Structure-cytotoxic activity relationship of 3-arylideneflavanone and chromanone (E,Z isomers) and 3-arylflavones

Article abstract of DOI:10.1016/j.bmcl.2013.05.044

The E,Z-isomers of 3-arylidene substituted flavanone, chromanone and 3-aryl substituted flavone derivatives were tested in vitro for their cytotoxic activity against three cancer cell lines (HL-60, NALM-6, WM-115) and normal cell line (HUVEC). It was observed that substitution at C₃ position led to significant enhance in cytotoxicity. Isomeric configuration of 3-arylideneflavanones had an influence on the cytotoxic potential. Multiple regression analysis combined with variable selection by genetic algorithm was used to model relationships between molecular descriptors and the cytotoxic activity. The most accurate QSAR models were based on a combination between energy of LUMO, experimental value of log P and partial charge on carbonyl oxygen (δO₂).

Full text of DOI:10.1016/j.bmcl.2013.05.044

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4102–4106
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–cytotoxic activity relationship of 3-arylideneflavanone
and chromanone (E,Z isomers) and 3-arylflavones
b
c
d
Bogumiła Kupcewicz a, , Grazyna Balcerowska-Czerniak , Magdalena Małecka , Piotr Paneth ,
⇑
_
Urszula Krajewska e, Marek Rozalski e
a Department of Inorganic and Analytical Chemistry, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland
b Institute of Mathematics and Physics, University of Technology and Life Sciences, Kaliskiego 7, 85-796 Bydgoszcz, Poland
c Department of Structural Chemistry and Crystallography, University of Lodz, Pomorska 163/165, 90-236 Lodz, Poland
d Institute of Applied Radiation Chemistry, Technical University of Lodz, Zeromskiego 116, 90-924 Lodz, Poland
e Department of Pharmaceutical Biochemistry, Medical University of Lodz, Muszynskiego1, 90-151 Lodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The E,Z-isomers of 3-arylidene substituted flavanone, chromanone and 3-aryl substituted flavone
derivatives were tested in vitro for their cytotoxic activity against three cancer cell lines (HL-60,
NALM-6, WM-115) and normal cell line (HUVEC). It was observed that substitution at C3 position led
to significant enhance in cytotoxicity. Isomeric configuration of 3-arylideneflavanones had an influence
on the cytotoxic potential. Multiple regression analysis combined with variable selection by genetic algo-
rithm was used to model relationships between molecular descriptors and the cytotoxic activity. The
most accurate QSAR models were based on a combination between energy of LUMO, experimental value
of logP and partial charge on carbonyl oxygen (dO2).
Received 22 March 2013
Revised 13 May 2013
Accepted 14 May 2013
Available online 23 May 2013
Keywords:
Cytotoxicity
Arylideneflavanone
Arylidenechromanone
QSAR
Ó 2013 Elsevier Ltd. All rights reserved.
X-ray
Flavanone (2-phenyl-2,3-dihydrochromen-4-one) and flavone
(2-phenyl-4H-chromen-4-one) derivatives, belonging to numerous
flavonoids group, have recently gained increasing interest due to
their activity as anticarcinogenic agents.1–3 Chemoprevention, a
relatively new and promising strategy in preventing cancer is de-
fined as the use natural dietary compounds as well as synthetic
substance to block, inhibit, reverse or retard the process of carcino-
genesis. The role of flavonoids in this process is still widely dis-
cussed4 but many newly isolated and structurally modified
flavonoids could be a source of potential anticancer agents.5,6 Fla-
vanone derivatives possessing substituted benzyl moiety in posi-
tion 3 exhibit biological activity as antioxidants7 and inhibitors
of aromatase.8
In this study, series (Table 1) of six 3-arylideneflavanones, two
3-arylidenechromanones and five 3-arylflavones were synthesized
and examined in vitro for their cytotoxic efficacy. 3-Arylideneflav-
anones (1a–f) and 3-arylflavones (3a–e) were obtained by the
three step synthesis in which the substituted flavanones and flav-
ones were condensed with dedicated aldehydes in the presence of
piperidine as catalyst.7 3-Arylidenechromanones (2a, 2b) were also
prepared by the condensation method using commercially avail-
able chromanone and appropriate aldehydes. The structure of the
synthesized compounds were confirmed by elemental analysis, IR
and 1H and 13C NMR spectroscopy and X-ray crystal structure anal-
ysis (compd 1e—Fig. 1). NMR spectroscopy, HPLC analysis and X-
ray structure determination, showed that only (E)-isomers were
obtained. Z-Isomers were obtained by photoisomerization
(Scheme 1). UV irradiation at 365 nm gave Z-isomer in a predom-
inant amount (>95%) in mixture with E-isomer (less than 5%). The
progress of isomerization was monitored by HPLC method.
X-ray structure determination of compound 1e confirmed E-
isomer. Crystal data and structural determination details are pre-
sented in Table S1 and in 9. The dihedral angles C3–C2–C21–C22,
O2–C3–C2–C21 and C3–C2–C21–H21 are: 177.7(2)°, 15.3(2)° and
3.1(2)°, respectively. Main chroman skeleton consists of two fused
rings: benzene and pyran ring. The pyran ring adopts a distorted
conformation between half-chair and half-boat with puckering
parameters Q = 0.34 Å,
u = 226.1°, h = 120.3°. Two substituted ben-
zene rings are planar and the angle between their best planes is
52.8(1)°. The full crystal packing analysis is described in Supple-
mentary data (Fig. S2).
Cytotoxicity of compounds was determined by the MTT (3-(4,5-
dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) assay.10
The compounds were evaluated for their ability to cytotoxic effect
on three cancer cell lines: human skin melanoma (WM-115),
⇑
Corresponding author. Tel.: +48 52 585 35 00; fax: +48 52 585 38 04.
E-mail address: kupcewicz@cm.umk.pl (B. Kupcewicz).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.044

B. Kupcewicz et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4102–4106
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Table 1
Structure of 3-arylideneflavanones, 3-arylidenechromanones and 3-arylflavones
O
R2
R1
O
Compd
R1
H
R2
N
1a
1b
1c
1d
H
6-OH
H
CH3
Cl
Figure 1. Molecular structure of 1e and atom numbering scheme. Displacement
ellipsoids are drawn at 50% probability level.
1e
1f
H
H
h
O
O
R
O
O
R
Br
*
*
R2
R1
R1
O
O
R2
3-Arylidenechromanones
R2
R1
E-isomer
Z-isomer
Scheme 1. Photoisomerization of 3-arylideneflavanone (R = phenyl) and 3-arylid-
enechromanone (R = H).
2a
2b
H
H
OH
toxic activity of 1c. The substitution by pirydyl (1a) instead of phe-
nyl (R2) dramatically increased antiproliferative activity especially
against human leukemia cells (HL-60 and NALM-6). The IC50 values
of 1a (E and Z isomers) are comparable to that of cisplatin (Table 2).
The compound 1a exhibit similar activity as cytotoxic agent and as
aromatase inhibitor.8 E-Isomers of compounds containing halogen
atom (chloride or bromide) in para-position of the aryl substituent
(1e and 1f) have high activity against human leukemia cells; there-
fore Z-isomers show no cytotoxicity against these cancer cells. 3-
arylideneflavon with halogen atom (fluoride) (3d) exhibit less
cytotoxic activity. Replacement of the halogen group on flavanone
derivatives (1e, 1f) with the methyl group (compound 1d) led also
to approximately fivefold decrease of cytotoxic activity of E-iso-
mer. Both geometric isomers of all flavanone derivatives (except
of 1a) showed moderate activity against human skin melanoma
(WM 115) cells, whereas Z-isomers of 3-arylidenechromanone
were fourfold more active than E-isomers.
O
R2
3-Arylflavones
R1
O
NO2
CN
OH
F
3a
3b
3c
3d
H
H
H
H
3e
H
OH
In order to find similar compounds among E, Z-isomers with re-
gard to cytotoxic activity against all the three cancer cell lines a
hierarchical cluster analysis using Ward’s method applying
squared Euclidean Distance was carried out (Fig. 2). Results indi-
cate three clusters, two of them homogenous (only one type of iso-
mers) and third mixed. Six E-isomer compounds are classified to
group A and four Z-isomers to group B. Third group C consists both
isomers. Then one-way ANOVA with NIR post-hoc test has been
conducted to determine which variables (logIC50) are significantly
different between the groups. Compounds in group C demonstrate
the highest cytotoxic activity against all the three cancer cell lines.
Z-Isomers from group B exhibit the least cytotoxic activity against
leukemia cell lines whereas E-isomers from group A have weak
cytotoxicity against WM-115.
human leukaemia promyelocytic (HL-60) and lymphoblastic
(NALM-6). In the further study cytotoxicity against normal cells
(HUVEC—human umbilical vein endothelial cells) for five selected
compounds were examined.
The results of cytotoxicity against cancer cell lines for com-
pounds 1a–f, 2a–b and 3a–e are shown as IC50 values in Table 2.
Chromanone, flavanone, naringenin, quercetin and cisplatin were
used as reference compounds. The statistical significance (p-values
of unpaired t-test) between cytotoxicity of the tested and reference
compounds has been placed in Table S6 (see Supplementary data).
As can be seen, the tested compounds demonstrate extremely
different activity from very high cytotoxicity (IC50 = 0.9
lM) to lack
The studies of cytotoxic activity of flavones and flavanones
demonstrated that the presence of C2–C3 double bond in molecule
is an important feature for enhancing cytotoxicity against different
cancer cells.11–13 In our studies, addition of aryl substituent at C3
of such activity (IC50 >1000 M). The unsubstituted 3-arylidenef-
l
lavanone (1b) appeared to be a weak cytotoxic agent against all
the three cancer cells as well as flavanone. Addition of hydroxyl
group at C6 position (R1) resulted in significantly enhanced cyto-

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B. Kupcewicz et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4102–4106
Table 2
Cytotoxic activity of 3-arylidene-flavanones (1a–f), 3-arylidene-chromanones (2a–b) and 3-arylflavones (3a–e) against HL-60, NALM-6 and WM115 cancer cell lines. In
parenthesis: p-value from t-test for comparison of cytotoxicity of selected compounds against cancer cell line and against normal cell line (HUVEC).
a
Compound
IC50
(lM)
HL-60
NALM-6
WM-115
Z-Isomer
E-Isomer
Z-Isomer
E-Isomer
Z-Isomer
E-Isomer
1a
1b
1c
1d
1e
1f
0.9 0.2 (p <0.001)b
33.3 3.0
5.8 0.2
40.9 6.1
5.8 0.5
5.7 0.2 (p <0.001)
5.4 0.6
5.7 0.4
1.1 0.2 (p <0.001)
27.3 3.2
7.3 0.7
40.8 7.3
>1000
>1000 (p <0.001)
6.7 0.8
6.5 0.7
1.6 0.3(p <0.001)
29.5 4.7
8.7 0.5
51.4 3.8
7.4 0.6
6.9 0.1 (p = 0.071)
6.2 0.2
32.3 3.1
0.7 0.03 (p <0.001)
>1000
58.8 1.4
>1000
>1000
>1000 (p <0.001)
5.5 0.4
466.4 49.6
6.3 0.5 (p = 0.055)
59.4 0.9
44.5 3.2
60.1 2.4
52.0 3.5
25.9 2.3 (p <0.001)
53.7 4.3
69.0 2.7
4.6 0.4 (p = 0.023)
52.6 4.5
9.1 0.2
57.0 6.6
27.4 5.9
32.6 10.9 (p = 0.581)
13.5 2.6
12.1 2.9
2a
2b
3a
3b
3c
3d
3e
2.4 0.4 (p <0.001)
3.8 0.4
46.7 2.5
19.1 4.7
6.3 0.3
5.0 0.3 (p = 0.040)
4.8 0.2
49.8 2.2
8.2 0.5
7.3 0.4
6.1 0.4 (p = 0.008)
6.3 0.3
57.2 4.2
53.2 2.8
17.6 2.7
Chromanone
Flavanone
Naringenin
Quercetin
Cisplatin
676.7 32.6
51.1 1.7
413.7 33.8
58.0 4.0
0.8 0.1
673.7 22.5
57.6 8.6
426.3 20.5
77.1 7.8
0.7 0.3
>1000
71.2 3.2
524.8 37.8
177.5 37.8
18.2 4.3
a
IC50-concentration of a test compound required to reduce the fraction of surviving cells to 50% of that observed in the control, non-treated cells. Mean values of IC50 (in
l
M) standard deviation from 3 experiments each performed in quintuple are presented.
p-Value from unpaired t-test (each mean IC50 value against cancer cell line was compared with IC50 against normal cells HUVEC (from Table 3)).
b
3
Z-1a
E-1a
Z-1c
Z-2b
E-1f
8
5
8
5
O
O
C
7
6
7
6
1
1
2
2
9
9
3
3
3
3
R
R
4
4
10
10
18
11
11
Z-2a
Z-1b
Z-1d
Z-1e
Z-1f
E-1b
E-1d
E-1c
E-1e
E-2a
E-2b
O
O
2
2
a
b
B
Figure 3. The basic molecular structure of flavanone and chromanone (a) and
flavone (b) derivatives. Partial charges for atoms denoted by blue bold numbers
were calculated and used in QSAR study.
Table 4
A
Parameters of GA-MLR models
Cancer cell line
RMSEC
RMSECV
RMSEP
R2model
R2test
0
5
10
15
20
25
30
35
40
HL-60
NALM-6
WM-115
0.343
0.409
0.183
0.628
0.561
0.309
0.595
0.822
0.157
0.720
0.745
0.785
0.848
0.863
0.913
distance
Figure 2. Dendrogram based on cytotoxic activity (expressed as IC50 in
lM)
against Hl-60, NALM-6 and WM-115 cancer cell lines.
RMSE—Root mean square error of calibration (C), cross-validation (CV) and pre-
diction (P).
Table 3
Cytotoxic activity of selected compounds against normal cells (HUVEC)
normal cells. Unfortunately, against WM-115 cancer cell line and
HUVEC, 1a is toxic in similar manner.
Compound
IC50 (lM)
E-Isomer
Z-Isomer
The compound 1f was selected to test on normal cells due to the
extremely different cytotoxicity between E and Z-isomer. Unex-
pectedly, Z-isomer of 1f inactive against HL-60 shows moderate
toxicity against normal cells. The compound 3a (chosen as the
most cytotoxic among flavone derivatives) demonstrate higher
cytotoxic activity against cancer than normal cells for HL-60 only.
The structures of compounds were optimized using Gaussian
software14 by semi-empirical parametrization method RM115 and
continuum solvation model SMD.16 After optimization Mulliken17
charges on both O and selected C atoms (Fig. 3) were calculated.
Other molecular descriptors for the compound dataset were ob-
tained using QSAR properties utility of HYPERCHEM v.7.03.18 The val-
ues of the significant descriptors for all 21 compounds were given
1a
1f
3a
5.77 0.17
7.23 0.34
5.40 0.21
5.14 0.15
29.12 8.03
position resulted in similar diversification of antiproliferative
activity between flavone and flavanone derivatives. Thus, the pres-
ence of C2–C3 double in 3-substituted moiety seemed less impor-
tant. Table
3 contains results of cytotoxicity for selected
compounds: 3a and E,Z-isomers of 1a and 1f against normal hu-
man cells HUVEC. As can be seen, 1a exhibit statistically significant
(p <0.001) better cytotoxic activity against human leukaemia than

B. Kupcewicz et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4102–4106
4105
Figure 5. Williams plot, plot of standardized residuals versus leverages for each
compound in training and test set for WM-115 cancer cell line.
Figure 4. MLR model for cytotoxicity against WM-115 cancer cell line for training
set and test set.
partial charge on carbonyl oxygen (dO2). Electronic descriptor
in Supplementary data (Tables S3 and S4). Moreover, experimen-
tally (with the use of HPLC method) obtained logP values were
added to computational descriptors (Table S4).
(ELUMO) and hydrophobicity/lipophilicity (logP) are important
descriptors in the modelling of different (covalent and non-
covalent) mechanisms of toxicity.20–22 Covalent mechanism of
cytotoxicity requires electrophilic properties of active compounds.
The correlation between cytotoxic activity and structural prop-
erties was obtained using the multiple linear regression method
(MLR). Genetic algorithms (GA) was applied for modeling descrip-
Electrophilicity (x) of a molecule can be derived from energies of
frontier orbitals (HOMO, LUMO) as follows:
x
= (ELUMO + EHOMO)2/
x for tested compounds
Ò
tors subset selection. The calculation were made with the MATLAB
4 (ELUMO ꢀ EHOMO).22 The high values of
software.
correlated with the high cytotoxic activity. On the other hand
the efficient cytotoxic agent needs optimal lipophilicity that
allows it to get the reactive site (DNA, protein). Increase of logP
value of tested compounds leads to a reduction of cytotoxic
activity. The both isomers of 1a are characterized by relatively
low logPexp (2.85 and 2.98) and relatively high electrophilicity
which result in very good potential as cytotoxic agent. Whereas,
the loss of cytotoxic activity of Z-isomers of 1d, 1e and 1f might
be partially explained by concurrent factors, very high lipophilicity
(logPexp >4.4) and low electrophilicity.
A set of 17 compounds was used as a training set for a QSAR
modeling. Then the model was applied to a set of four new com-
pounds. The goodness of fit of each model, for both internal and
external validation was checked by determination coefficient (R2)
and root mean square errors of: calibration (RMSEC), cross-valida-
tion (RMSECV) and prediction (RMSEP). The results of statistical
parameters obtained for GA-MLR modeling of cytotoxic activity
can be found in Table 4.
As it can be seen the proposed models have potential for predic-
tive application (R2 test >0.84) although the fitting power verified
by R2 model not exceed 0.8. It might be related with relatively
small training set (17 compounds). In further study some new
compounds would have been helpful for the better validation of
the models. The predicted values of logIC50 for WM-115 cancer cell
line for the compounds in the training and test sets are plotted
against the measured values in Figure 4.
QSAR models are generally limited to query chemicals structur-
ally similar to the training compounds, therefore the chemical
applicability domain (AD), defined as theoretical space of the data
set of the model, was verified by the Williams plot. From plot in
Figure 5, the applicability domain was established inside an area
within
2 standard deviations and a
leverage threshold h⁄
(h⁄ = 3(p + 1)/n, where p is the number of model parameters and
n the number of compounds in training set).19 The plot indicate
that leverage values for the compounds from training and test sets
are lower than the critical value (the dotted line) and the residuals
are not greater than two standard deviation units. For the future,
predicted cytotoxic activity data must be considered reliable only
for those chemicals that fall within the applicability domain on
which the model was constructed.
The equations of GA-MLR models were obtained as follows:
log IC50ðHL60Þ ¼ 7:33 ꢀ 7:37 log Pexp ꢀ 31:91ELUMO
2
þ 0:80ðlog PexpÞ ꢀ 40:95E2
LUMO
ꢀ 2:39log Pexp ELUMO
log IC50 ðNALM6Þ ¼ ꢀ54:33 þ 15:8 log Pexp þ 4:8ELUMO
ꢀ 184:56dO2 þ 50:27log PexpdO2
In summary, the study of the relationship between the configu-
ration and cytotoxic activity against cancer cell lines of flavanone
derivatives, revealed that either both isomers exhibit very similar
cytotoxic activity or only Z-isomer is cytotoxic whilst E-isomer is
entirely inactive. The most promising compound is 1a, due to the
very high and independent of isomeric form cytotoxic activity
especially against human leukaemia cancer cell lines. Both leukae-
mia cancer cells are more sensitive than normal cells to the toxic
effect of 1a, therefore it is good candidate for anticancer lead com-
pound. However, further experiments are needed to understand
mechanism of cytotoxic action of these compounds.
log IC50 ðWM115Þ ¼ ꢀ29:12 þ 6:53 log Pexp þ 2:91ELUMO
2
ꢀ 89:39dO2 ꢀ 0:20ðlog Pexp
þ 14:54log PexpdO2
Þ
For HL-60 and WM-115 polynomial regression models with
interaction effect of the two variables were performed. All models
include two the same descriptors: energy of LUMO and logPexp
,
additionally equations for NALM-6 and WM-115 cell lines contain

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B. Kupcewicz et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4102–4106
geometrically and refined using a riding model, with Uiso(H) = x Ueq(C) where
Statistically significant equations describing structure–cytoto-
x = 1.2 for all. C–H distances were fixed for methine 0.95 Å, for aromatic 0.93 Å.
Final results are: 0.0370 and 0.0292 for all and observed reflections,
respectively. The largest difference peak and hole are: 0.266/ꢀ0.216 e/Å3.
Atomic coordinates and relevant data have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
929674. These data can be obtained free of charge from CCDC via http://
www.ccdc.cam.ac.uk/products/csd/request/.
toxic activity relationships in flavanone, chromanone and flavone
group were obtained. Models posses good regression statistics
indicating mechanistic importance of lipophilicity, electrophilicity
(ELUMO) and partial charge on carbonyl oxygen for prediction of
cytotoxic activity of tested compounds.
10. Budzisz, E.; Krajewska, U.; Rozalski, M. Pol. J. Pharmacol. 2004, 56, 473.
11. Fotsis, T.; Pepper, M. S.; Aktas, E.; Breit, S.; Rasku, S.; Adlecreutz, H.; Wähälä, K.;
Montesano, R.; Schweigerer, R. Cancer Res. 1997, 57, 2916.
Acknowledgment
12. Kawai, S.; Tomono, Y.; Katase, E.; Ogawa, K. Biosci., Biotechnol., Biochem. 1999,
63, 896.
We are thankful for funding support from Nicolaus Copernicus
University, Collegium Medicum, Grant No. 411.
13. Mutrhy, K. N. C.; Kim, J.; Vikram, A.; Patil, B. S. Food Chem. 2012, 132, 27.
14. (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T. J. Org. Chem. 2012, 77, 5120; (b) Honda,
Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro,
F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,
S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J.
B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;
Fox, D. J. GAUSSIAN 09, Revision A.02; Gaussian, Inc.: Wallingford, CT, 2009.
15. Rocha, G. B.; Freire, R. O.; Simas, A. M.; Stewart, J. J. P. J. Comput. Chem. 2006, 27,
1101.
16. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378.
17. Mulliken, R. S. J. Chem. Phys. 1955, 23, 1833.
18. HyperChem, Ver. 7.03, Hypercube Inc., Florida, USA, 2002.
19. Gramatica, P. In Recent Advances in QSAR Studies. Methods and Application;
Puzyn, T., Leszczynski, J., Cronin, M. T. D., Eds.; Science+Business Media B.V.,
2010.
20. Enoch, S. J. In Recent Advances in QSAR Studies. Methods and Application; Puzyn,
T., Leszczynski, J., Cronin, M. T. D., Eds.; Springer Science+Business Media B.V.,
2010.
21. Bober, L.; Kawczak, P.; Baczek, T. Int. J. Mol. Sci. 2012, 13, 6665.
22. Schwöbel, J. A. H.; Koleva, Y. K.; Enoch, S. J.; Bajot, F.; Hewitt, M.; Madden, J. C.;
Roberts, D. W.; Schultz, T. W.; Cronin, M. T. D. Chem. Rev. 2011, 111, 2562.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
05.044.
References and notes
1. Ren, W.; Qiao, Z.; Wang, H.; Zhu, L.; Zhang, L. Med. Res. Rev. 2003, 23, 519.
2. Li-Weber, M. Cancer Treat. Rev. 2009, 35, 57.
3. Ramos, S. J. Nutr. Biochem. 2009, 18, 427.
4. Chahar, M. K.; Sharma, N.; Dobha, M. P.; Joshi, Y. C. Pharmacogn. Rev. 2011, 5, 1.
5. Kollar, P.; Barta, T.; Zavalova, V.; Smejkal, K.; Hampl, A. Br. J. Pharmacol. 2011,
162, 1534.
6. Musthapa, I.; Juliawaty, L. D.; Syah, Y. M.; Hakim, E. H.; Latip, J.; Ghisalberti, E.
L. Arch. Pharmacol. Res. 2009, 32, 191.
7. Foroumadi, A.; Samzadeh-Kermani, A.; Emani, S.; Dehghan, G.; Sorkhi, M.;
Arabsorkhi, F.; Heidari, M. R.; Abdollahi, M.; Shafiee, A. Bioorg. Med. Chem. Lett.
2007, 17, 6764.
8. Pouget, C.; Fagnere, C.; Basly, J. P.; Habrioux, G.; Chulia, A. J. Bioorg. Med. Chem.
Lett. 2002, 12, 1059.
9. The structure was solved by direct methods with the program SHELXS-97 and
refined by full-matrix least-squares method on F2 with SHELXS-97. The non-H
atoms were refined anisotropically. All hydrogen position were placed