Organotin complexes of pyruvic acid thiosemicarbazone: Synthesis, crystal structures and antiproliferative activity of neutral and cationic diorganotin complexes

Article abstract of DOI:10.1016/j.poly.2009.05.012

The synthesis and spectral characterization of novel neutral and cationic organotin complexes with pyruvic acid thiosemicarbazone, H₂pt (1), [SnPh₂(pt)] (2), [SnMe₂(Hpt)(H₂O)]Cl (3) and [SnPh₂(Hpt)(H<

Full text of DOI:10.1016/j.poly.2009.05.012

Polyhedron 28 (2009) 3298–3304
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Organotin complexes of pyruvic acid thiosemicarbazone: Synthesis, crystal
structures and antiproliferative activity of neutral and cationic diorganotin
complexes
Joanna Wiecek a, Vaso Dokorou a, Zbigniew Ciunik b, Dimitra Kovala-Demertzi a,
*
a Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45100 Ioannina, Greece
b Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie Street, 50-383 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 13 May 2009
The synthesis and spectral characterization of novel neutral and cationic organotin complexes with pyru-
vic acid thiosemicarbazone, H2pt (1), [SnPh2(pt)] (2), [SnMe2(Hpt)(H2O)]Cl (3) and [SnPh2(Hpt)(H2O)]Cl (4)
are reported. The crystal structure of the complexes [SnPh2(pt)] (2) and [SnMe2(Hpt)(H2O)]Cl (3) have been
solved by single-crystal X-ray diffraction. The crystal structure of complex 2 showed that the ligand is
doubly deprotonated at the oxygen and amide nitrogen atoms and is coordinated to the SnPh2 fragment
via two five-membered chelate rings. The monomers of 2 are linked through intermolecular hydrogen
This paper is dedicated to Dr. Aris Terzis for
his contribution to the advancement of
Inorganic Chemistry in Greece through
X-ray crystallography.
bonds of CÀH–O type and through
pÀp intermolecular interactions. The crystal structure of
[SnMe2(Hpt)(H2O)]Cl (3) showed that the ligand is mono-deprotonated at the oxygen atom and is coordi-
nated to the SnMe2 fragment via two five-membered chelate rings. The counter ion chloride is participated
in intermolecular hydrogen bonds. An extended network of intermolecular hydrogen bonds leads to aggre-
gation and a supramolecular assembly. The IR and NMR spectroscopic data of the complexes are reported.
The in vitro cytotoxic activity has been evaluated against the cells of three human cancer cell lines: MCF-7
(human breast cancer cell line), T-24 (bladder cancer cell line), A-549(non-small cell lung carcinoma) and a
mouse L-929 (a fibroblast-like cell line cloned from strain L). The most active of all was found the diorga-
notin complex 2. The cytotoxic activity shown by these compounds against all these cancer cell lines indi-
cates that coupling of 1 with R2Sn(IV) metal center result in metallic complexes with important biological
Keywords:
Diorganotin
Thiosemicarbazonato metal complexes
Cationic and neutral complexes, crystal
structure
Spectroscopic studies
Antineoplastic activity
properties and remarkable cytotoxic activity, since they are display IC50 values in a lM range the same or
better to that of the antitumor drug cisplatin. Compound 2 is considered as agent with potential antitumor
activity, and can therefore be candidate for further stages of screening in vitro and/or in vivo.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
have been carried out to test their anti-tumor activity and it has
been observed that indeed several diorganotin adducts show po-
Thiosemicarbazone derivatives are of considerable interest due
to their antibacterial, antimalarial, antiviral and antitumor activity
[1,2]. In our laboratory, the chemistry of thiosemicarbazones has
been an extremely active area of research, primarily because of
the beneficial biological (viz., antiviral and antitumor) activities
of their transition-metal complexes [3–5]. The coordination chem-
istry of H2pt has been studied to some extend; the reports include
monomers, dimers and trimers [6].
Organotin(IV) compounds form an important series of com-
pounds and have been receiving increasing attention in recent
years. Some examples find wide applications as catalysts and sta-
bilizers, and certain derivatives are used as biocides, as antifouling
agents and for wood preservation. In recent years, investigations
tential as antineoplastic and antituberculosis agents [7,8].
The present paper includes the interaction of SnPh2O and
SnR2Cl2 (where R is methyl and phenyl groups) with pyruvic acid
thiosemicarbazone (H2pt) and the crystal structure of the com-
plexes [SnPh2(pt)] (2) and [SnMe2(Hpt)(H2O)]Cl (3). IR and NMR
spectroscopic data are reported. The results of the cytotoxic activ-
ity of diorganotin complexes have been evaluated for antiprolifer-
ative activity in vitro against cancer cell lines: MCF-7, T-24, A-549
and a mouse L-929.
2. Experimental
2.1. General and instrumental
All reagents were commercially available (Aldrich or Merck)
and used as supplied. Solvents were purified and dried according
* Corresponding author. Tel.: +30 2651098425; fax: +30 2651098786.
E-mail address: dkovala@cc.uoi.gr (D. Kovala-Demertzi).
0277-5387/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2009.05.012

J. Wiecek et al. / Polyhedron 28 (2009) 3298–3304
3299
to standard procedures. Melting points (m.p.) were determined in
open capillaries and are uncorrected. IR and far-IR spectra were re-
corded on a Perkin–Elmer Spectrum GX Fourier transform spectro-
photometer using KBr pellets (4000–400 cmÀ1) and nujol mulls
dispersed between polyethylene disks (400–40 cmÀ1). NVR spectra
were recorded on a Bruker AV-400 spectrometer operating at 400
and 100 MHz for 1H and 13C acquisition, respectively, or on a Bru-
ker AV-250 spectrometer operating at 250.13 and 62.90 MHz for
1H and 13C acquisition, respectively. The spectra were acquired at
room temperature (298 K). The chemical shifts are reported in
ppm for 1H and 13C NMR). Samples were dissolved in dimethylsulf-
oxide-d6 and spectra were obtained at room temperature with the
signal of free dimethylsulfoxide-d6 (at 2.50 ppm 1H NMR,
39.5 ppm 13C NMR) as a reference. Elemental analyses were carried
out by the microanalytical service of the University of Ioannina,
Greece.
2.1.4. Preparation of [Ph2Sn(Hpt)(H2O)]Cl (4)
Pyruvic thiosemicarbazone hemihydrate (0.04 g, 0.24 mmole)
and equimolar quantity of KOH in methanol (10 ml) were mixed
and diphenyltin(IV) dichloride (0.0825 g, 0.24 mmole) was added.
The reaction mixture was stirred for 2 h. The resulting clear solu-
tion evaporated and triturated with distilled diethyl ether to give
a pale white solid. The pale white powder was recrystallized from
distilled diethyl ether and dried in vacuo over silica gel. Yield: 46%.
M.p. 124–126 °C. IR (cmÀ1): 3409 m,
m
(H2O; 3299s,
sym(COO); 1066s,
(Sn–O);
m
(NY2);
1597 m,
N); 766 m,
397 m,
v
(C@N); 1618s,
m
as(COO); 1391,
m
v(N–
v
(C@S); 340 m,
v
(Sn–C); 329 m, 315sh,
v
m
(Sn–S); 279 m,, v
(Sn–N). 1H NMR (DMSO): d 12.03 (s, 1H,
H2O); 10.65 (s, 1H, NH); 8.68 (d, 2H, NH2, J(H)–(H) = 20.9); 8.18 (m,
Ho-Ph); 7.87 (m, Hp-Ph); 7.61 (m, Hm-Ph); 2.22 (s, 3H, Me); 13C
NMR: d 207.4, 180.7, 175.2 (C@S); 165.7, 164.6 (C@O); 148.9 (Co-
Ph); 146.2 (Cm-Ph); 139.5 (Cp-Ph); 129.5 (C–CH3); 15.2 (Me). Anal.
Calc. for C16H18N3O3SSnCl (Vw: 486.5): C, 39.5; H, 3.7; N, 8.6; S,
6.6. Found: C, 39.1; H, 3.5; N, 8.4; S, 6.4%.
2.1.1. Preparation of pyruvic acid thiosemicarbazone hemihydrate
(H2pt.1/2H2O) (1)
The ligand was synthesized according to a published procedure
[6d]. The white powder was recrystallized from diethyl ether and
was dried in vacuo over silica gel. Yield: 85%. V.p. 188–190 °C. IR
2.2. X-ray crystallography
X-ray data for 2 and 3 were collected at low temperature using
an Oxford Cryosystem device on a Kuma KM4CCD -axis diffrac-
tometer with graphite-monochromated Mo Ka radiation
(cmÀ1) [6d]: 3431 m,
1733s, 1702 m,
m
(H2O); 3294 m,
m
(NY2); 1626s,
v
(C@N);
j
v
(C@O), 1046 m, (NAN); 859 m,
v
v
(C@S). 1H NMR
(DMSO): d 12.10 (s, 1H, OH); 10.74 (s, 1H, NH); 8.67 (d, 2H, NH2,
JH–H = 16.8); 2.11 (s, 3H, Me); 13C NMR: d 180.3 (C@S); 165.3
(C@O); 139.1 (CACH3); 12.6 (Me). Anal. Calc. for C4H7N3O2S.1/
2Y2J (Mw: 170.2): C, 28.2; H, 4.7; N, 24.7, S, 18.8. Found: C,
28.0; H, 4.8; N, 24.5; S, 18.9%.
(k = 0.71073 Å). Crystals were positioned at 65 mm from the CCD
camera. Six hundred and twelve frames were measured at 0.75°
intervals with a counting time of 10–20 s. Accurate cell parameters
were determined and refined by least-squares fit of 11 200 and
12 000 the strongest reflections for 1 and 2, respectively. The data
were corrected for Lorentz and polarization effects. Analytical
absorption correction was applied for both crystals. Data reduction
and analysis were carried out with the Oxford Diffraction (Poland)
Sp. z o.o programs [9]. Crystal structures were solved by direct
methods (program SHELXS97 [9a]) and refined by the full-matrix
least-squares method on all F2 data using the SHELXL97 [9b] pro-
grams. Non-hydrogen atoms were refined with anisotropic dis-
placement parameters; hydrogen atoms were included from
2.1.2. Preparation of [Ph2Sn(pt)] (2)
Diphenyltin(IV) oxide (0.0867 g, 0.3 mmole) and pyruvic acid
thiosemicarbazone hemihydrate (H2pt) (0.0511 g, 0.3 mmole) in
benzene (20 ml) were refluxed overnight under azeotropic removal
of water (Dean-Stark trap). The resulting clear solution was rotary
evaporated under vacuum to a small volume (2 ml), chilled and
triturated with diethyl ether to give a white solid. The white pow-
der was recrystallized from diethyl ether and dried in vacuo over
geometry of molecules and
Dq maps. During the refinement pro-
silica gel. Yield: 15%. M.p. 196–198 °C. IR (cmÀ1): 3285s,
1610, 1593 m, (C@N); 1667s, as(COO); 1431s, sym(COO);
1070 m, (N–N); 766 ms, (C@S); 333 m, (Sn–C); 310 m, (Sn–
O); 396 m, (Sn–S); 278 m,
(Sn–N). 1H NMR (DMSO): d 8.28 (s,
m(NY2);
cess they treated as riding atoms [9a–d]. Crystal data are given in
Table 1, together with refinement details.
v
m
m
v
v
v
v
m
v
2.3. Antiproliferative assay in vitro
2H, NH2); 7.67 (Ho-Ph); 7.45–7.40 (m, Hm, p-Ph); 2.30 (s, 3H,
Me); 13C NMR: d 175.2 (C@S); 164.6 (C@O); 148.9 (Co-Ph); 146.0
(Cm-Ph); 135.9 (Cp-Ph); 129.5 (C–CH3); 15.2 (CH3). Anal. Calc. for
C16H15N3O2SSn (Vw: 432.1): C, 44.5; H, 3.5; N, 9.7; S, 7.4. Found:
C, 44.2; H, 3.7; N, 9.4, S, 7.5%.
2.3.1. Compounds
Test solutions of the compounds tested (1 mg/ml) were pre-
pared by dissolving the substance in 100
with 900 l of tissue culture medium. Afterwards, the tested com-
pounds were diluted in culture medium to reach the final concen-
trations of 100, 50, 10, 1 and 0.1 ng/ l. The solvent (DMSO) in the
ll of DMSO completed
l
2.1.3. Preparation of [SnMe2(Hpt)(H2O)]Cl (3)
l
Pyruvic thiosemicarbazone hemihydrate (0.04 g, 0.24 mmole)
and equimolar quantity of KOH in methanol (10 ml) were mixed
and dimethyltin(IV) dichloride (0.053 g, 0.24 mmole) was added.
The reaction mixture was stirred for 2 h. The resulting clear solu-
tion evaporated and triturated with distilled diethyl ether to give
a pale white solid. The pale white powder was recrystallized from
distilled diethyl ether and dried in vacuo over silica gel. Yield: 61%.
highest concentration used in test did not reveal any cytotoxic
activity.
2.3.2. Cells
The cell lines are maintained in the Cell Culture Collection of the
University of Ioannina. Twenty-four hours before addition of the
tested agents, the cells were plated in 96-well plates at a density
of 104 cells per well. The MCF-7 cells were cultured in the D-
MEM (Modified Eagle’s Medium) medium supplemented with 1%
antibiotic and 10% fetal calf serum. L-929 cells were grown in
Hepes-buffered RPMI 1640 medium supplemented with 10% fetal
calf serum, penicillin (50 U/ml) and streptomycin (50 mg/ml). A-
549 cells were grown in F-12 K Ham’s medium supplemented with
1% glutamine, 1% antibiotic/antimycotic, 2% NaHCO3 and 10% fetal
calf serum. The cell cultures were maintained at 37 °C in a humid
atmosphere saturated with 5% CO2. Cell number was counted by
the Trypan blue dye exclusion method. MCF-7, L-929 and A-549
M.p. 157–159 °C. IR (cmÀ1): 3420 m,
1560 m, (C@N); 1625s, as(COO); 1393s,
(N–N); 768 m, (C@S); 517 m, 493 (Sn–C); 331sh, 311 m
O); 403 m, (Sn–S); 277 m,
(Sn–N). 1H NMR (DMSO): d 12.12 (s,
m
(H2O); 3244s,
sym(COO); 1062 m,
(Sn–
m(NY2);
v
m
m
v
v
v
v
m
v
1H, H2O); 10.70 (s, 1H, NH); 8.75 (d, 2H, NH2, J((H)–(H) = 21.5);
2.28 (s, 3H, Me); 1.06/0.81 (s, Sn–Me, J(Sn)–(Me) = 63.6); 13C NMR:
d 185.5; 180.9(C@S); 170.5, 169.4, 156.2 (C@O); 121.3 (C–CH3);
14.4 (Me); 9. (Me–Sn). Anal. Calc. for C6H14N3O3SSnCl (Vw:
362.37): C, 19.9; H, 3.9; N, 11.6, S, 8.8. Found: C, 19.4; H, 3.8; N,
12.0, S, 9.1%.

3300
J. Wiecek et al. / Polyhedron 28 (2009) 3298–3304
Table 1
cated tetrahedral cavities [6e]. When diphenyltin(IV) oxide was
reacted with H2pt the monomer [SnPh2(pt)] (2) was formed. Prob-
ably, the steric hindrance effect of phenyl groups prevent the for-
mation of a trimer. The stoichiometry of the complex indicates
that SnR2(IV) is coordinated by the doubly charged anion pt2À
formed on the loss of the two protons from the carboxylato oxy-
gen and thioamide nitrogen, N. The doubly deprotonated ligand,
pt2À, is coordinated as a tridentate ligand via the carboxylato oxy-
gen O, the azomethine nitrogen N and the thiolato sulfur S atoms.
In the trimer the carboxylato group OCO bridge two tin centers.
Reaction of potassium pyruvic thiosemicarbazone with SnR2Cl2
(where R = Me or Ph) gives the cationic complexes [SnMe2(Hpt)
(H2O)]Cl (3) and [SnPh2(Hpt)(H2O)]Cl (4). The stoichiometries of
the cationic complexes indicate that SnR2(IV) is coordinated by
the singly charged anion HptÀ and one molecule of water. The
formula of these diorganotin(IV) complexes were confirmed by
elemental analysis, spectroscopic studies and by X-ray analysis,
Scheme 1.
Crystal data, data collection and structure refinement for 2 and 3.
2
3
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a (Å)
C16H15N3O2SSn
432.09
100(2)
Mo K
triclinic
P1 (No. 2)
8.8155(4)
9.2944(6)
11.6818(6)
89.314(4)
77.578(4)
65.230(5)
845.44(9)
2
1.697
1.646
428
0.11 Â 0.22 Â 0.26
Kuma KM4CCD
3.1, 36.6
C6H14ClN3O3SSn
362.40
100(2)
a
0.71073
0.71073
monoclinic
P21=c (No. 14)
9.6415(5)
8.9202(5) A
15.0583(8)
90
101.665(5)
90
1268.33(12)
4
1.898
2.382
712
0.30 Â 0.27 Â 0.24
Kuma KM4CCD
3.14, 36.58
ꢀ
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
V (Å3)
Z
Dcalcd (Mg mÀ3
)
l(Mo K
a
) (mmÀ1
)
F(0 0 0)
Unit cell dimensions
Diffractometer
h Range (°)
3.2. Structural characterization
Ranges of h, k, l
À14 to 14; À13 to 15; À12 to 16, À14 to 14,
À19 to 19
À24 to 22
Complexes 2 and 3 were recrystallized from C6H6/toluene/
DMSO/CH3CN and distilled diethyl ether respectively, to furnish
white prisms suitable for single-crystal X-ray analysis. Selected
interatomic distances and bond angles are collected in Table 2.
Reflections collected
Independent reflections [Rint
13 268
20 481
]
7105 [Rint = 0.036]
6180
7105, 268
1.04
5801 [Rint = 0.0318]
5009
5801, 192
1.097
Observed data [I > 2.0 sigma(I)]
Data/parameters
Goodness-of-fit (F2)
Final R indices [I > 2 sigma(I)]
Minimum and maximum
residential density [e/Å3]
0.0283/0.0714
À1.17/1.80
0.0289/0.0684
À0.885/2.508
3.2.1. Crystal structure of [SnPh2(pt)] (2)
The crystal structure of compound 2 is shown in Fig. 1. The
dianionic, tridentate ligand has a ZEZ configuration based on the
C(1)–C(2), C(2)–N(1) and N(2)–C(4) bonds. The double deproto-
nated ligand is coordinated as tridentate ligand via the carboxylato
oxygen O(1), the azomethine nitrogen N(1) and thiolato sulfur S(1)
atoms. The penta-coordination number is completed by two car-
bon atoms of phenyl groups. The coordinated part of the ligand
is made of two chelate rings Sn(1)S(1)N(1)N(2)C(4) and
Sn(1)O(1)N(1)C(1)C(2) (I and II). The dihedral angles between the
planes of the rings I and II is 4.60(6)°, indicating that the ligand
is nearly planar.
cells were determined by the sulforhodamine B assay [10a], while
T-24 cells by the MTT assay [10b]. The in vitro tests were per-
formed as described previously [10c].
3. Results and discussion
3.1. Synthetic aspects
Analysis of the shape determining angles using the approach of
Pyruvic acid thiosemicarbazone hemihydrate (H2ptÁ1/2H2O)
was prepared by the condensation of pyruvic acid and thiosemi-
carbazide hydrochloride [6d]. The reaction of dimethyl-
tin(IV)oxide with pyruvic acid thiosemicarbazone (H2pt) and
subsequent recrystallization from THF leads to the formation
two pseudo-polymorfs based on triangular [(CH3)2Sn(pt)]3 units;
one of them [(CH3)2Sn(pt)]3Á3THF with tubular cavities while the
other [(CH3)2Sn(pt)]3Á1.5THF is a H-bonded 3D network with trun-
Reedijk and coworkers [11] yields
s
((a À b)/60) value of 0.44 for
Sn(1) ( = 0.0 and 1.0 for SPY and TBPY geometries, respectively).
s
The metal coordination geometry is therefore described as dis-
torted SPY with the C(11) occupying the apical position for Sn(1).
The donor C(11) is chosen as apex by the simple criterion that nei-
ther should be any of the four donor atoms which define the two
largest angles, a and b [11]. The angles S(1)–Sn(1)–C(11) and
O(1)–Sn(1)–C(11), are 101.16(4)° and 93.46(6)° respectively, and
Scheme 1. The reaction scheme for the synthesis of 1–4.

J. Wiecek et al. / Polyhedron 28 (2009) 3298–3304
3301
Table 2
Summary of crystal, intensity collection and refinement data.
2
3
Sn(1)–C(11)
Sn(1)–C(5)
Sn(1)–O(1)
Sn(1)–N(1)
Sn(1)–S(1)
S(1)–C(4)
O(1)–C(1)
O(2)–C(1)
N(1)–C(2)
N(1)–N(2)
N(2)–C(4)
N(3)–C(4)
2.1195(17)
2.1237(17)
2.1536(11)
2.2087(14)
2.4986(4)
1.7466(17)
1.289(2)
1.2304(19)
1.2952(19)
1.3632(19)
1.3252(19)
1.339(2)
Sn(1)–C(6)
Sn(1)–C(5)
Sn(1)–O(1W)
Sn(1)–O(1)
Sn(1)–N(1)
Sn(1)–S(1)
S(1)–C(4)
O(1)–C(1)
O(2)–C(1)
N(1)–C(2)
N(1)–N(2)
N(2)–C(4)
2.1065(19)
2.1127(18)
2.2975(14)
2.3166(12)
2.3879(15)
2.6080(5)
1.7003(19)
1.282(2)
1.238(2)
1.291(2)
1.364(2)
1.356(2)
C(11)–Sn(1)–C(5)
C(11)–Sn(1)–O(1)
C(5)–Sn(1)–O(1)
C(11)–Sn(1)–N(1)
C(5)–Sn(1)–N(1)
O(1)–Sn(1)–N(1)
C(11)–Sn(1)–S(1)
C(5)–Sn(1)–S(1)
O(1)–Sn(1)–S(1)
N(1)–Sn(1)–S(1)
C(4)–S(1)–Sn(1)
C(1)–O(1)–Sn(1)
C(2)–N(1)–N(2)
C(2)–N(1)–Sn(1)
N(2)–N(1)–Sn(1)
123.25(6)
93.46(5)
90.85(6)
110.47(6)
124.92(6)
73.79(5)
101.16(4)
101.46(4)
151.06(4)
77.71(3)
C(6)–Sn(1)–C(5)
162.50(8)
C(6)–Sn(1)–O(1W)
C(5)–Sn(1)–O(1W)
C(6)–Sn(1)–O(1)
C(5)–Sn(1)–O(1)
O(1W)–Sn(1)–O(1)
C(6)–Sn(1)–N(1)
C(5)–Sn(1)–N(1)
O(1W)–Sn(1)–N(1)
O(1)–Sn(1)–N(1)
C(6)–Sn(1)–S(1)
C(5)–Sn(1)–S(1)
O(1W)–Sn(1)–S(1)
O(1)–Sn(1)–S(1)
N(1)–Sn(1)–S(1)
84.86(7)
89.73(6)
87.02(6)
87.20(6)
142.48(5)
99.36(7)
93.76(6)
149.41(5)
68.10(5)
96.60(5)
98.23(5)
76.02(4)
141.39(3)
73.40(4)
95.93(5)
118.31(10)
119.34(14)
117.09(11)
123.55(9)
Fig. 2. A view of the extended network of 2 along the b axis.
3.2.2. Crystal structure of [SnMe2(Hpt)(H2O)]Cl (3)
A perspective view of 3 is shown in Fig. 3. The mono deproto-
nated ligand is coordinated as tridentate ligand via the carboxylato
oxygen O(1), the azomethine nitrogen N(1) and thiolato sulfur S(1)
atoms. The molecule of H2O is coordinated to the tin through oxy-
gen O(1W) atom. The six coordination number is completed by two
carbon atoms of methyl groups. Two axial places are occupied by
the two carbon atoms and the basal plane by the three donor
atoms of ligand and the O(1W) donor atom. The charge of the
organotin fragment is balanced by an ionic chloride anion. The
Fig. 1. Molecular structure of the neutral diorganotin complex 2.
the angles C(5)–Sn(1)–C(11) and N(1)–Sn(1)–C(11) are 123.26(7)°
and 110.47(6)° respectively, and deviate by ꢀ20–33° from the
90° expected for a square-base pyramid, so the polyhedron formed
is far from being a square pyramid.
The C(3)–N(1) bond length is 1.299(3) Å and is close to a double
bond (1.28 Å). The deprotonation of N(2)H produces a negative
charge, which is delocalized in the C(3)–N(1)–N(2)–C(4) group.
All the metal-donor bond distances, Sn–O and Sn–N were similar
to other organotin complexes presented in literature [8c,d].
p
? p intermolecular interactions and intra- and intermolecular
hydrogen bonds stabilize this structure. The polar hydrogen atom
on N(3) participates in intermolecular hydrogen bond. For 2 the
monomers of Sn(1) are linked through intermolecular hydrogen
bonds of N(3)–H(3A)–O(2) type. A strong
p–p interaction is that
between the rings Sn(1)–N(1)–N(2)–C(4)–S {Cg(1)–Cg(1); symme-
try operation; 1 À x, 1 À y, 1 À z} at a center to center separation of
˘
4.0360(9) A, Fig. 2.
Fig. 3. Molecular structure of the cationic diorganotin complex 3.

3302
J. Wiecek et al. / Polyhedron 28 (2009) 3298–3304
Table 3
structure is distorted octahedral. The distortion from the ideal
octahedral configuration is shown by the C(5)–Sn(1)–C(6) angle
of 162.50(7). Also, the angles S(1)–Sn(1)–O(1) and O(1W)–Sn(1)–
N(1) in the basal plane are 141.39(3) and 149.41(5) respectively,
which deviates from the ideal value of 180°, probably due to the li-
gand constraint. The organic molecule acts as anionic tridentate
with the ONS donors placed in the same side. The tridentate ligand
has a ZEZ configuration. The coordinated ligand consists of two
chelate rings, SnSNNC and SnONCC, I and II, respectively. The
dihedral angle between the planes of the rings I and II is 3.17(6)
indicating that the ligand does not deviate appreciably from pla-
narity. The distance between the metal centers is 4.2960(3) Å.
The counter anion participates in five hydrogen bonds. The Cl(1)
anion participates in three hydrogen bonds of N(2)–H(2N)Á Á ÁCl(1),
N(3)–H(31N)Á Á ÁCl(1) and O(1W)–H(2W)Á Á ÁCl(1) with one mono-
mer of 3. The polar hydrogen atoms on N(3) partcipate in two
intermolecular hydrogen bonds [12]. The monomers of 3 form
hydrogen-bonded dimers linked by two N(3)–H(32N)Á Á ÁCl(1)
hydrogen bonds involving the amino N(3)–H(32N) hydrogen atom
and the adjacent Cl(1) chloride and vice versa of centrocymetrically
related pairs of molecules. The observed hydrogen-bonding pat-
tern is of the DA = AD type. Another centrosymmetric pair of
hydrogen bonds of the DA = AD type involving the methyl carbon
C(3)–H(3) and the same chloride Cl(1) atom connects the dimers
and results in the formation of infinite layers, Fig. 4 [12]. Intra
and inter molecular hydrogen bonds stabilize this structure and
leads to a supramolecular assembly, Table 3.
p–
p
, inter- and intramolecular hydrogen bonds for 2, inter and intra-molecular
hydrogen bonds for 3a.
p–p
, intra- and intermolecular hydrogen bonds for 2
Cg–Cgb
4.0360(9)
Ab
bc
CgI-Perpd
3.7131(6)
HÁ Á ÁA
2.00(3)
2.51(3)
CgJ-Perpe
3.7131(6)
D–HÁ Á ÁA
169(3)
107(3)
Cg(1) ? Cg(1)i
23.08
DÁ Á ÁA
2.844(2)
2.884(2)
D
H
N(3)
C(3)
H(3B)
H(3D
O(2)ii
O(2)
Intra- and intermolecular hydrogen bonds for 3
D
H
Ab
D–H
DÁ Á ÁA
D–HÁ Á ÁA
O(1W)
N(2)
O(1W)
N(3)
N(3)
C(3)
H(1W)
H(2N)
H(2W)
H(31N)
H(32N)
H(3A)
H(3B)
O(2)iii
Cl(1)iv
Cl(1)v
Cl(1)iv
Cl(1)
1.95(4)
2.39(4)
2.15(4)
2.39(3)
2.41(3)
2.76(4)
2.42(4)
2.57(4)
2.659(2)
3.174(2)
3.048(2)
3.226(2)
3.245(2)
3.505(2)
2.840(2)
3.411(2)
172(4)
164(4)
176(3)
155(3)
174(3)
136(3)
109(3)
153(3)
Cl(1)vi
O(2)
C(3)
C(6)
H(6A)
O(2)vi
a
Cg(1) refer to the centroid Sn(1)–N(1)–N(2)–C(4)–S for 2, (i) 1 À x, 1 À y, 1 À z;
(ii) x, 1 + y, z; (iii) Àx, Ày, 2Àz; (iv) 1 À x, 1/2 + y, 3/2 À z;v,1 À x, À1/2 + y, 3/2 À z;
(vi) x, 1/2 À y, 1/2 + z.
b
Cg–Cg is the distance between ring centroids.
Where b is the angle Cg(I) ? Cg(J).
CgI-Perp is the perpendicular distance of Cg(I) on ring J.
CgJ-Perp is the perpendicular distance of Cg(J) on ring I.
c
d
e
complexing are the decrease in
m
(C@N) and increase in
m(N–N) and
the absence of the large systematic shifts of
quencies. These data indicate coordination through the nitrogen of
m
as(NH2) to lower fre-
3.3. Spectroscopy
the azomethine group and no interaction between the terminal
3.3.1. Infrared spectroscopy
amino nitrogen and the metal ion. The m
(CS) bands at 859 cmÀ1
The three medium-strong intensity bands at around 3294, 3210
and 3120 sh cmÀ1 in the spectra of H2tptÁ1/2H2O, are assigned to
are less intense in the complexes 2–4 and are shifted to a lower fre-
quency, suggesting coordination of the metal through sulfur after
deprotonation. From the metal–ligand stretching vibrations, which
are below 600 cmÀ1, it is possible to assign the bands characteristic
v
asNH2, vsNH2 and vNH, respectively, while the bands at 3430
and 3407 are assigned to vOH mode. These bands are superim-
posed upon the broader more intense O–H stretching absorption
typical of the carboxylic acid functions. The broad band at 3000–
for
and
m
m
(SnC). Also,
m , m
(SnS) at 403–395 cmÀ1 (SnN) at 270–250 cmÀ1
(SnO) at 330–310 cm-1 [8c,d,13,14].
2980 cmÀ1 is taken to represent the
v
(NHÁ Á ÁO) mode, due to intra-
or intermolecular hydrogen bonding [8c,d,13,14]. In the NH
stretching frequency region the spectral band (NH) disappears
in the complex 2, indicating the deprotonation of the NH group.
The difference, sym(COO)] between these frequencies
3.3.2. NMR spectra
m
In the 1H NMR spectra of (H2pt) (1) the appearance of the signal
2NH at d 10.74 ppm, indicates that this proton is involved in hydro-
gen bonding [13]. The absence of peak corresponding to the imino
proton in the spectrum of 2 indicates that this nitrogen is present
in the deprotonated form. The existence of the 2NH resonance in
the 1H NMR spectra of the complexes 3 and 4 indicates that the
nitrogen atoms remain protonated. The signals corresponding to
the hydroxyl groups for 2–4 disappear upon interaction with the
metal, indicating deprotonation of these atoms and possible coor-
dination to the tin atom. The C@S resonances of the thiosemicarba-
zone moieties in the free ligand resonated at 180.3 ppm. In the
complex 2 an upfield shift was observed, indicating increased elec-
D[vas(COO)Àv
for 2–4 is close to that found for monodentate carboxylato group
(230–240 cmÀ1). The significant changes in the ligand bands upon
tron density at this site on complexation, due probably to
p-back
bonding for thiolato sulfur [8c,d,14]. 13C NMR spectra for 3 and 4
clearly show the existence of two-three signals for most of the li-
gand’s atoms. For this case, the contemporary presence of two
structural isomers or two different complexes could be concluded
[14c].
3.4. Pharmacology: Antiproliferative activity in vitro
Platinum(II) complexes of N4-ethyl 2-formyl and 2-acetylpyri-
dine thiosemicarbazones showed cytotoxicity and were found to
be able to overcome the cisplatin resistance of A2780/Cp8 cells
[3a]. Pt(II) or Pd(II) complexes with 2-acetyl pyridine N(4)-ethyl-
thiosemicarbazone, HAc4Et were tested in a panel of human tumor
Fig. 4. Arrangement of the intermolecular hydrogen bonds in 3.

J. Wiecek et al. / Polyhedron 28 (2009) 3298–3304
3303
Table 4
based on triangular [(CH3)2Sn(pt)]3 units [6e]. When diphenyl-
tin(IV) oxide was reacted with H2pt the monomer [SnPh2(pt)] (2)
was formed. The stoichiometry of the complex indicates that
SnR2(IV) is coordinated by the doubly charged anion pt2À formed
on the loss of the two protons from the carboxylato oxygen and
thioamide nitrogen, N. Reaction of potassium pyruvic thiosemicar-
bazone with SnR2Cl2 (where R = Me or Ph) gives the cationic com-
plexes [SnMe2(Hpt)(H2O)]Cl (3) and [SnPh2(Hpt)(H2O)]Cl (4). The
stoichiometries of the cationic complexes indicate that SnR2(IV)
is coordinated by the singly charged anion HptÀ and one molecule
of water. The formula of these diorganotin(IV) complexes were
confirmed by elemental analysis, spectroscopic studies and by X-
ray analysis.
The antiproliferative activity in vitro of 1–4 (expressed as as IC50 SD (
MCF-7, T-24, A-549 and L-929 cancer cell lines.
l
M)) against
MCF-7
L-929
A-549
T-24
H2pt
2
3
4
Me2SnCl2
Ph2SnCl2
Cisplatin
34.7 1.5
0.88 0.04
1.02 0.03
0.95 0.02
20.5 1.0
1.45 0.08
0.69 0.03
n.a.
18.2 0.5
0.43 0.03a
19.73 0.9
4.52 0.14
n.a.
160.4 5.1
0.69 0.03
1.24 0.30
0.62 0.03
8.5 0.05
0.84 0.02
7.99 0.31
7.2 0.18
0.91 0.05
4.83 0.31
12.7 0.9
9.89 0.14
1.53 0.10
n.a.
41.66 2.2
a
In this case the IC50 is Â10À10
.
The in vitro cytotoxic activity has been evaluated against the
cells of three human cancer cell lines: MCF-7 (human breast cancer
cell line), T-24 (bladder cancer cell line), A-549 (non-small cell lung
carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned
from strain L). Selectivity was observed for complexes 2–4, which
were found especially active against MCF-7 and T-24 cancer cell
lines. The most active of all was found the diorganotin complex
2. Compound 2 is considered as agent with potential antitumor
activity, and can therefore be candidates for further stages of
screening in vitro and/or in vivo.
cell lines of different origins (breast, colon, and ovary cancers), and
cisplatin-refractory/resistant cell lines and were found to exhibit
very remarkable growth inhibitory activities with mean IC50 values
of 0.9–0.5 nM and support the hypothesis that both [Pt(Ac4Et)2]
and [Pd(Ac4Et)2] complexes can be characterized by cellular phar-
macological properties distinctly different from those of cisplatin
[4d].
The compounds 1–4 were tested for their antiproliferative
activity in vitro against the cells of three human cancer cell lines:
MCF-7 (human breast cancer cell line), T-24 (bladder cancer cell
line), A-549 (non-small cell lung carcinoma) and a mouse fibro-
blast L-929 cell line. The results of cytotoxic activity in vitro are ex-
Supplementary data
pressed as IC50 – the concentration of compound (in
lM) that
inhibits a proliferation rate of the tumor cells by 50% as compared
to control untreated cells, Table 4.
The ligand 1 is less cytotoxic compared to cisplatin against the
L929, MCF7, non-toxic against A549 cell lines and more cytotoxic
against T-24 cancer cell line. The diorganotin complexes 2–4 are
CCDC 721898 and 721899 contain the supplementary crystallo-
graphic data for 2 and 3. 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, Cam-
bridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk.
in the same
lM range compared to cisplatin against L929 cancer
cell line. The diorganotin complexes 2–4 and Ph2SnCl2 are more
cytotoxic compared to cisplatin against MCF-7 and T-24 cancer cell
lines.
Acknowledgments
The IC50 values for 2 against MCF-7 and T-24 cell lines are
J.W. thanks I.K.Y. for a scholarship for her Ph.D. We also thank
the NMR centrum of University of Ioannina.
0.69
l
M and 0.43 Â 10À10 M, respectively and against A-549 and
L-929 cell lines are 7.2 and 0.88 lM, respectively. Complex 2 is
11.6 and 106 times more active than cisplatin against MCF-7 and
T-24 cell lines, respectively. The IC50 values for 3 against MCF-7
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