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European Journal of Medicinal Chemistry 70 (2013) 568e578

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European Journal of Medicinal Chemistry

journal homepage: http: / /www.elsevier .com/locate/ejmech

Original article

Synthesis and antiproliferative activity of a-branched a,b-unsaturatedketones

Ieva Karpaviciene a, Inga Cikotiene a,**, José M. Padrón b,*

aDepartment of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, Vilnius LT 03225, LithuaniabBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidadde La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain

a r t i c l e i n f o

Article history:Received 30 May 2013Received in revised form27 August 2013Accepted 13 October 2013Available online 22 October 2013

Keywords:Antitumor agentsa-Branched a,b-unsaturated ketonesChalconesLewis acidsStructureeactivity relationships

* Corresponding author. Tel.: þ34 922 316 502x612** Corresponding author. Tel.: þ370 52193195; fax:

E-mail addresses: inga.cikotiene@chf.vu.lt (I. CikM. Padrón).

0223-5234/$ e see front matter � 2013 Elsevier Mashttp://dx.doi.org/10.1016/j.ejmech.2013.10.041

a b s t r a c t

A series of a-branched a,b-unsaturated ketones were prepared in a straightforward manner by the acidcatalyzed coupling between arylalkynes and carbaldehydes. The method also allows producing as sideproduct chalcone analogs bearing an additional a,b-unsaturated arylketone in the molecular scaffold. Theevaluation 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 structureeactivityrelationship. Overall, the compounds presented active against the resistant cancer cells T-47D. Theresulting lead, displaying an unprecedented chalcone scaffold, showed GI50 values in the range 0.32e0.53 mM against all cell lines tested. The methoxy group present in the lead might play an importantrole in the activity.

� 2013 Elsevier Masson SAS. All rights reserved.

1. Introduction

Chalcones (1,3-diaryl-2-propen-1-ones, I, Fig. 1) represent aclass of flavonoids that occur naturally in fruits and vegetables. Thisclass of natural products and their synthetic derivatives has showninteresting biological properties [1,2], among which, anticanceractivity [3,4] is of particular interest to us. For the chalcones withvarious antitumor activities reported in the literature in the lastdecade, their mechanism of action could be organized into diversecategories 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 werenot toxic to normal cells, while have shown in clinical trialsreasonable plasma concentrations and did not cause toxicity [6].Besides all these advantages, there is still room for exploding thepharmacological potential of chalcones by modifications on themolecular scaffold [7]. In this particular context, we have reportedearlier that a-branched a,b-unsaturated ketones (II, Fig. 1) and b0-

6; fax: þ34 922 318 571.þ370 52330987.otiene), jmpadron@ull.es (J.

son SAS. All rights reserved.

acyloxy-a,b-unsaturated ketones (III, Fig. 1) prepared via iron (III)catalyzed tandem processes, show remarkable biological activitytowards human cancer cell lines, including cell cycle arrest andapoptosis induction [8,9].

Chemically, chalcones are defined as open chain flavonoidsconsisting of two aromatic rings joined by a three carbon a,b-un-saturated carbonyl system (I, Fig. 1). Although chalcones may existin 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 condensationbetween 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 carbonylativeHeck coupling with aryl halides and styrenes in the presence ofcarbon monoxide [13] and MeyereSchuster rearrangement ofpropargylic alcohols [14] have been reported. For the synthesis of a-substituted chalcones the Knoevenagel [15], Aldol-Grob [16] typecondensations as well as Horner-Wadsworth-Emmons olefination[17] reactions can be applied. Another useful alternative for theconstruction of the C]C bond is through an alkyne carbonylmetathesis. This transformation represents a completely atom-economical alternative to the use of stabilized Wittig reagents incarbonyl olefination reactions [18]. The metathesis reaction

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].

Having inmind that the chalcone scaffold and a-substituted a,b-unsaturated ketones are important pharmacophores, we exploredthe possibility of a-substituted chalcones as antitumor agents.Herein we report on the synthesis and biological activity of a seriesof functionalized a-substituted chalcones and structural analogs.The compounds were obtained by the Lewis acid catalyzedcoupling of alkynes and aldehydes. As a model system to study thebiological 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. Astructureeactivity relationship (SAR) is also discussed.

2. Chemistry

For the preparation of a-branched a,b-unsaturated ketones, weutilized the reaction between arylalkynes and carbaldehydes. Firstof all, we tested the reactivity of starting alkynes towards Lewisacid-catalyzed coupling reaction with aldehydes. Several Lewisacids such as BF3$Et2O, FeCl3, AgSbF6, SbF5, BBr3, TMSOTf, diversesolvents (DCM, DCE, CH3CN, THF, CH3NO2) and different reactiontemperatures were examined. After this brief searching of the mostsuitable reaction conditions we came to conclusion that 1 equiva-lent of BF3$Et2O in dichloromethane at room temperature gave thebest results. It should be noted that using nitromethane as a solventresulted in smoother reactions; however side condensation ofbenzaldehydes with solvent occurs. Moreover, we found that theoutcome of the reaction strongly depends on the structure of bothstarting materials and, in some cases together with main E-configuration enone 2, smaller amounts of Z-isomer 3 or 2:1 adduct4 formed (Scheme 1). The data of reactions between alkynes 1aefand 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 ofenones 2 took place (Table 1, entries 1e6). However, during thereaction of 1,2-diphenylethyne 1c and cyclohexylcarbaldehyde, twoproducts e major E (2) and minor Z (3) were isolated (entry 7). Onthe other hand, during the reaction between 1,2-diphenylethyne 1cand 2,4-dichlorobenzencarbaldehyde, Z-enone (3) was isolated assole product (entry 8).

Results of the reactions between 3-arylprop-2-inylcarboxylates1def and carbaldehydes were much more intriguing. While in allcases when aliphatic carbaldehydes were used (entries 9, 10, 21, 24)the selective formation of E-configurated alkyneecarbonylmetathesis products 2 took place in low or moderate yields. Lowoverall yields can be explained by possible side self-condensationreaction between two aliphatic aldehydes molecules. However,the mixtures of E (2) and Z (3) isomers of the corresponding a,b-unsaturated ketones were formed during reaction of 1def witharomatic aldehydes, especially those having an ortho-substituent(Table 1, entries 14,15, 17e19, 22, 23, 26). The reaction of 1dwith 4-methoxybenzaldehyde was complicated and took longer times forthe full conversion of the alkyne; and also a lot of tars were

Fig. 1. General structure of chalcones (I) and previou

produced. After thework-up of the reactionmixture, 2:1 adduct 4dlwas isolated in poor yield as sole reaction product (entry 20).Moreover, the formation of 2:1 adducts 4 was observed in the casewhen plain benzaldehyde (entry 11) or halogenated benzaldehydes(entries 12, 13, 16, 25) were used.

3. Antiproliferative activity

From the set of 43 synthesized chalcone analogs, a total of 40compounds were submitted for biological assays. The in vitro ac-tivity was assessed in HBL-100, HeLa, SW1573, T-47D and WiDrhuman 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 obtaineddoseeresponse data. The standard anticancer drugs cisplatin andetoposide were used as positive controls. Overall, the data onantiproliferative activity show that all tested compounds exhibitedgrowth inhibition in at least two of the cell lines of the panel. Forthe most active compound of the series 4dl the GI50 values were inthe range 0.32e0.53 mM.

The analysis of the GI50 values allowed us to establish someSARs. A first comparison was done between E (2) and Z (3) isomers.In most cases, E isomers (2ca, 2di, 2dj, 2dk, 2ec, 2fc) appear moreactive than the corresponding Z isomer (3ca, 3di, 3dj, 3dk, 3ec, 3fc).However, E compounds 2dg, 2eb and 2fb did not show a clearenhanced activity when compared to the corresponding Z analogs3dg, 3eb and 3fb, respectively. When considering the substituent atthe 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 isconsistent with our past observations [8]. In the same context, thepresence of halogenated substituents on the aryl ring tend toameliorate the antiproliferative activity (2bd > 2bc > 2bb;2dd > 2dc) if they are allocated at the para position. In contrast, asubstituent at the ortho position (2dc vs 2dg, 2dh) does not influ-ence positively the antiproliferative effect. Next, the presence ofchloromethyl (2bb, 2bc, 2bd), acetoxymetyl (2dc, 2dd, 2di, 2fb,2fc), benzyloxymethyl (2eb, 2ec) groups in a-position of chalconemoiety enhances the antiproliferative activity. Finally, a chlorineatom in para position of the phenyl ring next to the ketone does notproduce 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 improvedbiological activity only in the most resistant cell line T-47D.

In addition to E (2) and Z (3) chalcones, our synthetic procedureproduces 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 themost potent compound from thewhole study.These adducts possess in their structure an additional a,b-unsatu-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 onlycompound of the series with a methoxy group in para position ofthe phenyl ring at the b position of the unsaturated ketone.

sly described anticancer compounds II and III.

Scheme 1. BF3$Et2O catalyzed reaction of arylalkynes and aldehydes: a) R2CHO, BF3$Et2O, CH2Cl2, r.t. See Table 1 for substituents.

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578570

Unfortunately, the corresponding E and Z chalcones of 4dl could notbe obtained by the reported methodology. Thus, it was not possibleto establish the role in the activity of methoxy group, although wespeculate that it should be favorable. Contrary to what holds forcompound II, a direct comparison of linear product III with thosebranched analogs reported in this work is not possible due to thedifferences in structure. Nevertheless, the lead 4dl is more potent inall cell lines tested than the reference compound III (GI50 in therange 1.8e3.9 mM against the same cell lines).

4. Conclusions

In summary, we have described a straightforward syntheticmethodology to obtain a series of E and Z a-substituted chalcones inaddition to unprecedented adducts bearing two a,b-unsaturatedarylketone frameworks. We evaluated their ability to inhibit tumorcell growth and from the results some structureeactivity re-lationships have been derived. Although the experiments are pre-liminary, these compounds show remarkable biological activitytowards human cancer cell lines. Overall, the compounds showactive against the resistant breast cancer cell line T-47D. In partic-ular, the lead compound displays similar activity profile againstdrug sensitive (HBL-100, HeLa and SW1573) and resistant (T-47Dand WiDr) cell lines. More experiments are needed to establish thescope and limitations of the methoxy group present in the mostactive compound of the series. This general methodology allows thequick production of a variety of chalcones useful for the discovery ofnovel bioactive compounds.

5. Experimental

5.1. Chemistry

IR spectra were run in KBr discs on a PerkineElmer FT spec-trophotometer Spectrum BX II. 1H and 13C NMR spectra wererecorded with a Varian Unity INOVA spectrometer (300 MHz) orBrucker (400MHz) in chloroform-d, using residual solvent signal asinternal standard. HRMS spectra were obtained on a mass spec-trometer Dual-ESI Q-TOF 6520 (Agilent Technologies). All reactionsand the purity of the synthesized compounds monitored by TLCusing Silica gel 60 F254 aluminum plates (Merck). Visualization wasaccomplished by UV light. Final purification of synthesized com-pounds was performed on Flash Chromatography system Combi-Flash (Teledyne Isco), using hexaneeethyl acetate mixtures.

5.1.1. General procedure for the preparation of 2e4To 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. Theresulting solution was stirred at room temperature. When thecompletion of the reaction was observed by TLC, the solution wasquenched with aqueous sodium bicarbonate. The organic layer wasseparated, washed with water (2*20 mL), dried over anhydrousNa2SO4. After the evaporation of solvent under reduced pressure,the residue was purified by Flash Column chromatography elutingwith hexaneeethyl acetate mixtures.

5.1.1.1. (E)-3-Cyclohexyl-1-phenylprop-2-en-1-one (2aa) [22].Yellow oil. Yield 16%. 1H NMR (300MHz, CDCl3) d: 1.19e1.35 (5H, m,cHex), 1.76e1.86 (5H, m, cHex), 2.20e2.30 (1H, m, cHex), 6.83 (1H,dd, 3JH,H ¼ 15.6 Hz, 4JH,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,CDCl3) d: 7.30 (1H, ddd, 3JH,H ¼ 8.4 Hz, 4JH,H ¼ 2.1 Hz, 5JH,H ¼ 0.6 Hz,ArH), 7.45e7.54 (4H, m,]CH, ArH), 7.60 (1H, t, 3JH,H ¼ 7.5 Hz, ArH),7.68 (1H, d, 3JH,H¼ 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.

5.1.1.3. (Z)-2-(Chloromethyl)-3-cyclohexyl-1-phenylprop-2-en-1-one(2ba). Yellow oil. Yield 34%. IR (KBr): nmax ¼ 1651 (C]O) cm�1. 1HNMR (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,3JH,H ¼ 9.9 Hz, ]CH), 7.43 (2H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.54 (1H, t,3JH,H¼ 7.5 Hz, ArH), 7.66e7.70 (2H, m, ArH) ppm. 13C NMR (75MHz,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, found285.1013. 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) cm�1. 1H NMR(300MHz, 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 (75MHz, CDCl3)d: 38.99, 128.33, 128.86, 129.38, 129.59, 129.66, 132.34, 133.99,136.35, 137.73, 144.36, 196.40 ppm. HRMS (ES): M þ Naþ, found279.0551. C16H13ClNaO requires 279.0547.

5.1.1.5. (Z)-2-(chloromethyl)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (2bc). Yellowish oil. Yield 32%. IR (KBr): nmax ¼ 1651 (C]O) cm�1. 1H NMR (300MHz, CDCl3) d: 4.63 (2H, s, CH2Cl), 7.21 (1H, s,]CH), 7.41e7.51 (6H, m, ArH), 7.59 (1H, t, 3JH,H¼ 7.5 Hz, ArH), 7.78e7.82 (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. C16H12Cl2NaOrequires 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) cm�1. 1H NMR (300MHz, CDCl3) d: 4.52 (2H, s, CH2Cl), 7.27 (1H, s,]CH), 7.38 (1H, ddd, 3JH,H ¼ 8.1 Hz, 4JH,H ¼ 2.1 Hz, 5JH,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(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 requires346.9768.

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) cm�1. 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),

Table 1Data on the reactions between selected alkynes and aldehydes.

Entry Alkyne Aldehyde (R2) Products (yields,%)

1 1a: Ar ¼ Ph; R1 ¼ H cHex 2aa (16)2 1a 2,4-Cl2C6H3 2ab (42)3 1b: Ar ¼ Ph; R1 ¼ CH2Cl cHex 2ba (34)4 1b Ph 2bb (50)5 1b 4-ClC6H4 2bc (32)6 1b 2,4-Cl2C6H3 2bd (55)7 1c: Ar ¼ Ph; R1 ¼ Ph cHex 2ca (26); 3ca (14)8 1c 2,4-Cl2C6H3 3cb (24)9 1d: Ar ¼ Ph; R1 ¼ CH2OAc cHex 2da (49)10 1d Et2CH 2db (39)11 1d Ph 2dc (24); 4dc (11)12 1d 4-ClC6H4 2dd (21); 4dd (12)13 1d 4-FC6H4 2de (16); 3de (6)a;

4de (22)14 1d 2-ClC6H4 2df (26); 3df (27)b

15 1d 2-BrC6H4 2dg (31); 3dg (20)16 1d 2-FC6H4 2dh (33); 3dh (26);

4dh (15)17 1d 2,4-Cl2C6H3 2di (46); 3di (23)18 1d 4-NO2C6H4 2dj (48); 3dj (13)c

19 1d 2-NO2C6H4 2dk (28); 3dk (10)20 1d 4-MeOC6H4 4dl (12)21 1e: Ar ¼ Ph; R1 ¼ CH2OBz cHex 2ea (24)22 1e 2,4-Cl2C6H3 2eb (50); 3eb (11)23 1e 2-NO2C6H4 2ec (22), 3ec (23)b

24 1f: Ar ¼ 4-ClC6H4;R1 ¼ CH2OAc

cHex 2fa (34)

25 1f 4-ClC6H4 2fb (29); 3fb (13);4fb (22)

26 1f 2,4-Cl2C6H3 2fc (30); 3fc (12)

a Compound 3de was isolated as a mixture with 2de, due to very similar Rf’s.b The reaction was carried out in nitromethane at room temperature. Product 2df

was isolated as a mixture together with side condensation product 1-(2-chlorophenyl)-2-nitroethanol.

c Small amount of the rearranged 3-aroyl-1-arylallylcarboxylates was formed.See Ref. [20] for details.

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578 571

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 (75MHz,CDCl3) d: 25.14, 25.69, 32.34, 38.29, 127.37, 128.07, 128.19, 129.35,129.68, 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).Yellowish oil. Yield 14%. IR (KBr): nmax ¼ 1670 (C]O) cm�1. 1H NMR(300 MHz, CDCl3) d: 1.13e1.19 (5H, m, cHex), 1.58e1.78 (5H, m,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 (75MHz,CDCl3) d: 25.34, 25.75, 32.73, 38.86, 125.97, 127.54, 128.59, 128.65,129.66, 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(3 cb). Yellow solid; m. p. ¼ 69e71 �C. Yield 24%. IR (KBr):nmax ¼ 1655 (C]O) cm�1. 1H NMR (300 MHz, CDCl3) d: 6.84 (1H, d,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(2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3) d: 126.71, 128.20,128.36,128.65,129.30,129.53,129.98,131.85,132.48,132.74,133.70,134.61, 135.09, 135.27, 137.15, 142.84, 196.79 ppm. HRMS (ES):M þ Naþ, found 375.0311. C21H14Cl2NaO requires 375.0314.

5.1.1.10. (E)-2-benzoyl-3-cyclohexylallyl acetate (2da).Yellowish oil. Yield 49%. IR (KBr): nmax ¼ 1738, 1657 (C]O) cm�1. 1HNMR (300 MHz, CDCl3) d: 1.04e1.38 (5H, m, cHex), 1.60e1.75 (5H,

m, cHex), 2.01 (3H, s, COCH3), 2.49e2.63 (1H, m, cHex), 4.98 (2H, s,CH2OAc), 6.26 (1H, d, 3JH,H ¼ 10.2 Hz, ]CH), 7.41 (2H, t,3JH,H ¼ 7.5 Hz, ArH), 7.51 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.66 (2H, d,3JH,H ¼ 6.9 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3) d: 20.81, 25.15,25.54, 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, found309.1449. C18H22NaO3 requires 309.1461.

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) cm�1. 1HNMR (300 MHz, CDCl3) d: 0.87 (6H, t, 3JH,H ¼ 7.5 Hz,CH(CH2CH3)2),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),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.

5.1.1.12. (E)-2-benzoyl-3-phenylallyl acetate (2dc). Yellowish oil.Yield 24%. IR (KBr): nmax ¼ 1739, 1652 (C]O) cm�1. 1H NMR(300 MHz, CDCl3) d: 2.05 (3H, s, COCH3), 5.15 (2H, s, CH2OAc), 7.37(1H, s, ]CH), 7.38e7.43 (5H, m, ArH), 7.47 (2H, t, 3JH,H ¼ 7.2 Hz,ArH), 7.57 (1H, t, 3JH,H ¼ 6.9 Hz, ArH), 7.81e7.84 (2H, m, ArH) ppm.13C NMR (75 MHz, CDCl3) d: 20.77, 59.79, 128.27, 128.65, 129.26,129.46, 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. C18H16NaO3requires 303.0992.

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):nmax ¼ 1642, 1641 (C]O) cm�1. 1H NMR (300 MHz, CDCl3) d: 3.92(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 (75MHz, CDCl3)d: 30.51,125.84,128.10,128.18,128.31,128.68, 129.11,129.24,129.56,129.63, 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. C25H20NaO2requires 375.1356.

5.1.1.14. (E)-2-benzoyl-3-(4-chlorophenyl)allyl acetate (2dd).Yellowish oil. Yield 21%. IR (KBr): nmax ¼ 1740, 1651 (C]O) cm�1. 1HNMR (300 MHz, CDCl3) d: 2.05 (3H, s, COCH3), 5.10 (2H, s, CH2OAc),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, 129.58,130.61, 132.45, 132.50, 135.60, 137.47, 143.44, 170.64, 196.68 ppm.HRMS (ES): M þ Naþ, found 337.0603. C18H15ClNaO3 requires337.0602.

5 .1.1.15 . (E)-2-(4-ch lorobenzyl idene)-4-methylene-1,5-diphenylpentane-1,5-dione (4dd). Yellowish oil. Yield 12%. IR (KBr):nmax ¼ 1648 (C]O) cm�1. 1H NMR (300 MHz, CDCl3) d: 3.88 (2H, br.s, ]CCH2C ¼ ), 5.68 (1H, t, 4JH,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(75 MHz, CDCl3) d: 30.62, 126.17, 128.22, 128.36, 128.93, 129.55,129.62, 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, found409.0953. C25H19ClNaO2 requires 409.0966.

5.1.1.16. (E)-2-benzoyl-3-(4-fluorophenyl)allyl acetate (2de).Yellowish oil. Yield 16%. IR (KBr): nmax ¼ 1739, 1651 (C]O) cm�1. 1HNMR (400 MHz, CDCl3) d: 2.06 (3H, s, COCH3), 5.11 (2H, s, CH2OAc),

Table 2Antiproliferative activity (GI50) against human solid tumor cells of compounds produced via Scheme 1.a,b

Compound HBL-100 (breast) HeLa (cervix) SW1573 (lung) T-47D (breast) WiDr(Colon)

2aa 18 (�2.9) 21 (�2.5) 10 (�4.7) 15 (�4.3) 21 (�3.9)

2ab 17 (�1.1) 18 (�0.3) 12 (�1.5) 14 (�1.6) 20 (�1.8)

2ba 22 (�1.8) 30 (�5.1) 23 (�3.9) 29 (�9.2) 22 (�1.5)

2bb 12 (�1.9) 23 (�1.8) 3.6 (�0.3) 18 (�3.5) 18 (�3.7)

2bc 3.2 (�0.7) 22 (�3.7) 3.9 (�0.6) 17 (�4.9) 19 (�1.6)

2bd 3.1 (�0.8) 15 (�2.7) 3.8 (�0.6) 6.3 (�0.7) 13 (�1.8)

2ca 57 (�2.6) 47 (�16) 29 (�8.0) 39 (�4.5) 34 (�3.7)

3ca 59 (�6.7) 63 (�6.5) 64 (�1.0) 74 (�30) 64 (�22)

3cb >100 47 (�14) 41 (�16) 52 (�13) 46 (�15)

2da 21 (�1.3) 21 (�2.1) 19 (�3.3) 22 (�1.5) 21 (�2.3)

2db >100 50 (�6.0) 77 (�17) 89 (�9.8) 52 (�2.0)

2dc 17 (�4.2) 20 (�8.5) 4.8 (�0.9) 16 (�3.2) 17 (�4.9)

4dc 10 (�5.0) 19 (�5.7) 3.0 (�1.1) 15 (�4.5) 18 (�4.8)

2dd 2.3 (�0.5) 3.2 (�0.7) 2.6 (�0.7) 5.3 (�2.5) 4.8 (�1.5)

4dd 17 (�2.6) 22 (�2.8) 6.1 (�2.4) 19 (�3.5) 20 (�2.9)

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Table 2 (continued )

Compound HBL-100 (breast) HeLa (cervix) SW1573 (lung) T-47D (breast) WiDr(Colon)

2de 17 (�3.9) 25 (�4.2) 4.2 (�0.5) 14 (�2.8) 13 (�1.3)

4de 14 (�1.9) 18 (�5.0) 3.5 (�0.5) 15 (�3.0) 19 (�3.2)

3df 21 (�3.8) 24 (�4.5) 14 (�0.8) 19 (�1.2) 22 (�4.5)

2dg 22 (�4.3) 20 (�2.7) 14 (�1.7) 17 (�2.2) 21 (�3.0)

3dg 21 (�2.2) 19 (�1.4) 21 (�3.7) 18 (�1.0) 18 (�4.8)

2dh 17 (�3.3) 22 (�0.8) 6.1 (�1.4) 18 (�1.6) 19 (�5.8)

4dh 15 (�3.2) 20 (�6.0) 3.5 (�0.6) 14 (�2.6) 17 (�3.8)

2di 3.1 (�1.2) 16 (�3.7) 3.5 (�0.3) 9.5 (�1.8) 14 (�1.9)

3di 23 (�2.6) 22 (�2.5) 22 (�3.5) 20 (�1.8) 19 (�1.4)

2dj 10 (�3.3) 26 (�4.6) 3.8 (�0.5) 16 (�4.8) 23 (�1.0)

3dj 41 (�7.7) 36 (�5.4) 32 (�6.5) 36 (�4.8) 83 (�18)

2dk 26 (�3.9) 25 (�2.6) 18 (�1.7) 21 (�6.5) 18 (�6.3)

3dk >100 78 (�5.8) >100 52 (�3.7) >100

(continued on next page)

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Table 2 (continued )

Compound HBL-100 (breast) HeLa (cervix) SW1573 (lung) T-47D (breast) WiDr(Colon)

4dl 0.53 (�0.28) 0.32 (�0.02) 0.45 (�0.25) 0.37(�0.04) 0.47 (�0.05)

2ea 23 (�5.2) 24 (�2.4) 17 (�3.3) 20 (�0.7) 19 (�2.5)

2eb 3.1 (�0.6) 20 (�1.0) 3.3 (�0.5) 17 (�5.8) 17 (�4.0)

3eb 26 (�4.6) 8.3 (�1.3) 29 (�6.3) 5.4 (�0.5) 8.7 (�3.9)

2ec 3.9 (�1.4) 22 (�7.3) 4.3 (�1.8) 16 (�2.2) 18 (�1.8)

3ec >100 30 (�6.8) >100 18 (�6.1) 21 (�1.9)

2fa 31 (�14) 24 (�2.6) 18 (�3.9) 18 (�2.9) 21 (�5.5)

2fb 4.0 (�1.6) 19 (�3.5) 3.4 (�0.5) 5.4 (�1.5) 18 (�3.2)

3fb 16 (�0.9) 5.7 (�1.2) 5.3 (�1.8) 12 (�3.3) 17 (�1.4)

4fb 16 (�1.1) 21 (�3.4) 5.3 (�1.1) 17 (�5.0) 24 (�4.6)

2fc 3.2 (�0.8) 4.6 (�0.9) 3.4 (�0.6) 5.2 (�0.9) 8.1 (�1.9)

3fc 22 (�4.0) 19 (�0.4) 21 (�3.9) 20 (�1.4) 20 (�1.1)

Cisplatin 1.9 (�0.2) 2.0 (�0.3) 3.0 (�0.4) 15 (�2.3) 26 (�5.3)Etoposide 1.4 (�0.1) 3.3 (�1.6) 15 (�1.5) 22 (�5.5) 23 (�3.1)

a Values are given in mM and are means of two to five experiments; standard deviation is given in parentheses.b 2df, 3de, 3dh were not tested due to their small amounts or impurities.

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578574

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.

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578 575

7.08e7.14 (2H, m, ArH), 7.31 (1H, s, ]CH), 7.37e7.42 (2H, m, ArH),7.48 (2H, t, 3JH,H ¼ 7.6 Hz, ArH), 7.58 (1H, t, 3JH,H ¼ 7.6 Hz, ArH),7.79e7.82 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3) d: 20.81,59.74, 115.92 (d, 2JC,F ¼ 21.6 Hz), 128.38, 129.57, 130.24 (d,4JC,F ¼ 3.4 Hz), 131.40 (d, 3JC,F ¼ 8.4 Hz), 132.36, 134.98, 137.60,143.87, 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.

5 .1.1.17 . (E ) -2- (4-fluorobenzyl idene) -4-methylene-1,5-diphenylpentane-1,5-dione (4de). Yellowish oil. Yield 22%. IR (KBr):nmax ¼ 1655(C]O) cm�1. 1H NMR (400 MHz, CDCl3) d: 3.89 (2H, br.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,2JC,F ¼ 21.5 Hz), 125.95, 128.21, 128.34, 129.52, 129.63, 131.05 (d,4JC,F ¼ 3.4 Hz), 131.27 (d, 3JC,F ¼ 8.3 Hz), 131.98, 132.40, 137.29,137.49, 138.19, 143.07, 145.11, 162.95 (d, 1JC,F ¼ 249.0 Hz), 197.81,198.14 ppm. HRMS (ES): M þ Naþ, found 393.1257. C25H19FNaO2

requires 393.1261.

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) cm�1. 1HNMR (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,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, 129.63,129.76, 130.12, 130.38, 132.71, 132.87, 133.93, 136.57, 137.13, 141.00,

170.65, 196.50 ppm. HRMS (ES): M þ Naþ, found 337.0607.C18H15ClNaO3 requires 337.0602.

5.1.1.19. (Z)-2-benzoyl-3-(2-chlorophenyl)allyl acetate (3df).Orange oil. Yield 27%. IR (KBr): nmax ¼ 1742, 1655 (C]O) cm�1. 1HNMR (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(1H, t, 3JH,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, 129.03,129.08, 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.

5.1.1.20. (E)-2-benzoyl-3-(2-bromophenyl)allyl acetate (2dg).Yellow oil. Yield 31%. IR (KBr): nmax ¼ 1741, 1656 (C]O) cm�1. 1HNMR (300 MHz, CDCl3) d: 1.99 (3H, s, COCH3), 5.02 (2H, d,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), 7.93e7.97 (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.

5.1.1.21. (Z)-2-benzoyl-3-(2-bromophenyl)allyl acetate (3 dg).Yellow oil. Yield 20%. IR (KBr): nmax ¼ 1743, 1658 (C]O) cm�1. 1HNMR (400 MHz, CDCl3) d: 2.03 (3H, s, CH3CO), 5.04 (2H, d,4JH,H ¼ 1.2 Hz, CH2OAc), 6.88e6.95 (2H, m, ]CH, ArH), 7.21e7.26

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(3H, m, ArH), 7.33e7.39 (3H, m, ArH), 7.73e7.76 (2H, m, ArH) ppm.13C NMR (100 MHz, CDCl3) d: 20.73, 66.04, 123.35, 126.99, 128.21,129.01, 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.

5.1.1.22. (E)-2-benzoyl-3-(2-fluorophenyl)allyl acetate (2dh).Yellowish oil. Yield 33%. IR (KBr): nmax ¼ 1741, 1657 (C]O) cm�1. 1HNMR (300 MHz, CDCl3) d: 2.00 (3H, s, COCH3), 5.09 (2H, s, CH2OAc),7.07e7.13 (1H, m, ArH), 7.20 (1H, td, 3JH,H ¼ 7.65 Hz, 4JH,H ¼ 3.9 Hz,ArH), 7.37e7.44 (3H, m,]CH, ArH), 7.48 (2H, t, 3JH,H¼ 7.35 Hz, ArH),7.58 (1H, t, 3JH,H ¼ 7.35 Hz, ArH), 7.84e7.87 (2H, m, ArH) ppm. 13CNMR (75 MHz, CDCl3) d: 20.69, 60.04, 115.71 (d, 2JC,F ¼ 21.45 Hz),122.18 (d, 2JC,F¼ 13.80 Hz),124.25 (d, 4JC,F¼ 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, 136.73,137.01, 137.27, 160.19 (d, 1JC,F ¼ 248.92 Hz), 170.56, 196.36 ppm.HRMS (ES): M þ Naþ, found 321.0881. C18H15FNaO3 requires321.0897.

5.1.1.23. (Z)-2-benzoyl-3-(2-fluorophenyl)allyl acetate (3dh).Yellowish oil. Yield 26%. IR (KBr): nmax ¼ 1737, 1642 (C]O) cm�1. 1HNMR (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,m, ArH), 7.38e7.42 (1H, m, ArH), 7.80e7.82 (2H, m, ArH) ppm. 13CNMR (100 MHz, CDCl3) d: 20.69, 66.60, 115.18 (d, 2JC,F ¼ 21.4 Hz),122.66 (d, 3JC,F ¼ 13.5 Hz), 123.74 (d, 4JC,F ¼ 3.6 Hz), 128.36, 129.15,129.71, 130.31 (d, 3JC,F ¼ 2.2 Hz), 130.34 (d, 3JC,F ¼ 8.40 Hz), 133.37,136.05, 136.93, 159.89 (d, 1JC,F ¼ 247.9 Hz), 170.42, 197.60 ppm.HRMS (ES): M þ Naþ, found 321.0903. C18H15FNaO3 requires321.0897.

5 .1.1.24 . (E ) -2- (2-fluorobenzyl idene)-4-methylene-1,5-diphenylpentane-1,5-dione (4dh). Yellowish oil. Yield 15%. IR (KBr):nmax ¼ 1652 (C]O) cm�1. 1H NMR (400 MHz, CDCl3) d: 3.84 (2H, br.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,m, ArH), 7.68e7.70 (2H, m, ArH), 7.82e7.84 (2H, m, ArH) ppm. 13CNMR (100MHz, CDCl3) d: 30.74, 115.65 (d, 2JC,F ¼ 21.5 Hz), 123.09 (d,2JC,F ¼ 13.9 Hz), 124.24 (d, 4JC,F ¼ 3.8 Hz), 126.38, 128.16, 128.36,129.34, 129.51, 129.58, 129.69, 129.75 (d, 3JC,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, found393.1264. C25H19FNaO2 requires 393.1261.

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) cm�1. 1HNMR (300 MHz, CDCl3) d: 1.99 (3H, s, COCH3), 5.00 (2H, s, CH2OAc),7.31e7.32 (3H, m, ]CH, ArH), 7.45e7.52 (3H, m, ArH), 7.59 (1H, t,3JH,H ¼ 7.5 Hz, ArH), 7.89 (2H, d, 3JH,H ¼ 6.9 Hz, ArH) ppm. 13C NMR(75 MHz, CDCl3) d: 20.65, 59.67, 127.23, 128.42, 129.56, 129.71,130.83, 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. C18H15Cl2O3requires 349.0393.

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): nmax¼ 1731,1664(C]O) cm�1. 1H NMR (300 MHz, CDCl3) d: 2.02 (3H, s, COCH3), 5.03(2H, d, 4JH,H ¼ 1.2 Hz, CH2OAc), 6.88 (1H, dd, 3JH,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(1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.75 (2H, d, 3JH,H ¼ 7.2 Hz, ArH) ppm. 13CNMR (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,

170.41, 197.29 ppm. HRMS (ES): M þ Hþ, found 349.0378.C18H15Cl2O3 requires 349.0393.

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) cm�1. 1HNMR (300 MHz, CDCl3) d: 2.03 (3H, s, COCH3), 5.08 (2H, s, CH2OAc),7.29 (1H, br. s, ]CH), 7.49 (2H, t, 3JH,H ¼ 7.2 Hz, ArH), 7.57 (2H, d,3JH,H ¼ 8.7 Hz, ArH), 7.65 (1H, t, 3JH,H ¼ 7.2 Hz, ArH), 7.82e7.85 (2H,m, ArH), 8.26 (2H, d, 3JH,H ¼ 8.7 Hz, ArH) ppm. 13C NMR (75 MHz,CDCl3) d: 20.64, 59.57, 123.82, 128.51, 129.32, 129.60, 129.93, 132.88,136.81, 138.32, 140.50, 147.77, 170.44, 196.03 ppm. HRMS (ES):M þ Naþ, found 348.0854. C18H15NNaO5 requires 348.0842.

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) cm�1. 1HNMR (300 MHz, CDCl3) d: 2.00 (3H, s, COCH3), 5.02 (2H, d,4JH,H ¼ 1.2 Hz, CH2OAc), 7.05 (1H, br. s, ]CH), 7.28e7.36 (4H, m,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: 20.69,66.38, 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, found348.0856. C18H15NNaO5 requires 348.0842.

5.1.1.29. (E)-2-benzoyl-3-(2-nitrophenyl)allyl acetate (2dk).Yellow oil. Yield 28%. IR (KBr): nmax ¼ 1736, 1655 (C]O) cm�1. 1HNMR (300 MHz, CDCl3) d: 1.93 (3H, s, COCH3), 4.91 (2H, s, CH2OAc),7.37 (1H, d, 3JH,H¼ 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)ppm. 13C NMR (75 MHz, CDCl3) d: 20.63, 59.56, 125.12, 128.47,130.65, 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. C18H15NNaO5requires 348.0842.

5.1.1.30. (Z)-2-benzoyl-3-(2-nitrophenyl)allyl acetate (3dk).Orange oil. Yield 10%. IR (KBr): nmax ¼ 1741, 1656 (C]O) cm�1. 1HNMR (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, ]CH), 7.71 (2H, d, 3JH,H ¼ 7.2 Hz, ArH), 7.92 (1H, dd, 3JH,H ¼ 8.1 Hz,4JH,H ¼ 1.5 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3) d: 20.74, 65.54,124.63, 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.

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) cm�1. 1H NMR (300 MHz,CDCl3) d: 3.82 (3H, s, OCH3), 3.93 (2H, br. s, ]CCH2C]), 5.67 (1H, t,4JH,H ¼ 1.2 Hz, ]CHH), 5.86 (1H, t, 4JH,H ¼ 1.5 Hz, ]CHH), 6.92 (2H,d, 3JH,H ¼ 8.7 Hz, ArH), 7.39e7.58 (9H, m,]CH, ArH), 7.75e7.81 (4H,m, ArH) ppm. 13C NMR (75 MHz, CDCl3) d: 30.31, 55.26, 114.11,125.27, 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.

5.1.1.32. (E)-2-benzoyl-3-cyclohexylallyl benzoate (2ea). Yellowsolid; m. p. ¼ 66e68 �C. Yield 24%. IR (KBr): nmax ¼ 1716, 1651 (C]O) cm�1. 1H NMR (300 MHz, CDCl3) d: 1.09e1.35 (5H, m, cHex),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,ArH) ppm. 13C NMR (75 MHz, CDCl3) d: 25.19, 25.59, 32.22, 38.35,59.34, 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, found371.1612. C23H24NaO3 requires 371.1618.

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) cm�1. 1HNMR (300 MHz, CDCl3) d: 5.28 (2H, d, 3JH,H ¼ 0.6 Hz, CH2OBz), 7.30(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,H¼ 2.1 Hz, ArH), 7.48e7.54 (3H, m, ArH), 7.57e7.63 (1H, m, ArH), 7.88e7.96 (4H, m, ArH) ppm. 13C NMR (75 MHz,CDCl3) d: 60.27,127.30,128.26,128.47,129.52,129.57,129.72, 130.81,131.46, 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. C23H16Cl2NaO3requires 433.0369.

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) cm�1. 1HNMR (300 MHz, CDCl3) d: 5.27 (2H, d, 3JH,H ¼ 1.5 Hz, CH2OBz), 6.90(1H, ddd, 3JH,H¼ 8.4 Hz, 4JH,H ¼ 2.1 Hz, 5JH,H¼ 0.6 Hz, ArH), 7.03 (1H,d, 3JH,H ¼ 8.4 Hz, ArH), 7.24 (1H, d, 4JH,H ¼ 2.1 Hz, ArH), 7.26e7.32(3H, m, ]CH, ArH), 7.36 (2H, t, 3JH,H ¼ 7.8 Hz, ArH), 7.43 (1H, t,3JH,H ¼ 7.5 Hz, ArH), 7.52 (1H, t, 3JH,H ¼ 7.5 Hz, ArH), 7.80e7.83 (2H,m, ArH), 7.88e7.92 (2H, m, ArH) ppm. 13C NMR (75 MHz, CDCl3) d: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. C23H16Cl2NaO3requires 433.0369.

5.1.1.35. (E)-2-benzoyl-3-(2-nitrophenyl)allyl benzoate (2ec).Yellow oil. Yield 22%. IR (KBr): nmax ¼ 1715, 1651 (C]O) cm�1. 1HNMR (300 MHz, CDCl3) d: 5.20 (2H, s, CH2OBz), 7.35 (2H, t,3JH,H ¼ 7.2 Hz, ArH), 7.43e7.64 (7H, m, ]CH, ArH), 7.69 (1H, td,3JH,H ¼ 7.5 Hz, 4JH,H ¼ 1.2 Hz, ArH), 7.84e7.87 (2H, m, ArH), 8.00e8.04 (2H, m, ArH), 8.21 (1H, td, 3JH,H ¼ 8.4 Hz, 4JH,H ¼ 1.2 Hz, ArH)ppm. 13C NMR (75 MHz, CDCl3) d: 60.12, 125.21, 128.27, 128.55,129.49, 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.

5.1.1.36. (Z)-2-benzoyl-3-(2-nitrophenyl)allyl benzoate (3ec).Yellow oil. Yield 23%. IR (KBr): nmax ¼ 1724, 1659 (C]O) cm�1. 1HNMR (400 MHz, CDCl3) d: 5.31 (2H, d, 4JH,H ¼ 1.2 Hz, CH2OBz), 7.19e7.27 (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), 8.92e8.96 (2H, m, ArH) ppm. 13C NMR (100MHz, CDCl3) d: 66.087,124.66,128.35, 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 requires410.0999.

5.1.1.37. (E)-2-(4-chlorobenzoyl)-3-cyclohexylallyl acetate (2fa).Yellow oil. Yield 34%. IR (KBr): nmax ¼ 1739, 1654 (C]O) cm�1. 1HNMR (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,CH2OAc), 6.22 (1H, d, 3JH,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.

5.1.1.38. (E)-2-(4-chlorobenzoyl)-3-(4-chlorophenyl)allyl acetate(2fb). Yellow oil. Yield 29%. IR (KBr): nmax¼ 1738,1651 (C]O) cm�1.1H 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,H¼ 8.7 Hz, ArH), 7.45 (2H, d, 3JH,H¼ 8.7 Hz, ArH), 7.75 (2H,d, 3JH,H ¼ 8.7 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3) d: 20.77,59.69, 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, found371.0206. C18H14Cl2NaO3 requires 371.0212.

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)cm�1. 1H NMR (300 MHz, CDCl3) d: 1.97 (3H, s, COCH3), 4.96 (2H, d,4JH,H ¼ 1.2 Hz, CH2OAc), 7.00 (1H, br. s, ]CH), 7.04 (2H, d,3JH,H ¼ 8.7 Hz, ArH), 7.10 (2H, d, 3JH,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(75 MHz, CDCl3) d: 20.72, 66.90, 128.66, 129.00, 130.08, 130.63,132.71, 132.90, 134.20, 134.67, 135.46, 140.26, 170.50, 196.92 ppm.HRMS (ES): M þ Naþ, found 371.0206. C18H14Cl2NaO3 requires371.0212.

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):nmax ¼ 1648 (C]O) cm�1. 1H NMR (300 MHz, CDCl3) d: 3.84 (2H, br.s, ]CCH2C ¼ ), 5.65 (1H, t, 4JH,H ¼ 1.2 Hz, ]CHH), 5.85 (1H, t,4JH,H ¼ 1.5 Hz, ]CHH), 7.36e7.41 (7H, m, ]CH, ArH), 7.44 (2H, d,3JH,H ¼ 8.4 Hz, ArH), 7.67 (2H, d, 3JH,H ¼ 8.7 Hz, ArH), 7.72 (2H, d,3JH,H ¼ 8.7 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3) d: 30.76, 126.18,128.61, 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 requires455.0367.

5.1.1.41. (E)-2-(4-chlorobenzoyl)-3-(2,4-dichlorophenyl)allyl acetate(2fc). White solid; m. p. ¼ 80e82 �C. Yield 30%. IR (KBr):nmax ¼ 1740, 1662 (C]O) cm�1. 1H NMR (300 MHz, CDCl3) d: 1.99(3H, s, COCH3), 4.99 (2H, s, CH2OAc), 7.28 (1H, br. s,]CH), 7.32 (2H,m, ArH), 7.45e7.49 (3H, m, ArH), 7.84 (2H, d, 3JH,H ¼ 8.7 Hz, ArH),ppm. 13C NMR (75 MHz, CDCl3) d: 20.66, 59.64, 127.32, 128.82,129.65, 130.84, 131.14, 134.72, 135.24, 135.89, 137.02, 139.19, 139.34,170.40, 194.86 ppm. HRMS (ES): M þ Naþ, found 404.9818.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) cm�1.1H NMR (300 MHz, CDCl3) d: 2.03 (3H, s, COCH3), 5.00 (2H, d,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,3JH,H ¼ 9.0 Hz, ArH), ppm. 13C NMR (75 MHz, CDCl3) d: 20.70, 65.99,126.95, 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.

5.2. Biology

All starting materials were commercially available researchgrade chemicals and used without further purification. RPMI 1640medium was purchased from Flow Laboratories (Irvine, UK), fetalcalf serum (FCS) was from Gibco (Grand Island, NY), trichloroaceticacid (TCA) and glutamine were from Merck (Darmstadt, Germany),and penicillin G, streptomycin, DMSO and sulforhodamine B (SRB)were from Sigma (St Louis, MO).

5.2.1. Cells, culture and platingThe human solid tumor cell lines HBL-100, HeLa, SW1573, T-47D

and WiDr were used in this study. These cell lines were a kind giftfrom Prof. G. J. Peters (VU Medical Center, Amsterdam, TheNetherlands). Cells were maintained in 25 cm2 culture flasks inRPMI 1640 supplemented with 5% heat inactivated fetal calf serumand 2 mM L-glutamine in a 37 �C, 5% CO2, 95% humidified airincubator. Exponentially growing cells were trypsinized and re-suspended in antibiotic containing medium (100 units penicillinG and 0.1 mg of streptomycin per mL). Single cell suspensionsdisplaying >97% viability by trypan blue dye exclusion were

I. Karpaviciene et al. / European Journal of Medicinal Chemistry 70 (2013) 568e578578

subsequently counted. After counting, dilutions were made to givethe appropriate cell densities for inoculation onto 96-well micro-titer plates. Cells were inoculated in a volume of 100 mL per well atdensities of 10,000 (HBL-100, HeLa and SW1573), 15,000 (T-47D),and 20,000 (WiDr) cells per well, based on their doubling times.

5.2.2. Chemosensitivity testingCompounds were initially dissolved in DMSO at 400 times the

desired final maximum test concentration. Control cells wereexposed to an equivalent concentration of DMSO (0.25% v/v,negative control). Each agent was tested in triplicate at differentdilutions in the range of 1e100 mM. The drug treatment was startedon day 1 after plating. Drug incubation times were 48 h, after whichtime cells were precipitated with 25 mL ice-cold TCA (50% w/v) andfixed for 60min at 4 �C. Then the SRB assaywas performed [21]. Theoptical density (OD) of each well was measured at 492 nm, usingBioTek’s PowerWave XS Absorbance Microplate Reader. Valueswere corrected for background OD from wells only containingmedium.

Acknowledgments

The research was funded by the European Social Fund under theGlobal 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 DevelopmentFund (FEDER) and the Spanish Instituto de Salud Carlos III (PI11/00840).

Appendix A. Supplementary data

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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