Organoplatinum(II) complexes with 2-acetylthiophene thiosemicarbazone: Synthesis, characterization, crystal structures, and in vitro antitumor activity

Article abstract of DOI:10.1021/om201178q

Novel organoplatinum(II) complexes with 2-acetylthiophene thiosemicarbazone (ATTSC) were synthesized. The reaction of K₂PtCl₄ with ATTSC in 1:1 and 1:2 metal to ligand ratios yielded 1 [Pt₄(ATTSC-2H) ₄?4DMF] and 2 [Pt(ATTSC-H)(ATTSC)Cl?3CH₃OH)]. The crystal structures of these platinum chelates have been solved by single-crystal X-ray diffraction structure determinations and revealed metalation of the thiophene ring at C2 through platinum atoms. Further characterization of 1 and 2 was performed using electronic, IR, UV/vis, and NMR spectroscopies and elemental analysis. The in vitro antitumor activity of the ligand as well as 1 and 2 was determined against two different human tumor cell lines (HT-29 and HuTu-80). These tests revealed that the platinum(II) complexes are more cytotoxic than their ligand. The tetranuclear complex 1 shows higher antiproliferative activity (IC₅₀ = 1.2 and 1.5 μM) when compared to 2 (IC₅₀ = 3 and 5.9 μM), while the ligand has IC₅₀ values of 8.6 and >10 μM. Compounds 1 and 2 can therefore be considered as agents with potential antitumor activity.

Full text of DOI:10.1021/om201178q

Article
pubs.acs.org/Organometallics
Organoplatinum(II) Complexes with 2-Acetylthiophene
Thiosemicarbazone: Synthesis, Characterization, Crystal Structures,
and in Vitro Antitumor Activity
Awadelkareem A. Ali,† Hassan Nimir,† Cenk Aktas,‡ Volker Huch,§ Ulrich Rauch,⊥ Karl-Herbert Schafer,⊥
̈
and Michael Veith*,‡,§
†Department of Chemistry, University of Khartoum, P.O. Box 321, Khartoum 11115, Sudan
‡INM−Leibniz Institute for New Materials, Campus D2 2, 66123 Saarbruecken, Germany
§Institute of Inorganic Chemistry, Saarland University, 66041, Saarbruecken, Germany
⊥University of Applied Science, Amerikastraße 1, 66482 Zweibruecken, Germany
S
* Supporting Information
ABSTRACT: Novel organoplatinum(II) complexes with 2-acetylthiophene
thiosemicarbazone (ATTSC) were synthesized. The reaction of K2PtCl4
with ATTSC in 1:1 and 1:2 metal to ligand ratios yielded 1 [Pt4(ATTSC-
2H)4·4DMF] and 2 [Pt(ATTSC-H)(ATTSC)Cl·3CH3OH)]. The crystal
structures of these platinum chelates have been solved by single-crystal X-
ray diffraction structure determinations and revealed metalation of the
thiophene ring at C2 through platinum atoms. Further characterization of 1
and 2 was performed using electronic, IR, UV/vis, and NMR spectroscopies
and elemental analysis. The in vitro antitumor activity of the ligand as well
as 1 and 2 was determined against two different human tumor cell lines
(HT-29 and HuTu-80). These tests revealed that the platinum(II)
complexes are more cytotoxic than their ligand. The tetranuclear complex
1 shows higher antiproliferative activity (IC50 = 1.2 and 1.5 μM) when
compared to 2 (IC50 = 3 and 5.9 μM), while the ligand has IC50 values of 8.6 and >10 μM. Compounds 1 and 2 can therefore be
considered as agents with potential antitumor activity.
were found to be able to overcome the cisplatin resistance of
A2780/Cp8 cells.14 Pd(II) and Pt(II) complexes of phenyl-
acetaldehyde thiosemicarbazone15 and binuclear chloro-bridged
palladated and platinated complexes derived from p-isopro-
pylbenzaldehyde thiosemicarbazone showed activity against
several human and murine cell lines (HL-60, U937, HeLa, and
3T3) that were resistant to the clinically used cisplatin.16 The
great majority of antitumor metal complexes synthesized and
characterized are those that are structurally analogous to
cisplatin. However, due to severe neurotoxicity, nephrotox-
icity,17 myelosuppression, and cross-resistance against cisplatin-
resistant cell lines,18 there has been a decrease in the number of
new compounds of this type,19 possibly because it has just
started to be revealed that substantial advances are unlikely to
be reached with such molecules.20 At the same time there has
been an emergence of new structural types of metallic
complexes often with promising activity and the ability to
circumvent cisplatin resistance. This focus on the design of new
coordination compounds with antitumoral properties, increased
efficiency, and decreased toxicity along with the establishment
INTRODUCTION
■
The synthesis of transition metal complexes with thiosemi-
carbazone ligands has received considerable attention due to
the pharmacological properties of both ligands and com-
plexes.1−3 Thiosemicarbazone derivatives exhibit a great variety
of biological activities, which include notably their antitumor,4
antifungal,5,6 antibacterial,6,7 and antiviral8 properties depend-
ing on the parent aldehyde and ketone and, of course, metal
ion. The deprotonated thiosemicarbazone ligands usually
coordinate to platinum, palladium, copper, ruthenium, and
osmium through oxygen, nitrogen, and sulfur donor atoms in
their (N, S) bidentate form or (N, N, S or O, N, S) tridentate
form to give metallic complexes of different molecular
geometry.9−11 Many complexes of Pd(II) and Pt(II) with
thiosemicarbazone derived from different aldehydes and
ketones have been synthesized, and their cytotoxic activities
were investigated using different cell line cultures: complexes of
pyridine carboxyaldehyde thiosemicarbazone were active in
vivo against leukemia P388 cells,12 and Pd(II) complexes of N4-
alkyl-2-acetylpyridine thiosemicarbazones showed in vitro
inhibitory activity of DNA syntheses in L1210 and P388 cell
cultures.13 Platinum(II) complexes of N4-ethyl 2-formyl and 2-
acetylpyridine thiosemicarbazones showed cytotoxicity and
Received: November 24, 2011
Published: March 8, 2012
© 2012 American Chemical Society
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Figure 1. Thione (A) and thiol (B) tautomeric forms of the synthesized Schiff base.
355, 509. Crystals of 1 are subject to loss of DMF. This explains the
lower C value compared to the calculated one.
of new biological targets led to the emergence of the
bioinorganic chemistry of palladium and platinum complexes.
We here present our results with 2-acetylthiophene thiosemi-
carbazone and some platinum complexes obtained with this
ligand.
Synthesis of 2, Pt(ATTSC)(ATTSC-H)Cl·3CH3OH. A solution of
K2PtCl4 (0.208 g, 0.5 mmol) in methanol was added dropwise to a
stirred solution of ATTSC (1.0 mmol) in 30 mL of methanol. The
solution was refluxed for 2 h and stirred for 24 h at room temperature.
The colored solution was condensed to half of its volume under
reduced pressure (10−2 atm) and kept in a refrigerator overnight.
Small, dark red rectangular crystals were obtained. These crystals were
collected by filtration, washed with cold ethanol and diethyl ether, and
dried at 10−2 atm. These crystals were suitable for structure analysis by
X-ray diffraction.
Yield: 86.82%, mp 209−210 °C. Anal. Calcd for C17H29ClN6O3PtS4
(724.23 g/mol): C, 28.18; H, 4.04; N, 11.60. Found: C, 20.54; H,
2.83; N, 10.75. IR (solid state, cm−1): ν(NH2) 3390.68, 3244.62;
ν(CN) 1592.59; ν(CS) 853.89; ν(N−N)1089.22. 1H NMR
(DMSO-d6): δ 1.06(s, 3H), 7.46, 7.48 (d, 2H ring); 7.52, 7.54 (b, 2H,
NH2). 13C NMR (DMSO-d6): δ 14.72(CH3); 128.16−159.05 (C4H3S
ring); 163.77 (HCN); 172.36 (CS). Electronic spectra (λmax
nm): 277, 303, 349, 521. Compound 2 contains three methanol
molecules per platinum atom: As the crystals decompose slowly at
room temperature with loss of methanol (NMR proof), especially the
carbon content shows a discrepancy.
EXPERIMENTAL SECTION
■
General Procedures and Measurements. The experimental
work was carried out under atmospheric pressure. Reagents were used
as obtained from commercial sources (Alfa Aesar and Aldrich) without
further purification. Solvents were purified and dried according to
standard procedures. Melting points were determined using an EZ-
Melt automated melting point apparatus. Elemental analyses were
determined on an Leco CHN-932 analyzer. The infrared (IR) spectra
were recorded in the solid state on a Varian 2000 FTIR
spectrophotometer in the 4000−400 cm−1 range. The H and 13C
1
NMR spectra were recorded on a Bruker 300, using DMSO-d6 as a
solvent. The chemical shifts (δ) in ppm were measured relative to
tetramethylsilane (TMS). The electronic spectra were recorded using a
Varian 5000 spectrophotometer.
Synthesis of the Ligand. The ligand 2-acetylthiophene
thiosemicarbazone (ATTSC) was prepared similarly to the literature
procedure.21
To a hot solution of thiosemicarbazide (1.08 g, 11.88 mmol) in 70
mL of methanol was added dropwise a solution of 2-acetylthiophene
(11.88 mmol) in 30 mL of methanol. A few drops of glacial acetic acid
were also added to the mixture. The mixture was stirred and refluxed
for 10 h (70−80 °C) and then filtered. The volume of the filtrate was
reduced to half through solvent removal at 10−2 atm and was kept in
the refrigerator. After several hours, small rectangular pale yellow
crystals were obtained. These crystals were collected by filtration,
washed with cold ethanol, and dried in vacuo.
In Vitro Growth Inhibition Assay. Cell Culture. The
antitumor assays were performed employing the following
cell lines: HT-29 (human colon adenocarcinoma); HuTu-80
(human duodenal adenocarcinoma). Cells were maintained in
Dulbecco’s modified Eagle’s medium (DMEM) supplemented
with 10% fetal calf serum and 50 μg/mL gentamycin and grown
at 37 °C in a 5% CO2 humidified environment.
Assessment of Cytotoxicity. Cells were inoculated into 24-well
tissue culture plates at a density of 10 000 cells per well and incubated
at 37 °C with their corresponding growth medium for 24 h to allow
cells to attach. A plate containing each of these cells was fixed in situ
with formaldehyde in order to obtain the number of cells at zero time
before adding the test compounds. The rest of the plates containing
the different cell lines received serial dilutions (0.1−10 μM) of the
ligand and platinum complexes in aqueous DMSO and were incubated
at 37 °C for 48 h. The control cultures were supplemented with the
same amount of solvent containing DMSO. The assay was terminated
by the addition of cold formaldehyde. The number of cells in each well
was determined using the 4,6-diamidino-2-phenylindole (DAPI) assay.
Formaldehyde-treated plates were incubated at room temperature for
30 min, and then the cells were washed with phosphate-buffered saline
(PBS). The cells were stained for 20 min with a solution of 1.0% DAPI
in PBS. At the end of the staining period, unbound dye was removed
by washing with PBS. The pictures of the bound dye were taken using
a fluorescent microscope, and the number of living cells was calculated
using imaging software. The IC50 value was defined as the
concentration of test sample resulting in a 50% reduction of the
number of cells as compared with untreated controls that received a
serial dilution of the solvent in which the test samples were dissolved.
Yield: 84.91%, mp 135−136 °C. Anal. Calcd for C7H9N3S2 (199.30
g/mol): C, 42.19; H, 4.55; N, 21.08. Found: C, 42.31; H, 4.61; N,
20.93. IR (cm−1): ν(NH2) 3403.95, 3228.17; ν(NH) 3142.02; ν(C
1
N) 1581.39; ν(CS) 950.65; ν(N−N)1042.68. H NMR (DMSO-
d6): δ 1.62 (s, 3H, CH3), 6.19−6.69 (m, C4H3S ring); 7.44, 6.71 (d,
2H, NH2); 9.49 (s,1H, N−NH). 13C NMR (DMSO-d6): δ
15.17(CH3); 128.16−143.27 (C4H3S ring); 145.32 (HCN);
178.95 (CS). Electronic spectra (λmax nm): 292.
Synthesis of Complexes. Synthesis of 1, Pt4(ATTSC-
2H)4·4DMF. A solution of K2PtCl4 (0.208 g, 0.5 mmol) in
methanol was added dropwise to a stirred solution of ATTSC
(0.5 mmol) in 20 mL of methanol. The solution was refluxed
for 2 h and stirred for 24 h at room temperature. The yellowish-
brown solid precipitate was collected by filtration, washed with
ethanol and ether, dried at 10−2 atm, and recrystallized from
DMF. These crystals were suitable for structural analysis by X-
ray diffraction.
Yield: 73.60%. Mp dec > 335 °C. Anal. Calcd for C28H28N12Pt4S8
(1569.41 g/mol): C, 21.43; H, 1.80; N, 10.71. Found: C, 20.52; H,
2.14; N, 10.28. IR (solid state, cm−1): ν(NH2) 3307.73; ν(CN)
1597.83; ν(CS) 875.26; ν(N−N) 1072.56. 1H NMR (DMSO-d6): δ
1.08 (s, 3H, CH3), 7.35, 7.36 (d, 2H ring); 7.44 (b, 2H, NH2). 13C
NMR (DMSO-d6): δ 13.98(CH3); 128.99−159.28 (C4H3S ring);
163.87 (HCN); 172.56 (CS). Electronic spectra (λmax nm): 277,
RESULTS AND DISCUSSION
■
Spectroscopy. Compounds containing the thioamide
functional group −NH−C(S) are capable of exhibiting
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thione−thiol tautomerism, and therefore, the Schiff base, in
principle, can also exist as either the thione (A) or the thiol (B)
tautomeric form or as a mixture of both tautomers22 (Figure 1).
However, on the basis of IR data, it is easy to distinguish
between them in the solid state; no peak in the range 2150−
2600 cm−1 attributed to the −SH vibration is observed,
indicating that the Schiff base exists in the thione form in the
Table 1. IR and Electronic Spectral Data for the Synthesized
Schiff Base (ATTSC) and Its Pt(II) Complexes
electronic
spectra
IR bands (cm−1
)
compound
ATTSC
−NH
−CN
−CS
N−N
λmax (nm)
3142.02
1581.39
1597.83
950.65
875.26
1042.68 292
1
Pt4(ATTSC-
2H)4·4DMF
(1)
1072.56 277, 355,
509
solid state. H NMR spectra of the Schiff base in DMSO-d6
exhibit the secondary −NH− proton signal at 9.49 ppm. No
signal at 4.00 ppm (attributed to the −SH proton) is observed
Pt(ATTSC)
(ATTSC-1H)
Cl·3CH3OH
(2)
1592.59
853.89
1089.22 277, 303,
349, 521
1
in the H NMR spectra of the Schiff base, indicating that it
remains solely as the thione form, even in a polar solvent such
as DMSO. In addition to the possibility of thione and thiol
tautomers, the Schiff base is also capable of existing as E and Z
isomeric forms (Figure 2) or as a mixture of both isomers. In
nitrogen atom (shift of the hydrazinic μ(N−N) band of the
ligand to higher value in the spectra of the complexes) and via
the sulfur atom (shifting of the CS band of the free ligand to
higher value in the spectra of the complexes).
The electronic spectra of the complexes showed the
intraligand bands in the 277−292 and 348−402 nm ranges,
corresponding to the n → π* and π → π* transitions,
respectively. These spectra also exhibit a strong absorption
band at 509−521 nm. These absorption bands can be assigned
to S → M charge-transfer bands. The presence of an S → M
(LMCT) band in the electronic spectra of these complexes
further supports bonding of the ligand to the Pt(II) ion via a
sulfur atom. As shown by crystal structure analyses, the
complex 2 is monomeric and has a square-planar structure
around platinum, while 1 is tetrameric. Two-dimensional
chemical formulas of the complexes 1 and 2, as confirmed by
X-ray structure analysis, are shown in Scheme 1. The
platinum(II) ion having a 4d8 electronic configuration is
expected to exhibit three bands in a square-planar environment,
Figure 2. E and Z isomeric forms of the synthesized Schiff base: (A) E-
form; (B) Z-form.
solution, the related N heterocyclic NNS thiosemicarbazones
have been shown to exist as a mixture of E and Z isomers,23 and
it was possible to assign the correct configuration to the
24
1
1
1
1
corresponding to the transitions A1g → A2g,1A1g → B1g, and
different products using H NMR spectroscopy. The most
sensitive signal that has been used to distinguish between the E
and Z isomers is that belonging to the NH group. Compounds
possessing the Z isomer generally exhibit the NH signal in the
14−15 ppm range, whereas those having an E form exhibit the
signal in the 9−12 ppm range. The presence of a signal at 9.49
ppm due to the NH proton and the absence of any signal at
14−15 ppm in the 1H NMR spectra of the present Schiff base is
strong evidence for only the E isomer in DMSO.
1A1g 1Eg.27 However, the electronic spectra of Pt(II)
→
complexes are complicated due to the presence of S and N
donor atoms in the ligands since the tails of the strong S → M
(LMCT) bands may extend up to the visible portion of the
spectrum, thereby masking the expected d−d bands.
Therefore, the electronic spectra of the present complexes
are of little help in assigning a definitive structure to these
1
complexes. However, based on IR and H and 13C NMR
Although the Schiff base remains in the thione forms both in
the solid state and in solution, it, nonetheless, undergoes a rapid
conversion to the thiol forms in the presence of Pt(II) salt. This
conversion is concomitant with the formation of its Pt(II)
complexes, which have the empirical formulas ML2 and MnLn
(L = deprotonated forms of the Schiff base). The related
tridentate NNS thiosemicarbazones derived from heterocyclic
carbonyls have been shown to coordinate to metal ions in both
the protonated thione and deprotonated thiolate25 forms.
There are also interesting examples of metal−thiosemicarba-
zone complexes in which both the protonated thione and
deprotonated thiolate forms of the ligand are present in the
same complex.26
The IR spectra of the synthesized complexes 1 and 2 do not
contain a sharp μ NH band of the free ligand, indicating that
the proton on the imine nitrogen atom of the ligand is lost
during coordination with the metal ion or is involved in
hydrogen bridging, giving a broad undissolved signal. The IR
spectral data containing the relevant vibrational bands of the
ligand and its platinum(II) complexes are given in Table 1. The
data support coordination of the ligands via the azomethine
results, a square-planar structure may be tentatively assigned to
these complexes.
1
The H and 13C NMR spectral data of the Schiff base,
together with assignments of relevant signals, are compiled in
Tables 2 and 3. The assignments are based on those made
previously for structurally related compounds.25 An examina-
tion of the NMR data shows that the spectra of the complexes 1
and 2 do not contain the NH proton signals of the free ligand,
lending further support to the IR results that the Schiff base
might be coordinated to the metal ion in its deprotonated
mercaptide form. As may be seen from the X-ray diffraction
results below, this is clearly the case for 1, whereas in
compound 2, at least in the solid state, the N−H bond is still
present being engaged in a hydrogen bridge. A comparison of
the 1H NMR spectral data for the platinum(II) complexes with
those of the free ligand (Table 2) reveals the following points:
(1) The peaks at 9.49 ppm due to the imino proton in the free
ligand disappeared after complexation, indicating that the ligand
in 1 is deprotonated and coordinated with the metal ion
through the mercaptide sulfur ion. For the bonding in 2, the
solution spectrum does not correspond to the solid state, which
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Scheme 1
1
Table 2. H NMR Spectra for the Schiff Base (ATTSC) and
thiolate sulfur atom, and a carbene species created by
abstraction of a hydrogen atom of the β-carbon atom, in the
thiophene part of the ligand. It should be mentioned here that
ATTSC ligands may be metalated at the β-C carbon atom if the
aromatic ring leads to a chelate coordination via C, N, and S. As
may be seen from the X-ray structural analyses (see below), this
is indeed the case here in compound 1 and partly in compound
2, as the two ligands are either singly negatively charged or
neutral.
Structural Data. Structure of Pt4(ATTSC-2H)4·4DMF
(1).28 As result of the X-ray structure determination on single
crystals of 1,28 the molecular part of 1 (omitting DMF) is
shown in Figure 3. The ATTSC had reacted with K2PtCl4 in
Its Pt(II) Complexes
δ of
(NH2)
ppm
δ of NH δ of CH3− δ of ring
compound
ppm
9.49
C ppm
1.62
1.08
3H ppm
ATTSC
7.44, 6.71
7.44
6.19, 6.69
7.35, 7.36
Pt4(ATTSC-2H)4·4DMF
(1)
Pt(ATTSC)(ATTSC-1H) 7.52, 7.54
Cl·3CH3OH (2)
2.33, 1.07 7.46, 7.48
Table 3. 13C NMR Spectra for the Schiff Base (ATTSC) and
Its Pt(II) Complexes 1 and 2
δ of
δ of ring (C4H3S
compound
ATTSC
CH3C
ring) 3C
δ of CN
δ of CS
178.95
15.17
13.98
128.16−143.27
128. 99−159.28
145.32
163.87
Pt4(ATTSC-
2H)4·4DMF
(1)
172.56
Pt(ATTSC)
(ATTSC-1H)
Cl·3CH3OH
(2)
14.72
128.16−159.05
163.77
172.36/1.72
(broad)
might indicate that the structures are different. (2) The signal
due to the azomethine CH3 proton in the spectra of the free
ligand undergoes a downfield shift in the spectra of the
complexes, indicating that coordination occurs via the
azomethine nitrogen atom.
Because of the conversion of the ligand from the thione to
the thiol form and consequent deprotonation during
coordination in 1, shielding of the CS carbon atom causes an
upfield shifting of the signal due to the CS carbon atom in the
13C NMR spectra of the complexes relative to those in the free
ligand. This observation is commensurate with coordination of
the ligands via one of the sulfur atoms to the Pt(II) ion. The
spectral data for 2 are similar as well as different, the most
remarkable feature being the two signals for the CH3 group in
Figure 3. Stereographic representation of part of the structure of
Pt4(ATTSC-2H)4 (1). The ellipsoids of atoms are represented at the
50% level. The coordinating diethylformanide (DMF) molecules are
omitted for clarity.
1:1 ratio, eliminating 2KCl and 2HCl. The molecule is
tetrameric with four platinum atoms, each metal atom
displaying almost square-planar geometry and being coordi-
nated by the dianion of ATTSC (ATTSC-2H) through sulfur,
nitrogen, and a carbene (thiophene ring). The fourth
coordination site at each platinum atom is occupied by a sulfur
atom of a neighboring ligand. As each of the ATTSC-2H
ligands has two negative charges, the oxidation number of the
platinum atoms is +2. The sulfur interaction by an adjacent
ligand leads to an eight-membered puckered central ring of
1
the H and 13C NMR. As found by X-ray diffraction, the
splitting of the CH3 signal in 2 is explained by two different
ligands, one being charged −1 and tridentate, while the other is
neutral and monodentate. The signal due to the carbon atoms
of the azomethine (CN) also shows downfield shifts, lending
1
further support to the IR and H NMR evidence presented
before. This coordination of the ligand to the platinum ion in 1
and partly in 2 occurs via the azomethine nitrogen atom, the
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Figure 4. Representation of the hydrogen-bridged one-dimensional alignment of cluster molecules 1 in the crystal. For better viewing, the DMF
molecules are represented as wire models.
alternating Pt and S atoms. The molecule in the crystal has no
higher symmetry, but, in an approximation, this molecular
cluster does not deviate much from S4-symmetry. Furthermore,
in the crystal, two chiral and enantiomeric forms are present,
which are related by an inversion center of the space group
ones (Pt(1)−Pt(2) 3.444(1) and Pt(3)−Pt(4) 3.364(1) Å) and
four longer ones, with a mean value of 3.78(6) Å. Apparently,
the parallel orientation of chelates with Pt(1) and Pt(2) and
also Pt(3) and Pt(4) could give some platinum−platinum
electronic interaction. Within the chelate rings one observes a
lengthening of the C−S bonds in proximity to platinum (mean
value: 1.793(7) Å) and a shortening of the neighboring N−C
bond (mean value: 1.314(9) Å), compared to the free ligand, in
accordance with the fact that in the chelate C−S is almost a
single bond and C−N has almost a double-bond character.21
Structure of Pt(ATTSC)(ATTSC-H)Cl·3CH3OH (2).29 Using
two molar ratios of thiosemicarbazone (ATTSC) with respect
to K2PtCl4 results in the formation of complex 2, which has two
ATTSC molecules coordinated to platinum. Interestingly, only
one of the chlorides is replaced by the monoanion (ATTSC-H)
and the second ATTSC ligand coordinates in its neutral form.
The compound can be described as the ion pair [Pt(ATTSC)-
(ATTSC-H)]+ with Cl− as counterion and with three methanol
molecules serving as links between the chloride anion and the
platinum formal cationic moiety (Figure 5). The ATTSC-H
(P1).
̅
The crystal structure of 1 is dominated by the interaction of
Pt4(ATTSC-2H)4 with four dimethylformamide (DMF)
molecules, resulting in a hydrogen-bridged superstructure. In
the form of pairs always two of the four DMF molecules
through their oxygen atoms are participating in double N−
H···O bridges (N···O ranging from 2.912(9) to 3.004(9) Å),
thus creating a one-dimensional hydrogen-bridged aggregate. A
view of this superstructure is shown in Figure 4.
As stated above, the platinum atoms are in a distorted square-
planar environment (d8 configuration) with mean Pt−C and
Pt−N distances of 2.006(6) and 2.010(4) Å (Table 4). The
Table 4. Selected Bond Lengths of “Heavy Atoms” within
[Pt4(ATTSC-2H)4] (1)
bond
length [Å]
bond
length [Å]
Pt(1)−C(5)
Pt(1)−N(2)
Pt(1)−S(5)
Pt(1)−S(1)
Pt(2)−C(12)
Pt(2)−N(5)
Pt(2)−S(7)
Pt(2)−S(3)
Pt(3)−N(8)
Pt(3)−C(19)
Pt(3)−S(3)
Pt(3)−S(5)
Pt(4)−C(26)
Pt(4)−N(11)
2.006(9)
2.014(9)
2.302(4)
2.353(4)
2.010(9)
2.016(9)
2.307(4)
2.351(4)
1.997(9)
2.013(9)
2.306(4)
2.346(4)
1.995(9)
2.014(9)
Pt(4)−S(1)
Pt(4)−S(7)
S(1)−C(6)
S(2)−C(3)
S(2)−C(2)
S(3)−C(13)
S(4)−C(10)
S(4)−C(9)
S(5)−C(20)
S(6)−C(17)
S(6)−C(16)
S(7)−C(27)
S(8)−C(24)
S(8)−C(23)
2.289(4)
2.334(4)
1.81(2)
1.70(2)
1.72(2)
1.79(2)
1.73(2)
1.75(2)
1.77(2)
1.70(2)
1.74(2)
1.80(2)
1.70(2)
1.75(2)
platinum−sulfur distances vary with their bonding: those that
belong to the five-membered Pt−N−N−S−C cycle have mean
values of 2.346(8) Å, whereas those that are created by the
interaction of a second ligand are shorter, with mean values of
2.301(5) Å. This difference may be attributed to the acute bite
angles of the chelates with N−Pt−S mean values of 82.8(4)°,
which is due to the fact that each platinum atom is a member of
two fused five-membered rings (Pt−C−C−C−N and Pt−N−
N−C−S). As two of the four chelates are oriented in parallel,
the six intramolecular Pt−Pt distances can be divided into short
Figure 5. Part of the crystal structure of Pt(ATTSC-1H)(ATTSC)-
Cl·3CH3OH (2).
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ligand is singly negatively charged, has a hydrogen atom
bonded to one of the hydrazine atoms (N(2)), and bonds to
platinum very similarly to the ATTSC-2H ligands in compound
1 in a chelate fashion through the ring carbene, nitrogen, and
sulfur. The fourth coordination place at the distorted square-
planar platinum atom is occupied by sulfur of a neutral ATTSC
ligand. The chloride anion in the crystal structure is bonded
through hydrogen bridges to the three methanol molecules and
to two nitrogen atoms of the N(2)−C(6)−N(3) part of the
chelating ATTSC-H ligand. All hydrogen atoms at the oxygen
atoms of the methanol molecules and at the nitrogen atoms of
ATTSC and ATTSC-H are involved in hydrogen bridges
(mean values: Cl···O[Cl···H−O] 3.19(2), Cl···N[Cl···H−N]
3.20(2), O···N[O···H−N] 2.83(1), N(5)···S(1) [N···H−S]
3.313(9) Å); by simple geometrical calculations, the positions
of the hydrogen atoms can thus be calculated, without relying
on the diffraction data, with good precision.
The most remarkable differences between the platinum
bonding in 1 and 2 are the following: because of the lesser
steric constraint in 2, the S(3)−Pt(1) bond (2.264(2) Å) is
0.037 Å shorter than the comparable bond in 1. The longer
Pt(1)−S(1) bond in 2 (2.366(2) versus the mean Pt−S
distance in the chelate 2.346(8) Å in 1) seems to relate to the
different nature of sulfur, which is sulfidic in 1, while it is
engaged in a CS double bond in 2 (C(6)−S(1) = 1.712(9)
Å). Interestingly, the C−Pt and N−Pt bonds in 1 and 2 are
almost the same, which is in line with the similar chemical
bonding (in 1: Pt−C = 2.006(6), Pt−N 2.010(4) Å, in 2:
Pt(1)−C(5) 2.015(8), Pt(1)−N(1) = 2.016(7) Å).
Table 6. IC50 (μM) Values for the Tested Ligand and
Complexes against Two Different Human Cancerous Cell
Lines
IC50% (μM)
compound
HT-29
HuTu-80
HATTSC
8.6
3.0
1.5
>10.0
5.9
Pt(ATTSC)2
Pt4(ATTSC)4
1.2
may be related to the intercalation of the metal complex
between nitrogen bases of the DNA tumor cells, causing greater
conformational changes in the double helix of DNA and then
producing cell death.28 On the other hand, these results also
show that the synthesized ligand and complexes have more
effectiveness against HT-29 cancerous cell line in comparison
to the HuTu-80 cell lines in the concentration range used
(0.1−10 μM) and are thus more effective in comparison to
cisplatin. Here the IC50 has been shown to be 11.9 μM for the
HT29 cells.31
CONCLUSIONS
■
New potential anticancer Pt(II) complexes were synthesized
through the reaction of a heterocyclic thiosemicarbazone ligand
with Pt(II) ion in 1:1 and 1:2 molar ratios.
The structures of the synthesized compounds were
elucidated on the basis of spectroscopic and diffraction data
1
(IR, H and 13C NMR, UV−vis, and XRD).
As the experimental results show, the used Schiff base reacts
with Pt(II) ions in different modes of bonding. In one case, the
ligand is twice deprotonated at the β-C carbon atom of the
thiophene ring and at the sulfur atom, forming a dinegative
tridentate chelate around platinum. By intermolecular coordi-
nation, a planar C, N, S2-configuration around platinum atoms
is obtained, resulting in a tetranuclear cluster. In the other case,
a mononuclear complex of platinum is obtained with two
different Schiff base ligands (one is neutral bonding through
sulfur, the other is single negative bonding through carbon,
nitrogen, and sulfur).
All ligands and complexes tested show a concentration-
dependent reduction of cell proliferation. The test results show
that the change of the ligand metal ratio has significant effects
on the antiproliferative activities of the platinum(II) complexes.
In general, it was found that complexes were more active than
the corresponding metal-free ligand. The complex with the
general formula Pt4L4 was found to be slightly more active than
the complexes with formula PtL2 against HT-29 and HuTu
cancer cell line.
Biological Activity. The preliminary investigation for the
anticancer activity of ATTSC using two different human tumor
cell lines (HT-29 and HuTu-80) shows that the ligand ATTSC
alone has a 50% inhibitory concentration (IC50) > 10.0 μM
against these human tumor cell lines (Table 6). The
Table 5. Selected Bond Lengths within
[Pt(ATTSC)(ATTSC-H)Cl] (2)
bond
length [Å]
bond
length [Å]
Pt(1)−C(5)
Pt(1)−N(1)
Pt(1)−S(3)
Pt(1)−S(1)
S(1)−C(6)
S(2)−C(3)
S(2)−C(2)
N(1)−C(1)
N(2)−C(6)
N(3)−C(6)
C(1)−C(2)
C(1)−C(7)
C(2)−C(5)
C(3)−C(4)
2.015(8)
2.016(7)
2.264(2)
2.366(2)
1.712(9)
1.702(9)
1.726(9)
1.30(1)
1.34(1)
1.34(1)
1.40(1)
1.49(1)
1.42(1)
1.34(1)
C(4)−C(5)
S(3)−C(13)
S(4)−C(10)
S(4)−C(9)
1.44(1)
1.720(9)
1.709(9)
1.735(9)
1.29(1)
1.38(1)
1.34(1)
1.32(1)
1.45(1)
1.49(1)
1.38(1)
1.33(1)
1.41(1)
1.44(1)
N(4)−C(8)
N(4)−N(5)
N(5)−C(13)
N(6)−C(13)
C(8)−C(9)
C(8)−C(14)
C(9)−C(12)
C(10)−C(11)
C(11)−C(12)
C(4)−C(5)
ASSOCIATED CONTENT
■
S
* Supporting Information
CIF files giving crystallographic data for compounds 1 and 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
synthesized complexes 1 and 2 exhibit stronger cytotoxicity
in comparison to the ligand. These results reveal that the
cytotoxic activity increases considerably when ligands are
coordinated to the metal ion.30 The tetranuclear Pt(II) complex
with formula Pt4(L)4 shows the highest cytotoxicity among the
three compounds against the two tested human tumor cell
lines. These results indicate that the cytotoxic activity is
enhanced when four ligands are coordinated to four platinum
atoms. Probably, the high cytotoxicity of the Pt4(L)4 complex
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Michael.veith@inm-gmbh.de.
Notes
The authors declare no competing financial interest.
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Organometallics
Article
2748.1(7) Å3; Z: 2; density (calcd): 2.250 Mg/m3; absorption
coefficient: 10.509 mm−1; F(000): 1760; crystal size: 0.13 × 0.04 ×
0.03 mm3; theta range for data collection: 1.70 to 21.67°; index ranges:
−10 ≤ h ≤ 9, −12 ≤ k ≤ 12, −25 ≤ l ≤ 24; reflections collected:
25874; independent reflections: 6299 [R(int) = 0.1068]; completeness
to theta = 21.67°: 97.4%; absorption correction: multiscan; max. and
min. transmission: 0.7791 and 0.3487; refinement method: full-matrix
least-squares on F2; data/restraints/parameters: 6299/0/661; good-
ness-of-fit on F2: 1.034; final R indices [I > 2σ(I)]: R1 = 0.0433, wR2
= 0.0947; R indices (all data): R1 = 0.0687, wR2 = 0.1055; largest diff
peak and hole: 1.504 and −1.151 e·Å−3.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by DAAD. The
experimental part of this work was performed at INM−Leibniz
Institute for New Materials and at the Institute of Inorganic
Chemistry, Saarbruecken/Germany. A.A.A. would like to thank
Prof. Yosif Sulfab, Hameed Ullah Wazir, and Siddieg Elsiddieg
for kind discussions.
REFERENCES
■
(1) Kovala-Demertzi, D.; Boccarelli, A.; Demertzis, M. A.; Coluccia,
M. Chemotherapy 2007, 53, 148.
(2) Kovala-Demertzi, D.; Varadinova, T.; Genova, P.; Souza, P.;
Demertzis, M. A. Bioinorg. Chem. Appl. 2007, 56165.
(3) Scovill, J. P.; Klayman, D. L.; Franchino, C. F. J. Med. Chem.
1982, 25, 1261.
(29) Crystal data for Pt(ATTSC)(ATTSC-H)Cl·3CH3OH], 2:
Empirical formula: C17H29Cl7N6O3PtS4; formula weight: 715.17;
temperature: 222(2) K; wavelength: 0.71073 Å; crystal system and
space group: triclinic (P1); unit cell dimensions: a = 7.701(1) Å, b =
̅
12.887(2) Å, c = 15.119(3) Å, α = 70.480(8)°, β = 75.639(9)°, γ =
75.383(9)°; V: 1346.3(4) Å3; Z: 2; density (calcd): 1.764 Mg/m3;
absorption coefficient: 5.649 mm−1; F(000): 694; crystal size: 0.863 ×
0.39 × 0.07 mm3; theta range for data collection: 1.45 to 31.68°; index
ranges: −11 ≤ h ≤ 11, −18 ≤ k ≤ 17, −22 ≤ l ≤ 22; reflections
collected: 28 946; independent reflections: 8866 [R(int) = 0.0775];
completeness to theta = 21.67°: 97.4%; absorption correction:
multiscan; refinement method: full-matrix least-squares on F2; data/
restraints/parameters: 8866/0/264; goodness-of-fit on F2: 1.732; final
R indices [I > 2σ(I)]: R1 = 0.0748, wR2 = 0.1976; R indices (all data):
R1 = 0.0839, wR2 = 0.2017; largest diff peak and hole: 7.181 and
−4.070 e·Å−3.
(4) Quiroga, A. G.; Per
́ ́
ez, J. M.; Lopez-Solera, I.; Masaguer, J. R.;
Luque, A.; Roman, P.; Edwards, A.; Alonso, C.; Navarro-Ranninger, C.
́
J. Med. Chem. 1998, 41, 1399.
(5) Costa, R. F. F.; Rebolledo, A. P.; Matencio, T.; Calado, H. D. R.;
Ardisson, J. D.; Cortes
Chem. 2005, 58, 1307.
́
, M. E.; Rodrigues, B. L.; Beralso, H. J. Coord.
(6) Agarwal, R. K.; Singh, L.; Sharma, D. K. Bioinorg. Chem. Appl.
2006, 59509.
(7) Pandey, O. P.; Sengupta, S. K.; Mishra, M. K.; Tripathi, C. M.
Bioinorg. Chem. Appl. 2003, 1, 35.
(8) Shipman, C. Jr.; Smith, S. H.; Drach, J. C.; Klayman, D. L.
Antiviral Res. 1986, 6, 197.
(9) Basuli, I.; Pal, F.; Bhattacharya, S. Proc. Indian Acad. Sci.: Chem.
Sci. 2002, 114, 255.
(10) Bakkar, M. S.; Yamin, S. M.; Monshi, M. S. Synth. React. Inorg.,
Met.-Org., Nano-Met. Chem. 2003, 33, 1157.
(11) El-Shazly, R. M.; Al-Hazmi, G. A. A.; Ghazy, S. E.; El- Shahawi,
M. S.; El-Asmy, A. A. J. Coord. Chem. 2006, 59, 845.
(12) Kovala, D.; Miller, J. R.; Koukoumelis, N.; Hadjikakou, S. K.;
Demetzis, M. A. Polyhedron 1999, 18, 1005.
(30) Wilfredo, H.; Paz, J.; Vaisberg, A.; Sodine, E.; Richter, R.; Beyer,
L. Bioinorg. Chem. Appl. 2008, Article ID 690952, DOI: 10.1155/
2008/690952.
(31) Lovejoy, K. S.; Serova, M.; Bieche, I.; Emami, S.; D’Incalci, M.;
Broggini, M.; Erba, E.; Gespach, C.; Cvitkovic, E.; Faivre, S.; Raymond,
E.; Lippard, S. J. Mol. Cancer Ther. 2011, 10, 1709.
(13) Kovala, D.; Domopoulou, A.; Demetzis, M. A.; Papageorgiou,
A.; West, D. X. Polyhedron 1997, 16, 3625.
(14) Kovala, D.; Yadav, P. N.; Demetzis, M. A.; Coluccia, M. J. Inorg.
Biochem. 2000, 78, 347.
(15) Quiroga, A. G.; Perez, J. M.; Montero, E. I.; Masaguer, J. R.;
Alonso, C.; Navarro, C. J. Inorg. Biochem. 1998, 70, 117.
(16) Quiroga, A. G.; Perez, J. M.; Lopez, S. I.; Montero, E. I.;
Masaguer, J. R.; Alonso, C.; Navarro, C. J. Inorg. Biochem. 1998, 69,
275.
(17) Fillastre, J. P.; Ranguenez, V. Toxicol. Lett. 1989, 46, 163.
(18) Noji, M.; Kizu, R.; Takeda, Y.; Akiyama, N.; Yoshikazi, I.;
Eriguchi, M.; Kidani, Y. Biomed. Pharmacother. 2005, 59, 224.
́
(19) Matesanz, A.; Perez, J. M.; Navarro, P.; Moreno, J. M.; Colacio,
E.; Souza, P. J. Inorg. Biochem. 1999, 76, 29.
(20) Kelland, L. R. Crit. Rev. Oncol. Hematol. 1993, 15, 191.
(21) De Lima, G. M.; Neto, J. L.; Beraldo, H.; Seibald, H. G. L;
Duncalf, D. J. J. Mol. Struct. 2001, 604, 287.
(22) Mohammad, A.; Mahbub, S. M.; Ray, J.; Jerry, P.; John, M.
Polyhedron 1997, 16, 2749.
(23) West, D. X.; Scovill, J. P.; Silverton, J.; Bareso, A. Transition Met.
Chem. 1986, 11, 123.
(24) Koch, K. R. J. Coord. Chem. 1991, 22, 289.
(25) Tarlok, S. L.; Rekha, S.; Gagandeep, B.; Sonia, K. Coord. Chem.
Rev. 2009, 253, 977.
(26) Souza, P.; Matesanz, A. I.; Fernandez, V. J. Chem. Soc., Dalton
Trans. 1996, 3011.
(27) Lever, A. B. P. Inorganic Electronic Spectroscopy; Elsevier:
NewYork, 1984.
(28) Crystal data for [Pt4(ATTSC-2H)4·4DMF], 1: Empirical
formula: C40H56N16O4Pt4S8; formula weight: 1861.85; temperature:
134(2) K; wavelength: 0.71073 Å; crystal system and space group:
triclinic (P1); unit cell dimensions: a = 9.785(1) Å, b = 11.775(2) Å, c
̅
= 24.179(4) Å, α = 96.994(6)°, β = 94.403(7)°, γ = 94.925(6)°; V:
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