Synthesis, structural characterization and in vitro inhibitory studies against human breast cancer of the bis-(2,6-di-tert-butylphenol)tin(iv) dichloride and its complexes

Article abstract of DOI:10.1039/c2dt31527k

Four new organotin(iv) complexes of bis-(2,6-di-tert-butylphenol)tin(iv) dichloride [(tert-Bu-)₂(HO-Ph)]₂SnCl₂ (1) with the heterocyclic thioamides 2-mercapto-pyrimidine (PMTH), 2-mercapto-4-methyl- pyrimidine (MPMTH), 2-mercapto-pyridine (PYTH) and 2-mercapto-benzothiazole (MBZTH), of formulae {[(tert-Bu-)₂(HO-Ph)]₂Sn(PMT) ₂} (2), {[(tert-Bu-)₂(HO-Ph)]₂Sn(MPMT) ₂} (3), {[(tert-Bu-)₂(HO-Ph)]₂SnCl(PYT)} (4) and {[(tert-Bu-)₂(HO-Ph)]₂SnCl(MBZT)} (5), have been synthesized and characterized by elemental analysis, ¹H-, ¹³C-, ¹¹⁹Sn-NMR, EPR, FT-IR, Raman and M?ssbauer spectroscopic techniques. The crystal and molecular structures of compounds 1-5 have been determined by X-ray diffraction. The geometries around the metal center adopted in complexes 1-5 varied between tetrahedral in 1, trigonal bipyramidal in 3, 4, 5 and distorted octahedral in 2. Two carbon atoms from aryl groups and two chlorine atoms form a distorted tetrahedron in the case of 1. Two carbon, two sulfur and two nitrogen atoms from thione ligands form a distorted octahedral geometry around tin(iv) with trans-C₂, cis-N₂, cis-S₂-configurations in 2. However, in the case of 4 and 5 complexes two carbon, one sulfur, one nitrogen and one chloride atom form a distorted trigonal bipyramidal arrangement. Finally, in the case of 3 the trigonal bipyramidal geometry is achieved by two carbon, two sulfur and one nitrogen atom in a unique coordination mode of thioamides toward the tin(iv) cation. Compounds 1-5 were tested for their in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) cell line. Compound 3 exhibits strong cytotoxic activity against MCF-7 cells (IC₅₀ = 0.58 ± 0.1 μM).

Full text of DOI:10.1039/c2dt31527k

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Dalton
Transactions
Cite this: Dalton Trans., 2012, 41, 14568
www.rsc.org/dalton
PAPER
Synthesis, structural characterization and in vitro inhibitory studies against
human breast cancer of the bis-(2,6-di-tert-butylphenol)tin(IV) dichloride and
its complexes†
D. B. Shpakovsky,a,b C. N. Banti,a,c G. Beaulieu-Houle,a,d N. Kourkoumelis,e M. Manoli,f M. J. Manos,f
A. J. Tasiopoulos,f S. K. Hadjikakou,*a E. R. Milaeva,b K. Charalabopoulos,c,g T. Bakas,h I. S. Butlerd and
N. Hadjiliadisa
Received 11th July 2012, Accepted 14th September 2012
DOI: 10.1039/c2dt31527k
Four new organotin(IV) complexes of bis-(2,6-di-tert-butylphenol)tin(IV) dichloride
[(tert-Bu-)2(HO-Ph)]2SnCl2 (1) with the heterocyclic thioamides 2-mercapto-pyrimidine (PMTH),
2-mercapto-4-methyl-pyrimidine (MPMTH), 2-mercapto-pyridine (PYTH) and 2-mercapto-benzothiazole
(MBZTH), of formulae {[(tert-Bu-)2(HO-Ph)]2Sn(PMT)2} (2), {[(tert-Bu-)2(HO-Ph)]2Sn(MPMT)2} (3),
{[(tert-Bu-)2(HO-Ph)]2SnCl(PYT)} (4) and {[(tert-Bu-)2(HO-Ph)]2SnCl(MBZT)} (5), have been
synthesized and characterized by elemental analysis, 1H-, 13C-, 119Sn-NMR, EPR, FT-IR, Raman and
Mössbauer spectroscopic techniques. The crystal and molecular structures of compounds 1–5 have been
determined by X-ray diffraction. The geometries around the metal center adopted in complexes 1–5
varied between tetrahedral in 1, trigonal bipyramidal in 3, 4, 5 and distorted octahedral in 2. Two carbon
atoms from aryl groups and two chlorine atoms form a distorted tetrahedron in the case of 1. Two carbon,
two sulfur and two nitrogen atoms from thione ligands form a distorted octahedral geometry around tin
(IV) with trans-C2, cis-N2, cis-S2-configurations in 2. However, in the case of 4 and 5 complexes two
carbon, one sulfur, one nitrogen and one chloride atom form a distorted trigonal bipyramidal arrangement.
Finally, in the case of 3 the trigonal bipyramidal geometry is achieved by two carbon, two sulfur and one
nitrogen atom in a unique coordination mode of thioamides toward the tin(IV) cation. Compounds 1–5
were tested for their in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) cell line.
Compound 3 exhibits strong cytotoxic activity against MCF-7 cells (IC50 = 0.58 0.1 μM).
1. Introduction
Organotin compounds are widely used as agricultural and indus-
trial biocides due to their antifungal properties.1 The intensive
study of organotin compounds had begun after the discovery of
their anti-tumor activity by M. Gielen in the 1980s.2,3 The mech-
aSection of Inorganic and Analytical Chemistry, Department of
Chemistry, University of Ioannina, 45110 Ioannina, Greece.
anism of anti-tumour activity is still under investigation.4 It is
E-mail: shadjika@uoi.gr; Fax: +30-26510-08786;
Tel: +30-26510-08374
well known that the Sn-atom interacts with free sulfhydryl
groups in proteins leading to distortion of the protein structure.
The thymotoxic di-n-butyltin dichloride and tri-n-butyltin chloride
affect macromolecular DNA synthesis in rat thymocytes in vivo.5
Organotin complexes with heterocyclic thioamides demonstrated
high antiproliferative activity which was correlated to the lipoxy-
genase (LOX) inhibiting activity by depleting HS-groups in pro-
teins which are restricted when the organotin complexes possess
the S-bonded ligands.6 The inhibition activity of tin–thioamide
complexes was found to be influenced by the nature of the
ligand to a great extent.6,7
bChemistry Department Moscow State Lomonosov University, Moscow,
Russian Federation
cDepartment of Experimental Physiology, Medical School, University of
Ioannina, Greece
dDepartment of Chemistry, McGill University, 801 Sherbrooke,
Montreal, Quebec, Canada
eMedical Physics Laboratory, Medical School, University of Ioannina,
Ioannina, Greece
fDepartment of Chemistry, University of Cyprus, 1678 Nicosia, Cyprus
gDepartment of Physiology, Democritus University Medical School,
Greece
hPhysics of Material Laboratory, Department of Physics, University of
Ioannina, Greece
Organotin(IV) complexes with ligands containing phenolic
–OH groups and heterocyclic nitrogen donor atoms, e.g.
4,6-dihydroxypyrimidine or 2-thiobarbituric acid, represent a
peculiar class due to their ability to form the phenoxyl radical
†Electronic supplementary information (ESI) available. CCDC 891289
(1), 891290 (2), 891291 (3), 891292 (4) and 891293 (5). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2dt31527k
14568 | Dalton Trans., 2012, 41, 14568–14582
This journal is © The Royal Society of Chemistry 2012

View Article Online
during oxidation.7,8 These complexes were synthesized by
refluxing a methanol solution of the sodium salt of the ligands
with organotin halides. The complexes of tri-n-butyltin(IV)
and triphenyltin(IV) with 2-thiobarbituric acid, [(n-Bu)3Sn-
(O-HTBA)·H2O] and {[Ph3Sn(O-HTBA)·0.7H2O]}n,7 were
found to exhibit better cytotoxic activity than that of cisplatin
against cancer cells, which in the case of breast cancer cells
(MCF-7) (ER positive) their IC50 values were 272 and 179-fold
lower than that of cisplatin respectively.7a
Breast cancer, on the other hand, is the most prevalent cancer
in the world today, because of its high incidence and relatively
good prognosis.9a It is estimated that 4.4 million women alive
have breast cancer diagnosed within the last 5 years and the inci-
dence rates are increasing.9a The MCF-7 cell line has been pre-
viously used as a model for human breast cancer.9b Recently,
Kobakhidze et al.9c reported that di-n-butyltin(IV) or diphenyltin(IV)
complexes with the Schiff bases which derived from
α-amino acids (isoleucine, leucine, methionine, phenylalanine
and aminophenylacetic acid) with aldehydes (2,4-dihydroxybenz-
Scheme 2 Reactions for the preparation of 2–5.
Results and discussion
General aspects
The synthesis of R2SnCl2 (1) was carried out by the re-metalla-
tion reaction of RHgCl and Sn in o-xylene under reflux accord-
ing to a previously reported method.12 Organotin(IV) complexes
2–5 have been synthesized by reacting a methanolic solution of
organotin dichloride R2SnCl2 (1) with an aqueous solution of
the appropriate ligand (thioamides) containing an equivalent
amount of potassium hydroxide as shown in Scheme 2.
Compounds 1–5 are stable in air and in solution. Crystals suit-
able for X-ray analysis were obtained by slow evaporation of
methanol–acetonitrile solutions (1 : 1) for compounds 2, 4 or by
slow diffusion of hexane in chloroform solution in the case of 3,
5. Crystals of 1 were obtained by slow evaporation of an
o-xylene solution.
aldehyde,
2-hydroxy-4-methoxybenzaldehyde)
exhibited
selective activity against MCF-7 cells.9c Complexes {[Ph3Sn-
(O-HTBA)]·0.7H2O}n and [(n-Bu)3Sn(O-HTBA)·H2O]7a also
showed selective activity against MCF-7. This strong selective
activity of [(n-Bu)3Sn(O-HTBA)·H2O] and {[Ph3Sn(O-HTBA)·
7
0.7H2O]}n complexes against MCF-7 (ER positive) was not
observed when they were tested against breast cancer cells
(MDA-MB-231) (breast, ER negative), indicating that estrogen
receptors (ER) may be involved in their antitumor mechanism.7a
It is also reported that antiestrogen drugs such as tamoxifen
inhibit the growth of MCF-7 cells by blocking the steroid recep-
tors (ER-α and ER-β) which are located in human breast cancer
cells,9d,e since estrogen receptors are expressed in human breast
cancer.9f Therefore, this sex steroid plays an important role in the
development and propagation of the disease.9f
The organic derivatives of hindered 2,6-di-alkylphenols are
considered as synthetic antioxidants and models of vitamin E.10
Metal complexes bearing antioxidative groups of 2,6-di-tert-
butylphenols act as polyfunctional antioxidants, anti-inflamma-
tory agents, and scavengers for reactive oxygen species11 which
make them promising agents in cancer therapy.
In the present paper, we report on the synthesis and character-
ization of diorganotin complexes with the 2,6-di-tert-butylphenol
moiety with various thioamides and aromatic thiols (Scheme 1).
The X-ray crystal structures of the complexes are described
herein. The in vitro anti-tumor activity of the complexes against
the human breast adenocarcinoma (MCF-7) tumor cell line is
also studied.
Spectroscopy
(a) Vibrational spectroscopy. Characteristic infrared bands
of the complexes and the ligands are presented in Table 1
(Fig. S1–S5†). The IR spectra of 1–5 in KBr feature character-
istic narrow absorptions in the region of 3595–3640 cm−1 which
was assigned to the free hindered phenol group. Complexes 4, 5
with S-substituted pyridine and benzothiazole also demonstrate
another wide band at 3440–3420 cm−1 related to hydrogen bond
formation between the phenol group and the neighboring pyri-
dine and carboxylate moiety of the complex molecule that is
nontrivial for hindered phenols. The IR spectra of the complexes
also show distinct vibrational bands at 1595–1420 and
1320–1240 cm−1, which can be assigned to ν(CvN) vibrations
of thioamide (I and II bands), and at 1100–1005 and
950–640 cm−1, which can be attributed to the v(CS) vibrations
(thioamide III and IV bands). No bands due to the ν(NH) or
ν(SH) vibrations are observed in the IR spectra of the complexes,
indicating the de-protonation of all ligands. Significant changes
between the IR spectra of the ligands and the complexes were
also observed (Table 1). Thioamide bands are shifted to lower
frequencies in the spectra of the complexes, supporting sulfur
donation and de-protonation of the ligands as well. Bands at
580–560 cm−1 have been assigned to the anti-symmetric and
symmetric vibrations of the Sn–C bond while the bands at
375–385 cm−1 are attributed to the ν(Sn–S) vibrations.6,7,13 Sn–S
and Sn–N vibrations are also Raman active.6d Thus, the bands at
240–270 cm−1 in the Raman spectra of complexes 1–5 are due
to ν(Sn–N), whereas those at 340–390 cm−1 are assigned to
ν(Sn–S) (Table 1)6d (Fig. S6–S9†).
Scheme 1 Molecular formulae of di-organotin dichloride and ligands
used in this work.
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 14568–14582 | 14569

View Article Online
Table 1 Characteristic vibration bands (cm−1) in the infrared and Raman spectra of complexes and ligands
Infrared
Raman
Thioamide I Thioamide II Thioamide III Thioamide IV ν(Sn–C) ν(Sn–S) ν(Sn–N)
Compound
ν(NH), ν(OH) ν(CH)
1
3614
2963–2872 1427 s
1241
1120
874
568 w
PMTH
2
3468
3420
3054–2930 1439
2872–2965 1427
1256
1220
1054
1121
984
989
—
575
—
238
399
333
374
335
MPMTH HCl 3440
3
3074
1463
1234
1239
1003
1025
916
885
3636, 3449 br 2877–2958 1430
573
574
251
281
PYTH
4
3163
3631
3050–2800 1496, 1439
2959–2873 1401 1429 s 1238
1238, 1256
983
1072
743
885
MBZTH
5
3112
3632
3077–2838 1497
2959–2874 1429
1320
1240
1013
1078, 1036
938
933
—
571
—
265
Table 2 119Sn Mössbauer spectroscopic data for complexes 1–5
Molecule Temp (K) δ (mm s−1
)
D (mm s−1
)
Area (%) δ (mm s−1
)
D (mm s−1
)
Area (%) δ (mm s−1
)
D (mm s−1
)
Area (%)
1
2
3
4
5
85
85
85
85
85
1.38
1.41
0.14
0.04
1.24
2.93
2.39
0.49
0.46
2.97
100
93
72
100
48
−0.27
0.00
2.08
7
22
0.58
1.24
3.30
6
0.17
0.39
52
—
—
—
Table 3 Characteristic signals in 1H, 13C NMR spectra of bis-(2,6-di-tert-butyl-4-hydroxyphenyl)tin derivatives
1H-NMR δ (ppm) 13C-NMR
Compound C(CH3)3 OH C6H2 (3JSn–H, Hz) δ (ppm)
1JC–Sn (Hz) Solvent
1
2
3
1.48
1.38
1.38
5.58 7.51 (84)
5.29 7.65 (80)
n.o. 7.24 (n.o.)
30.12, 34.67, 127.48, 131.85, 137.25, 157.00
30.41, 34.62, 115.60, 131.87, 132.13, 135.96, 153.31, 156.68, 175.35 458
31.03, 35.02, 35.30, 116.71, 124.95, 133.26, 139.33, 154.50, 157.42,
163.30, 180.59.
n.o.
401
CDCl3
CDCl3
DMSO-d6
4
5
1.44
1.39
5.39 7.72 (84)
5.43 7.78 (88)
29.12, 33.53, 117.65, 118.48, 123.17, 123.81, 131.12, 135.08, 137.93, 510
145.05, 154.72
30.39, 34.40, 111.80, 119.72, 121.62, 124.76, 125.02, 127.30, 131.95, 503
136.02, 137.37, 153.95, 159.38
CDCl3
CDCl3
n.o. = not observed.
(b) 119Sn Mössbauer spectroscopy. Solid state, 119Sn Möss-
bauer spectroscopic data at 85 K of complexes 1–5 are given in
Table 2 (Fig. S10–S14†).
complexes exhibit quadrupole splitting parameters in the region
of 2.40–5.50 mm s−1 14a
Complex 1 (R2SnCl2) with a D value
.
of 2.93 mm s−1 is within the tetrahedral complexes, the D value
of 2 (2.39 mm s−1) is in agreement for the tin complexes with
trans-R2Sn(L2) octahedral complexes. The quadrupole splitting
parameter of 3 is 2.09 mm s−1 in the borderline for cis-R2Sn(L2)
trigonal bipyramidal complexes or tetrahedral complexes (see
also Raman spectroscopy). The D value of 2.97 mm s−1
classified 5 in the cis-R2Sn(L2) type of complexes. However, the
low D value (0.46 mm s−1) in the case of 4 is inconsistent with
the cis-R2Sn(IV) trigonal bipyramidal geometry found from
X-ray diffraction analysis (see Crystal structures).
The spectra of 1, 2, 4 and 5 consist of one symmetric
Lorentzian doublet, while that of 3 consists of two symmetric
Lorentzian doublets. The occurrence of two symmetric Lorent-
zian doublets indicates the formation of two structural isomers
for complex 3.14 The values of δ (0.04–1.41 mm s−1) for com-
plexes 1–5 show that tin is at the (4+) oxidation state in all
cases.6d,14a Organotin complexes with R2Sn tetrahedral geome-
try exhibit quadrupole splitting parameters in the range of
1.70–3.10 mm s−1. Organotin complexes with trans-R2Sn(IV)
(R = alkyl) and trigonal bipyramidal arrangement around the
tin(IV) ion exhibit D values in the range of 2.00–4.00 mm s−1
,
(c) NMR spectroscopy. 1H NMR data for complexes 1–5 are
given in Table 3 (Fig. S15–S19†). No signals for amide protons
were observed in the spectra of thioamide complexes 2–5 in
while those of cis-R2Sn(IV) trigonal bipyramidal geometry in the
range of 2.17–3.82 mm s−1. trans-R2Sn distorted octahedral
14570 | Dalton Trans., 2012, 41, 14568–14582
This journal is © The Royal Society of Chemistry 2012

View Article Online
CDCl3 solution. The characteristic signals of tert-butyl protons
and hindered phenol groups are shifted to strong field in the
spectra of thiol complexes in comparison with those of the
chloride one (1) confirming the ligand–metal coordination.
Furthermore, the aromatic C–H protons show a coupling
constant with paramagnetic isotopes 117,119Sn (S = 1/2). The
J(Sn–H) coupling values can be used for the prediction of
the structure geometry. The value of 3J(Sn–H) in the case of
starting bis-aryltin dichloride 1 was found to be equal to 84 Hz
that is similar to the one of diorganotin benzoate complex
Ph2SnL2 (L = 2-[N-(2,6-dichloro-3-methylphenyl)amino] benzo-
ate) (76.3 Hz).15a The high value of J indicates the strong inter-
action of the ligand and the acceptors in solution. It was
previously demonstrated that the value of 3J(Sn–H) for organotin
derivatives which possess the same hybridization as that of R4Sn
(e.g. RnSnX4−n, where n = 1–4) could be calculated by using the
electronegativity term (Δχ) in the relationship
Scheme 3
Table 4 Parameters of ESR spectra of phenoxyl radicals (toluene,
293 K)
Compound
g-factor
a(2H) (G)
1
2
3
4
5
2.0041
2.0041
2.0063
2.0027
2.0033
1.5
2.0
3
3JðSn–H of compoundÞ ¼ JðSn–H of R4SnÞ þ AΔχ;
1.5
a
where A is a constant, Δχ = ΣχA − ΣχB; ΣχA = sum of electro-
negativities of the groups attached to the tin in the calculated
compound; ΣχB = sum of the electronegativities of the groups
2.0
a A broad singlet with low intensity was detected.
3
attached to the metal in the parent compound (R4Sn). A J of
Ph4Sn equal to 68 Hz has been previously reported.15b
To deal with the low solubility of 3 in CDCl3 we used
DMSO-d6, the absence of a hydroxyl group signal in the spec-
trum can be explained by the exchange effect during hydrogen
bond formation in this solvent.
(4B) and 124.79(13)° (5) respectively (Table 5)) indicating that
these complexes retain their geometry in solution.
(d) EPR spectroscopy. The chemical oxidation of phenol
derivatives 1–5 was carried out in toluene using PbO2 yielding
phenoxyl radicals 1′–5′ (Scheme 3).
The assignment of the 13C-NMR spectrum of complex 1
15c
(Fig. S20†) was based on the data of Ph2SnCl2
and those of
the organometallic derivatives of 2,6-di-tert-butylphenols.15d
Complex 1 displays resonance signals at 30.12 (C(CH3)3), 34.67
(C(CH3)3), 127.48 (C1 in R), 131.85 (C2 in R), 137.25 (C3 in
R), 157.00 (C4 in R) ppm respectively which are assigned to the
CH3-groups of the tert-butyl substituent of phenols and to the
carbon atoms of aromatic rings (C1, C2, C3 and C4 (Scheme 1)).
The most intensive signal is attributed to the aromatic C2–H at
131.85 ppm which has satellites due to Sn–C coupling. The
The X-band EPR spectra measured at 293 K show the spin
density distribution in the organic ligands (Fig. S25–S29†). The
radicals are stable at room temperature in the absence of dioxy-
gen for several hours. The intensity of radicals derived from
diorganotin complexes with mercaptans was lower than that of
radical 1′ that may be explained by the influence of electron
donor ligands in the distribution of the unpaired electron in the
phenoxyl radical. The chloride atoms are electron-acceptor
groups and can be involved in radical transformations as well as
to increase the stability of radicals. In contrast, the thiol ligands
destabilize the corresponding radicals. The EPR spectrum of
radical 1′ exhibits multiple signals corresponding to the coupling
of the unpaired electron with two non-equivalent groups of
meta-protons of the phenoxyl ring (1H). The isotropic g-values
for the radicals 1′–5′ are in the range 2.0041–2.0063 with
hyperfine coupling constants derived from protons (Table 4).
However, the hyperfine coupling constants with 117/119Sn were
2
value of JSn–C = 80 Hz also points to the tetrahedral geometry
of 1 (see also Mössbauer spectroscopy). The signals due to the
C2 are observed in the spectra of the complexes 2–5 at 132.13 (2),
133.26 (3), 131.12 (4) and 125.02 (5) ppm respectively (Table 3,
Fig. S21–S24†). The chemical shifts of the carbon atoms of the
tert-butyl group observed at 30.12, 34.67 ppm in the spectrum
of 1 are shifted downfield in the case of bis substitution of
Cl atoms by S of PMTH and MPMTH ligands in complexes 2, 3
(30.41, 34.62 ppm (2) and 31.03, 35.30 ppm (3)), while in the
case of the mono substitution of Cl by MPYTH in complex 4,
they are shifted towards strong field (29.12, 33.53 ppm (4)).
Thus, these shifts in C(t-bu) signals are indicative of the nature of
substituents at the Sn atom in the spectra of complexes 2–5.
not registered due to the low intensity of spectra, moreover the
119
natural content of 117Sn and
Sn is 7.75 and 8.60%, respect-
ively. Organotin 2,6-di-tert-butylphenoxyl radicals generated in
the chemical oxidation have been studied earlier.16 The stability
and the values of hyperfine splitting constants of these radicals
are influenced by the electron-withdrawing or electron-donating
character of the para-substituent in the phenyl ring. For instance,
1
Moreover, the J(119Sn–13C) values observed in the 13C-NMR
spectra of 2–5 are reported in Table 3. The C–Sn–C bond angles
of organotin(IV) complexes calculated by the equation
1J(119Sn–13C) = 11.4 θ − 8757a,15d–f are 117° (2), 112° (3), 122°
(4) and 121° (5), respectively, which are in agreement with those
found in the solid state by X-ray analysis (127.17(19)° (2A),
119.0(2)° (2B), 111.44(12)° (3), 119.66(12)° (4A), 120.23(12)°
the values of a(2H) were 1.7
G (meta-protons of the
phenoxyl ring) and a(117/119Sn) were 57.2 and 59.4 G respect-
ively for the radical from bis-methyl-bis(3,5-di-tert-butyl-
4-hydroxyphenyl)tin.
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 14568–14582 | 14571

Table 5 Selected bond lengths (Å) and angles (°) for complexes 1–5 with e.s.d.’s in parentheses
Complex 1
Complex 2 Isomer-A
Complex 2 Isomer-B
Complex 3
Complex 4 Isomer-A
Complex 4 Isomer-B
Complex 5
(a) Bond lengths (Å)
(a) Bond lengths (Å)
(a) Bond lengths (Å)
(a) Bond lengths (Å)
(a) Bond lengths (Å)
(a) Bond lengths (Å)
(a) Bond lengths (Å)
Sn–Cl1
Sn–Cl2
Sn–C1
Sn–C15
O1–C4
O2–C18
2.3615(14)
Sn1–S2
Sn1–C9
S2–C1
Sn1–N1
O1–C12
O1–H1
2.4616(14)
Sn2–S3
Sn2–C23
S3–C5
Sn2–N3
O2–C26
O2–H2A
2.4631(14)
Sn1–S1
Sn1–S2
Sn1–C1
Sn1–C15
S1–C29
S2–C34
O1–C4
O2–C18
O1–H1
O2–H2A
2.4664(8)
Sn1–Cl1
Sn1–S1
Sn1–N1
Sn1–C1
Sn1–C15
S1–C29
O1–C4
2.4443(8)
Sn2–Cl2
Sn2–S2
Sn2–N2
Sn2–C34
Sn2–C47
S2–C65
O3–C37
O4–C51
2.4467(8)
Sn1–Cl1
Sn1–S1
Sn1–N1
Sn1–C8
Sn1–C22
S1–C1
S2–C1
S2–C3
O1–C11
O2–C25
2.4238(9)
2.3524(16)
2.103(6)
2.098(5)
1.373(7)
1.379(7)
2.118(5)
1.759(5)
2.815
1.370(7)
0.89(5)
2.123(5)
1.760(7)
2.873
1.372(7)
0.90(5)
2.4265(8)
2.115(3)
2.116(3)
1.767(3)
1.745(3)
1.377(4)
1.374(4)
0.8199
2.4504(8)
2.412(3)
2.136(3)
2.136(3)
1.756(3)
1.383(4)
1.368(5)
2.4543(8)
2.392(3)
2.118(3)
2.138(3)
1.763(4)
1.378(4)
1.388(4)
2.4796(10)
2.483(3)
2.126(3)
2.117(3)
1.728(4)
1.731(4)
1.741(4)
1.382(4)
1.383(6)
O2–C18
0.8209
(b) Angles (°)
(b) Angles (°)
(b) Angles (°)
(b) Angles (°)
(b) Angles (°)
(b) Angles (°)
(b) Angles (°)
Cl1–Sn–Cl2 103.16(5)
S2–Sn1–C9
106.46(14) S3_b–Sn2–C23 115.01(14) S1–Sn1–S2 101.57(3) Cl1–Sn1–S1 92.63(3) S2–Sn2–N2 64.67(7) Cl1–Sn1–S1 91.19(3)
Cl1–Sn–C1
Cl1–Sn–C15 103.18(16) S2–Sn1–C9_a 110.62(15) S3_b–Sn2–C23_b 107.85(15) S1–Sn1–C15 109.30(9) Cl1–Sn1–C1 97.31(9) S2–Sn2–C47 113.14(9) Cl1–Sn1–C8 99.32(8)
Cl2–Sn–C1 109.64(19) S2_a–Sn1–C9 110.62(15) S3–Sn2–C23_b 115.01(14) S2–Sn1–C1 113.11(8) Cl1–Sn1–C15 98.88(9) Cl2–Sn2–S2 93.81(3) Cl1–Sn1–C22 98.46(11)
Cl2–Sn–C15 111.47(16) C9–Sn1–C9_a 127.17(19) S3–Sn2–C23
C1–Sn–C15 123.5(2) S2_a–Sn1–C9_a 106.46(14) S3–Sn2–S3_b
103.32(17) S2–Sn1–S2_a 88.80(5) C23–Sn2–C23_b 119.0(2) S1–Sn1–C1 99.24(9) Cl1–Sn1–N1 157.16(7) S2–Sn2–C34 123.23(9) Cl1–Sn1–N1 155.32(7)
107.85(15) S2–Sn1–C15 119.56(9) S1–Sn1–N1 64.61(7) Cl2–Sn2–N2 158.43(7) S1–Sn1–N1 64.15(7)
88.07(5) C1–Sn1–C15 111.44(12) S1–Sn1–C1 117.24(9) Cl2–Sn2–C34 96.70(9) S1–Sn1–C8 115.34(8)
S1–Sn1–C15 119.53(9) Cl2–Sn2–C47 97.88(9) S1–Sn1–C22 116.05(11)
N1–Sn1–C1 92.01(11) N2–Sn2–C34 94.30(11) N1–Sn1–C8 92.47(10)
N1–Sn1–C15 94.47(11) N2–Sn2–C47 92.48(11) N1–Sn1–C22 92.34(13)
C1–Sn1–C15 119.66(12) C34–Sn2–C47 120.23(12) C8–Sn1–C22 124.79(13)

View Article Online
Fig. 1 (A) ORTEP diagram together with the labeling scheme of 1. (B) Hydrogen bonding interactions lead to a 1D polymeric assembly.
Crystal and molecular structures of [(tert-Bu-)2(HO-Ph)]2-
SnCl2 (1), {[(tert-Bu-)2(HO-Ph)]2Sn(PMT)2} (2), {[(tert-Bu-)2-
(HO-Ph)]2Sn(MPMT)2} (3), {[(tert-Bu-)2(HO-Ph)]2SnCl(PYT)}
(4) and {[(tert-Bu-)2(HO-Ph)]2SnCl(MBZT)} (5). ORTEP dia-
grams of complexes 1–5 are shown in Fig. 1–5, while selected
bond distances and angles are given in Table 5.
Compounds 1–5 are covalent monomers in the solid state with
distorted tetrahedral (1), distorted octahedral (2) and distorted tri-
gonal bipyramidal (3, 4 and 5) geometries around the metal
centers. In the case of complexes 2 and 4 two isomers were iso-
lated in their unit cells (Fig. 2 and 4).
than the corresponding bond distances found in complexes 4
and 5 (Sn1–Cl1 = 2.4443(8) Å (4-isomer A), Sn2–Cl2 =
2.4467(8) Å (4-isomer B) and Sn1–Cl1 = 2.4238(9) Å (5)) and
in [(C6H5)2SnCl(HMNA)] (H2MNA = 2-mercapto-nicotinic
acid) (Sn(1A)–Cl(1A)
=
2.4246(19), Sn(1B)–Cl(1B)
=
2.424(2) Å),6a where one chlorine atom has been replaced by the
S,N-thionate anion which chelates the metal ion. This is attribu-
ted to the variation in the coordination modes between complex
1 (four coordinated Sn(IV) ion) and 4 or 5 (five coordinated
Sn(IV) ion) which leads to different geometries (tetrahedral (1)
and trigonal bipyramidal (4, 5)).
In the case of complex 1, the bond angles around tin(IV)
varied between 103.16(5) and 123.5(2)° (Table 5) with the
smaller one corresponding to the Cl–Sn–Cl and the longer to the
C–Sn–C bond angle respectively due to the valence shell elec-
tron pair repulsions. The Sn–Cl bond distances (Sn–Cl1 =
2.3615(14) and Sn–Cl2 = 2.3524(16) Å respectively) are shorter
Intra-molecular interactions Cl1⋯O1_c = 3.103(4) Å [sym-
metry operation c = x, 1/2 − y, 1/2 + z] lead to a supra-molecular
assembly of 1 (Fig. 1B).
In the case of 2 two trans-aryl groups are bonded to the tin
atom (Sn1–C9 = 2.118(5) Å (2-isomer A) and Sn2–C23 =
2.123(5) Å (2-isomer B)) forming the axis of the octahedron.
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 14568–14582 | 14573

View Article Online
Fig. 2 (A) ORTEP diagram together with the labeling scheme of 2. (B) Hydrogen bonding interactions lead to a polymeric assembly which turns
out to be a ring.
Two deprotonated PMTH ligands are also bonded to the tin atom
via sulfur (Sn1–S2 = 2.4616(14) Å, Sn2–S3 = 2.4631(14) Å for
2A and 2B respectively). The Sn–S bond lengths are in accord-
ance with those previously reported for diorganotin complexes
with octahedral geometries as in the complexes [(C6H5)2Sn-
(cmbzt)2] (Hcmbzt = 5-chloro-2-mercaptobenzothiazole) where
Sn1–S12 = 2.4947(7), Sn1–S22 = 2.5020(7) Å (isomer A) and
Sn1–S12 = 2.4947(7), Sn1–S22 = 2.5020(7) Å (isomer B)6d and
in [(n-C4H9)2Sn(cmbzt)2] where Sn1–S12 = 2.5042(19), Sn1–
S22 = 2.5286(19) Å.6d Moreover, the Sn–S bond distances
found in 2 are in the range to those found for complexes with tri-
gonal bipyramidal geometry (Sn1–S2 = 2.4265(8) Å (3), Sn1–
S1 = 2.4504(8) Å (4A), Sn2–S2 = 2.4543(8) Å (4B) and Sn1–
S1 = 2.4796(10) Å (5)). Triorganotin complexes of thioamides
with trigonal bipyramidal geometry also exhibit similar Sn–S
bond distances (Sn1A–S2A = 2.4540(15) Å (isomer A) and
Sn1A–S2A = 2.4540(15) Å (isomer B) in [(C6H5)3Sn(mbzt)]
(Hmbzt = 2-mercaptobenzothiazole),6d Sn1–S12 = 2.4699(9) Å
in [(C6H5)3Sn(mbzo)] (Hmbzo = 2-mercaptobenzoxazole)6d and
Sn1–S1 = 2.458(3) Å (isomer A) and Sn2–S3 = 2.456(3) Å
14574 | Dalton Trans., 2012, 41, 14568–14582
This journal is © The Royal Society of Chemistry 2012

View Article Online
(isomer B) in [(C6H5)3Sn(cmbzt)] (Hcmbzt = 5-chloro-2-
mercaptobenzothiazole)).6d
The octahedral geometry is completed by two weak Sn–N
interactions between the nitrogen atoms of the ligands and the
metal center (Sn1–N1 = 2.815 Å (2A) and Sn2–N3 = 2.873 Å
(2B)). These bond distances are in accordance with the corres-
ponding bond lengths found in other complexes with octahedral
geometry as in [(C6H5)2Sn(cmbzt)2] (Hcmbzt = 5-chloro-2-mer-
captobenzothiazole) with Sn1–N13 = 2.653(2), Sn1–N23 =
2.7718(18) Å (isomer A) and Sn1–N13 = 2.653(2), Sn1–N23 =
2.7718(18) Å (isomer B)6d and in [(n-C4H9)2Sn(cmbzt)2] where
Sn1–N13 = 2.748(7), Sn1–N23 = 2.766(7) Å.6d However, the
Sn–N bond distances in 2 are significantly longer than those
found in complexes with trigonal bipyramidal geometries which
retain the chlorine atoms as in 4: Sn1–N1 = 2.412(3), Sn2–N2 =
2.392(3) Å and 5: Sn1–N1 = 2.483(3) Å. Furthermore, the Sn–N
bond lengths become significantly longer in complexes of trigo-
nal bipyramidal geometry without chlorine atoms as in
[(C6H5)3Sn(mbzt)] (Hmbzt = 2-mercaptobenzothiazole) (Sn1A–
N3A = 2.945(4) Å (isomer A) and (Sn1B–N3B = 2.898(4) Å
(isomer B)),6d in [(C6H5)3Sn(mbzo)] (Hmbzo = 2-mercapto-
benzoxazole) (Sn1–N11 = 3.067(3) Å)6d and in [(C6H5)3Sn-
(cmbzt)]
(Hcmbzt
=
5-chloro-2-mercaptobenzothiazole)
(Sn1–N8 = 3.007(4) Å (isomer A) and Sn1–N34 = 3.010(3) Å
(isomer B)).6d
The C–S–Sn–S torsion angles found in 2 (S2′–Sn1–S2–C1 =
173.3° for 2A and S3′–Sn2–S2–C5 = 173.9° for 2B respectively)
indicate the almost co-planar arrangement of the N, C, Sn and S
atoms. Thus, the conformation around the tin atom is trans-C2,
cis-N2, cis-S2. The C–Sn–C bond angles of 2 (C9–Sn1–C9_a =
127.17(19)° (2A), C23–Sn2–C23_b = 119.0(2)° (2B)) are
shorter than those previously found in [(C6H5)2Sn(cmbzt)2]
(Hcmbzt = 5-chloro-2-mercaptobenzothiazole) with C41–Sn1–
C31A = 137.7(5)° (isomer A) and C41–Sn1–C31B = 129.8(7)°
(isomer B)6d and in [(n-C4H9)2Sn(cmbzt)2] where C31–Sn1–
C41 is 131.8(3)°.6d
The supra-molecular assembly of 2 (Fig. 2B) is constructed by
strong hydrogen bonds O1[H1]⋯N4 = 2.931(6) Å.
In the case of complex 3 the trigonal bipyramidal geometry is
established by two carbon atoms from the aryl groups and one
sulfur (S2) atom from the MPMTH ligand which form the basal
triangle and one S1 and one N4 atom from the two MPMTH
ligands form the axis. Two de-protonated MPMTH ligands are
bonded to the tin atom (Sn1–S1 = 2.4664(8) and Sn1–S2 =
Fig. 3 (A) ORTEP diagram together with the labeling scheme of 3.
(B) Hydrogen bonding interactions lead to a 1D polymeric assembly.
Fig. 4 ORTEP diagram together with the labeling scheme of 4.
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 14568–14582 | 14575

View Article Online
Fig. 5 ORTEP diagram together with the labeling scheme of 5.
2.4265(8) Å). The Sn–C bonds are Sn1–C1 = 2.115(3) and Sn1–
C15 = 2.116(3) Å. It is noteworthy to mention that only one of
the two MPMTH ligands interacts with the tin(IV) ion through
Sn–N (Sn1–N4 = 2.763 Å) bonding interaction, while the corres-
ponding Sn1–N2 distance of the second MPMTH is 3.028 Å.
To ensure the trigonal bipyramidal geometry adopted by 3, the
geometric parameter tau17a (τ = (α − β)/60 where α is the great-
est and β the second greatest bond angle around the metal
center) is determined.17a The τ value is equal to zero for
perfectly tetragonal pyramidal geometry and unity for perfectly
trigonal bipyramidal geometry. The calculated value for 3 is
0.68, indicating distorted trigonal bipyramidal geometry.
Strong hydrogen bonds are also formed O1[H1]⋯N3 = 2.993(3)
Å (Fig. 3B). The strong hydrogen bonding interaction which
may prohibit the free rotation of phenol groups together with the
variation in the coordination mode of the MPMTH ligands
towards Sn(IV) might be affected in the environment of the
H[C2] atoms of the phenyl rings resulting in the two signals
observed in the H-NMR spectrum of 3 (see Experimental part).
The structures of compounds 4, 5 consist of [Ar2Sn(IV)] moi-
eties. The stereochemistry around the Sn(1) atom is trigonal
bipyramidal, with the equatorial plane being defined by N1, S1
and Cl1 atoms (4A) and N2, S2 and Cl2 atoms (4B). Thus, a
unique structure with an axial–equatorial arrangement of the
phenyl groups at Sn(1) is formed. These complexes (4, 5) are
examples of a pentacoordinated Ph3SnXY system with an axial–
equatorial arrangement of the phenyl groups at the Sn(1) center.
The calculated τ values17a are 0.63 (4A), 0.59 (4B) and 0.51 (5)
respectively.
The C–O bond distances found in complexes 1–5 lie between
1.368(5) (4A) to 1.388(4) (4B) Å which are shorter than the
av. value of 1.43 Å of alcoholic C–O[H] and longer than the
av. value of 1.24 Å of the CvO bond,17b indicating partial
double bonding interaction. This might be due to the de-
protonation of these oxygen atoms with the simultaneous for-
mation of the radical (Scheme 3).
Biological tests. The cytotoxicity of the complexes 1–5
against human breast adenocarcinoma (MCF-7) has been evalu-
ated by means of the Trypan blue method. The IC50 (μM) values
are 3.12 0.38 (1), 7.86 0.87 (2), 0.58 0.10 (3), >30 (4) and
>30 (5) μM (Table 6). The corresponding IC50 value of cisplatin
is 18.5 μM.7a Thus complexes 1–3 exhibit stronger activity than
cisplatin against MCF-7. Among 1–5, the strongest activity was
found for 3 (with trigonal bipyramidal geometry), which is 32-
fold stronger than that of cisplatin. It is mentioned that com-
plexes 4 and 5 show almost negligible activity although they
both have trigonal bipyramidal geometry. These two complexes
retain the chlorine atoms on the tin(IV) cation, while they both
exhibit strong metal–ligand linkage (Sn–N bond 2.412(3) (4A),
2.392(3) (4B) and 2.483(3) (5) Å, see Crystal structures).
Table 6 summarizes the IC50 values for cell viability found for
organotin(IV)–thioamide compounds against MCF-7 (human
breast adenocarcinoma), HeLa (human cervix carcinoma), WiDr
14576 | Dalton Trans., 2012, 41, 14568–14582
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 6 IC50 values for cell viability found for compounds 1–5 and other organotin(IV)–thioamide complexes against MCF-7 (human breast
adenocarcinoma), HeLa (human cervix carcinoma), WiDr (human colon carcinoma), OAW-42 (ovarian), A549 (lung), MDA-MB-231 (breast, ER
negative), Caki-1 (renal), LMS (leiomyosarcoma) cell lines
IC50 (μM)
Compounds
MCF-7
HeLa WiDr OAW-42 A-549 MDA-MB-231 Caki-1 LMS
Geometry
Ref.
1
2
3.12 0.38
7.86 0.87
Tetrahedral
Disorder
octahedral
Trigonal
bipyramidal
Trigonal
bipyramidal
Trigonal
*
*
3
4
5
0.58 0.1
>30
*
*
*
>30
bipyramidal
6.53 0.43 Square planar
Cisplatin
{{[Ph3Sn(O-HTBA)·0.7H2O]}n}n
18.5
0.103
7a,18
7a
a
0.105
0.065
0.2
0.235 0.203
0.24 0.106
0.12
0.133
Trigonal
bipyramidal
Trigonal
bipyramidal
Trigonal
[(n-Bu)3Sn(O-HTBA)·H2O]a
0.068
0.072
0.406 0.125
0.02
7b
{[Ph3Sn]2(MNA)·[(CH3)2CO]}b
0.0299
19
bipyramidal
Skew-trapezoidal 19a
bipyramid
[(n-Bu)2Sn(2-pyridinethiolato-N-oxide)2] 0.1154
0.43
2.26
1.68
[Ph2Sn(2-pyridinethiolato-N-oxide)2]
0.5636
0.5404
Distorted cis
octahedral
Distorted cis
octahedral
Trigonal
bipyramidal
Disorder
octahedral
Disorder
octahedral
Disorder
octahedral
Trigonal
bipyramidal
Trigonal
bipyramidal
Trigonal
bipyramidal
Distorted
octahedral
Distorted
octahedral
Distorted
octahedral
Distorted
octahedral
19a
19a
19b
19b
19b
19b
19c
19c
19c
19c
19c
19c
19c
[(Ph-CH2−)2Sn(2-pyridinethiolato-N-
oxide)2]
[Ph3Sn(PMTH)]c
0.1
[(n-Bu)2Sn(PMTH)2]c
[Ph2Sn(PMTH)2]c
0.65
1.0–2.0
[Me2Sn(PMTH)2]c
[Ph3Sn(MBZO)]d
20–60
1.3–3
1.5–3
0.5–0.8
2.5
[Ph3Sn(MBZT)]e
[Ph3Sn(CMBZT)]f
[(n-Bu)2Sn(MBZT)2]e
[Me2Sn(CMBZT)2·1.7(H2O)]f
[Bu2Sn(CMBZT)2]f
[Ph2Sn(CMBZT)2]f
5–7.5
0.6–0.8
0.3–0.5
*This work. a H2TBA = 2-thiobarbituric acid. b H2MNA = 2-mercapto-nicotinic acid. c PMTH = 2-mercapto-pyrimidine. d MBZOH = 2-mercapto-
benzoxazole. e MBZTH = 2-mercapto-benzothiazole. f CMBZTH = 5-chloro-2-mercapto-benzothiazole.
(human colon carcinoma), OAW-42 (ovarian), A549 (lung),
MDA-MB-231 (breast, ER negative), Caki-1 (renal), LMS (leio-
myosarcoma) cancer cell lines. It is shown that diorganotin(IV)
complexes with disorder octahedral geometry exhibit less
activity than those of triorganotin(IV) with trigonal bipyramidal
geometry. Also the complexes {[Ph3Sn(O-HTBA)·0.7H2O]}n
and [(n-Bu)3Sn(O-HTBA)·H2O] show selective cytotoxic
activity against carcinoma cells, especially against HeLa (human
cervical carcinoma) and MCF-7 (human breast adenocarcinoma)
cells, than against sarcoma (leiomyosarcoma cells) or other cell
were tested against breast cancer cells (MDA-MB-231) (breast,
ER negative), indicating that estrogen receptors (ER) may be
also involved in their antitumor mechanism.7a The high cyto-
toxic activity of complex 3 against MCF-7 cells might also be
attributed to the stable radical detected (see EPR studies) and its
blocking capacity of estrogen receptors as observed in the case
of [(n-Bu)3Sn(O-HTBA)·H2O] and [Ph3Sn(O-HTBA)·0.7H2O]
complexes.
Apart from thioamides, polyoxaalkyltin complexes of car-
boxylic acids were also tested for their antitumor activity.3b
Thus, complexes with formulae (n-Bu)8Sn4O2(L1)4 (MW =
1496.24 g mol−1) (n-Bu)8Sn4O2(L2)4 (MW = 1672.45 g mol−1),
Ph3Sn(L3) (MW = 661.33 g mol−1), and (n-Bu)3Sn(L3) (MW =
lines of carcinoma.7a This strong selective activity of [(n-Bu)3Sn-
7
(O-HTBA)·H2O] and {[Ph3Sn(O-HTBA)·0.7H2O]}n
com-
plexes against MCF-7 (ER positive) is not observed when they
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 14568–14582 | 14577

View Article Online
Fig. 6 PCA scores and correlation loadings plot for PC1 and PC2. A clustering pattern is achieved for samples with IC50 > 1 (low) and IC50 < 1
(high).
601.36 g mol−1) (where HL1 = CH3O(CH2CH2O)CH2COOH or
C5H9O4, HL2 = CH3O(CH2CH2O)2CH2COOH or C7H13O3 and
HL3 = benzocrownCOOH or C15H13O3) have been tested
against human tumor cell lines, MCF-7, EVSA-T (breast cancer
cells), WiDr (a colon cancer), IGROV (an ovarian cancer), M19
MEL (a melanoma), A498 (a renal cancer) and H226 (a lung
cancer). Among them, complex (n-Bu)8Sn4O2(L2)4 exhibits the
strongest activity against cancer cell lines with IC50 values less
than 0.0006 μM (or 1 ng ml−1) against MCF-7, EVSA-T,
IGROV, M19 MEL, A498 and H226 cell lines respectively,
while against WiDr its IC50 value is less than 0.0026 μM (or
<1.8 ng ml−1).3b These IC50 values indicate far higher cytotoxic
activity of this type of organotin complex than that of 1–5.
However, in contrast to the organotin complexes of thioamides
with formulae [(n-Bu)3Sn(O-HTBA)·H2O] and [Ph3Sn-
(O-HTBA)·0.7H2O], the complexes of benzocrown carboxylic
acid HL3 (Ph3Sn(L3) and (n-Bu)3Sn(L3)) show higher activity
against the ER-negative cell line (EVSA-T) (the IC50 value is
<0.003 μM or <2 ng ml−1 for both complexes) than against the
MCF-7 cell line (ER-positive cell line) (where the IC50 values
are 0.0044 μM or 2.9 ng ml−1 and 0.0055 μM or 3.3 ng ml−1
respectively).3b Since both types of organotin(IV) complexes
with either the thioamide (H2TBA) or the benzocrown car-
boxylic acid (HL3) adopt similar geometry (trigonal bipyrami-
dal), the alteration in biological activity might be due to the
different kinds of ligands (thioamides or polyoxa-carboxylic
acids) used.
Computational studies – multivariate statistical analysis. In
an effort to quantify the inhibition activity against MCF-7 of
similar organotin complexes (included in Table 6), as this is
expressed by the corresponding IC50 values, we used a combi-
nation of a descriptive analysis based on density functional
theory (DFT) methods and principal components analysis (PCA)
algorithms. The first two PCs are depicted in Fig. 6 explaining
almost the total variance of the data. The plot shows distinct
group clustering especially for the cases with low inhibitory
action (IC50 > 1) indicating that IC50 is a significant discriminat-
ing factor effectively explained by the physicochemical charac-
teristics under study. The Hotelling T2 ellipse, indicating the
14578 | Dalton Trans., 2012, 41, 14568–14582
This journal is © The Royal Society of Chemistry 2012

View Article Online
95% confidence limit, reveals no potential outliers lying outside
the ellipse. By inspecting the correlation loadings plot, we con-
clude that significant properties for the complexes with limited
inhibition activity (IC50 > 1) are DM, CE and TNE while for
complexes with IC50 < 1 the most statistically significant proper-
ties are DG(sol) and DE which are negatively correlated with CE
and TNE. Far less significant, in this case, is DM. Thus, DM is
inversely correlated with biological activity and decreasing the
polarity of a molecule belonging to a related organotin set of
complexes will increase its biological effectiveness.
To relate the variation of the IC50 values (dependent variable)
to the variations of energetic parameters (independent variables)
calculated from DFT studies and statistically indexed by PCA,
we have carried out partial least squares (PLS) regression analy-
sis. This method performs particularly well when the X-data are
correlated like in this case (energy related terms). In the calcu-
lations we have included the descriptors which were shown as
highly significant by the PCA, namely DM, CE and TNE for the
complexes with low activity and DG(sol), CE, TNE, RE and
DM for the complexes with high activity. In constructing the
latent components in PLS from the available set of descriptors
we have found that the most relevant descriptors are DM and
DG(solv) as expected from the initial PCA analysis. The models
developed by PLS regression analysis are given by the following
expressions:
Conclusions
Aiming at the development of new antitumor agents, the antioxi-
dant 2,6-di-tert-butylphenol fragments and different S-donor
ligands were combined with tin(IV) cations. Thus, five diorgano-
tin(IV) complexes with the 2,6-di-tert-butylphenol moiety with
various thioamides were synthesized and structurally character-
ized. The geometries adopted varied from the tetrahedron
dichloride [(tert-Bu-)2(HO-Ph)]2SnCl2 (1), distorted octahedral
in {[(tert-Bu-)2(HO-Ph)]2Sn(PMT)2} (2) and trigonal bipyrami-
dal in {[(tert-Bu-)2(HO-Ph)]2Sn(MPMT)2} (3), {[(tert-Bu-)2-
(HO-Ph)]2SnCl(PYT)} (4) and {[(tert-Bu-)2(HO-Ph)]2SnCl-
(MBZT)} (5). The cytotoxicity of 1–5 against MCF-7 has been
also evaluated. Complex 3 shows strong such activity (IC50
0.58 0.1 μM).
=
According to Huber et al.20 the structures of all active com-
pounds are characterized by (i) the availability of coordination
positions at Sn and (ii) the occurrence of relatively stable ligand–
Sn bonds, e.g. Sn–N and Sn–S, and their slow hydrolytic
decomposition. In agreement with that, the significant strong
anti-cancer activity evaluated for 3 is attributed to the availability
of coordination positions around Sn(IV) ions of the five coordi-
nated tin(IV) atom. The negligible anti-tumor activity shown by
compounds 4 and 5, on the other hand, can be ascribed to their
high stability as a result of the very strong ligand–tin(IV) coordi-
nation bonding interactions (Sn–S, Sn–N bonds), which might
be due to the presence of chlorine atoms on the tin ion.
IC50 ðlowÞ ¼ ꢀ0:079 ꢁ CE ꢀ 1:77 ꢁ TNE ꢀ 1:29 ꢁ DM
þ 154:06
Organotin(IV) complexes of thioamides show selective activity
against human breast adenocarcinoma (MCF-7) cells (Table 6).
This strong selective activity in the case of [(n-Bu)3Sn-
7
(O-HTBA)·H2O] and {[Ph3Sn(O-HTBA)·0.7H2O]}n
com-
and
plexes was observed against MCF-7 (ER positive) but not
against breast cancer cells (MDA-MB-231) (breast, ER nega-
tive). This indicates that estrogen receptors (ER) may be
involved in their antitumor mechanism.7a Complexes of benzo-
crown carboxylic acid Ph3Sn(L3) and (n-Bu)3Sn(L3),3b on the
other hand, adopt trigonal bipyramidal geometry, however they
show higher activity against the ER-negative cell line (EVSA-T)
IC50 (high) = −0.002 * DG(sol) − 0.013 * CE + 0.110 * DE
− 0.005 * TNE + 0.030 * DM − 0.62.
Fig. 7 depicts the graphical representations of the above linear
equations and the fitting parameters (r2 = 0.93 for both cases).
Fig. 7 PLS regression analysis for organotin complexes with low (a) and high (b) biological activity.
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 14568–14582 | 14579

View Article Online
than against the MCF-7 cell line (ER-positive cell line),3b indi-
cating that this alteration might be due to the different kinds of
ligands (thioamides or polyoxa-carboxylic acids) used.
The high cytotoxic activity of complex 3 against MCF-7 cells
might also be attributed to the stable radical detected (see EPR
studies) and its blocking capacity of estrogen receptors.
N: 7.18; S: 8,52%, calculated for C36H48N4O2S2Sn: C: 57.53;
H: 6.44; N: 7.45; S: 8.53%. IR (cm−1): 3648 w, 3420 broad,
2967 s, 2872 m, 1715 m, 1565 m, 1543 m, 1427 m, 1377 s,
1220 w, 1181 m, 1121 w, 989 w, 872 w, 803 w, 773 w, 748 w,
640 w, 575 w, 375 s. 1H-NMR (δ (ppm), CDCl3): 1.38 (s, 36 H,
3
C(CH3)3); 5.29 (s, 2 H, OH); 6.89 (t, 2 H, JHH = 5 Hz, C5H in
3
PMT); 7.65 (s, JH–Sn = 80 and 83 Hz, 4H, C2H in R); 8.33 (d,
3
4 H, JHH = 5 Hz, C4H in PMT). 13C- NMR (δ (ppm), CDCl3):
4. Experimental
30.41 (C(CH3)3), 34.62 (C(CH3)3), 115.60 (C5 in PMT), 131.87
(C3 in R), 132.13 (2JC–Sn = 68 Hz, C2 in R), 135.96 (1JC–Sn
=
Materials and instruments
458 Hz, C1 in R), 155.31 (C4 in R), 156.68 (C4,6 in PMT),
175.35 (C2 in PMT). 119Sn-NMR (δ (ppm), CDCl3): −406.87
(Fig. S30†).
All solvents used were of reagent grade, while thioamides
(Aldrich, Merck) were used with no further purification.
2-Mercapto-4-methyl-pyrimidine was used in the form of hydro-
chloride MPMTH·HCl (Aldrich, 99%). Di-(3,5-di-tert-butyl-
4-hydroxyphenyl)tin dichloride was prepared as described pre-
viously.12 Infrared spectra in the region of 4000–370 cm−1 were
obtained in KBr pellets. The 1H, 13C-NMR spectra were
recorded on a Bruker AC 250, 400 MHFT-NMR instrument in
CDCl3 or DMSO-d6. Chemical shifts are given in ppm using
1H-TMS as an internal reference. Elemental analysis for C, H, N
and S was carried out with a Carlo Erba EA MODEL 1108. The
samples were dissolved in CHCl3 and put at target. The 119Sn
Mössbauer spectra were collected at various sample temperatures
(85–150 K) with a constant acceleration spectrometer equipped
with a CaSnO3 source kept at low temperature. ESR spectra were
recorded on the Bruker EMX spectrometer at X-band frequency
(9.8 GHz). The measurements were carried out after pre-evacua-
tion (10−2 Torr) of tubes with solutions in toluene of samples
(concentration 1 × 10−4 mol L−1). The oxidant PbO2 (Aldrich)
was taken in a tenfold excess.
3; R2Sn(MPMT)2: Mol. Wt.: 779.69; Yield 56%;
m.p. 200–210 °C (decomp.). Elemental analysis, found: C: 58.31;
H: 6.49; N: 7.24; S: 8.76%, calculated for C38H52N4O2S2Sn: C:
58.54; H: 6.72; N: 7.19; S: 8.23%. IR (cm−1): 3636 s, 3449
wide, 2958 s, 2874 m, 1430 s, 1401 w, 1320 m, 1239 s, 1147 m,
1122 s, 1025 w, 885 w, 864 w, 745 w, 573 w, 525 w,
382 w. 1H-NMR (δ (ppm), DMSO d6): 1.38 (s, 36 H, C(CH3)3);
2.31 s (br, 6 H, CH3C4 in MPMT), 6.90 (s, 2 H, C2H in R);
3
3
7.04 (d, 2 H, JHH = 5 Hz, C5H in MPMT); 7.24 (s, 2 H, JH–Sn
= 60 Hz, C2H in R); 8.32 (d, 2 H, 3JHH = 5 Hz, C6H in MPMT).
13C-NMR (δ (ppm), DMSO d6): 31.03 (C(CH3)3), 35.02
(CH3C4 in MPMT), 35.30 (C(CH3)3), 116.71 (C5 in MPMT),
124.95 (1JC–Sn = 401 Hz, C1 in R), 133.26 (C2 in R), 139.33
(C3 in R), 154.50 (C4 in R), 157.42 (C6 in MPMT), 163.30
(C4 in MPMT), 180.59 (C2 in MPMT).
4; R2Sn(PYT)Cl: Mol. Wt.: 674.95; Yield 60%;
m.p. 180–190 °C (decomp.). Elemental analysis, found: C: 58.10;
H: 6.78; N: 1.47; S: 4.33%, calculated for C33H46ClNO2SSn: C:
58.72; H: 6.87; N: 2.08; S: 4.76%. IR (cm−1): 3631 s, 2959 s,
2873 m, 1708 w, 1585 w, 1429 s, 1401 w, 1362 w, 1238 m,
1203 m, 1121 m, 1001 w, 885 w, 808 w, 760 w, 727 w, 682 w,
574 w, 502 w, 375 s. 1H-NMR (δ (ppm), CDCl3): 1.44 (s, 36 H,
Synthesis of complexes 2–5
Complexes 2–5 were prepared as follows. 0.4 mmol of the
appropriate thiol ligand (45 mg PMTH, 50 mg MPMTH, 45 mg
PYTH, 65 mg MBZTH) was suspended in 5 ml H2O and 0.4 ml
1 M KOH (0.4 mmol) was then added. The mixture was stirred
until clearness. In the case of MPMTH·HCl 2 equiv. of KOH
were added. A solution of 120 mg of 1 (0.2 mmol) in 3 ml
MeOH was then added to the previous solution. A white precipi-
tate formed immediately, while the mixture was stirred for 1 h.
The precipitate was filtered off, washed with 5 ml of cold dis-
tilled water and dried in air overnight.
3
C(CH3)3); 5.39 (s, 2 H, OH); 7.13 (dd, 1 H, JHH = 6.5 Hz,
3JHH = 6.0 Hz, C5H in PYT); 7.39 (d, 1 H, 3JHH = 8 Hz, C3H in
3
3
4
PYT); 7.63 (ddd, 1 H, JHH = 8 Hz, JHH = 6.5 Hz, JHH
=
1.8 Hz, C4H in PYT); 7.72 (s, 4H, JH–Sn = 84 Hz, C2H in R);
3
8.25 (d, 1 H, JHH = 6 Hz, C6H in PYT). 13C- NMR (δ (ppm),
3
CDCl3): 29.18 (C(CH3)3), 33.53 (C(CH3)3), 117.65 (C3 in
PYT), 118.48 (C5 in PYT), 123.17 (1JC–Sn = 510 Hz, C1 in R),
123.81 (C4 in PYT), 131.12 (C2 in R), 135.08 (C4 in PYT),
137.93 (C3 in R), 145.05 (C4 in R), 154.72 (C2 in PYT).
Crystals of 1 were obtained by slow evaporation of an
o-xylene solution. Colorless crystals of 2 and 4 suitable for
X-ray analysis were formed by slow evaporation of a methanol–
acetonitrile solution (1 : 1), while crystals of 3 and 5 were
obtained by slow diffusion of hexane in CHCl3 solutions.
1; R2SnCl2: Mol. Wt.: 600.24; m.p. 234–235 °C. IR (cm−1):
3614 s, 2963 s, 2872 m, 1571 m, 1480 m, 1446 m, 1427 s,
1317 s, 1241 s, 1143 s, 1120 s, 930 w, 874 m, 808 w, 776 m,
606 w, 568 m, 376 s. 1H-NMR (δ (ppm), CDCl3): 1.49 (s, 36 H,
5; R2Sn(mbzt)Cl: Mol. Wt.: 731.04; Yield 82%; m.p. 180 °C
(decomp.). Elemental analysis, found: C: 57.49; H: 6.48; N:
1.95; S: 8.57%; calculated for C35H46ClNO2S2Sn: C: 57.50; H:
6.34; N: 1.92; S: 8.77%. IR (cm−1): 3632 s, 3430 wide, 2959 s,
2874 m, 2344 m, 2362 m, 1429 s, 1402 m, 1320 m, 1240 s,
1203 w, 1121 s, 1078 w, 1036 m, 885 w, 752 m, 670 w, 571 w,
1
381 w. H-NMR (δ (ppm), CDCl3): 1.39 (s, 36 H, C(CH3)3);
5.43 (s, 2 H OH), 7.32–7.38 (m, 1 H, C7H in MBZT); 7.42–7.48
(m, 1 H, C8H in MBZT); 7.73–7.77 (m, 2 H, C9H, C6H in
3
3
C(CH3)3); 5.58 (s, 2 H, OH); 7.52 (s, JH–Sn = 82 and 86 Hz,
MBZT), 7.78 (s, 4 H, JH–Sn = 88 Hz, C2H in R). 13C-NMR
4 H, C2H in R). 13C- NMR (δ (ppm), CDCl3): 30.12 (C(CH3)3),
34.67 (C(CH3)3), 127.48 (C1 in R), 131.85 (2JC–Sn = 76 Hz,
C2 in R), 137.25 (C3 in R), 157.00 (C4 in R).
(δ (ppm), CDCl3): 30.39 (C(CH3)3), 34.40 (C(CH3)3),
111.80 (C9 in MBZT), 119.72 (1JC–Sn = 503 Hz, C1 in R),
121.62 (C6 in MBZT), 124.76 (C7 in MBZT), 125.02 (C2 in R),
127.30 (C8 in MBZT), 131.95 (C5 in MBZT), 136.02 (C3 in R),
137.37 (C4 in MBZT), 153.95 (C4 in R), 159.38 (C2 in MBZT).
2; R2Sn(PMT)2: Mol. Wt.: 751.63; Yield 71%; m.
p. 189–191 °C. Elemental analysis, found: C: 57.39; H: 6.66;
14580 | Dalton Trans., 2012, 41, 14568–14582
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 7 Crystal data and the structure refinement details for the complexes 1–5
1
2
3
4
5
Empirical formula
Fw
C28H40Cl2O2Sn
598.21
C36H48N4O2S2Sn
751.63
C38H52N4O2S2Sn
779.69
C33H41ClNO2SSn
671.41
C35H44ClNO2S2Sn
729.01
Temperature (K)
Cryst. size (mm)
Cryst. system
Space group
a (Å)
b (Å)
c (Å)
100(1)
100(1)
0.03 × 0.03 × 0.10
Orthorhombic
C2221
9.2953(4)
24.9586(8)
30.4963(12)
90
100(1)
100(1)
100(1)
0.01 × 0.02 × 0.04
Monoclinic
P21/c
13.8030(4)
10.6301(4)
20.1254(7)
90
0.05 × 0.07 × 0.09
Monoclinic
P21/c
10.8406(2)
19.1873(4)
18.7686(4)
90
0.04 × 0.07 × 0.21
Monoclinic
C2/c
36.0304(13)
11.0367(3)
33.5317(12)
90
0.03 × 0.04 × 0.13
Monoclinic
P21/n
13.0191(4)
10.1141(3)
27.4822(9)
90
α (°)
β (°)
102.781(3)
90
2879.78(17)
4
1.380
8.9
90
90
7075.1(5)
8
1.411
7.1
0.0329, 0.1365, 1.14
95.944(2)
90
3882.91(14)
4
1.334
0.8
93.048(3)
90
13315.2(8)
8
1.340
7.6
102.059(3)
90
3538.90(19)
4
1.368
7.8
γ (°)
V (Å3)
Z
ρcalcd (g cm−3
)
μ (mm−1
R, wR2 [I > 2σ(I)], S
)
0.0835, 0.1589, 1.09
0.0357, 0.0884, 1.03
0.0505, 0.1449, 1.08
0.0381, 0.1052, 1.05
Crystallography: X-ray structure determination
RE. Evaluated electronic properties include the energy of the
Kohn–Sham’s frontier orbitals (HOMO and LUMO), the chemi-
cal potential (CP), global hardness (CH) and electrophilicity
(EP). The three latter descriptors were calculated within the finite
difference approximation and Koopman’s approach23 according
to the equations CP = (HOMO + LUMO)/2, CH = (LUMO −
HOMO)/2 and EP = CP2/2CH. Finally, the dipole moment
(DM) was calculated as an electrostatic descriptor which
efficiently explains the molecular charge distribution.
Multivariate statistical methods were employed for the analy-
sis of the above physicochemical descriptors. PCA was per-
formed on the produced 11 × 12 (compounds × 11 calculated
descriptors plus IC50) correlation matrix to effectively remove
the redundancy of the original data set by compressing it into a
few orthogonal uncorrelated principal components (PCs) con-
structed by weighted linear combinations of the original vari-
ables. These new composite variables describe most of the initial
information which is actually the physicochemical properties of
the complexes. The first PC explains as much of the variance as
possible followed by the second one and so on. Scores are the
coordinates related to PCs and loadings are the related coeffi-
cients between the original variables and the new PCs. The
spatial relationship of the data is visualized by plotting a
2-dimensional score plot of the PCs in which possible clustering
patterns are depicted.
Intensity data for the crystals of 1–5 were collected on an Oxford
Diffraction CCD instrument, using graphite monochromated Mo
radiation (λ = 0.71073 Å). Cell parameters were determined by
least-squares refinement of the diffraction data from 25
reflections.21a
All data were corrected for Lorentz-polarization effects and
absorption.21a,b The structures were solved with direct methods
with SHELXS9721c and refined by full-matrix least-squares pro-
cedures on F2 with SHELXL97.21d All non-hydrogen atoms
were refined anisotropically, hydrogen atoms were located at cal-
culated positions and refined via the “riding model” with isotro-
pic thermal parameters fixed at 1.2 (1.3 for CH3 groups) times
the Ueq value of the appropriate carrier atom. Significant crystal
data are given in Table 7.
Biological tests
These studies were performed as previously reported.18
Computational studies – theoretical methods
Eleven organotin compounds were analyzed regarding their cyto-
toxic activity against MCF-7 cells (Table 6) and divided into two
groups according to IC50 values (lower and higher than 1).
Single point direct SCF calculations were carried out at the
B3LYP/3-21G*/LANL2DZ(Sn) level using the Gaussian03W22
software package. Calculations were performed on the PM3 opti-
mized molecular geometries initially derived from X-ray diffrac-
tion methods. Eleven descriptors were obtained at the DFT/
polarizable continuum model (PCM) level in aqueous solutions.
These included electrostatic and non-electrostatic interactions
due to solvation effects and electronic structure calculations of
the organotin complexes. The electrostatic term is essentially the
total free energy in solution (DG(sol)) while the non-electrostatic
terms include the cavitation energy (CE) based on the surface
defined by the van der Waals spheres and the dispersion (DE)/
repulsion (RE) energy based on the solvent’s accessible surface.
The total non-electrostatic term (TNE) is given by CE + DE +
Acknowledgements
The NATO grant PDD(CP)-(CBP.NR.NRCLG 983167) for the
exchange of scientists is acknowledged for financial support
during the visit of Dr D.S. to the University of Ioannina, Greece.
The work was also supported by the Russian Foundation
for Basic Research (grants No. 12-03-00776, 11-03-01165,
11-03-12088).
References
1 A. G. Davies, Organotin Chemistry, VCH, Verlagsgesellschaft, Wein-
heim, Germany, 1997.
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 14568–14582 | 14581

View Article Online
2 M. Gielen and E. R. T. Tiekink, Tin compounds and their therapeutic
potential, in Metallotherapeutic Drugs and Metal-Based Diagnostic
Agents: The Use of Metals in Medicine, ed. M. Gielen and E. R. T.
Tiekink, John Wiley & Sons, Ltd., 2005.
3 (a) M. Gielen, Appl. Organomet. Chem., 2002, 16, 481–494;
(b) M. Gielen, M. Biesemans and R. Willem, Appl. Organomet. Chem.,
2005, 19, 440–450.
14 (a) P. J. Smith, Chemistry of Tin, Blackie Academic & Professional an
imprint of Thomson Science, London UK, 1998; (b) R. Schmiedgen,
F. Huber, A. Silvestri, G. Ruisi, M. Rossi and R. Barbieri, Appl. Organo-
met. Chem., 1998, 12, 861–871; (c) R. V. Parish, In Mossbauer Spec-
troscopy Applied to Inorganic Chemistry, ed. G.J, Long, Plenum Press,
New York, 1984; (d) G. M. Bancroft and R. H. Platt, Adv. Inorg. Chem.
Radiochem., 1972, 15, 59–133.
4 S. K. Hadjikakou and N. Hadjiliadis, Coord. Chem. Rev., 2009, 253,
235–249.
15 (a) S. Mahmood, S. Ali, M. H. Bhatti, M. Mazhar and K. Shahid,
Turk. J. Chem., 2004, 28, 17–26; (b) P. C. Srivastava, A. Trivedi and
P. Singh, Polyhedron, 1990, 1, 125–128; (c) I. A. Portnyagin, V. V. Lunin
and M. S. Nechaev, J. Organomet. Chem., 2008, 693, 3847–3850;
(d) N. N. Meleshonkova, D. B. Shpakovsky, A. V. Fionov,
A. V. Dolganov, T. V. Magdesieva and E. R. Milaeva, J. Organomet.
Chem., 2007, 692, 5339–5344; (e) T. P. Lockhart, W. F. Manders and
J. J. Zuckerman, J. Am. Chem. Soc., 1985, 107, 4546; (f) W. Rehman,
K. M-Baloch and A. Badshah, Eur. J. Med. Chem., 2008, 43,
2380–2385; (g) W. Rehman, A. Badshah, S. Khan and L.-T.-A. Tuyet,
Eur. J. Med. Chem., 2009, 44, 3981–3985.
16 A. G. Milaev, V. B. Panov and O. Yu. Okhlobystin, J. Gen. Chem., 1978,
48, 2715–2720.
17 (a) A. W. Addison, T. Nageswara Rao, J. Reedijk, J. Van Rijn and
G. C. Verschoor, J. Chem. Soc., Dalton Trans., 1984, 1349–1356;
(b) D. F. Shiver, P. W. Atkins and C. H. Langford, in Inorganic Chemstry,
3rd edn, Oxford University Press, Oxford, U.K., 1999.
5 A. Gennari, R. Bleumink, B. Vivani, C. L. Galli, M. Marinovich,
R. Pieters and E. Corsini, Toxicol. Appl. Pharmacol., 2002, 181, 27–131.
6 (a) M. N. Xanthopoulou, S. K. Hadjikakou, N. Hadjiliadis, M. Kubicki,
S. Karkabounas, K. Charalabopoulos, N. Kourkoumelis and T. Bakas,
J. Organomet. Chem., 2006, 691, 1780–1789; (b) M. N. Xanthopoulou,
S. K. Hadjikakou, N. Hadjiliadis, M. Schurmann, K. Jurkschat,
A. Michaelides, S. Skoulika, T. Bakas, J. Binolis, S. Karkabounas and
K. Charalabopoulos, J. Inorg. Biochem., 2003, 96, 425–434;
(c) I. I. Verginadis, S. Karkabounas, Y. Simos, E. Kontargiris,
S. K. Hadjikakou, A. Batistatou, A. Evangelou and K. Charalabopoulos,
Eur. J. Pharm. Sci., 2011, 42, 253–261; (d) M. N. Xanthopoulou,
S. K. Hadjikakou, N. Hadjiliadis, M. Kubicki, S. Skoulika, T. Bakas,
M. Baril and I. S. Butler, Inorg. Chem., 2007, 46, 1187–1195.
7 (a) V. I. Balas, I. I. Verginadis, G. D. Geromichalos, N. Kourkoumelis,
L. Male, M. B. Hursthouse, K. H. Repana, E. Yiannaki,
K. Charalabopoulos, T. Bakas and S. K. Hadjikakou, Eur. J. Med. Chem.,
2011, 46, 2835–2844; (b) V. I. Balas, S. K. Hadjikakou, N. Hadjiliadis,
N. Kourkoumelis, M. E. Light, M. Hursthouse, A. K. Metsios and
S. Karkabounas, Bioinorg. Chem. Appl., 2008, Article ID 654137.
8 A. Szorcsik, L. Nagy, M. Scopelliti, A. Deak, L. Pellerito and
K. Hegetschweiler, J. Organomet. Chem., 2005, 690, 2243–2253.
9 (a) D. M. Parkin, F. Bray, J. Ferlay and P. Pisani, CA Cancer J. Clin.,
2005, 55, 74–108; (b) S. Leporatti, D. Vergara, A. Zacheo, V. Vergaro,
G. Maruccio, R. Cingolani and R. Rinaldi, Nanotechnology, 2009, 20,
055103; (c) N. Kobakhidze, N. Farfan, M. Romero, J. M. Mendez-Stiva-
let, M. G. Ballinas-Lopez, H. Garcia-Ortega, O. Dominguez,
R. Santillan, F. Sanchez-Bartez and I. Gracia-Mora, J. Organomet.
Chem., 2010, 695, 1189–1199; (d) A. W. Norman, M. T. Mizwicki and
D. P. G. Norman, Nat. Rev. Drug Discovery, 2004, 3, 27–41;
(e) A. S. Levenson and V. C. Jordan, Cancer Res., 1997, 57, 3071–3078;
(f) M. Razandi, A. Pedram and E. R. Levin, Mol. Endocrinol., 2000, 14,
1434–1447.
18 C. N. Banti, A. D. Giannoulis, N. Kourkoumelis, A. M. Owczarzak,
M. Poyraz, M. Kubicki, K. Charalabopoulos and S. K. Hadjikakou,
Metallomics, 2012, 4, 545–560.
19 (a) C. Ma and J. Zhang, Appl. Organomet. Chem., 2003, 17, 788–794;
(b) M. N. Xanthopoulou, S. K. Hadjikakou, N. Hadjiliadis,
N. Kourkoumelis, E. R. Milaeva, J. A. Gracheva, V.-Y. Tyurin,
I. I. Verginadis, S. Karkabounas, M. Baril and I. S. Butler, Russ. Chem.
Bull., 2007, 56, 767–773; (c) M. N. Xanthopoulou, S. K. Hadjikakou,
N. Hadjiliadis, E. R. Milaeva, J. A. Gracheva, V.-Y. Tyurin,
N. Kourkoumelis, K. C. Christoforidis, A. K. Metsios, S. Karkabounas
and K. Charalabopoulos, Eur. J. Med. Chem., 2008, 43, 327–335.
20 A. K. Saxena and F. Huber, Coord. Chem. Rev., 1989, 95, 109–123.
21 (a) CrysAlis RED, version 1.171.31.5; Oxford Diffraction Ltd. (release
28–08–2006 CrysAlis171.NET); (b) Oxford Diffraction, CRYSALIS
CCD and CRYSALIS RED, version p171.29.2; Oxford Diffraction Ltd:
Abingdon, Oxford, England, 2006; (c) G. M. Sheldrick, Acta Crystal-
logr., Sect. A: Fundam. Crystallogr., 1990, 46, 467; (d) G. M. Sheldrick,
Acta Crystallogr., Sect. A: Fundam. Crystallogr., 2008, 64, 112–122.
22 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery Jr., T. Vreven, K. N. Kudin,
J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone,
B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson,
H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li,
J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma,
G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul,
S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-
Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill,
B. Johnson, W. Chen, M. W. Wong, C. Gonzalez and J. A. Pople, GAUS-
SIAN 03 (Revision C.02), Gaussian, Inc., Wallingford CT, 2004.
10 E. Denisov, Handbook of Antioxidants, CRC Press, Boca Raton, USA,
1995.
11 (a) E. R. Milaeva, S. I. Filimonova, N. N. Meleshonkova, L. G. Dubova,
E. F. Shevtsova, S. O. Bachurin and N. S. Zefirov, Bioinorg. Chem. Appl.,
2010, DOI: 10.1155/2010/165482, Article ID 165482; (b) E. R. Milaeva,
Yu. A. Gracheva, D. B. Shpakovsky, O. A. Gerasimova, V. Yu. Tyurin
and V. S. Petrosyan, J. Porphyrins Phthalocyanines, 2003, 7, 719–724;
(c) E. R. Milaeva, V. Yu. Tyurin, D. B. Shpakovsky, O. A. Gerasimova,
Z. Jingwei and Yu. A. Gracheva, Heteroat. Chem., 2006, 17, 475–480;
(d) E. R. Milaeva, O. A. Gerasimova, Z. Jingwei, D. B. Shpakovsky,
S. A. Syrbu, A. S. Semeykin, O. I. Koifman, E. G. Kireeva,
E. F. Shevtsova, S. O. Bachurin and N. S. Zefirov, J. Inorg. Biochem.,
2008, 102, 1348–1358; (e) E. R. Milaeva, V. Yu. Tyurin, Yu.
A. Gracheva, M. A. Dodochova, L. M. Pustovalova and
V. N. Chernyshev, Bioinorg. Chem. Appl., 2006, DOI: 10.1155/bca/2006/
64927, Article ID64927.
12 A. G. Milaev and O. Yu. Okhlobystin, Russ. J. Gen. Chem., 1978, 48,
1186.
13 K. C. Molloy, T. G. Purcell, D. Cunningham, P. McCardle and
T. Higgins, Appl. Organomet. Chem., 1987, 1, 119–131.
23 P. Geerlings, F. De Prof and W. Langenaeker, Conceptual density func-
tional theory, Chem. Rev., 2003, 103, 1793–1874.
14582 | Dalton Trans., 2012, 41, 14568–14582
This journal is © The Royal Society of Chemistry 2012