Complexes of platinum and palladium with β-diketones and DMSO: Synthesis, characterization, molecular modeling, and biological studies

Article abstract of DOI:10.1016/j.molstruc.2014.07.023

This work reports on the synthesis and characterization of new complexes of the type [MCl(L)DMSO], where L = 4,4,4-trifluoro-1-phenyl-1,3-butanedione (HTPB) or 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (HTTA) and M = Pt²⁺or Pd²⁺. These complexes were characterized by elemental analyses, conductivity measurements, FT-IR, UV-Vis, high-resolution mass spectra (HRESIMS) and TG/DTA. In the complexes, the metallic ions bind to β-diketone via the oxygen atoms and to DMSO molecule via sulfur atom. The structures of complexes were optimized and theoretical data showed good agreement with the experimental results. The cytotoxic activity of the compounds was evaluated in a chronic myelogenous leukemia cell line. The platinum complexes were more cytotoxic than the free ligands and carboplatin and are promising candidates for further investigations. As example, the compound [PtCl(TPB)(DMSO)] inhibits the growth of K562 cells with an IC₅₀value equal to 2.5 μM. Furthermore, microbiological assays against Mycobacterium tuberculosis showed that all complexes exhibit low cytotoxicity against this bacterial strain while the free ligands exhibited MIC values of approximately 10 μg mL^-1.

Full text of DOI:10.1016/j.molstruc.2014.07.023

Journal of Molecular Structure 1075 (2014) 370–376
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Complexes of platinum and palladium with b-diketones and DMSO:
Synthesis, characterization, molecular modeling, and biological studies
J. do Couto Almeida a, I.M. Marzano b, F.C. Silva de Paula b, M. Pivatto a, N.P. Lopes c, P.C. de Souza d,
F.R. Pavan d, A.L.B. Formiga e, E.C. Pereira-Maia b, W. Guerra a,
⇑
a Instituto de Química, Universidade Federal de Uberlândia, Campus Santa Mônica, 38.400-902 Uberlândia, MG, Brazil
b Departamento de Química, Universidade Federal de Minas Gerais, Campus Pampulha, 31.270-901 Belo Horizonte, MG, Brazil
c Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14.040-903 Ribeirão Preto, SP,
Brazil
d Faculdade de Ciências Farmacêuticas, Departamento de Ciências Biológicas, Universidade Estadual Paulista, Campus Araraquara, 14.801-902 Araraquara, SP, Brazil
e Instituto de Química, Universidade de Campinas, 13083-970 Campinas, SP, Brazil
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
ꢀ
ꢀ
ꢀ
ꢀ
Four new complexes with mixed
ligands were synthesized and
characterized.
Theoretical data show good
agreement with the experimental
results.
The platinum complexes are more
cytotoxic than the free ligands and
carboplatin.
Microbiological assays against
Mycobacterium tuberculosis were
performed.
a r t i c l e i n f o
a b s t r a c t
Article history:
This work reports on the synthesis and characterization of new complexes of the type [MCl(L)DMSO],
where L = 4,4,4-trifluoro-1-phenyl-1,3-butanedione (HTPB) or 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedi-
one (HTTA) and M = Pt2+ or Pd2+. These complexes were characterized by elemental analyses, conductiv-
ity measurements, FT-IR, UV–Vis, high-resolution mass spectra (HRESIMS) and TG/DTA. In the complexes,
the metallic ions bind to b-diketone via the oxygen atoms and to DMSO molecule via sulfur atom. The
structures of complexes were optimized and theoretical data showed good agreement with the experi-
mental results. The cytotoxic activity of the compounds was evaluated in a chronic myelogenous leuke-
mia cell line. The platinum complexes were more cytotoxic than the free ligands and carboplatin and are
promising candidates for further investigations. As example, the compound [PtCl(TPB)(DMSO)] inhibits
Received 14 April 2014
Received in revised form 18 June 2014
Accepted 9 July 2014
Available online 18 July 2014
Keywords:
Metal complexes
Molecular modeling
b-Diketones
Mycobacterium tuberculosis
Cytotoxic activity
the growth of K562 cells with an IC50 value equal to 2.5
Mycobacterium tuberculosis showed that all complexes exhibit low cytotoxicity against this bacterial
strain while the free ligands exhibited MIC values of approximately 10
g mLꢁ1
Ó 2014 Elsevier B.V. All rights reserved.
lM. Furthermore, microbiological assays against
l
.
⇑
Corresponding author. Address: Instituto de Química, Universidade Federal de Uberlândia, Av. João Naves de Ávila, 2121, Campus Santa Mônica, 38.400-902 Uberlândia,
MG, Brazil. Tel.: +55 34 3239 4143; fax: +55 34 3239 4208.
E-mail address: wg@iqufu.ufu.br (W. Guerra).
http://dx.doi.org/10.1016/j.molstruc.2014.07.023
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.

J. do Couto Almeida et al. / Journal of Molecular Structure 1075 (2014) 370–376
371
Introduction
600 °C, in a dynamic nitrogen atmosphere (flow rate of 200 mL/
min).
Cisplatin, one of the most important chemotherapeutic agents
for the treatment of a wide spectrum of solid tumors, has several
side effects. These undesirable effects led to the development of
a second generation of drugs, such as carboplatin and oxaliplatin
[1,2]. However, carboplatin has a spectrum of action similar to that
observed for cisplatin and, the oxaliplatin exhibits a specificity to
treat colon cancer. Moreover, for all platinum complexes used in
cancer chemotherapy, an intrinsic or acquired resistance leads to
a failure in the treatment [3]. Thus, in an attempt to reduce toxic-
ity, the resistance and wide spectrum of activity, thousands of plat-
inum complexes have been prepared by varying the nature of the
leaving groups and the carrier ligands [4,5]. Indeed, much attention
has been focused on designing new platinum complexes with
improved pharmacological properties and a broader range of anti-
tumor activity [6]. It should be noted that the development of new
non-platinum compounds with antitumoral activity also is a field
in full development with results very interesting. In this aspect,
several palladium complexes have been obtained aiming to pro-
duce new drugs. These compounds have potential as anticancer
and anti-infective agents [7–9].
Starting materials
The compound cis-[PtCl2(DMSO)2] was prepared according to
the literature [16]. The reagents (ligands and metal salts) are com-
mercially available (Aldrich). All other chemicals reagents were of
analytical grade, purchased from different sources, and used
without prior purification.
Preparation of the complexes
The complexes were synthesized following the procedures
described below:
a) [Pd(TTA)2]
This complex was first synthesized by Okeya et al. using a differ-
ent method [17]. In this work, 0.163 g of K2PdCl4 (0.5 mmol) previ-
ously dissolved in water was added to 5 mL of an ethanolic solution
of 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (1.0 mmol). The
mixture was stirred for 48 h and the solid formed was separated
by filtration, washed with water, ethanol and dried under reduced
pressure.
Yield: 81%. Color: Yellow. Anal. Calcd. for [Pd(C8H4F3O2S)2]: C,
35.02; H, 1.47; S, 11.69; Pd, 19.39%; Found: C, 34.80; H, 1.36; S,
11.39; Pd 18.91%. IR spectra in KBr,
On the other hand, the properties of b-diketones are of great
interest because these compounds are useful as metal extracting
agents [10,11] and most recently as potential drugs [12–14]. For
example, Wilson et al. showed that platinum complexes containing
b-diketones exhibit anticancer activity against several tumoral
cells strains [13]. Our research group also showed that a copper(II)
complex with 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione and
2,2-bipyridine inhibits the growth of K562 cells with an IC50 value
m
(cmꢁ1): 3100, 3095, 3079,
1578, 1536, 1507, 1434, 1405, 1354, 1317, 1261, 1234, 1185,
1151, 1068, 942, 861, 795, 727, 713, 609, 565, 523, 493, 476,
458, 423. UV–Vis (ethanol): kmax (nm) = 283 (9.36 ꢂ 103 molꢁ1
L cmꢁ1), 330 (1.86 ꢂ 104 molꢁ1 L cmꢁ1), 364 (2.27 ꢂ 104 molꢁ1
equal to 28.2 l
mol Lꢁ1 [15]. These findings can lead to a more
rational design of new complexes in order to establish a struc-
ture–activity relationship. Thus, these observations encourage us
to synthesize a new series of complexes containing b-diketones
as possible antitumoral and antibacterial agents. Therefore, this
paper reports on the synthesis of new complexes of Pt(II) and Pd(II)
containing 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (HTTA)
and 4,4,4-trifluoro-1-phenyl-1,3-butanedione (HTPB), their
characterization and antimicrobial and cytotoxic activities.
L cmꢁ1).
KM = 2.20 ls/cm.
b) [PtCl(TTA)(DMSO)]
0.25 mmol of cis-[PtCl2(DMSO)2] previously dissolved in warm
water (5 mL, 60–70 °C) was added to 5 mL of an aqueous solution
of 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (1.0 mmol). The
mixture was stirred for 48 h and the solid formed was separated
by filtration, washed with water, ethanol and dried under reduced
pressure.
Experimental
Physical measurements
Yield: 71%. Color: Yellow. Anal. Calcd. for [Pt(C8H4F3O2S)(C2H6-
SO)Cl]: C, 22.67; H, 1.90; S, 12.10; Pt, 36.82%; Found: C, 22.95; H,
Conductivity studies were carried out with a Digimed DM 31
conductivity meter using a cell of constant 1.00 cmꢁ1, spectro-
scopic grade dimethyl sulfoxide (Merck) (KM = 0.96
tetraethylammonium bromide (KM = 79.19
a standard compounds.
1.91; S, 12.06; Pt, 36.94%. IR spectra in KBr, m
(cmꢁ1): 3083, 3016,
2922, 1573, 1537, 1411, 1349, 1312, 1270, 1260, 1197, 1133,
1029, 939, 793, 745, 691, 608, 561, 532, 446. UV–Vis (ethanol):
kmax (nm) = 295 (4.58 ꢂ 103 molꢁ1 L cmꢁ1), 361 (1.41 ꢂ 104
l
s/cm) and
ls/cm) were used as
molꢁ1 L cmꢁ1).
K
M = 1.98
ls/cm.
Elemental analyses were performed using a Perkin-Elmer 2400
CHNS Elemental Analyser. Analyses by atomic absorption (% metal)
were made in a spectrophotometer Hitachi 8200.
c) [PdCl(TTA)(DMSO)]
IR spectra were registered in KBr pellets on a Shimadzu FTIR-
Irprestige-21 spectrometer.
Spectrophotometer UV-2501 PC Shimadzu was used for UV and
visible absorption measurements.
High-resolution mass spectra (HRESIMS) with electrospray ion-
ization were measured on an ultrOTOF (Bruker Daltonics) spec-
trometer, operating in the positive mode. Acetonitrile was used
as solvent system and the samples were infused into the ESI source
To a solution containing 0.163 g of K2PdCl4 (0.5 mmol) previ-
ously dissolved in water, was added 0.5 mmol of DMSO. After 1 h
of stirring, 0.5 mmol of 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedi-
one previously dissolved in ethanol was added. The mixture was
stirred for 24 h and the solid formed was separated by filtration,
washed with water, methanol and dried under reduced pressure.
Yield: 48%. Color: Yellow. Anal. Calcd. for [Pd(C8H4F3O2S)(C2H6-
SO)Cl]: C, 27.22; H, 2.28; S, 14.54; Pd, 24.12 Found: C, 27.22; H,
at a flow rate of 5
l
L/min. The calculated values for the charged
1.80; S, 14.01; Pd, 24.44. IR spectra in KBr, m
(cmꢁ1): 3083, 3023,
complex ions were made using ChemDraw Ultra 12.0.
2365, 1571, 1404, 1306, 1208, 1132, 1018, 936, 860, 785, 747,
671, 603. UV–Vis (ethanol): kmax (nm) = 283 (1.06 ꢂ 104 molꢁ1
L cmꢁ1), 332 (1.77 ꢂ 104 molꢁ1 L cmꢁ1), 361 (2.13 ꢂ 104 molꢁ1
Thermogravimetric analyses (TG/DTA) were obtained on a TGA-
50 Shimadzu, using 6.0 mg samples packed in aluminum crucible.
Samples were heated at 10 °C/min from room temperature to
L cmꢁ1).
KM = 2.73 ls/cm.

372
J. do Couto Almeida et al. / Journal of Molecular Structure 1075 (2014) 370–376
d) [Pd(TPB)2]
Time Dependent-DFT was used to obtain electronic spectra of
all structures under the same level of theory with the calculation
of the 30 lowest singlet states. Simulated UV–Vis spectra were
obtained from the sum of Gaussian functions with 2000 cmꢁ1
half-bandwidths. All the models and figures were plotted using
Jmol [23].
This complex was also first synthesized by Okeya et al. using a
different method [17]. In this work, 0.082 g of K2PdCl4 (0.25 mmol)
previously dissolved in water was added to 5 mL of an methanolic
solution of 4,4,4-trifluoro-1-phenyl-1,3-butanedione (0.50 mmol)
with triethylamine to a pH 6.3. The mixture was stirred for 24 h
and the solid formed was separated by filtration, washed with
water, methanol and dried under reduced pressure.
Cells and culture
Yield: 61%. Color: Yellow. Anal. Calcd. for [Pd(C10H6F3O2)2]: C,
44.76; H, 2.24; Pd, 19.83. Found: C, 45.08; H, 1.53; Pd, 19.81. IR
spectra in KBr,
The K562 cell line was purchased from the Rio de Janeiro Cell
Bank (number CR083 of the RJCB collection). This cell line was
established from pleural effusion of a 53 year-old female with
chronic myelogenous leukemia in terminal blast crisis. Cells were
cultured in RPMI 1640 (Sigma Chemical Co.) medium supple-
mented with 10% fetal calf serum (CULTILAB, São Paulo, Brazil) at
37 °C in a humidified 5% CO2 atmosphere. Cultures grow exponen-
tially from 105 cells mLꢁ1 to about 8 ꢂ 105 cells mLꢁ1 in three days.
Cell viability was checked by Trypan Blue exclusion. The cell
number was determined by coulter counter analysis.
m
(cmꢁ1): 2370, 2345, 1593, 1568, 1540, 1529,
1509, 1490, 1451, 1437, 1420, 1324, 1312, 1297, 1255,
1193,1181, 1163, 1147, 1097, 1075, 1027, 1000, 975, 949, 930,
843, 816, 804, 766, 730, 708, 691, 612, 565, 525, 458, 420. UV–Vis
(ethanol): kmax (nm) = 272 (1.88 ꢂ 104 molꢁ1 L cmꢁ1), 300 (2.17 ꢂ
104 molꢁ1 L cmꢁ1), 359 (1.12 ꢂ 104 molꢁ1 L cmꢁ1).
KM = 1.20 ls/
cm.
For cytotoxicity assessment, 1 ꢂ 105 cells mLꢁ1 was cultured for
72 h in the absence and presence of a range of concentrations of
tested compounds. The sensitivity to compound was evaluated
by the concentration that inhibits cell growth by 50%, IC50. Stock
solutions were prepared in DMSO.
e) [PtCl(TPB)(DMSO)]
To cis-[PtCl2(DMSO)2] (0.25 mmol) in warm water (5 mL, 60–
70 °C), 4,4,4-trifluoro-1-phenyl-1,3-butanedione (0.25 mmol) dis-
solved in methanol (5 mL) was added. After stirring for 48 h at
room temperature the solid formed was separated by filtration,
washed with water, methanol and dried under reduced pressure.
Yield: 40%. Color: Yellow. Anal. Calcd. for [Pt(C10H6F3O2)
(C2H6SO)Cl]: C, 27.51; H, 2.31; S, 6.12; Pt, 37.25. Found: C, 28.08;
Anti-Mycobacterium tuberculosis activity assay
The anti-MTB activity of the compounds was determined by the
REMA (Resazurin Microtiter Assay) method according to Palomino
et al., [24]. Stock solutions of the tested compounds were prepared
in dimethyl sulfoxide (DMSO) and diluted in Middlebrook 7H9
broth (Difco) supplemented with oleic acid, albumin, dextrose
H, 2.01; S, 6.25, Pt, 36.83. IR spectra in KBr,
m
(cmꢁ1): 3029, 3010,
2931, 1599, 1566, 1539, 1486, 1460, 1394, 1322, 1302, 1256,
1190, 1144, 1032, 939, 808, 774, 735, 689, 603, 557, 452. UV–Vis
(ethanol): kmax (nm) = 271 (8.04 ꢂ 103 molꢁ1 L cmꢁ1), 319
(1.57 ꢂ 104 molꢁ1 L cmꢁ1).
KM = 2.29 ls/cm.
and catalase (OADC enrichment
obtain final drug concentration ranges of 0.09–25
–
BBL/Becton–Dickinson), to
g/mL. A serial
l
f) [PdCl(TPB)(DMSO)]
dilution was performed on the equipment Precision™ XS (Biotek).
The rifampicin was dissolved in distilled water, and used as a stan-
dard drug. A suspension of the MTB H37Rv ATCC 27294 was cul-
tured in Middlebrook 7H9 broth supplemented with OADC and
0.05% Tween 80. The culture was frozen at ꢁ80 °C in aliquots. After
two days was carried out the CFU/mL of an aliquot. The concentra-
This complex was synthesized using the same method
described for the compound [PdCl(TTA)(DMSO)].
Yield: 19%. Color: Yellow. Anal. Calcd. for [Pd(C10H6F3O2)
(C2H6SO)Cl]: C, 33.12; H, 2.78; S, 7.37; Pd, 24.46. Found: C,
33.08; H, 2.94; S, 7.01; Pd, 23.96. IR spectra in KBr,
m
(cmꢁ1):
tion was adjusted by 5 ꢂ 105 UFC/mL and 100
lL of the inoculum
3031, 2924, 2365, 1593, 1571, 1541, 1488, 1457, 1420, 1321,
was added to each well of a 96-well microtiter plate together
1291, 1268, 1185, 1132, 1079, 1034, 951, 807, 761, 717, 679,
100
lL the compounds. Samples were set up in triplicate. The plate
596, 557. UV–Vis (ethanol): kmax (nm) = 274 (5.47 ꢂ 104 molꢁ1
-
was incubated for 7 days at 37 °C. After 24 h 30
lL of 0.01% resazu-
L cmꢁ1), 354 (2.61 ꢂ 104 molꢁ1 L cmꢁ1).
KM = 1.68 ls/cm.
rin (solubilized in water) was added. The fluorescence of the wells
was read after 24 h by TECAN SpectrafluorÒ. The MIC was defined
as the lowest concentration resulting in 90% inhibition of growth of
MTB.
Molecular modeling
Geometry optimizations were carried out using GAMESS soft-
ware [18] with a convergence criterion of 10ꢁ4 a.u. in a conjugated
gradient algorithm without constraints. The LANL2DZ effective
core potential [19] was used for platinum and palladium and the
atomic 6-31G(d) basis set [20] for all other atoms. Density
functional theory (DFT) calculations were carried out using PBE0
[21] gradient-corrected hybrid to solve the Kohn–Sham equations
with a 10ꢁ5 a.u. convergence criterion for the density change.
Vibrational frequency analyses were performed at the same
level of theory to confirm the structures as minima of the potential
energy surfaces (PES) showing no imaginary frequencies.
Zero-point energies from these calculations were used to cor-
rect total energies and compare the stability of isomers. The har-
monic frequencies (without scaling) and intensities were used to
generate the theoretical spectra. The corresponding simulated
vibrational spectra were obtained from the sum of Lorentzian func-
tions with 20 cmꢁ1 half-bandwidths as reported before [22].
Results and discussion
Four new complexes containing 4,4,4-trifluoro-1-(2-thienyl)
-1,3-butanedione (HTTA) or 4,4,4-trifluoro-1-phenyl-1,3-butanedi-
one (HTPB) and dimethylsulfoxide (DMSO) as ligands were synthe-
sized and characterized by elemental analyses, conductivity
measurements, FT-IR, UV–Vis, HRMS and TG/DTA. All of the com-
plexes are stable to air and light and soluble in organic solvents
such as DMSO and DMF. The chemical structures of the ligands
HTTA, HTPB and complexes containing HTTA are presented in
Fig. 1.
The results of the elemental analyses (C, H, S and metal) are in
accordance with the proposed structures.
The molar conductivity values of solutions (10ꢁ3 M; DMSO or
acetonitrile) for all complexes were far below that of the 1:1 stan-
dard electrolyte indicating that they are not charged [25].

J. do Couto Almeida et al. / Journal of Molecular Structure 1075 (2014) 370–376
373
3
3
3
3
3
3
3
2
3
3
3
Fig. 1. (A) Ligands (HTTA and HTPB). (B) Complexes with HTTA.
36.99% (calcd: 36.82%). The percentage of metal fits well with the
proposed formulas for all complexes with DMSO. % Pd calcd. for
complex [PdCl(TPB)(DMSO)] is 24.46 (found: 24.80). Curiously,
for the complex [PdCl(TTA)(DMSO)], between 390 and 590 °C
occurs the oxidation of the remaining Pd0 to PdII. Thus, at 600 °C
there is a residue (palladium oxide) corresponding to 27.21%
(calcd: 27.75%).
The TG and DTA curves for the decomposition of compound
[Pd(TTA)2] shows two events (exothermic and endothermic) of
weight loss between 120 and 450 °C, which can be attributed to
the loss of the ligands, corresponding to 80.67% (calcd: 81.25%).
At 500 °C there is a residue (elemental palladium) corresponding
to 19.32% (calcd: 18.52%). For the complex [Pd(TPB)2], at 500 °C
there is a residue (palladium) corresponding to 19.83% (calcd:
19.83%).
5,0
4,5
4,0
3,5
3,0
2,5
2,0
1,5
80
60
40
20
0
-20
100
200
300
400
500
Temperature (°C)
The inexistence of weight loss in the TG curve up to 150 °C
indicates the absence of water molecule in the compounds.
Fig. 2. TGA/DTA curve of complex [PtCl(TTA)(DMSO)].
IR spectra
The same pattern was found when the complexes were dissolved
in DMSO, even after 30 min.
The IR spectra of the free ligands were performed for compari-
son to the corresponding complexes isolated. Characteristic
absorptions in the 3158–2984 cmꢁ1 region were observed, corre-
sponding to mCH and mCH (thiophene ring). Vibrational frequencies
between 1660 and 1620 cmꢁ1 are due to C@O group.
In the IR spectra of the complexes, the peaks due to mC@O were
shifted to lower wavelengths indicating the complexation through
oxygen atoms [16]. The CAH stretching of the free respective
ligand is shifted toward higher frequency, as a result of metal coor-
dination to the carbonyl oxygen atoms. For the complexes contain-
ing DMSO, the coordination was verified by the SAO stretching
band near 1124 cmꢁ1, suggesting that this ligand is bound to the
platinum or palladium through the sulfur atom [26]. For the com-
plexes with HTTA, the symmetric and asymmetric CF3 stretching
Thermal analyses
The thermal analyses for all compounds with HTTA and HTPB
were carried out between room temperature and 600 °C in air
atmosphere. The events observed in the TG curves of the com-
plexes containing DMSO are very similar and only the TG curve
of the platinum complex will be discussed.
The TG/DTA curve for complex [PtCl(TTA)(DMSO)] (Fig. 2)
shows three events (exothermic and endothermic) of weight loss
at 130–480 °C range due to the complex thermal decomposition
(loss of the ligands) corresponding to 63.19.% (calcd: 63.18%). At
600 °C there is a residue (elemental platinum) corresponding to

374
J. do Couto Almeida et al. / Journal of Molecular Structure 1075 (2014) 370–376
frequencies are observed at 1138 and 1314 cmꢁ1, respectively.
These absorption bands appear in the infrared spectrum of the free
ligand at 1120 and 1278 cmꢁ1. The absorption around 1072 cmꢁ1
in the IR spectra of the complexes with HTTA should be assigned
For the complexes [PtCl(TTA)(DMSO)] and [PtCl(TPB)(DMSO)],
the results indicate that these compounds suffer solvolysis, i.e.,
there is a replacement of chloride ion by a molecule of the solvent
(acetonitrile), thus the isotopic pattern in mass spectrum also
change [28]. As example (see Fig. 4), the charged complex ion peak
with m/z 529.0371 [M ꢁ Clꢁ + CH3CN]+ (calcd for [Pt(TPB)(DMSO)
(CH3CN)], 529.0372).
to m
(CAS). Some of the weak bands in the range of 500–463 cmꢁ1
in the spectra of the complexes could tentatively be ascribed to
MAO stretchings [26].
The mass spectrum of complex [Pd(TPB)2] exhibited the cation-
ized ion at m/z 558.9583 [M + Na]+ (calcd for Pd(TPB)2Na, 558.
9572). The same pattern was found for the complex [Pd(TTA)2]
exhibiting a sodiated ion at m/z 570.8715 [M + Na]+ (calcd for
Pd(TTA)2Na, 570.8701).
UV–Vis spectra
In order to confirm the coordination, we have analysed the
spectra in the UV–visible regions in ethanol.
The UV–visible absorption spectrum of the ligand HTTA in
ethanol (5 ꢂ 10ꢁ5 M) displays three bands centered at 263, 288
and 338 nm. According to Chen et al. [27], the bands centered at
Molecular modeling
338 and 263 nm can be assigned to
the whole conjugation and delocalization electronic system of
the ligand and the transition of the thiophene ring moiety. The
band centered at 288 nm may be attributed to n ? p* transition
p ? p* transitions involving
The obtained heteroleptic Pd(II) and Pt(II) complexes have two
possible isomers with DMSO bonded cis or trans to the thiophenyl
or phenyl groups of the b-diketones. In order to evaluate their rel-
ative stabilities, we have performed a theoretical investigation of
all possible structures. As expected, all structures show a square-
planar coordination of the d8 M(II) ions and the bond distances
are in good agreement with similar complexes. For example,
MAOTTA bonds range from 2.01 to 2.03 Å and MACl bonds are
2.31–2.32 Å. In all structures, thiophenyl and phenyl groups were
found to be planar and almost co-planar with the b-diketone
group. All the optimized structures, bond distances and angles
can be found as Supporting Information (Figs. S1 and S2). In the
cases of [PdCl(TTA)(DMSO)] and [PtCl(TTA)(DMSO)], the trans iso-
of the keto carbonyl and enol carbonyl group of the tautomer. In
Fig. 3, the spectra of ethanolic solutions of the ligand HTTA and
their respective metal complexes are shown. A bathochromic shift
in relation to free ligand confirms the presence of the complexes in
solution. One can also notice that the band localized at 288 nm in
the free ligand disappears or is observed as a shoulder of low inten-
sity in all compounds. This result confirms the complexation and
suggests that the oxygen of the b-diketone group is involved in
the coordination sphere. On the other hand, the absorption spec-
trum of the ligand HTPB in ethanol (5 ꢂ 10ꢁ5 M) displays two
bands centered at 249 and 327 nm. In the spectra of complexes,
the band localized at 249 nm present a red shift ( 22 nm) when
compared to the organic compound free, which confirms the
presence of complexes in solution.
mers were found to be more stable by 1.3 and 0.9 kcal molꢁ1
,
respectively. For [PdCl(TPB)(DMSO)] and [PtCl(TPB)(DMSO)], the
situation is reversed and the cis isomer is more stable by 1.6 and
2.1 kcal molꢁ1, respectively. Even if these energies are higher than
kT at 298 K (0.59 kcal molꢁ1), the differences are very small result-
ing in non-zero Boltzmann distributions and co-existance of both
isomers cannot be ruled out using these data.
Mass spectrometry
Simulated vibrational spectra can be seen in Fig. S3 of the Sup-
porting Information. The spectra are very similar and cannot be
used to differentiate cis and trans isomers in the 400–4000 cmꢁ1
range. All the spectra show the expected vibrational modes and,
as an example, for complex cis-[PtCl(TTA)(DMSO)] the C@O and
C@C stretching modes of the diketone are predicted at 1662 and
1617 cmꢁ1, respectively. The in-plane angular deformation of the
C@O is found at 1384 cmꢁ1 and the in-plane angular deformation
of CAH from thiophenyl is predicted at 1270 cmꢁ1. The stretching
mode of the CAH of the diketone is seen at 1200 cmꢁ1. These
assignments are the same for all isomers and corroborate with
the experimental spectra.
Mass spectra of platinum compounds (see Fig. 4) containing
chlorine are typical by an isotopic cluster pattern demonstrating
the presence of isotopes 194Pt (32.97%), 195Pt (33.83%), 196Pt
(25.24%), 198Pt (7.16%), 35Cl (75.77%) and 37Cl (24.23%), with the
nuclide abundance in parentheses (A%) [28]. The high-resolution
mass spectra of the synthesized complexes were recorded and
the obtained data confirm the proposed structures. In this work,
the m/z values listed below in the text refer to the peak of the
isotopic cluster corresponding to the 195Pt and 35Cl isotopes.
Using TD-DFT, the electronic spectra of all structures were pre-
dicted and can be seen in Fig. 5. Oscillator strengths and excitation
energies for all calculated states can be found as Supporting Infor-
mation (Tables S1 and S2). For all complexes, the simulated spec-
trum of the most stable isomer is very similar with the
experimental profile. For Pt(II) complexes, the calculations predict
two intense bands at 220 nm and 300 nm that can be compared to
bands at 295 and 361 nm observed experimentally for
[PtCl(TTA)(DMSO)] and 271 and 319 nm for [PtCl(TPB)(DMSO)].
Based on the orbital analysis (Supporting Information), the most
intense band of the experimental spectra (ꢃ300 nm) can be
HTTA
[Pd(TTA)2]
1,0
[PtCl(TTA)(DMSO)]
[PdCl(TTA)(DMSO)]
0,5
ascribed to a
p ? p* transition from the b-diketone ligand for both
complexes with an important contribution from the thiophenyl
and phenyl rings. In all cases, there is a relevant contribution of
the M(II) in the ground state, suggesting a mixing of MLCT states
for these bands. The observed difference between predicted and
experimental transition energies was expected for TD-DFT and it
has been observed before for other complexes [29].
0,0
300
400
500
λ
(nm)
Fig. 3. Electronic spectra in ethanol (1.0 ꢂ 10ꢁ5 M).

J. do Couto Almeida et al. / Journal of Molecular Structure 1075 (2014) 370–376
375
Intens.
x105
+MS, 7.4min #443
529.0371
528.0346 530.0372
529.0371
8
6
4
2
0
CH3
S
H3C
O
O
Pt
O
H
H3CCN
CF3
532.0380
531.0366
[M − Cl− + CH3CN]+
533.0394
526.0257
726.0311
200
400
600
800
1000
1200
m/z
Fig. 4. HRESIMS spectrum of complex [PtCl(TPB)(DMSO)] (chloride ion was exchanged for a molecule of solvent (acetonitrile) and the charged complex ion observed was
[M ꢁ Clꢁ + CH3CN]+).
Fig. 5. TD-DFT simulated UV–Vis spectra using PBE0/LANL2DZ/6-31G(d) for (A) [PtCl(TTA)(DMSO)], (B) [PtCl(TPB)(DMSO)], (C) [PdCl(TTA)(DMSO)], and
(D) [PdCl(TPB)(DMSO)]. Solid lines represent the spectra of the most stable isomers.
The theoretical spectra of Pd(II) complexes are very similar to
Table 1
the platinum analogs as is also seen in experiment. The only differ-
IC50 values for HTTA, HTPB, cisplatin, carboplatin and complexes.
ence is the presence of a shoulder in the experimental spectra.
Compound
aIC50
(lM)
Calculations also predict this feature and revealed that it is due
to a splitting of the same transitions already observed for the Pt(II)
complexes. Orbital plots, transitions and Kohn–Sham orbital
compositions can be found as Supporting Information.
HTTA
HTPB
[Pd(TTA)2]
[PdCl(TTA)(DMSO)]
[Pd(TPB)2]
[PdCl(TPB)(DMSO)]
[PtCl(TTA)(DMSO)]
[PtCl(TPB)(DMSO)]
Carboplatin
51.46 2.1
7.6 0.7
51.92 3.7
14.3 1.2
12.2 1.2
23.0 2.3
7.7 0.8
2.5 0.3
10.0 1.2
1.1 0.1
Cytotoxic studies
The cytotoxic efficacy of the ligands HTTA, HTPB and their com-
plexes was examined on K562 cells. All compounds inhibit the
growth of K562 cells with IC50 values between 2.5 and 51.92 lM
Cisplatin
a
IC50 is the concentration required to inhibit 50% of K562 cell growth.
(Table 1). IC50 values obtained for two platinum complexes used
in chemotherapy, cisplatin and carboplatin, are also shown for
the sake of comparison. As expected, the platinum complexes
tested were found to be more potent than the palladium analogs
and these findings were consistent with other studies conducted
on platinum and palladium complexes [30–33]. For the complexes
with HTTA, [Pd(TTA)2] was as active as the free ligand, whereas the
activity of [PtCl(TTA)(DMSO)] was 7-fold higher when compared to

376
J. do Couto Almeida et al. / Journal of Molecular Structure 1075 (2014) 370–376
Table 2
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This work was supported by grants of CNPq (Conselho Nacional
de Desenvolvimento Científico e Tecnológico, Brazil), RMQ (Rede
Mineira de Química), Universidade Federal de Uberlândia (UFU),
FAPEMIG (Fundação de Amparo à Pesquisa de Minas Gerais, Brazil)
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Appendix A. Supplementary material
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2014.07.
023.