Synthesis, characterization and cytotoxicity of a new palladium(II) complex with a coumarin-derived ligand. Crystal structure of 4-hydroxy-3-(1-(p- tolylimino)ethyl)-2H-chromen-2-one-palladium(II) complex

Article abstract of DOI:10.1016/j.molstruc.2013.03.013

The new coumarine derivative, 4-hydroxy-3-(1-(p-tolylimino)ethyl)-2H- chromen-2-one, and corresponding palladium(II) complex have been synthesized and characterized by microanalysis, infrared, ¹H and ¹³C NMR spectroscopy. The proposed structure of the complex was confirmed on the basis of an X-ray structural study. In vitro antitumor activity for the ligand and complex was investigated.

Full text of DOI:10.1016/j.molstruc.2013.03.013

Journal of Molecular Structure 1040 (2013) 216–220
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, characterization and cytotoxicity of a new palladium(II) complex
with a coumarin-derived ligand. Crystal structure of 4-hydroxy-
3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one-palladium(II) complex
a
b
c
a
a
´
´
´
´
´
Verica V. Jevtic , Milica Pešic , Gordana P. Radic , Nenad Vukovic , Slobodan Sukdolak ,
d
b
b
a,
⇑
´
´
´
´
Olivera Klisuric , Ana Podolski-Renic , Nikola Tanic , Srecko R. Trifunovic
a
´
Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovica 12, 34000 Kragujevac, Serbia
b Institute for Biological Research ‘‘Siniša Stankovi´c’’, University of Belgrade, Bulevar Despota Stefana 142, 11060 Beograd, Serbia
c Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovi´ca 69, 34000 Kragujevac, Serbia
d University of Novi Sad, Department of Physics, Faculty of Sciences, Trg Dositeja Obradovi´ca 4, 21000 Novi Sad, Serbia
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
ꢀ
Synthesis of a new palladium(II)
complex with coumarine-derived
ligand.
ꢀ
ꢀ
Crystal structure of palladium(II)
complex.
Cytotoxicity of obtained compounds.
a r t i c l e i n f o
a b s t r a c t
Article history:
The new coumarine derivative, 4-hydroxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one, and corre-
sponding palladium(II) complex have been synthesized and characterized by microanalysis, infrared,
1H and 13C NMR spectroscopy. The proposed structure of the complex was confirmed on the basis of
an X-ray structural study. In vitro antitumor activity for the ligand and complex was investigated.
Ó 2013 Elsevier B.V. All rights reserved.
Received 2 February 2013
Received in revised form 5 March 2013
Accepted 5 March 2013
Available online 14 March 2013
Keywords:
Coumarine-derived ligand
Palladium(II) complex
Cytotoxicity
Crystal structure
1. Introduction
resistance to cisplatin [3]. The toxic side-effects of the cisplatin
limit the doses that can be applied to patients [4].
After the Rosenberg0s discovery of the cisplatin antitumor activ-
ity [1], the scientists synthesized a lot of platinum-based drugs
that could be less toxic to healthy tissue [2] and overcome the
Palladium(II) complexes have also been a subject of wide exam-
ination due to their structural analogy with platinum(II) com-
plexes. However, initial results were not very encouraging
because the palladium(II) complexes generally showed lower anti-
tumor activity than cisplatin. This could be explained by the more
labile nature of the palladium(II) complexes in comparison to the
corresponding platinum(II) complexes [5]. However, some of
⇑
Corresponding author. Phone: +381 34300263; fax: +381 34335040.
E-mail address: srecko@kg.ac.rs (S.R. Trifunovic´).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.03.013

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V.V. Jevtic et al. / Journal of Molecular Structure 1040 (2013) 216–220
palladium(II) complexes exerted higher antitumor activity in com-
parison with cisplatin and carboplatin. Budzisz et al. found that
palladium(II) complex with 4-hydroxy-3-(1-iminoethyl)-2H-
chromen-2-one was 7800 times more active than carboplatin [6].
Coumarine and its derivatives are natural compounds with
spasmolitic, antiarrhytmic, cardiotonic and photodynamic proper-
ties [7]. Weber et al. [8] tested coumarine and its major metabolite
7-hydroxycoumarin against several human tumor cell lines (Caco-
2 colorectal carcinoma, Hep-G2 hepatoma and CCRF-CEM lympho-
blastoma). Egan et al. [9] investigated cytostatic and cytotoxic nat-
ure of 8-nitro-7-hydroxycoumarin against both human (K-562 and
HL-60) and animal cell lines grown in vitro. Also, coumarin and its
4-hydroxy and 7-hydroxy derivatives were tested against P-815
and P-388 tumor cells in vitro [10]. Metal complexes with couma-
rine derivatives showed significant anticoagulant [11,12] and anti-
tumor activity [13,7]. Also, some cerium(III), zirconium(IV),
copper(II), zinc(II), bismuth(III) and cadmium(II) were significantly
cytotoxic in vitro [14,15].
Reaction of condensation of 3-acetyl-4-hydroxychromene-2-
one 1 with p-tolylamine 2 was successfully performed by two dif-
ferent methods (conventional and microwave method).
Conventional method: Mixture of 3-acetyl-4-hydroxy-chromene-
2-one 1 (0.01 mol, 2.0418 g), p-tolylamine 2 (0.01 mol, 1.0715 g) and
catalytic amount of p-toluene sulfonic acid in anhydrous toluene
(50 mL) was heated with azeotropic removal of water in the period
of 10–12 h. Progress of reaction was monitored by TLC (toluene: ace-
tone = 7:3). At the end of reaction, solvent was removed under re-
duced pressure. The solid products were filtered, dried, purified via
column chromatography (benzene: acetone = 8:2) to give compound
3 (see Scheme 1). Yield: 2.1412 g (73%).
Microwave method: Catalytic amount of p-toluene sulfonic acid
was added to 50 mL toluene solution of equimolar amounts
(0.01 mol) of 3-acetyl-4-hydroxy-chromene-2-one
1 and p-
tolylamine 2. The mixture was heated under microwave for 3 min.
After cooling, the solvent was removed, and then the obtained solid
was filtered and recrystallized from methanol. Yield 2.7865 g (95%).
4-Hydroxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one (3):
Anal. Calcd. for C18H15NO3 (Mr = 293.32): C, 73.71; H, 5.15; N,
4.78; found: C, 73.72; H, 5.12; N, 4.79. M.P. 147–149 °C. IR (KBr,
cmꢁ1): 3421 (OH), 3073 (=CH)ar, 2985, 2922 and 2852 (CH3),
1709 (lactone C@O), 1611 (imino C@N), 1597, 1569, 1513 and 1483
Herein we described the synthesis and characterization of the 4-
hydroxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one and corre-
sponding palladium(II) complex. The crystal structure of 4-
Hydroxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one-palladium(II)
complex was also reported. In addition, antitumor activities of both
4-hydroxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one and cor-
responding palladium(II) complex were tested.
1
(C@C)ar. H NMR (CDCl3, 200 MHz): d 2.41 (s, 3H, CH3AC400), 2.69
00
00
00
00
(s, 3H, CH3AC@N), 7.09–7.65 (ABq, 4H, J = 8.43 Hz, C2 ,
,
, 6 AH),
3
5
7.3 (m, 1H, C6AH), 7.4 (dd, 1H, J = 8.3 Hz, J = 1.1 Hz, C8AH), 7.6
(dd, 1H, J = 7.8 Hz, J = 1.7 Hz, C5AH), 7.7 (m, 1H, C-7-H), 16.07
2. Experimental
13
(bs, 1H, C4AOH). C NMR (CDCl3, 50 MHz): d 20.6 (CH3AC400),
20.8 (CH3AC@N), 97.3 (C3), 116.6 (C10), 116.8 (C8), 119.3
2.1. Materials and methods
00
00
00
(C5), 119.9 (C2 , C6 ), 125.9 (C6), 129.3 (C7), 129.9 (C4 ), 131.7
00
00
00
0
(C3 , C5 ), 138.4 (C1 ), 163.5 (C2), 152.4 (C9), 180.4 (C4), 180.5 (C1 ).
All applied chemicals and reagents were of the highest purity
available and purchased from the Sigma–Aldrich Chemical Com-
pany (St. Louis, MO), Difco and Merck Laboratory Supplies (Darms-
tadt, Germany).
2.2.1. Synthesis of 4-hydroxy-3-(p-tolylimino)ethyl)-2H-chromen-2-
one-palladium(II) complex (C3)
Complex was obtained by mixing K2[PdCl4] (0.25 mmol,
0.0816 g) in 10 cm3 of water and ligand (0.5 mmol, 0.1467 g) in
10 cm3 of methanol in molar ratio 1:2. The solution was mixed for
5 h. Within this period, pale yellow precipitates of the complex were
obtained, filtered off and air dried. Yield of 4-hydroxy-3-(1-(p-
tolylimino)ethyl)-2H-chromen-2-one-palladium(II) (C3) 0.1274 g
(72%). Anal. Calcd. for C36H30N2O6Pd (Mr = 693.05): C, 62.39; H,
4.36; N, 4.04; found: C, 62.66; H, 4.50; N, 4.28. IR (KBr, cmꢁ1):
3054 (@CH)ar, 2979, 2923 and 2855 (CH3), 1705 (lactone C@O),
1607 (imino C@N), 1562, 1480 and 1475 (C@C)ar, 532 (PdAO), 435
Infrared spectra were recorded by a Perkin–Elmer Spectrum
One FT-IR spectrometer using the KBr pellet technique (4000–
400 cmꢁ1). 1H and 13C NMR spectra were recorded by a Varian
Gemini-2000 (200 MHz) spectrometer in CDCl3 using tetramethyl-
silane as internal standard. Elemental microanalyses for C, H and N
were performed by standard methods by a Vario EL III C, H, N Ele-
mental Analyzer. The microwave assisted reaction was carried out
in the MICROSYNTH Microwave Synthesis System (Milestone Inc.
25 Controls Dr. Shelton), the microwaves were generated by mag-
netron at the frequency of 2450 MHz having an output energy
range of 100–500 W. Melting point of ligand was determined by
using Kofler-hot stage apparatus.
1
(PdAN). H NMR (CDCl3, 200 MHz): d 2.25 (s, 6H, CH3AC400), 2.38
00
00
00
00
(s, 6H, CH3AC@N), 6.98–7.45 (ABq, 8H, J = 8.51 Hz, C2 , 3
,
,
AH),
5
6
7.59 (m, 2H, C6AH), 7.28 (dd, 2H, J = 8.33 Hz, J = 1.1 Hz, C8AH),
8.05 (dd, 2H, J = 7.83 Hz, J = 1.6 Hz, C5AH), 7.58 (m, 2H, C-7-H).
13C NMR (CDCl3, 50 MHz): d 21.1 (CH3AC400), 24.6 (CH3AC@N),
2.2. Chemical synthesis
00
00
105.8 (C3), 115.2 (C10), 115.8 (C8), 117.9 (C5), 122.7 (C2 , C6 ),
00
00
00
00
Chemical synthesis of ligand 4-hydroxy-3-(1-(p-tolylimino)
ethyl)-2H-chromen-2-one was published earlier [16].
124.7 (C6), 129.8 (C7), 130.2 (C4 ), 133.1 (C3 , C5 ), 144.5 (C1 ),
0
162.5 (C2), 152.7 (C9), 169.8 (C4), 172.7 (C1 ).
OH
O
O
O
OH
N
O
O
NH2
3
1
2
Scheme 1. Synthesis of the 4-hydroxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one (3).

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Table 1
2.3. Structure determination
Crystal data and structure refinement for 4-hydroxy-3-(1-(p-tolylimino)ethyl)-2H-
chromen-2-one-palladium(II) complex (C3).
The crystal of complex C3 suitable for X-ray measurements
was obtained from an oversaturated chloroform solution at
20 °C. A single crystal of complex C3 was selected and mounted
on a glass fiber. Diffraction data were collected using a Oxford
Diffraction Gemini S four-circle goniometer equipped with Sap-
phire CCD detector. The crystal to detector distance was
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C38H29Cl3N2O6Pd
929.74
293(2) K
0.71069 Å
Triclinic
P-1
Unit cell dimensions
a = 10.022(5) Å a = 111.224(5)°
45.0 mm and graphite monochromated MoKa (k = 0.71073 Å)
b = 10.534(5) Å b = 110.920(5)°
radiation was used for the experiments. The data were reduced
using the program CrysAlisPRO [17]. A semiempirical absorp-
tion–correction based upon the intensities of equivalent reflec-
tions was applied, and the data were corrected for Lorentz,
polarization, and background effects. The structure was solved
by direct methods using Sir 97 program [18] and refined by
full-matrix least-squares procedures on F2 using SHELXL-97 pro-
grams [19] as implemented in the WinGX program suite [20].
The non-H atoms were refined anisotropically. The positions of
hydrogen atoms were found from the inspection of the difference
Fourier maps. At the final stage of the refinement, H atoms from
the methyl group were positioned geometrically (CAH = 0.96 Å)
and refined using a riding model with fixed isotropic displace-
ment parameters. Crystallographic data and refinement parame-
ters are listed in Table 1. The figures representing molecular
structure were made using ORTEP-3 [21] and PLATON [22]
programs.
c = 10.735(5) Å
956.8(8) Å3
1
c = 94.812(5)°
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to h = 25.00°
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
1.614 Mg/m3
0.953 mmꢁ1
468
0.354 ꢂ 0.261 ꢂ 0.212 mm3
3.46–25.00°
ꢁ11 6 h 6 11, ꢁ12 6 k 6 11, ꢁ9 6 l 6 12
5920
3358 [R(int) = 0.0282]
99.8 %
Semi-empirical from equivalents
1.00000 and 0.99246
Full-matrix least-squares on F2
3358/0/279
1.032
Final R indices [I > 2
R indices (all data)
Largest diff. peak and hole
r
(I)]
R1 = 0.0449, wR2 = 0.0911
R1 = 0.0505, wR2 = 0.0951
0.614 and ꢁ0.741 e Åꢁ3
The perspective view of molecular structure of compound 4-hy-
droxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one-palladium(II)
complex (C3) is shown in Fig. 1. Fig. 2 presents crystal packing for
compound 4-hydroxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-
one-palladium(II) complex (C3). Selected bond lengths are given
in Table 2, bond angles are given in Table 3. Torsion angles are gi-
ven in Table 4.
2.4. Cells and cell culture
NCI-H460 cell line was purchased from the American Type Cul-
ture Collection, Rockville, MD. NCI-H460/R cells were selected orig-
inally from NCI-H460 cells and cultured in a medium containing
Fig. 1. Molecular structure of the complex with the non-H atom numbering scheme with thermal ellipsoids at 30% probability level. Symmetry transformations used to
generate equivalent atoms: ꢁx, ꢁy, ꢁz + 1.

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V.V. Jevtic et al. / Journal of Molecular Structure 1040 (2013) 216–220
Fig. 2. PLATON drawing showing crystal packing for complex C3. H atoms are not shown for clarity.
Table 2
Table 4
Selected bond lengths (Å) for C3.
Selected torsion angles (°) for C3.
Pd(1)AO(1)
Pd(1)AN(1)
N(1)AC(1)
N(1)AC(12)
O(1)AC(3)
O(2)AC(6)
O(2)AC(5)
O(3)AC(5)
C(2)AC(3)
C(2)AC(1)
C(2)AC(5)
C(7)AC(3)
1.985(2)
2.014(3)
1.307(4)
1.440(4)
1.289(4)
1.380(5)
1.382(5)
1.201(5)
1.389(5)
1.456(5)
1.460(5)
1.466(5)
N(1)1APd(1)AO(1)AC(3)
N(1)APd(1)AO(1)AC(3)
O(1)1APd(1)AN(1)AC(1)
O(1)APd(1)AN(1)AC(1)
N(1)1APd(1)AN(1)AC(1)
O(1)1APd(1)AN(1)AC(12)
O(1)APd(1)AN(1)AC(12)
N(1)1APd(1)AN(1)AC(12)
Pd(1)AN(1)AC(1)AC(2)
Pd(1)AN(1)AC(1)AC(4)
Pd(1)AO(1)AC(3)AC(2)
143.7(3)
ꢁ36.3(3)
ꢁ154.4(3)
25.6(3)
ꢁ123(3)
29.3(3)
ꢁ150.7(3)
61(3)
ꢁ1.3(5)
ꢁ174.9(3)
24.0(5)
Symmetry transformations used to generate equivalent atoms: 1
ꢁx, ꢁy, ꢁz + 1.
2.4.1. Sulforhodamine B assay (SRB)
Table 3
Cells grown in 25 cm2 tissue flasks were trypsinized, seeded into
flat-bottomed 96-well tissue culture plates, and incubated over-
night. NCI-H460 was seeded at 2000 cells/well, while NCI-H460/R
cells were seeded at 4000 cells/well. Treatment with coumarine-
derived ligand (1–500 lM) and C3 (0.01–200 lM) lasted 72 h. The
cancer cell growth inhibition was assessed and the cellular proteins
Selected bond angles (°) for C3.
O(1)APd(1)AN(1)
C(3)AO(1)APd(1)
C(1)AN(1)APd(1)
C(12)AN(1)APd(1)
N(1)AC(1)AC(2)
N(1)AC(1)AC(4)
C(1)AN(1)AC(12)
O(1)AC(3)AC(2)
O(1)AC(3)AC(7)
C(1)AC(2)AC(5)
C(2)AC(3)AC(7)
C(2)AC(1)AC(4)
C(3)AC(2)AC(1)
C(3)AC(2)AC(5)
88.73(11)
121.7(2)
125.7(2)
114.7(2)
120.8(3)
120.2(3)
119.5(3)
126.1(3)
114.9(3)
117.2(3)
119.0(3)
118.7(3)
122.8(3)
119.9(3)
were stained with SRB, following a slightly modified protocol [24].
3. Results and discussion
The structure of synthesized complex C3 was determined by
means of spectral (IR, 1H NMR and 13C NMR) and elemental analy-
sis, as well as X-ray diffraction study. In comparison to IR spectral
data of ligand 3, obtained Pd complex showed significant differ-
ences. The characteristic band assigned to the OH vibration in li-
gand 3 was not observed in complex C3, which indicated that
oxygen from position C-4 of coumarine moiety participated in for-
mation of bond with Pd. This is confirmed by identification of
PdAO stretching vibration at 532 cmꢁ1. The stretching vibration
of C@N group in ligand 3 was observed at 1611 cmꢁ1, while in
100 nM doxorubicin [23]. Cells were subcultured at 72 h intervals
using 0.25% trypsin/EDTA and seeded into a fresh medium at the
following densities: 8000 cells/cm2 for NCI-H460 and 16,000
cells/cm2 for NCI-H460/R.

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V.V. Jevtic et al. / Journal of Molecular Structure 1040 (2013) 216–220
220
Pd complex it was shifted to lower frequency (1607 cmꢁ1). The
involving of imino nitrogen in coordination with Pd was confirmed
by identification of PdAN band at 434 cmꢁ1. Also, in obtained com-
plex, lactone C@O group was identified at lower energy, showing
4. Conclusion
The prepared complex (C3) has been characterized by elemental
analyses, infrared and NMR (1H and 13C) spectroscopy. The X-ray
analysis of the crystal confirmed the Pd(II) coordination with li-
gand in molar ratio 1:2. The coordination geometry of the Pd(II)
ion is square-planar with expected values for PdAO and PdAN dis-
tances. The investigation of cancer cell growth inhibition showed
that ligand 3 did not decrease the cell growth of both tested cancer
cell lines, while the corresponding Pd(II) complex showed signifi-
cantly lower growth inhibition effect than cisplatin.
intensive band at 1705 cmꢁ1
.
In comparison to the 1H NMR spectra of obtained complex C3,
which does not have broadened signal from OH group, the 1H
NMR spectra of ligand 3 C4AOH proton showed resonance at
16.07 ppm. On the other hand, it is evident that formation of com-
plex influenced decrease of chemical shifts of CH3AC400 and CH3-
AC@N protons (2.41 ppm and 2.69 ppm, respectively).
The 13C NMR spectral study showed that coordination has
strong effect on C-4 carbon, decreasing the chemical shift from
180.4 ppm (in ligand) to 169.8 ppm (in complex). The signal of car-
bon from methyl group bonded to imino group (CH3AC@N) was at
lower frequency in ligand 3 than in complex C3 (20.8 ppm and
24.6 ppm, respectively).
Supplementary material
CCDC 920512 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: (+44) 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
3.1. The crystal structure of 4-hydroxy-3-(1-(p-tolylimino)ethyl)-2H-
chromen-2-one-palladium(II) complex (C3)
Acknowledgements
The X-ray diffraction study of C3 (Fig. 1) shows that in the PdL2
molecule two L-ligands chelate to the Pd ion through their N and
O donors, giving a four-coordinate Pd(II) center with a trans-N2O2
donor set. The coordination geometry at Pd(II) is square-planar, with
standard values for the distances from the metal atom to the coordi-
nated atoms [PdAN1: 2.014(3); PdAO1: 1.985(2) Å]. The bond angle
values of O1APd1AN1: 88.73(11) and O1APd1AN1 1[1ꢁx, ꢁy,
ꢁz + 1]: 91.27(11) around the Pd(II) ion confirms the square-planar
coordination geometry. The Pd(II) ion lies in the least-squares plane
of the coordinated atoms. While the N1AC1 bond in the six-
membered chelate rings possess the character of a localized double
bond that deviates only marginally from the ideal value of 1.28 Å,
[25] a substantial lengthening of the O1AC3 bond is observed when
compared to the localized double O3AC5 bond (Table 2). The distri-
bution of the bond lengths over the fragments C1AC2AC3 indicates
significant delocalization of the electron density (Table 2).
The authors are grateful to the Ministry of Education, Science
and Technological Development of the Republic of Serbia (Projects
Nos. OI172016, OI172021, III41010 and III41031) and Research
Center of Serbian Academy of Arts and Sciences and the University
of Kragujevac for financial support.
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u
The crystal packing is dominantly arranged by Van Der Waals
forces. We have not found classic hydrogen bond in intra or inter
molecular space (Fig. 2). The distances between Pd atoms in the
unit cell are shown in the Fig. 2. Fig. 2 shows that the crystal struc-
ture corresponds to a discrete arrangement of PdL2 molecules cer-
tainly due to the presence within the unit cell of molecules of
solvent of crystallization (CHCl3).
´
´
´
´
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and 3.9
l
M in NCI-H460 and NCI-H460/R, respectively, whereas
the IC50 values for C3 were 19.4 and 147.2
lM. Coumarine-derived
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´
´
´
´
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transport activity in NCI-H460/R cells must be considered as a rea-
son for resistance to C3.
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