¼ 7.5 Hz, ArH), 7.54 (1H, t,
3JH,H ¼ 7.5 Hz, ArH), 7.66e7.70 (2H, m, ArH) ppm. 13C NMR (75 MHz,
CDCl3) d: 25.22, 25.60, 31.93, 37.41, 38.47, 128.20, 129.49, 132.05,
134.87, 137.88, 154.35, 196.50 ppm. HRMS (ES): M þ Naþ, found
285.1013. C16H19ClNaO requires 285.1017.
5.1.1.4. (Z)-2-(Chloromethyl)-1,3-diphenylprop-2-en-1-one
(2bb).
Yellow oil. Yield 45%. IR (KBr): nmax ¼ 1651 (C]O) cmꢁ1. 1H NMR
(300 MHz, CDCl3) d: 4.68 (2H, s, CH2Cl), 7.29 (1H, s, ]CH), 7.44e7.61
(8H, m, ArH), 7.81e7.84 (2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d
: 38.99, 128.33, 128.86, 129.38, 129.59, 129.66, 132.34, 133.99,
5. Experimental
136.35, 137.73, 144.36, 196.40 ppm. HRMS (ES): M þ Naþ, found
279.0551. C16H13ClNaO requires 279.0547.
5.1. Chemistry
5.1.1.5. (Z)-2-(chloromethyl)-3-(4-chlorophenyl)-1-phenylprop-2-
IR spectra were run in KBr discs on a PerkineElmer FT spec-
trophotometer Spectrum BX II. 1H and 13C NMR spectra were
recorded with a Varian Unity INOVA spectrometer (300 MHz) or
Brucker (400 MHz) in chloroform-d, using residual solvent signal as
internal standard. HRMS spectra were obtained on a mass spec-
trometer Dual-ESI Q-TOF 6520 (Agilent Technologies). All reactions
and the purity of the synthesized compounds monitored by TLC
using Silica gel 60 F254 aluminum plates (Merck). Visualization was
accomplished by UV light. Final purification of synthesized com-
pounds was performed on Flash Chromatography system Combi-
Flash (Teledyne Isco), using hexaneeethyl acetate mixtures.
en-1-one (2bc). Yellowish oil. Yield 32%. IR (KBr): nmax ¼ 1651 (C]
O) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 4.63 (2H, s, CH2Cl), 7.21 (1H, s,
]CH), 7.41e7.51 (6H, m, ArH), 7.59 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.78e
7.82 (2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 38.72, 128.40,
129.17, 129.59, 130.70, 132.40, 132.48, 135.79, 136.80, 137.55, 142.84,
196.16 ppm. HRMS (ES): M þ Naþ, found 313.0164. C16H12Cl2NaO
requires 313.0157.
5.1.1.6. (Z)-2-(chloromethyl)-3-(2,4-dichlorophenyl)-1-phenylprop-
2-en-1-one (2bd). Orange oil. Yield 55%. IR (KBr): nmax ¼ 1659 (C]
O) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 4.52 (2H, s, CH25Cl), 7.27 (1H, s,
3
4
]CH), 7.38 (1H, ddd, JH,H ¼ 8.1 Hz, JH,H ¼ 2.1 Hz, JH,H ¼ 0.3 Hz,
ArH), 7.46e7.52 (3H, m, ArH), 7.60 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.65
(1H, d, 3JH,H ¼ 8.4 Hz, ArH), 7.85e7.89 (2H, m, ArH) ppm. 13C NMR
5.1.1. General procedure for the preparation of 2e4
To the solution of the corresponding alkyne 1 (1 mmol) and
aldehyde (1 mmol) in dry dichloromethane (5 mL), boron tri-
fluoride etherate (0.142 g, 0.13 mL, 1 mmol) was added. The
resulting solution was stirred at room temperature. When the
completion of the reaction was observed by TLC, the solution was
quenched with aqueous sodium bicarbonate. The organic layer was
separated, washed with water (2*20 mL), dried over anhydrous
Na2SO4. After the evaporation of solvent under reduced pressure,
the residue was purified by Flash Column chromatography eluting
with hexaneeethyl acetate mixtures.
(75 MHz, CDCl3) d: 38.64, 127.48, 128.45, 129.69, 129.73, 130.75,
131.19, 132.79, 134.88, 135.96, 137.11, 138.13, 138.79, 195.65 ppm.
HRMS (ES): M þ Naþ, found 346.9770. C16H11Cl3NaO requires
346.9768.
5.1.1.7. (E)-3-cyclohexyl-1,2-diphenylprop-2-en-1-one
(2ca).
Yellowish oil. Yield 26%. IR (KBr): nmax ¼ 1667 (C]O) cmꢁ1. 1H NMR
(300 MHz, CDCl3) d: 1.11e1.18 (5H, m, cHex), 1.63e1.78 (5H, m,
cHex), 2.29e2.42 (1H, m, cHex), 6.27 (1H, d, 3JH,H ¼ 10.5 Hz, ]CH),

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
571
Table 1
m, cHex), 2.01 (3H, s, COCH3), 2.49e2.63 (1H, m, cHex), 4.98 (2H, s,
3
Data on the reactions between selected alkynes and aldehydes.
CH2OAc), 6.26 (1H, d, JH,H
¼
10.2 Hz, ]CH), 7.41 (2H, t,
3
3JH,H ¼ 7.5 Hz, ArH), 7.51 (1H, t, JH,H ¼ 7.5 Hz, ArH), 7.66 (2H, d,
Entry
Alkyne
Aldehyde (R2)
Products (yields,%)
3JH,H ¼ 6.9 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 20.81, 25.15,
1
2
3
4
5
6
7
8
1a: Ar ¼ Ph; R1 ¼ H
cHex
2,4-Cl2C6H3
cHex
2aa (16)
2ab (42)
2ba (34)
2bb (50)
2bc (32)
2bd (55)
2ca (26); 3ca (14)
3cb (24)
2da (49)
25.54, 32.11, 32.18, 32.21, 38.21, 58.77, 128.10, 129.44, 131.94, 133.05,
137.83, 154.79, 170.82, 196.92 ppm. HRMS (ES): M þ Naþ, found
309.1449. C18H22NaO3 requires 309.1461.
1a
1b: Ar ¼ Ph; R1 ¼ CH2Cl
1b
1b
1b
Ph
4-ClC6H4
2,4-Cl2C6H3
cHex
2,4-Cl2C6H3
cHex
Et2CH
Ph
4-ClC6H4
4-FC6H4
1c: Ar ¼ Ph; R1 ¼ Ph
5.1.1.11. (E)-2-benzoyl-4-ethylhex-2-enyl
acetate
(2db).
Yellowish oil. Yield 39%. IR (KBr): nmax ¼ 1740, 1655 (C]O) cmꢁ1. 1H
1c
9
1d: Ar ¼ Ph; R1 ¼ CH2OAc
NMR (300 MHz, CDCl3)
d
: 0.87 (6H, t, 3JH,H ¼ 7.5 Hz,CH(CH2CH3)2),
10
11
12
13
1d
1d
1d
1d
2db (39)
1.18e1.33 (2H, m, CH(CH2CH3)(CH2CH3)), 1.46e1.60 (2H, m,
CH(CH2CH3)(CH2CH3)), 2.01 (3H, s, COCH3), 2.39e2.51 (1H, m,
CH(CH2CH3)2), 4.98 (2H, s, CH2OAc), 6.15 (1H, d, 3JH,H ¼ 10.5 Hz, ]
CH), 7.42 (2H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.52 (1H, t, 3JH,H ¼ 7.5 Hz, ArH),
2dc (24); 4dc (11)
2dd (21); 4dd (12)
2de (16); 3de (6)a;
4de (22)
14
15
16
1d
1d
1d
2-ClC6H4
2-BrC6H4
2-FC6H4
2df (26); 3df (27)b
2dg (31); 3dg (20)
2dh (33); 3dh (26);
4dh (15)
7.67e7.70 (2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 11.87,
20.80, 27.58, 42.76, 58.83, 128.16, 129.36, 131.97, 135.58, 137.92,
154.39, 170.77, 196.81 ppm. HRMS (ES): M þ Naþ, found 297.1463.
C17H22NaO3 requires 297.1461.
17
18
19
20
21
22
23
24
1d
1d
1d
1d
2,4-Cl2C6H3
4-NO2C6H4
2-NO2C6H4
4-MeOC6H4
cHex
2,4-Cl2C6H3
2-NO2C6H4
cHex
2di (46); 3di (23)
2dj (48); 3dj (13)c
2dk (28); 3dk (10)
4dl (12)
5.1.1.12. (E)-2-benzoyl-3-phenylallyl acetate (2dc). Yellowish oil.
Yield 24%. IR (KBr): nmax ¼ 1739, 1652 (C]O) cmꢁ1
.
1H NMR
1e: Ar ¼ Ph; R1 ¼ CH2OBz
2ea (24)
(300 MHz, CDCl3) d: 2.05 (3H, s, COCH3), 5.15 (2H, s, CH2OAc), 7.37
1e
1e
2eb (50); 3eb (11)
2ec (22), 3ec (23)b
2fa (34)
3
(1H, s, ]CH), 7.38e7.43 (5H, m, ArH), 7.47 (2H, t, JH,H ¼ 7.2 Hz,
ArH), 7.57 (1H, t, 3JH,H ¼ 6.9 Hz, ArH), 7.81e7.84 (2H, m, ArH) ppm.
1f: Ar ¼ 4-ClC6H4;
R1 ¼ CH2OAc
1f
13C NMR (75 MHz, CDCl3)
d: 20.77, 59.79, 128.27, 128.65, 129.26,
25
4-ClC6H4
2fb (29); 3fb (13);
4fb (22)
2fc (30); 3fc (12)
129.46, 129.53, 132.25, 134.01, 134.95, 137.57, 145.15, 170.64,
196.87 ppm. HRMS (ES): M þ Naþ, found 303.0993. C18H16NaO3
requires 303.0992.
26
1f
2,4-Cl2C6H3
a
Compound 3de was isolated as a mixture with 2de, due to very similar Rf’s.
The reaction was carried out in nitromethane at room temperature. Product 2df
b
was isolated as
a mixture together with side condensation product 1-(2-
5.1.1.13. (E)-2-benzylidene-4-methylene-1,5-diphenylpentane-1,5-
dione (4dc). White solid; m. p. ¼ 45e47 ꢀC. Yield 11%. IR (KBr):
chlorophenyl)-2-nitroethanol.
c
Small amount of the rearranged 3-aroyl-1-arylallylcarboxylates was formed.
nmax ¼ 1642, 1641 (C]O) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 3.92
See Ref. [20] for details.
(2H, br. s, ]CCH2C ¼ ), 5.69 (1H, t, 4JH,H ¼ 1.2 Hz, ]CHH), 5.89 (1H,
t, 4JH,H ¼ 1.5 Hz, ]CHH), 7.37e7.56 (12H, m, ]CH, ArH), 7.73e7.77
(2H, m, ArH) 7.79e7.82 (2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3)
7.24e7.28 (2H, m, ArH), 7.32e7.44 (5H, m, ArH), 7.51 (1H, t,
3JH,H ¼ 7.5 Hz, ArH), 7.76e7.80 (2H, m, ArH) ppm. 13C NMR (75 MHz,
d: 30.51, 125.84, 128.10,128.18,128.31, 128.68, 129.11, 129.24, 129.56,
CDCl3)
d: 25.14, 25.69, 32.34, 38.29, 127.37, 128.07, 128.19, 129.35,
129.63, 131.92, 132.30, 134.95, 137.68, 138.28, 144.48, 145.40, 197.85,
198.27 ppm. HRMS (ES): M þ Naþ, found 375.1339. C25H20NaO2
requires 375.1356.
129.68, 131.85, 136.34, 138.45, 139.43, 150.10, 197.52 ppm. HRMS
(ES): M þ Naþ, found 313.1572. C21H22NaO requires 313.1563.
5.1.1.8. (Z)-3-cyclohexyl-1,2-diphenylprop-2-en-1-one
(3ca).
5.1.1.14. (E)-2-benzoyl-3-(4-chlorophenyl)allyl
acetate
(2dd).
Yellowish oil. Yield 14%. IR (KBr): nmax ¼ 1670 (C]O) cmꢁ1. 1H NMR
Yellowish oil. Yield 21%. IR (KBr): nmax ¼ 1740, 1651 (C]O) cmꢁ1. 1H
(300 MHz, CDCl3)
d
: 1.13e1.19 (5H, m, cHex), 1.58e1.78 (5H, m,
NMR (300 MHz, CDCl3) d: 2.05 (3H, s, COCH3), 5.10 (2H, s, CH2OAc),
cHex), 2.00e2.09 (1H, m, cHex), 6.07 (1H, d, 3JH,H ¼ 10.2 Hz, ]CH),
7.21e7.34 (5H, m, ArH), 7.41 (2H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.53 (1H, t,
3JH,H ¼ 7.5 Hz, ArH), 7.95e7.98 (2H, m, ArH) ppm. 13C NMR (75 MHz,
7.28 (1H, s, ]CH), 7.31e7.41 (4H, m, ArH), 7.48 (2H, t, 3JH,H ¼ 7.5 Hz,
ArH), 7.58 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.79e7.82 (2H, m, ArH) ppm.
13C NMR (75 MHz, CDCl3)
d: 20.80, 59.69, 128.39, 129.00, 129.58,
CDCl3)
d: 25.34, 25.75, 32.73, 38.86, 125.97, 127.54, 128.59, 128.65,
130.61, 132.45, 132.50, 135.60, 137.47, 143.44, 170.64, 196.68 ppm.
HRMS (ES): M þ Naþ, found 337.0603. C18H15ClNaO3 requires
337.0602.
129.66, 133.39, 136.93, 137.28, 137.68, 138.90, 198.49 ppm. HRMS
(ES): M þ Naþ, found 313.1576. C21H22NaO requires 313.1563.
5.1.1.9. (Z)-3-(2,4-dichlorophenyl)-1,2-diphenylprop-2-en-1-one
5.1.1.15. (E)-2-(4-chlorobenzylidene)-4-methylene-1,5-
(3 cb). Yellow solid; m. p. ¼ 69e71 ꢀC. Yield 24%. IR (KBr):
diphenylpentane-1,5-dione (4dd). Yellowish oil. Yield 12%. IR (KBr):
nmax ¼ 1655 (C]O) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 6.84 (1H, d,
nmax ¼ 1648 (C]O) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 3.88 (2H, br.
3JH,H ¼ 8.4 Hz, ArH), 6.94 (1H, dd, 3JH,H ¼ 8.4 Hz, 4JH,H ¼ 2.1 Hz, ArH),
7.22e7.30 (6H, m, ]CH, ArH), 7.41 (1H, d, 4JH,H ¼ 2.1 Hz, ArH), 7.45
(2H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.55 (1H, t, 3JH,H ¼ 7.5 Hz, ArH),7.92e7.95
s, ]CCH2C ¼ ), 5.68 (1H, t, JH,H ¼ 1.2 Hz, ]CHH), 5.88 (1H, t,
4JH,H ¼ 1.5 Hz, ]CHH), 7.30 (1H, br. s, ]CH), 7.38e7.53 (10H, m,
ArH), 7.72e7.75 (2H, m, ArH), 7.77e7.80 (2H, m, ArH) ppm. 13C NMR
4
(2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 126.71, 128.20,
(75 MHz, CDCl3) d: 30.62, 126.17, 128.22, 128.36, 128.93, 129.55,
128.36,128.65,129.30,129.53,129.98,131.85,132.48,132.74,133.70,
134.61, 135.09, 135.27, 137.15, 142.84, 196.79 ppm. HRMS (ES):
M þ Naþ, found 375.0311. C21H14Cl2NaO requires 375.0314.
129.62, 130.54, 132.07, 132.40, 133.38, 135.06, 137.27, 138.05, 138.26,
142.61, 145.01, 197.74, 198.03 ppm. HRMS (ES): M þ Naþ, found
409.0953. C25H19ClNaO2 requires 409.0966.
5.1.1.10. (E)-2-benzoyl-3-cyclohexylallyl
acetate
(2da).
5.1.1.16. (E)-2-benzoyl-3-(4-fluorophenyl)allyl
acetate
(2de).
Yellowish oil. Yield 49%. IR (KBr): nmax ¼ 1738, 1657 (C]O) cmꢁ1. 1H
Yellowish oil. Yield 16%. IR (KBr): nmax ¼ 1739, 1651 (C]O) cmꢁ1. 1H
NMR (300 MHz, CDCl3)
d: 1.04e1.38 (5H, m, cHex), 1.60e1.75 (5H,
NMR (400 MHz, CDCl3) d: 2.06 (3H, s, COCH3), 5.11 (2H, s, CH2OAc),

572
I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
Table 2
Antiproliferative activity (GI50) against human solid tumor cells of compounds produced via Scheme 1.a,b
Compound
HBL-100 (breast)
HeLa (cervix)
SW1573 (lung)
10 (ꢂ4.7)
T-47D (breast)
15 (ꢂ4.3)
WiDr
(Colon)
2aa
2ab
18 (ꢂ2.9)
21 (ꢂ2.5)
21 (ꢂ3.9)
20 (ꢂ1.8)
17 (ꢂ1.1)
18 (ꢂ0.3)
12 (ꢂ1.5)
14 (ꢂ1.6)
2ba
2bb
2bc
2bd
22 (ꢂ1.8)
12 (ꢂ1.9)
3.2 (ꢂ0.7)
3.1 (ꢂ0.8)
30 (ꢂ5.1)
23 (ꢂ1.8)
22 (ꢂ3.7)
15 (ꢂ2.7)
23 (ꢂ3.9)
3.6 (ꢂ0.3)
3.9 (ꢂ0.6)
3.8 (ꢂ0.6)
29 (ꢂ9.2)
18 (ꢂ3.5)
17 (ꢂ4.9)
6.3 (ꢂ0.7)
22 (ꢂ1.5)
18 (ꢂ3.7)
19 (ꢂ1.6)
13 (ꢂ1.8)
2ca
3ca
57 (ꢂ2.6)
59 (ꢂ6.7)
47 (ꢂ16)
63 (ꢂ6.5)
29 (ꢂ8.0)
64 (ꢂ1.0)
39 (ꢂ4.5)
74 (ꢂ30)
34 (ꢂ3.7)
64 (ꢂ22)
3cb
>100
47 (ꢂ14)
41 (ꢂ16)
52 (ꢂ13)
46 (ꢂ15)
2da
2db
21 (ꢂ1.3)
>100
21 (ꢂ2.1)
50 (ꢂ6.0)
19 (ꢂ3.3)
77 (ꢂ17)
22 (ꢂ1.5)
89 (ꢂ9.8)
21 (ꢂ2.3)
52 (ꢂ2.0)
2dc
4dc
17 (ꢂ4.2)
10 (ꢂ5.0)
20 (ꢂ8.5)
19 (ꢂ5.7)
4.8 (ꢂ0.9)
3.0 (ꢂ1.1)
16 (ꢂ3.2)
15 (ꢂ4.5)
17 (ꢂ4.9)
18 (ꢂ4.8)
2dd
4dd
2.3 (ꢂ0.5)
17 (ꢂ2.6)
3.2 (ꢂ0.7)
22 (ꢂ2.8)
2.6 (ꢂ0.7)
6.1 (ꢂ2.4)
5.3 (ꢂ2.5)
19 (ꢂ3.5)
4.8 (ꢂ1.5)
20 (ꢂ2.9)

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
573
Table 2 (continued )
Compound
HBL-100 (breast)
HeLa (cervix)
SW1573 (lung)
T-47D (breast)
WiDr
(Colon)
2de
4de
17 (ꢂ3.9)
14 (ꢂ1.9)
25 (ꢂ4.2)
18 (ꢂ5.0)
4.2 (ꢂ0.5)
3.5 (ꢂ0.5)
14 (ꢂ2.8)
15 (ꢂ3.0)
13 (ꢂ1.3)
19 (ꢂ3.2)
3df
21 (ꢂ3.8)
24 (ꢂ4.5)
14 (ꢂ0.8)
19 (ꢂ1.2)
22 (ꢂ4.5)
2dg
3dg
22 (ꢂ4.3)
21 (ꢂ2.2)
20 (ꢂ2.7)
19 (ꢂ1.4)
14 (ꢂ1.7)
21 (ꢂ3.7)
17 (ꢂ2.2)
18 (ꢂ1.0)
21 (ꢂ3.0)
18 (ꢂ4.8)
2dh
4dh
17 (ꢂ3.3)
15 (ꢂ3.2)
22 (ꢂ0.8)
20 (ꢂ6.0)
6.1 (ꢂ1.4)
3.5 (ꢂ0.6)
18 (ꢂ1.6)
14 (ꢂ2.6)
19 (ꢂ5.8)
17 (ꢂ3.8)
2di
3di
3.1 (ꢂ1.2)
23 (ꢂ2.6)
16 (ꢂ3.7)
22 (ꢂ2.5)
3.5 (ꢂ0.3)
22 (ꢂ3.5)
9.5 (ꢂ1.8)
20 (ꢂ1.8)
14 (ꢂ1.9)
19 (ꢂ1.4)
2dj
3dj
10 (ꢂ3.3)
41 (ꢂ7.7)
26 (ꢂ4.6)
36 (ꢂ5.4)
3.8 (ꢂ0.5)
32 (ꢂ6.5)
16 (ꢂ4.8)
36 (ꢂ4.8)
23 (ꢂ1.0)
83 (ꢂ18)
2dk
3dk
26 (ꢂ3.9)
>100
25 (ꢂ2.6)
78 (ꢂ5.8)
18 (ꢂ1.7)
>100
21 (ꢂ6.5)
52 (ꢂ3.7)
18 (ꢂ6.3)
>100
(continued on next page)

574
I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
Table 2 (continued )
Compound
HBL-100 (breast)
HeLa (cervix)
SW1573 (lung)
T-47D (breast)
WiDr
(Colon)
4dl
2ea
0.53 (ꢂ0.28)
23 (ꢂ5.2)
0.32 (ꢂ0.02)
24 (ꢂ2.4)
0.45 (ꢂ0.25)
17 (ꢂ3.3)
0.37(ꢂ0.04)
20 (ꢂ0.7)
0.47 (ꢂ0.05)
19 (ꢂ2.5)
2eb
3eb
3.1 (ꢂ0.6)
26 (ꢂ4.6)
20 (ꢂ1.0)
8.3 (ꢂ1.3)
3.3 (ꢂ0.5)
29 (ꢂ6.3)
17 (ꢂ5.8)
5.4 (ꢂ0.5)
17 (ꢂ4.0)
8.7 (ꢂ3.9)
2ec
3ec
3.9 (ꢂ1.4)
>100
22 (ꢂ7.3)
30 (ꢂ6.8)
4.3 (ꢂ1.8)
>100
16 (ꢂ2.2)
18 (ꢂ6.1)
18 (ꢂ1.8)
21 (ꢂ1.9)
2fa
31 (ꢂ14)
24 (ꢂ2.6)
18 (ꢂ3.9)
18 (ꢂ2.9)
21 (ꢂ5.5)
2fb
3fb
4.0 (ꢂ1.6)
16 (ꢂ0.9)
19 (ꢂ3.5)
5.7 (ꢂ1.2)
3.4 (ꢂ0.5)
5.3 (ꢂ1.8)
5.4 (ꢂ1.5)
12 (ꢂ3.3)
18 (ꢂ3.2)
17 (ꢂ1.4)
4fb
16 (ꢂ1.1)
21 (ꢂ3.4)
5.3 (ꢂ1.1)
17 (ꢂ5.0)
24 (ꢂ4.6)
2fc
3fc
3.2 (ꢂ0.8)
22 (ꢂ4.0)
4.6 (ꢂ0.9)
19 (ꢂ0.4)
3.4 (ꢂ0.6)
21 (ꢂ3.9)
5.2 (ꢂ0.9)
20 (ꢂ1.4)
8.1 (ꢂ1.9)
20 (ꢂ1.1)
Cisplatin
Etoposide
1.9 (ꢂ0.2)
1.4 (ꢂ0.1)
2.0 (ꢂ0.3)
3.3 (ꢂ1.6)
3.0 (ꢂ0.4)
15 (ꢂ1.5)
15 (ꢂ2.3)
22 (ꢂ5.5)
26 (ꢂ5.3)
23 (ꢂ3.1)
a
Values are given in
2df, 3de, 3dh were not tested due to their small amounts or impurities.
m
M and are means of two to five experiments; standard deviation is given in parentheses.
b

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
575
Fig. 2. Mean graph profiles for compounds 2e4. The middle line represents the median GI50 (mM) value of the set of compounds against each individual cell line.
7.08e7.14 (2H, m, ArH), 7.31 (1H, s, ]CH), 7.37e7.42 (2H, m, ArH),
170.65, 196.50 ppm. HRMS (ES): M þ Naþ, found 337.0607.
3
3
7.48 (2H, t, JH,H ¼ 7.6 Hz, ArH), 7.58 (1H, t, JH,H ¼ 7.6 Hz, ArH),
C18H15ClNaO3 requires 337.0602.
7.79e7.82 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.81,
2
59.74, 115.92 (d, JC,F ¼ 21.6 Hz), 128.38, 129.57, 130.24 (d,
5.1.1.19. (Z)-2-benzoyl-3-(2-chlorophenyl)allyl
acetate
(3df).
3
4JC,F ¼ 3.4 Hz), 131.40 (d, JC,F ¼ 8.4 Hz), 132.36, 134.98, 137.60,
Orange oil. Yield 27%. IR (KBr): nmax ¼ 1742, 1655 (C]O) cmꢁ1. 1H
143.87, 163.26 (d, 1JC,F ¼ 249.6 Hz), 170.68, 196.80 ppm. HRMS (ES):
M þ Naþ, found 321.0874. C18H15FNaO3 requires 321.0897.
NMR (300 MHz, CDCl3) d: 2.02 (3H, s, COCH3), 5.04 (2H, d,
4JH,H ¼ 1.5 Hz, CH2OAc), 6.88 (1H, td, 3JH,H ¼ 7.5 Hz, 4JH,H ¼ 0.6 Hz,
ArH), 6.98e7.04 (2H, m, ]CH, ArH), 7.19e7.30 (4H, m, ArH), 7.36
3
5.1.1.17. (E)-2-(4-fluorobenzylidene)-4-methylene-1,5-
diphenylpentane-1,5-dione (4de). Yellowish oil. Yield 22%. IR (KBr):
(1H, t, JH,H ¼ 7.2 Hz, ArH), 7.74e7.77 (2H, m, ArH) ppm. 13C NMR
(75 MHz, CDCl3) d: 20.73, 66.21, 126.39, 128.11, 128.26, 129.03,
nmax ¼ 1655(C]O) cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
: 3.89 (2H, br.
129.08, 129.66, 129.71, 130.75, 131.66, 133.26, 136.34, 137.04, 170.47,
197.53 ppm. HRMS (ES): M þ Hþ, found 315.0768. C18H16ClO3 re-
quires 315.0782.
s, ]CCH2C ¼ ), 5.68 (1H, br. s, ]CHH), 5.88 (1H, t, 4JH,H ¼ 1.6 Hz, ]
CHH), 7.07e7.12 (2H, m, ArH), 7.33 (1H, br. s, ]CH), 7.41e7.49 (6H,
m, ArH), 7.51e7.53 (2H, m, ArH), 7.73e7.76 (2H, m, ArH), 7.77e7.80
(2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d
: 30.52, 115.80 (d,
5.1.1.20. (E)-2-benzoyl-3-(2-bromophenyl)allyl
acetate
(2dg).
1H
2JC,F ¼ 21.5 Hz), 125.95, 128.21, 128.34, 129.52, 129.63, 131.05 (d,
Yellow oil. Yield 31%. IR (KBr): nmax ¼ 1741, 1656 (C]O) cmꢁ1
.
3
4JC,F ¼ 3.4 Hz), 131.27 (d, JC,F ¼ 8.3 Hz), 131.98, 132.40, 137.29,
NMR (300 MHz, CDCl3) d: 1.99 (3H, s, COCH3), 5.02 (2H, d,
1
137.49, 138.19, 143.07, 145.11, 162.95 (d, JC,F ¼ 249.0 Hz), 197.81,
4JH,H ¼ 0.3 Hz, CH2OAc), 7.21e7.27 (1H, m, ArH), 7.33e7.37 (3H, m,
ArH, ]CH), 7.47e7.52 (2H, m, ArH), 7.57e7.64 (2H, m, ArH), 7.93e
198.14 ppm. HRMS (ES): M þ Naþ, found 393.1257. C25H19FNaO2
requires 393.1261.
7.97 (2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 20.70, 59.75,
123.89, 127.42, 128.38, 129.79, 130.19,130.44, 132.69, 132.78, 134.78,
136.40, 137.11, 142.82, 170.50, 196.36 ppm. HRMS (ES): M þ Naþ,
found 381.0086. C18H15BrNaO3 requires 381.0097.
5.1.1.18. (E)-2-benzoyl-3-(2-chlorophenyl)allyl
acetate
(2df).
Yellow oil. Yield 26%. IR (KBr): nmax ¼ 1740, 1652 (C]O) cmꢁ1. 1H
NMR (300 MHz, CDCl3) d: 1.99 (3H, s, COCH3), 5.02 (2H, s, CH2OAc),
7.30e7.35 (4H, m, ArH), 7.42 (1H, s, ]CH), 7.49 (2H, t, 3JH,H ¼ 7.5 Hz,
5.1.1.21. (Z)-2-benzoyl-3-(2-bromophenyl)allyl acetate (3 dg).
Yellow oil. Yield 20%. IR (KBr): nmax ¼ 1743, 1658 (C]O) cmꢁ1. 1H
ArH), 7.59 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.89e7.92 (2H, m, ArH) ppm.
13C NMR (75 MHz, CDCl3)
d
: 20.69, 59.83, 127.49, 128.40, 129.63,
NMR (400 MHz, CDCl3) d: 2.03 (3H, s, CH3CO), 5.04 (2H, d,
129.76, 130.12, 130.38, 132.71, 132.87, 133.93, 136.57, 137.13, 141.00,
4JH,H ¼ 1.2 Hz, CH2OAc), 6.88e6.95 (2H, m, ]CH, ArH), 7.21e7.26

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I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
(3H, m, ArH), 7.33e7.39 (3H, m, ArH), 7.73e7.76 (2H, m, ArH) ppm.
13C NMR (100 MHz, CDCl3)
: 20.73, 66.04, 123.35, 126.99, 128.21,
170.41, 197.29 ppm. HRMS (ES):
C18H15Cl2O3 requires 349.0393.
M
þ
Hþ, found 349.0378.
d
129.01, 129.75, 130.89, 132.23, 133.21, 133.76, 135.19, 136.38, 136.85,
170.45, 197.42 ppm. HRMS (ES): M þ Naþ, found 381.0083.
C18H15BrNaO3 requires 381.0097.
5.1.1.27. (E)-2-benzoyl-3-(4-nitrophenyl)allyl
acetate
(2dj).
Yellow oil. Yield 48%. IR (KBr): nmax ¼ 1739, 1657 (C]O) cmꢁ1. 1H
NMR (300 MHz, CDCl3) d: 2.03 (3H, s, COCH3), 5.08 (2H, s, CH2OAc),
3
5.1.1.22. (E)-2-benzoyl-3-(2-fluorophenyl)allyl
acetate
(2dh).
7.29 (1H, br. s, ]CH), 7.49 (2H, t, JH,H ¼ 7.2 Hz, ArH), 7.57 (2H, d,
Yellowish oil. Yield 33%. IR (KBr): nmax ¼ 1741, 1657 (C]O) cmꢁ1. 1H
3JH,H ¼ 8.7 Hz, ArH), 7.65 (1H, t, 3JH,H ¼ 7.2 Hz, ArH), 7.82e7.85 (2H,
3
NMR (300 MHz, CDCl3)
d
: 2.00 (3H, s, COCH3), 5.09 (2H, s, CH2OAc),
m, ArH), 8.26 (2H, d, JH,H ¼ 8.7 Hz, ArH) ppm. 13C NMR (75 MHz,
7.07e7.13 (1H, m, ArH), 7.20 (1H, td, 3JH,H ¼ 7.65 Hz, 4JH,H ¼ 3.9 Hz,
CDCl3) d: 20.64, 59.57, 123.82, 128.51, 129.32, 129.60, 129.93, 132.88,
ArH), 7.37e7.44 (3H, m, ]CH, ArH), 7.48 (2H, t, 3JH,H ¼ 7.35 Hz, ArH),
136.81, 138.32, 140.50, 147.77, 170.44, 196.03 ppm. HRMS (ES):
3
7.58 (1H, t, JH,H ¼ 7.35 Hz, ArH), 7.84e7.87 (2H, m, ArH) ppm. 13
C
M þ Naþ, found 348.0854. C18H15NNaO5 requires 348.0842.
2
NMR (75 MHz, CDCl3)
d
: 20.69, 60.04, 115.71 (d, JC,F ¼ 21.45 Hz),
122.18 (d, 2JC,F ¼ 13.80 Hz),124.25 (d, 4JC,F ¼ 3.67 Hz),128.38,129.66,
130.16 (d, 3JC,F ¼ 2.40 Hz), 131.28 (d, 3JC,F ¼ 8.40 Hz), 132.58, 136.73,
5.1.1.28. (Z)-2-benzoyl-3-(4-nitrophenyl)allyl
acetate
(3dj).
Orange oil. Yield 13%. IR (KBr): nmax ¼ 1745, 1667 (C]O) cmꢁ1. 1H
1
137.01, 137.27, 160.19 (d, JC,F ¼ 248.92 Hz), 170.56, 196.36 ppm.
NMR (300 MHz, CDCl3) d: 2.00 (3H, s, COCH3), 5.02 (2H, d,
HRMS (ES): M þ Naþ, found 321.0881. C18H15FNaO3 requires
4JH,H ¼ 1.2 Hz, CH2OAc), 7.05 (1H, br. s, ]CH), 7.28e7.36 (4H, m,
321.0897.
ArH), 7.48 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.80e7.84 (2H, m, ArH), 7.97
(2H, d, 3JH,H ¼ 8.7 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 20.69,
5.1.1.23. (Z)-2-benzoyl-3-(2-fluorophenyl)allyl
acetate
(3dh).
66.38, 123.54, 128.77, 129.25, 129.46, 130.57, 134.14, 135.42, 139.44,
140.90, 147.17, 170.42, 197.31 ppm. HRMS (ES): M þ Naþ, found
348.0856. C18H15NNaO5 requires 348.0842.
Yellowish oil. Yield 26%. IR (KBr): nmax ¼ 1737, 1642 (C]O) cmꢁ1. 1H
NMR (400 MHz, CDCl3)
d: 1.99 (3H, s, COCH3), 5.02 (2H, d,
4JH,H ¼ 1.2 Hz, CH2OAc), 6.76e6.80 (1H, m, ArH), 6.85e6.90 (1H, m,
ArH), 7.01e7.07 (2H, m, ArH), 7.18 (1H, br. s, ]CH), 7.26e7.30 (2H,
5.1.1.29. (E)-2-benzoyl-3-(2-nitrophenyl)allyl
acetate
(2dk).
m, ArH), 7.38e7.42 (1H, m, ArH), 7.80e7.82 (2H, m, ArH) ppm. 13
C
Yellow oil. Yield 28%. IR (KBr): nmax ¼ 1736, 1655 (C]O) cmꢁ1. 1H
2
NMR (100 MHz, CDCl3)
d
: 20.69, 66.60, 115.18 (d, JC,F ¼ 21.4 Hz),
NMR (300 MHz, CDCl3) d: 1.93 (3H, s, COCH3), 4.91 (2H, s, CH2OAc),
122.66 (d, 3JC,F ¼ 13.5 Hz), 123.74 (d, 4JC,F ¼ 3.6 Hz), 128.36, 129.15,
7.37 (1H, d, 3JH,H ¼ 7.5 Hz, ArH), 7.49e7.61 (4H, m, ArH), 7.63 (1H, br.
s, ]CH), 7.70 (1H, td, 3JH,H ¼ 7.5 Hz, 4JH,H ¼ 1.5 Hz, ArH), 7.98 (2H, d,
3JH,H ¼ 7.2 Hz, ArH), 8.23 (1H, dd, 3JH,H ¼ 8.1 Hz, 4JH,H ¼ 1.2 Hz, ArH)
129.71, 130.31 (d, 3JC,F ¼ 2.2 Hz), 130.34 (d, 3JC,F ¼ 8.40 Hz), 133.37,
1
136.05, 136.93, 159.89 (d, JC,F ¼ 247.9 Hz), 170.42, 197.60 ppm.
HRMS (ES): M þ Naþ, found 321.0903. C18H15FNaO3 requires
ppm. 13C NMR (75 MHz, CDCl3)
d: 20.63, 59.56, 125.12, 128.47,
321.0897.
130.65, 130.80, 132.81, 133.83, 136.18, 136.77, 140.77, 147.08, 170.43,
195.96 ppm. HRMS (ES): M þ Naþ, found 348.0858. C18H15NNaO5
requires 348.0842.
5.1.1.24. (E)-2-(2-fluorobenzylidene)-4-methylene-1,5-
diphenylpentane-1,5-dione (4dh). Yellowish oil. Yield 15%. IR (KBr):
nmax ¼ 1652 (C]O) cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
: 3.84 (2H, br.
5.1.1.30. (Z)-2-benzoyl-3-(2-nitrophenyl)allyl
acetate
(3dk).
s, ]CCH2C ¼ ), 5.66 (1H, br. s, ]CHH), 5.88 (1H, t, 4JH,H ¼ 1.6 Hz, ]
CHH), 7.05e7.12 (1H, m, ArH), 7.17e7.21 (1H, m, ArH), 7.37e7.41
(4H, m, ]CH, ArH), 7.47 (2H, t, 3JH,H ¼ 7.2 Hz, ArH), 7.51e7.58 (3H,
Orange oil. Yield 10%. IR (KBr): nmax ¼ 1741, 1656 (C]O) cmꢁ1. 1H
NMR (300 MHz, CDCl3)
d: 2.06 (3H, s, COCH3), 5.06 (2H, d,
4JH,H ¼ 1.2 Hz, CH2OAc), 7.15e7.36 (6H, m, ArH), 7.44 (1H, br. s, ]
m, ArH), 7.68e7.70 (2H, m, ArH), 7.82e7.84 (2H, m, ArH) ppm. 13
C
CH), 7.71 (2H, d, JH,H ¼ 7.2 Hz, ArH), 7.92 (1H, dd, JH,H ¼ 8.1 Hz,
3
3
NMR (100 MHz, CDCl3)
d
: 30.74, 115.65 (d, 2JC,F ¼ 21.5 Hz), 123.09 (d,
4JH,H ¼ 1.5 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 20.74, 65.54,
4
2JC,F ¼ 13.9 Hz), 124.24 (d, JC,F ¼ 3.8 Hz), 126.38, 128.16, 128.36,
124.63, 128.34, 128.80, 129.24, 131.28, 131.45, 132.05, 133.35, 133.37,
136.77, 137.37, 146.79, 170.41, 197.16 ppm. HRMS (ES): M þ Naþ,
found 348.0873. C18H15NNaO5 requires 348.0842.
3
129.34, 129.51, 129.58, 129.69, 129.75 (d, JC,F ¼ 2.5 Hz), 130.76 (d,
3JC,F ¼ 8.4 Hz), 132.22, 132.27, 137.35, 137.85, 139.75, 162.42 (d,
1JC,F ¼ 181.1 Hz), 197.68, 197.74 ppm. HRMS (ES): M þ Naþ, found
393.1264. C25H19FNaO2 requires 393.1261.
5.1.1.31. (E)-2-(4-methoxybenzylidene)-4-methylene-1,5-
diphenylpentane-1,5-dione (4dl). Brown solid; m. p. ¼ 102e104 ꢀC.
Yield 12%. IR (KBr): nmax ¼ 1652 (C]O) cmꢁ1. 1H NMR (300 MHz,
5.1.1.25. (E)-2-benzoyl-3-(2,4-dichlorophenyl)allyl acetate (2di).
Yellowish oil. Yield 46%. IR (KBr): nmax ¼ 1738, 1659 (C]O) cmꢁ1. 1H
CDCl3) d: 3.82 (3H, s, OCH3), 3.93 (2H, br. s, ]CCH2C]), 5.67 (1H, t,
NMR (300 MHz, CDCl3)
d: 1.99 (3H, s, COCH3), 5.00 (2H, s, CH2OAc),
4JH,H ¼ 1.2 Hz, ]CHH), 5.86 (1H, t, 4JH,H ¼ 1.5 Hz, ]CHH), 6.92 (2H,
7.31e7.32 (3H, m, ]CH, ArH), 7.45e7.52 (3H, m, ArH), 7.59 (1H, t,
d, 3JH,H ¼ 8.7 Hz, ArH), 7.39e7.58 (9H, m, ]CH, ArH), 7.75e7.81 (4H,
3JH,H ¼ 7.5 Hz, ArH), 7.89 (2H, d, 3JH,H ¼ 6.9 Hz, ArH) ppm. 13C NMR
m, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 30.31, 55.26, 114.11,
(75 MHz, CDCl3)
d: 20.65, 59.67, 127.23, 128.42, 129.56, 129.71,
125.27, 127.32, 128.12, 128.17, 129.37, 129.61, 131.27, 135.31, 137.33,
138.63, 145.00, 145.24, 160.40, 197.97, 198.35 ppm. HRMS (ES):
M þ Hþ, found 383.1645. C26H23O2 requires 383.1642.
130.83, 131.39, 132.78, 134.67, 135.67, 136.94, 137.18, 139.30, 170.41,
196.07 ppm. HRMS (ES): M þ Hþ, found 349.0381. C18H15Cl2O3
requires 349.0393.
5.1.1.32. (E)-2-benzoyl-3-cyclohexylallyl benzoate (2ea). Yellow
solid; m. p. ¼ 66e68 ꢀC. Yield 24%. IR (KBr): nmax ¼ 1716, 1651 (C]
5.1.1.26. (Z)-2-benzoyl-3-(2,4-dichlorophenyl)allyl acetate (3di).
White solid; m. p. ¼ 96e97 ꢀC. Yield 23%. IR (KBr): nmax ¼ 1731, 1664
O) cmꢁ1 1H NMR (300 MHz, CDCl3)
. d: 1.09e1.35 (5H, m, cHex),
(C]O) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 2.02 (3H, s, COCH3), 5.03
1.71e1.75 (5H, m, cHex), 2.62e2.75 (1H, m, cHex), 5.26 (2H, s,
CH2OBz), 6.33 (1H, d, 3JH,H ¼ 9.9 Hz, ]CH), 7.37e7.46 (4H, m, ArH),
7.50e7.56 (2H, m, ArH), 7.70e7.74 (2H, m, ArH), 7.97e8.00 (2H, m,
4
3
(2H, d, JH,H ¼ 1.2 Hz, CH2OAc), 6.88 (1H, dd, JH,H ¼ 8.4 Hz,
4JH,H ¼ 2.4 Hz, ArH), 6.97 (1H, d, 3JH,H ¼ 8.4 Hz, ArH), 7.17 (1H, br. s,
]CH), 7.23 (1H, d, 4JH,H ¼ 2.4 Hz, ArH), 7.26e7.32 (2H, m, ArH), 7.42
ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 25.19, 25.59, 32.22, 38.35,
(1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.75 (2H, d, 3JH,H ¼ 7.2 Hz, ArH) ppm. 13
C
59.34, 128.20, 128.27, 129.53, 129.57, 130.02, 132.02, 132.89, 133.21,
137.96, 154.79, 166.36, 197.06 ppm. HRMS (ES): M þ Naþ, found
371.1612. C23H24NaO3 requires 371.1618.
NMR (75 MHz, CDCl3) d: 20.71, 35.36, 66.05, 126.79, 128.47, 129.02,
129.07, 130.01, 131.33, 131.96, 133.61, 133.95, 134.83, 136.08, 137.79,

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
577
5.1.1.33. (E)-2-benzoyl-3-(2,4-dichlorophenyl)allyl benzoate (2eb).
Yellowish oil. Yield 50%. IR (KBr): nmax ¼ 1721, 1658 (C]O) cmꢁ1. 1H
5.1.1.39. (Z)-2-(4-chlorobenzoyl)-3-(4-chlorophenyl)allyl
acetate
(3fb). Dark yellow oil. Yield 13%. IR (KBr): nmax ¼ 1745, 1660 (C]O)
NMR (300 MHz, CDCl3)
d
: 5.28 (2H, d, 3JH,H ¼ 0.6 Hz, CH2OBz), 7.30
cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 1.97 (3H, s, COCH3), 4.96 (2H, d,
(1H, dd, 3JH,H ¼ 8.4 Hz, 4JH,H ¼ 2.1 Hz, ArH), 7.34e7.40 (4H, m, ]CH,
ArH), 7.44 (1H, d, 4JH,H ¼ 2.1 Hz, ArH), 7.48e7.54 (3H, m, ArH), 7.57e
7.63 (1H, m, ArH), 7.88e7.96 (4H, m, ArH) ppm. 13C NMR (75 MHz,
4JH,H ¼ 1.2 Hz, CH2OAc), 7.00 (1H, br. s, ]CH), 7.04 (2H, d,
3
3JH,H ¼ 8.7 Hz, ArH), 7.10 (2H, d, JH,H ¼ 8.7 Hz, ArH), 7.29 (2H, d,
3JH,H ¼ 9.0 Hz, ArH), 7.76 (2H, d, 3JH,H ¼ 9.0 Hz, ArH) ppm. 13C NMR
CDCl3)
d
: 60.27,127.30,128.26, 128.47, 129.52, 129.57,129.72, 130.81,
(75 MHz, CDCl3) d: 20.72, 66.90, 128.66, 129.00, 130.08, 130.63,
131.46, 132.81, 133.04, 134.66, 135.68, 137.01, 137.30, 139.25, 165.92,
196.16 ppm. HRMS (ES): M þ Naþ, found 433.0398. C23H16Cl2NaO3
requires 433.0369.
132.71, 132.90, 134.20, 134.67, 135.46, 140.26, 170.50, 196.92 ppm.
HRMS (ES): M þ Naþ, found 371.0206. C18H14Cl2NaO3 requires
371.0212.
5.1.1.34. (Z)-2-benzoyl-3-(2,4-dichlorophenyl)allyl benzoate (3eb).
Yellowish oil. Yield 11%. IR (KBr): nmax ¼ 1721, 1663 (C]O) cmꢁ1. 1H
5.1.1.40. (E)-2-(4-chlorobenzylidene)-1,5-bis(4-chlorophenyl)-4-
methylenepentane-1,5-dione (4fb). Yellow oil. Yield 22%. IR (KBr):
NMR (300 MHz, CDCl3)
d
: 5.27 (2H, d, 3JH,H ¼ 1.5 Hz, CH2OBz), 6.90
nmax ¼ 1648 (C]O) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 3.84 (2H, br.
(1H, ddd, 3JH,H ¼ 8.4 Hz, 4JH,H ¼ 2.1 Hz, 5JH,H ¼ 0.6 Hz, ArH), 7.03 (1H,
s, ]CCH2C ¼ ), 5.65 (1H, t, JH,H ¼ 1.2 Hz, ]CHH), 5.85 (1H, t,
4
3
4
d, JH,H ¼ 8.4 Hz, ArH), 7.24 (1H, d, JH,H ¼ 2.1 Hz, ArH), 7.26e7.32
4JH,H ¼ 1.5 Hz, ]CHH), 7.36e7.41 (7H, m, ]CH, ArH), 7.44 (2H, d,
3
3
(3H, m, ]CH, ArH), 7.36 (2H, t, JH,H ¼ 7.8 Hz, ArH), 7.43 (1H, t,
3JH,H ¼ 8.4 Hz, ArH), 7.67 (2H, d, JH,H ¼ 8.7 Hz, ArH), 7.72 (2H, d,
3JH,H ¼ 7.5 Hz, ArH), 7.52 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.80e7.83 (2H,
3JH,H ¼ 8.7 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 30.76, 126.18,
m, ArH), 7.88e7.92 (2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d:
128.61, 128.73, 129.01, 130.54, 130.94, 131.02, 133.11, 135.30, 135.43,
136.23, 137.94, 138.58, 138.98, 142.65, 144.75, 196.40, 196.78 ppm.
HRMS (ES): M þ Hþ, found 455.0365. C25H18Cl3O2 requires
455.0367.
66.61, 126.83, 128.35, 128.51, 129.09, 129.54, 129.59, 129.84, 131.31,
131.93, 133.13, 133.65, 134.01, 134.85, 136.08, 137.87, 165.90,
197.42 ppm. HRMS (ES): M þ Naþ, found 433.0376. C23H16Cl2NaO3
requires 433.0369.
5.1.1.41. (E)-2-(4-chlorobenzoyl)-3-(2,4-dichlorophenyl)allyl acetate
5.1.1.35. (E)-2-benzoyl-3-(2-nitrophenyl)allyl
benzoate
(2ec).
(2fc). White solid; m. p. ¼ 80e82 ꢀC. Yield 30%. IR (KBr):
Yellow oil. Yield 22%. IR (KBr): nmax ¼ 1715, 1651 (C]O) cmꢁ1. 1H
nmax ¼ 1740, 1662 (C]O) cmꢁ1. 1H NMR (300 MHz, CDCl3)
d: 1.99
NMR (300 MHz, CDCl3)
d
: 5.20 (2H, s, CH2OBz), 7.35 (2H, t,
(3H, s, COCH3), 4.99 (2H, s, CH2OAc), 7.28 (1H, br. s, ]CH), 7.32 (2H,
3JH,H ¼ 7.2 Hz, ArH), 7.43e7.64 (7H, m, ]CH, ArH), 7.69 (1H, td,
m, ArH), 7.45e7.49 (3H, m, ArH), 7.84 (2H, d, JH,H ¼ 8.7 Hz, ArH),
3
4
3JH,H ¼ 7.5 Hz, JH,H ¼ 1.2 Hz, ArH), 7.84e7.87 (2H, m, ArH), 8.00e
ppm. 13C NMR (75 MHz, CDCl3)
d: 20.66, 59.64, 127.32, 128.82,
3
4
8.04 (2H, m, ArH), 8.21 (1H, td, JH,H ¼ 8.4 Hz, JH,H ¼ 1.2 Hz, ArH)
129.65, 130.84, 131.14, 134.72, 135.24, 135.89, 137.02, 139.19, 139.34,
ppm. 13C NMR (75 MHz, CDCl3)
d
: 60.12, 125.21, 128.27, 128.55,
170.40, 194.86 ppm. HRMS (ES): M þ Naþ, found 404.9818.
129.49, 129.53, 129.83,130.76,130.91, 132.85, 133.05, 133.92,136.30,
136.89, 140.72, 147.05, 165.94, 196.14 ppm. HRMS (ES): M þ Kþ,
found 426.0738. C23H17KNO5 requires 426.0738.
C18H13Cl3NaO3 requires 404.9822.
5.1.1.42. (Z)-2-(4-chlorobenzoyl)-3-(2,4-dichlorophenyl)allyl acetate
(3fc). Yellow oil. Yield 12%. IR (KBr): nmax ¼ 1746, 1662 (C]O) cmꢁ1
.
5.1.1.36. (Z)-2-benzoyl-3-(2-nitrophenyl)allyl
benzoate
(3ec).
1H NMR (300 MHz, CDCl3)
d: 2.03 (3H, s, COCH3), 5.00 (2H, d,
Yellow oil. Yield 23%. IR (KBr): nmax ¼ 1724, 1659 (C]O) cmꢁ1. 1H
4JH,H ¼ 1.5 Hz, CH2OAc), 6.90 (1H, dd, 3JH,H ¼ 8.1 Hz, 4JH,H ¼ 1.8 Hz,
ArH), 6.95, (1H, d, 3JH,H ¼ 8.1 Hz, ArH), 7.17 (1H, d, 4JH,H ¼ 1.2 Hz, ]
CH), 7.32 (2H, m, ArH), 7.24e7.29 (3H, m, ArH), 7.64 (2H, d,
NMR (400 MHz, CDCl3)
d
: 5.31 (2H, d, 4JH,H ¼ 1.2 Hz, CH2OBz), 7.19e
7.27 (4H, m, ArH), 7.31e7.39 (4H, m, ArH), 7.44 (1H, t, 3JH,H ¼ 7.6 Hz,
ArH), 7.50e7.55 (2H, m, ]CH, ArH), 7.76e7.79 (2H, m, ArH), 8.92e
3JH,H ¼ 9.0 Hz, ArH), ppm. 13C NMR (75 MHz, CDCl3)
d: 20.70, 65.99,
8.96 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 66.087,124.66,
126.95, 128.89, 129.26, 130.24, 130.37, 130.89, 131.27, 131.78, 133.95,
134.43, 135.18, 137.43, 140.19, 170.37, 196.08 ppm. HRMS (ES):
M þ Naþ, found 404.9820. C18H13Cl3NaO3 requires 404.9822.
128.35, 128.38, 128.53, 128.83, 129.27, 129.62, 130.07, 131.28, 131.44,
132.06, 133.11, 133.39, 133.42, 136.77, 137.38, 165.88, 197.22 ppm.
HRMS (ES): M þ Naþ, found 410.0995. C23H17NaNO5 requires
410.0999.
5.2. Biology
5.1.1.37. (E)-2-(4-chlorobenzoyl)-3-cyclohexylallyl acetate (2fa).
Yellow oil. Yield 34%. IR (KBr): nmax ¼ 1739, 1654 (C]O) cmꢁ1. 1H
All starting materials were commercially available research
grade chemicals and used without further purification. RPMI 1640
medium was purchased from Flow Laboratories (Irvine, UK), fetal
calf serum (FCS) was from Gibco (Grand Island, NY), trichloroacetic
acid (TCA) and glutamine were from Merck (Darmstadt, Germany),
and penicillin G, streptomycin, DMSO and sulforhodamine B (SRB)
were from Sigma (St Louis, MO).
NMR (300 MHz, CDCl3) d: 1.09e1.34 (5H, m, cHex), 1.66e1.75 (5H,
m, cHex), 2.01 (3H, s, COCH3), 2.49e2.62 (1H, m, cHex), 4.96 (2H, s,
3
CH2OAc), 6.22 (1H, d, JH,H ¼ 10.2 Hz, ]CH), 7.39 (2H, d,
3JH,H ¼ 8.7 Hz, ArH), 7.62 (2H, d, 3JH,H ¼ 8.7 Hz, ArH) ppm. 13C NMR
(75 MHz, CDCl3) d: 20.82, 25.15, 25.54, 32.13, 38.24, 58.74, 128.47,
130.86, 133.03, 136.13, 138.36, 154.78, 170.79, 195.67 ppm. HRMS
(ES): M þ Naþ, found 343.1073. C18H21ClNaO3 requires 343.1071.
5.2.1. Cells, culture and plating
The human solid tumor cell lines HBL-100, HeLa, SW1573, T-47D
and WiDr were used in this study. These cell lines were a kind gift
from Prof. G. J. Peters (VU Medical Center, Amsterdam, The
Netherlands). Cells were maintained in 25 cm2 culture flasks in
RPMI 1640 supplemented with 5% heat inactivated fetal calf serum
5.1.1.38. (E)-2-(4-chlorobenzoyl)-3-(4-chlorophenyl)allyl
acetate
(2fb). Yellow oil. Yield 29%. IR (KBr): nmax ¼ 1738,1651 (C]O) cmꢁ1
.
1H NMR (300 MHz, CDCl3)
d: 2.05 (3H, s, COCH3), 5.08 (2H, s,
CH2OAc), 7.23 (1H, br. s, ]CH), 7.33 (2H, d, 3JH,H ¼ 8.7 Hz, ArH), 7.39
(2H, d, 3JH,H ¼ 8.7 Hz, ArH), 7.45 (2H, d, 3JH,H ¼ 8.7 Hz, ArH), 7.75 (2H,
and 2 mM L
-glutamine in a 37 ꢀC, 5% CO2, 95% humidified air
3
d, JH,H ¼ 8.7 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d
: 20.77,
incubator. Exponentially growing cells were trypsinized and re-
suspended in antibiotic containing medium (100 units penicillin
G and 0.1 mg of streptomycin per mL). Single cell suspensions
displaying >97% viability by trypan blue dye exclusion were
59.69, 128.75, 129.08, 130.65, 130.99, 132.30, 135.48, 135.70, 135.82,
138.92, 143.29, 170.59, 195.42 ppm. HRMS (ES): M þ Naþ, found
371.0206. C18H14Cl2NaO3 requires 371.0212.

578
I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578
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subsequently counted. After counting, dilutions were made to give
the appropriate cell densities for inoculation onto 96-well micro-
titer plates. Cells were inoculated in a volume of 100 mL per well at
significance of chalcone scaffold: a review, Curr. Med. Chem. 19 (2012) 209e
225.
[8] J.M. Padrón, P.O. Miranda, J.I. Padrón, V.S. Martín, b a, b-unsaturated
0-Hydroxy-
ketones: a new pharmacophore for the design of anticancer drugs, Bioorg.
Med. Chem. Lett. 16 (2006) 2266e2269.
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and 20,000 (WiDr) cells per well, based on their doubling times.
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desired final maximum test concentration. Control cells were
exposed to an equivalent concentration of DMSO (0.25% v/v,
negative control). Each agent was tested in triplicate at different
dilutions in the range of 1e100
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m
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The research was funded by the European Social Fund under the
Global Grant measure (Grant No. VP1-3.1-SMM-07-K-01-002). Co-
financed by the EU Research Potential (FP7-REGPOT-2012-
CT2012-31637-IMBRAIN), the European Regional Development
Fund (FEDER) and the Spanish Instituto de Salud Carlos III (PI11/
00840).
ꢀ
Appendix A. Supplementary data
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.10.041.
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