The triphenyltin(VI) complexes of NSAIDs and derivatives. Synthesis, crystal structure and antiproliferative activity. Potent anticancer agents

Article abstract of DOI:10.1016/j.jinorgbio.2010.10.008

The novel triphenyltin(IV) esters of flufenamic acid (1), Hflu, [Ph ₃Sn(flu)] (2), and of [2-(2,3-dichlorophenylamino)benzoic acid] (3), Hdcpa, [Ph₃Sn(dcpa)] (4) have been structurally characterized by means of vibrational and ¹H, ¹³C NMR spectroscopic studies. The crystal and molecular structures of [SnPh₃(dcpa)(DMSO)] 4a are described. The molecular structure of 4a reveals that the Sn atom has a distorted trigonal bipyramidal coordination geometry with equatorial phenyl groups and the carboxylate and dimethylsulfoxide oxygen atoms occupying axial positions. The crystal structure of 4a is self-assembled by C-H - -π and π-π stacking interactions. The in vitro cytotoxic activity of 1-4 and of the related non-steroidal anti-inflammatory drugs, NSAIDs, [2-(2,6- dimethylphenylamino)benzoic acid], Hdmpa (5), [Ph₃Sn(dmpa)] (6), [2-(2,3-dimethylphenylamino)benzoic acid], mefenamic acid, Hmef (7) and [Ph ₃Sn(mef)] (8) has been evaluated against the cancer cell lines MCF-7, T-24, A-549 and L-929. The ligands exhibited very poor cytotoxic activity against the four cancer cell lines. Complex 6 exhibits the highest activity and selectivity against A-549 and MCF-7 cancer cell lines and complex 8 the highest activity and selectivity against T-24 cancer cell line. The cytotoxic results indicate that coupling of Hdmpa and Hmef with R₃Sn(IV) metal center results in complexes with important biological properties and remarkable cytotoxic activity, since they display IC₅₀ values in a μΜ range better to that of the antitumor drug cis-platin. Complexes 6 and 8 are considered as excellent antitumor compounds and the results of this study represent the discovery of triphenyltin(IV)esters as a potential novel class of anticancer agents.

Full text of DOI:10.1016/j.jinorgbio.2010.10.008

Journal of Inorganic Biochemistry 105 (2011) 195–201
Contents lists available at ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
The triphenyltin(VI) complexes of NSAIDs and derivatives. Synthesis, crystal
structure and antiproliferative activity. Potent anticancer agents
⁎
Vaso Dokorou, Alexandra Primikiri, Dimitra Kovala-Demertzi
Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110, Ioannina, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2010
Received in revised form 8 October 2010
Accepted 8 October 2010
Available online 16 October 2010
The novel triphenyltin(IV) esters of flufenamic acid (1), Hflu, [Ph3Sn(flu)] (2), and of [2-(2,3-dichlorophe-
nylamino)benzoic acid] (3), Hdcpa, [Ph3Sn(dcpa)] (4) have been structurally characterized by means of
vibrational and 1H, 13C NMR spectroscopic studies. The crystal and molecular structures of [SnPh3(dcpa)
(DMSO)] 4a are described. The molecular structure of 4a reveals that the Sn atom has a distorted trigonal
bipyramidal coordination geometry with equatorial phenyl groups and the carboxylate and dimethylsulf-
oxide oxygen atoms occupying axial positions. The crystal structure of 4a is self-assembled by C–H—π and π–π
stacking interactions. The in vitro cytotoxic activity of 1–4 and of the related non-steroidal anti-inflammatory
drugs, NSAIDs, [2-(2,6-dimethylphenylamino)benzoic acid], Hdmpa (5), [Ph3Sn(dmpa)] (6), [2-(2,3-
dimethylphenylamino)benzoic acid], mefenamic acid, Hmef (7) and [Ph3Sn(mef)] (8) has been evaluated
against the cancer cell lines MCF-7, T-24, A-549 and L-929. The ligands exhibited very poor cytotoxic activity
against the four cancer cell lines. Complex 6 exhibits the highest activity and selectivity against A-549 and
MCF-7 cancer cell lines and complex 8 the highest activity and selectivity against T-24 cancer cell line. The
cytotoxic results indicate that coupling of Hdmpa and Hmef with R3Sn(IV) metal center results in complexes
with important biological properties and remarkable cytotoxic activity, since they display IC50 values in a μΜ
range better to that of the antitumor drug cis-platin. Complexes 6 and 8 are considered as excellent antitumor
compounds and the results of this study represent the discovery of triphenyltin(IV)esters as a potential novel
class of anticancer agents.
Keywords:
Triphenyltin(IV)
Complexes
Crystal structure
Spectral studies
Antiproliferative activity
© 2010 Elsevier Inc. All rights reserved.
1. Introduction
and octanol–water partition coefficient (logP) was found to be 5.457 [5].
The anti-inflammatory activity of Hdcpa (3) was measured by the anti-
Flufenamic acid [2-(3-trifluorophenylamino)benzoic acid], Hflu (1)
(Scheme 1), belongs to the class of non-steroidal anti-inflammatory
drugs, NSAIDs, which are clinically used against a wide range of acute
and chronic disorders. The therapeutic activity of these analgesics is
believed to be due to their ability to inhibit the biosynthesis of
prostaglandins by competitive interaction with the cyclooxygenase–
arachidonic acid complex or by radical quenching agents that interfere
with the initiation of the cyclooxygenase reaction [1]. Flufenamic acid
was found to inhibit the proliferation and migration of human aortic
smooth muscle cells (HASMCs) in vitro [2]. The crystal structure of Hflu
[3] and of flufenamic acid with prostaglandin D (2) 11-ketoreductase
(AKR1C3) has been reported [4].
Flufenamic, mefenamic and meclofenamic belong to the class of
fenamates. [2-(2,3-dichlorophenylamino)benzoic acid], Hdcpa (3)
(Scheme 1) and [2-(2,6-dimethylphenylamino)benzoic acid], Hdmpa
(5) chemically resemble to fenamates in clinical use. Hdcpa (3) wasfound
to inhibit by 56.6% on triiodothyronine (T3) uptake by H4 hepatocytes
UV-erythema test and the minimum effective dose (MED) was found to
be 3.1 mg/kg, while for flufenamic and tolfenamic the MED value
was found to be 3.3 and 5.3 mg/kg, respectively [6]. Crystal structures
of dimeric tetraorganodistannoxanes of flufenamic, mefenamic, meclo-
fenac, Hdcpa and Hmpa have been reported [7–10]. The crystal structures
of triphenyltin(IV) esters of mefenamic acid, meclofenamic (9) and
Hdmpa (5) have been also reported and were tested for antimycobacter-
ial activity against Mycobacterium tuberculosis H37Rv. These triphenyltin
esters were found to be very good anti-tuberculosis agents [11–14].
The coordination chemistry of NSAIDs has been studied by several
groups worldwide. Some complexes have increased pharmaceutical
or biological activity with respect to the drug, or are interesting from a
purely chemical point of view [10,11,15]. The complex formation with
specific metals may improve the activity towards certain diseases and
hopefully may increase the activity spectrum. The combination of two
or more different species into the same compound may bring to a
multitherapeutic agent which can be expanded by the synergic action
of the metal residue once the coordination compound dissociates
inside the target tissue.
Metal complexes have been successfully applied in the treatment
of numerous human diseases. Very important progress in medicinal
⁎
Corresponding author. Tel.: +30 2651008425; fax: +30 2651008786.
E-mail address: dkovala@cc.uoi.gr (D. Kovala-Demertzi).
0162-0134/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.jinorgbio.2010.10.008

196
V. Dokorou et al. / Journal of Inorganic Biochemistry 105 (2011) 195–201
Scheme 1. The reaction scheme for synthesis of 1–8.
organo-metallic chemistry has been seen in the past few years,
allowing the rational design of novel, non-conventional, platinum
compounds, as well as innovative non-platinum metal-based anti-
tumor agents. Organotin(IV) compound in general and organotin(IV)
carboxylates in particular have emerged as potentially biologically
active compounds among non-platinum chemotherapeutic metallo-
pharmaceuticals. The biological significance of di and triorganotin(IV)
compounds widened because they are members of a potential class of
biologically active compounds exhibiting antitumor, antifungal,
antibacterial and anti-tuberculosis activities [9,11,12,15–17].
Herein, the goal is to define the probability to extend the phar-
macological profile of NSAIDs, in order to discover new properties
such as anticancer activity and to prepare new complexes of NSAIDs
with triorganotin(IV) ions, which would exhibit improved or different
biological behaviour compared to the “parent drugs”. In continuation
to our previous work [7–14] on biological organotin chemistry herein
we report the synthesis and structural studies of the complexes
[Ph3Sn(flu)] (2) (where flu is the deprotonated flufenamic acid), Hflu
(1) and [Ph3Sn(dcpa)] (4) (where dcpa is the deprotonated [2-(2,3-
dichlorophenylamino)benzoic acid], Hdcpa (3). The complexes have
been structurally characterized by means of vibrational and 1H, 13C
NMR spectroscopic studies. The crystal and molecular structure of
[Ph3Sn(dcpa)(DMSO)] 4a is described. The results of 1–4, Hdmpa (5),
[Ph3Sn(dmpa)] (6), [2-(2,3-dimethylphenylamino)benzoic acid],
mefenamic acid, Hmef (7) and [Ph3Sn(mef)] (8) against three
human cancer cell lines: MCF-7, T24, A-549 and a mouse L-929 cell
line are also reported.
transform spectrophotometer using KBr pellets (4000–400 cm−1) and
Nujol mulls dispersed between polyethylene disks (400–40 cm−1). IR
spectra were recorded on a Bruker AV-250 spectrometer operating at
250.13 and 62.90 MHz for 1H and 13C acquisitions respectively, or on a
Bruker AV-500 spectrometer operating at 500 and 126 MHz for 1H and
13C acquisitions, respectively. The splitting of proton resonances in the
reported 1H NMR spectra is defined as s = singlet, d = doublet, t =
triplet, and m = multiplet. The chemical shifts are reported in ppm for 1H
and 13C NMR. Samples were dissolved in d6-dimethylsulfoxide and
spectra were obtained at room temperature (298 K) with the signal of
free d6-dimethylsulfoxide (at 2.50 ppm 1H NMR, 39.5 ppm 13C NMR) as
a reference. Elemental analyses were carried out by the micro analytical
service of the University of Ioannina, Greece.
2.2. Preparations
Compounds 3, 5 and 7 were synthesized according to Ullmann-
Goldberg condensation [5]. The triphenyltin(IV) complexes Ph3Sn
(dmpa) (6) and [Ph3Sn(mef)] (8) were synthesized by the reaction of
(Hmef) or (Hdmpa) with Ph3SnOH in a molar ratio of 1:1 according to
published procedure [13,14].
2.2.1. Preparation of [2-(3-trifluorophenylamino)benzoate]triphenyltin
(IV) [Ph3Sn(flu)] (2)
Triphenyltin(IV) hydroxide (0.422 g, 1.15 mmol) and flufenamic
acid (0.281 g, 1.0 mmol) in benzene (40 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). The oily product was chilled and triturated with trifluoroacetic
acid (TFA) to give a pale yellow solid. The powder was recrystallized
from diethyl ether to give 2. The pale yellow powder was dried in
vacuo over silica gel. Yield 97%; m.p. 72–74 °C. Anal. calc. for C32H24-
NO2F3Sn (630.2 gmol−1): C, 61.01; H, 3.81; N, 2.2%. Found: C, 60.1; H,
2. Experimental
2.1. General and instrumental
All reagents were commercially available (Aldrich or Merck) and
used as supplied. Solvents were purified according to standard pro-
cedures. Flufenamic acid was purchased from Sigma-Aldrich. Melting
points (m.p.) were determined in open capillaries and are uncorrected.
Infrared spectra were recorded on a Perkin Elmer Spectrum GX Fourier
1
Although the values of elemental analyses for carbon and hydrogen are somewhat
unsatisfactory, the spectroscopic data (IR, 1H and 13C NMR) reasonably support the
formula [Ph3Sn(flu)].

V. Dokorou et al. / Journal of Inorganic Biochemistry 105 (2011) 195–201
197
3.1; N, 2.5%. IR (KBr): 3316 v(NH), 1649 vas(COO), 1414 vsym(COO); 363,
342 v(Sn–C); 288, 226, 211 v(Sn–O); 179, 154 δ(Sn–O). 1H NMR (DMSO):
programs [19]. All hydrogen atoms were located in their calculated
positions (C–H 0.93–0.97 Å) and refined using a riding model.
Molecular graphics were performed using PLATON2001 [20]. A
summary of the crystal data, experimental details and refinement
results are listed in Table 1.
Crystallographic data for the structural analyses have been
deposited at Cambridge Crystallographic Data Center, as deposition
number CCDC 748979 for 4a Copies of these data may be obtained,
free of charge, from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, via
fax (+44-1223-336-033), email (deposit@ccdc.cam.ac.uk), or inter-
net (www.ccdc.cam.ac.uk).
δ 9.72 (s, 1H, NH), 8.03 (d, H3, J(3)–(4) =8.74), 6.94 (t, H4, J(4)–(5)
=
7.57, J(4)–(6) =0.61), 7.32 (t, H5, J(5)–(6) =8.35, J(5)–(3) =1.30), 7.34
(m, H6), 7.59–7.56(m, H5′, H2′, C4′), 7.36 (m, H6′), 7.58 (d, Ho–Ph) 7.40–
7.38(m, Hm–Ph, Hp–Ph); 13C NMR: δ 170.7 (COOH), 145.6 (C1), 115.7
(C2), 132.9 (C3), 120.4 (C4), 133.4 (C5), 116.2 (C6), 140.8 (C1′), 119.3
(C2′), 131.7 (C3′), 124.9 (C4′), 131.1 (C5′), 116.3 (C6′) 122.6 (CF3), –(Co–
Ph), 129.8 (Cm, p-Ph).
2.2.2. Preparation of [2-(2,3-dichlorophenylamino)benzoic acid]
(Hdcpa) (3)
This compound was synthesized by Ullmann-Goldberg condensa-
tion [5]. 2,3 dichlorobenzenamine (14.99 g, 92.5 mmol), potassium 2-
bromobenzoate (22.75 g, 95 mmol), 4-ethylmorpholine (10.93 g,
95 mmol) and 1.0 g of anhydrous copper acetate in 40 mL of distilled
N,N-dimethylformamide under nitrogen atmosphere were refluxed
at 145° for 3 h. 25 mL of distilled N,N-dimethylformamide and 38 mL
of 12% hydrochloric acid was added in the resulting solution. The
aqueous layer was decanted and methanol was added. The solid
was collected and recrystallized three times from acetone. Yield 24%.
m.p. 250–251 °C. Anal. calc. for C13H9NO2Cl2 (210.04 gmol−1): C,
55.4; H, 3.2; N, 5.0%. Found: C, 55.5; H, 3.4; N, 4.9; %. IR (KBr): 3415,
3291 v(NH), 1580 vas(COO), 1419 vsym(COO). 1H NMR (DMSO): δ 9.90
2.4. Antiproliferative assay in vitro
2.4.1. Compounds
Test solutions of the compounds tested (1 mg/mL) were prepared
by dissolving the substance in 100 μL of DMSO completed with 900 μL
of tissue culture medium. Afterwards, the tested compounds were
diluted in culture medium to reach the final concentrations of 100, 50,
10, 1 and 0.1 ng/μL The solvent (DMSO) in the highest concentration
used in test did not reveal any cytotoxic activity.
(s, 1H, NH), 7.92 (d, H3, J(3)–(4) =7.89, J(3)–(5) =1.33), 6.88 (t, H4, J(4)–(5)
7.75, J(4)–(6) =0.81), 7.51 (t, H5, J(5)–(4) =7.09, J(5)–(3) =1.61), 7.24 (d, H6,
(6)–(5) =8.48), 7.27 (d, H5′, J(5′)–(6′)=8.02), 7.46 (d, C6′, J(6′)–(5′)=7.39,
(6′)–(4′)=1.63); 7.33 (d, C4′, J(4′)–(5′)=7.90, J(4′)–(6′)=1.50); 13C NMR: δ
170.6 (COOH), 145.0 (C1), 115.5 (C2), 132.8 (C3), 120.0 (C4), 133.4 (C5),
115.8 (C6), 140.8 (C1′), 123.4 (C2′), 135.2 (C3′), 124.3 (C4′), 129.3 (C5′),
119.0 (C6).
=
2.4.2. 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
(Dulbecco's-Modified Eagle's Medium) supplemented with 1% anti-
biotic 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-12K 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 cells
were determined by the sulforhodamine B assay [21], while T-24 cells
by the MTT assay [22]. The in vitro tests were performed as described
previously [12].
J
J
2.2.3. Preparation of [(2-(2,3-dichlorophenylamino)benzoate)
triphenyltin(IV)] (4)
Triphenyltin(IV) hydroxide (0.4221 g, 1.15 mmol) and 2-(2,3-
dichloroanilino)benzoic acid (Scheme 1), Hdcpa (0.2821 g, 1.0 mmol)
in benzene (40 mL) were refluxed for 24 h 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 TFA to give a pale white solid. The pale white powder
was recrystallized from acetone and was dried in vacuo over silica
gel. Yield 95%.; m.p. 108–109 °C. Anal. calc. for C31H23NO2Cl2Sn
(631.1 gmol−1): C, 59,0; H, 3,7; N, 2.2%. Found: C, 58.9; H, 3.8; N, 2.6%.
IR (KBr): 3246 v(NH), 1623 vas(COO), 1359 vsym(COO); 341 v (Sn–C);
283, 221, 207, v (Sn–O); 170, 157 δ(Sn–O). 1H NMR (DMSO): δ 9.94
(s,1H, NH), 7.94 (d, H3, J(3)–(4) =7.64), 6.89 (t, H4, J(4)–(5) =7.48), 7.42
Table 1
X-ray crystal data and structure refinement for 4a.
Empirical formula
Formula weight
Crystal system
Space group
C33 H29 Cl2 N O3 S Sn
709.25
Triclinic
P-1 (No. 2)
0.32×0.28×0.16
293(2)
(d, H5), 7.21 (m, H6), 7.27(m, H4′), 7.30 (d, H5′), 7.49 (d, H6′, J(6′)–(5′)
=
7.54, J(6′)–(4′)=2.04), –(Ho–Ph), 7.27–7.25 (m, Hm, p), 13C NMR: δ 170.8
(COOH), 145.7 (C1), 115.7 (C2), 133.8 (C3), 120.3 (C4), 132.4 (C5), 116.2
(C6), 140.8 (C1′), 123.6 (C2′), 135.2 (C3′), 124.5 (C4′), 129.8 (C5′), 119.4
(C6′), 135.2 (Co), 128.9 (Cm,p). Recrystallization of 4 from a solution of
dimethylsulfoxide gives single crystals of [Ph3Sn(dcpa)(DMSO)] (4a)
suitable for X-ray analysis.
Crystal size (mm)
Temperature (K)
´
˚
9.6873(9) 10.6527(11) 16.6847(16)
a, b, c (A)
α, β, γ (o)
81.560(2) 87.114(2) 66.295(2)
1559.4\(3\)s
´
3
˚
Volume (A )
Z
2
Dcalcd (g cm−3
)
1.510
1.092
716
2.3. X-ray crystallography
Absorption coefficient (mm−1
F(000)
)
The colorless prismatic crystal of 4a was mounted on a scale tube
and used for data collection. X-ray diffraction data were collected on a
Bruker SMART diffractometer equipped with a CCD area detector, a
graphite monochromator at 293 K using MoKα radiation (λ=
0.71073 Å) and corrected for Lorentz and polarization effects [18].
Cell constants and an orientation matrix for data collection were
obtained by least-squares refinement of the diffraction data in the
range of 1.23bθb25.68 for 3. The structure was solved by direct
methods (program SHELXS97) and refined by the full matrix least-
squares method on all F2 data using the WinGX version of SHELXL97
θ range for data collection (o)
Limiting indices
1.23–25.68
−11b=hb=11, −12b=kb=12,
−20b=lb=19
5867/4866
[R(int)=0.0396]
5867/0/374
Reflections collected/unique
Data/restraints/parameters
Goodness-of-Fit (F2)
Final R indices (IN2σ(I))
R indices (all data)
1.029
R1=0.0467, wR2=0.0868
R1=0.060, wR2=0.0953
0.40 and −0.86
Maximum and minimum residuals
´
−3
˚
(e. A
)

198
V. Dokorou et al. / Journal of Inorganic Biochemistry 105 (2011) 195–201
Table 2
3. Results and discussion
3.1. Synthetic aspects
Selected bond lengths (Å) and angles (°) for complex 4a.
Sn(1)–O(1)
Sn(1)–C(13)
2.126(3)
2.126(4)
O(1)–Sn(1)–C(13)
O(1)–Sn(1)–C(1)
96.98(14)
89.35(13)
114.44(15)
89.35(13)
131.11(16)
112.87(15)
177.95(10)
84.37(14)
85.08(14)
84.37(14)
104.6(3)
Sn(1)–C(7)
Sn(1)–C(1)
Sn(1)–O(3)
Cl(1)–C(27)
S(1)–O(3)
S(1)–C(33)
S(1)–C(32)
Cl(2)–C(28)
O(1)–C(19)
O(2)–C(19)
2.143(4)
2.141(4)
2.424(3)
1.734(4)
1.510(3)
1.778(6)
1.773(6)
1.735(4)
1.293(5)
1.236(5)
C(13)–Sn(1)–C(1)
O(1)–Sn(1)–C(1)
C(13)–Sn(1)–C(7)
C(7)–Sn(1)–C(1)
O(1)–Sn(1)–O(3)
C(13)–Sn(1)–O(3)
C(7)–Sn(1)–O(3)
C(1)–Sn(1)–O(3)
O(3)–S(1)–C(33)
O(3)–S(1)–C(32)
C(33)–S(1)–C(32)
C(19)–O(1)–Sn(1)
S(1)–O(3)–Sn(1)
Flufenamic acid (Hflu) (1), [2-(2,3-dichlorophenylamino)benzoic
acid] (Hdcpa) (3), mefenamic acid, [2-(2,3-dimethylphenylamino)
benzoic acid] (Hmef) (5), [2-(2,6-dimethylphenylamino)benzoic
acid], (Hdmpa) (7) were synthesized according to Ullmann-Goldberg
condensation [5]. 6 and 8 were synthesized according to published
procedure [13,14]. The triphenyltin(IV) complexes of 1 and 3 were
synthesized by the reaction of ligands with Ph3SnOH in a molar ratio
of 1:1 according to the reaction, Scheme 1.
105.2(2)
98.0(3)
118.7(3)
123.00(17)
Ph3SnOH þ HL→Ph3SnðLÞ þ H2O
3.2. Crystal structure of 4a
molecule. The dihedral angle between the planes of the phenyl rings
of dcpa in 4a is 49.7(2)°.
The molecular structure of 4a is shown in Fig. 1, and selected
interatomic parameters are collected in Table 2. Compound 4a
crystallizes in the triclinic P-1 space group and it comprises discrete
molecular units. The tin(IV) atom is five-coordinate defined by a C3O
(1)O(3) donor set. The molecular structure of 4a reveals that the
central Sn(IV) atom has a distorted trigonal bipyramidal coordination
geometry with equatorial phenyl groups and the carboxylate and
dimethylsulfoxide oxygen atoms O(1) and O(3) respectively occupy-
ing axial positions. Analysis of the shape-determining angles of 4a
using the approach of Reedijk and coworkers [23] yields a τ (α−β)/
60 value of 0.78 for Sn (τ=0 and 1 for sp and tbp geometries, resp.).
The O(2) atom approaches the tin atom at a distance of 3.094(3) Å.
Although this long Sn–O(2) distance is well inside the sum of the van
der Waals radii of the Sn and O atoms (ca. 3.6 Å), it is not considered to
represent a significant bonding interaction. Support for this is found in
the disparity in the C(19)–O(1) and C(19)–O(2) distances and there
does not appear to be any major distortion of the trigonal bipyramidal
Sn-coordination geometry as a result of this contact. In the triphenyl
esters of meclofenamic, mefenamic and dmpa the O(2) atom
approaches the tin atom at a distance of 2.629(4), 2.626(7) and
2.615(2) Å [12–14]. This long distance 3.094(3) Å in this case, is
probably due to steric hindrance effect from the coordination of DMSO
Triorganotin(IV) carboxylates were found of several structural
motifs ranging from monomeric four- or five-coordinate species to
five-coordinate polymers which usually involve bidentate, bridging
carboxylate groups [24,25]. A polymeric structure for triphenyl
carboxylates is associated with the R group, RCOO being electron-
withdrawing. The axial Sn-ligand bond lengths in both forms are
subject to variations that depend on substituents, electronegativity,
ring strain, H-bonds, and steric interactions [26]. The appearance of
one or other motif can be rationalized in terms of steric hindrance
of the triorganotin residue in that bulky substituents preclude inter-
molecular bond via Sn→O interactions.
In 4a centrosymetrically related pairs are associated via π–π
interactions. The crystal structures of 4a show ring stacking
interactions. For 4a, the phenyl ring C(26)–C(31) of the monomer
‘faces’ the corresponding phenyl ring of an adjacent monomer at a
distance of 3.457(2) Å showing significant π–π stacking interactions.
The polar amino H-atom participates in an intra-molecular H-bond
(Table 3). A similar hydrogen-bonded situation was found in
complexes of mefenamic acid and meclofenamic acid [Ph3Sn(mef)]
[13] and [Ph3Sn(meclo)] respectively [14]. The crystal structure of 4a
is stabilized by intra-molecular interactions and is self-assembled
Fig. 1. Perspective view of [Ph3Sn(dcpa)(DMSO)] showing the atomic numbering scheme.

V. Dokorou et al. / Journal of Inorganic Biochemistry 105 (2011) 195–201
199
Table 3
carboxylato ligand to tin(IV) has been attributed to the parameter
Δ[vasym (COO)−vsym (COO)]. The magnitude of Δv values for values
for 2 and 4 is 235 and 264 respectively and is close to that found for
the anisobidentate carboxylato group [27]. This parameter Δ is close
to that found for [Ph3Sn(dmpa)] (6), 254 [14], for [Ph3Sn(meclo)]
(10), 258 [12] and for [Ph3Sn(mef)] (8), 307 [13]. Medium absorp-
tions corresponding to the Sn–O (COO) stretching mode of vibration
appear between 290 and 210 cm−1. The absorption bands at 363,
342 cm−1 are attributed to v(Sn–C) stretching modes for 2 and at
341 cm−1 are attributed to v(Sn–C) stretching modes for 4 [7–14].
The magnitude of Δv values for values for 2 and 4 is 235 and 264
respectively and is close to that found for the anisobidentate or the
monodentate carboxylato group [27]. This value is in agreement with
the X-ray crystal data of 4. This parameter Δ is close to that found for
[Ph3Sn(dmpa)] (6), 254 [14], for [Ph3Sn(meclo)] (10), 258 [12] and
for [Ph3Sn(mef)] (8), 307 [13]. The structure and the mode of
coordination of the carboxylato group of 6, 8 and 10 are the same as
what was shown from the X-ray crystal structure [12–14]. Medium
absorptions corresponding to the Sn–O (COO) stretching mode of
vibration appear between 290 and 210 cm−1. The absorption bands at
363, 342 cm−1 are attributed to v(Sn–C) stretching modes for 2 and at
341 cm−1 are attributed to v(Sn–C) stretching modes for 4 [7–14].
π–π, C–H–π and intra-molecular hydrogen bonds for 4a. Cg(1) and Cg(2) refer to the
centroids C(1)…C(6) and C(7)…C(12) respectively, Cg(5) refers to the centroid C(26)…
C(31) respectively. D and A refers to the donor and the acceptor, respectively.
Cg–Cga,b
βc
CgI–Perpd
CgJ–Perpe
Cg(5)→Cg(5)i
3.458(2)
9.25
H–Cg
3.448(3)
D…A
2.933(4)
2.688(5)
3.413(2)
C–Cg
5.081(5)
H…A
2.65
2.01
3.413(2)
C–H–Cg
156(2)
D–H…A
101
C(27)–Cl(1)→Cg(1)ii
D
N(1)
N(1)
H
H(1)
H(1)
Ab
Cl(1)
O(2)
136
aSymmetry transformations, i, 2−x, 1−y, −z; ii, 1+x, y, z; bCg–Cg is the distance
between ring centroids; cwhere
β
is the angle Cg(I)→Cg(J); dCgI–Perp is the
perpendicular distance of Cg(I) on ring J; eCgJ–Perp is the perpendicular distance of
Cg(J) on ring I.
by C–H—(centroid of aromatic ring) and π–π stacking interactions
(Table 3, Fig. 2).
3.3. Spectroscopic studies
3.3.1. Infrared spectroscopy
The characteristic IR bands of compounds 1–4 have been identified
by comparing the data with the literature values [9,12–14]. In the IR
spectra of Hflu, and Hdcpa, the strong bands at 3320 and 3291 cm−1
respectively were assigned to the N–H stretching motion and the
broad bands at ca. 2870 and 3075 cm−1 respectively to the v(NH…O)
and v(OH....H) modes due to intra- and intermolecular H-bonding, as
confirmed by X-ray crystallography [3]. The infrared spectra of the
two free ligands show a strong band at ca. 1670 cm−1 corresponding
to the vibration frequency v(C O) of COOH, which indicates that there
are intermolecular hydrogen bonds of the type C O…H–O in the
uncoordinated carboxylic acids. After deprotonation and binding
to tin(IV) atoms, these bands are replaced by strong bands in
two different regions between 1650–1620 and 1420–1360 cm−1
respectively, of the COO moiety. The vasym(COO) bands appear at
1649, 1623 cm−1 for 2 and 4 respectively, and vsym(COO) at 1414,
1359 cm−1 for 2 and 4 respectively. The mode of coordination of the
3.3.2. NMR spectroscopy
The 1H and 13C NMR data for flufenamic acid (Hflu) and [2-(2,3-
dichlorophenylamino)benzoic acid], (Hdcpa) were assigned by the
use of proton–proton correlated spectroscopy (1H–1H COSY), proton–
carbon heteronuclear single-quantum coherence (1H–13C HSQC) and
proton–carbon heteronuclear multiple-bond correlation (1H–13C
HMBC) NMR experiments.
The combination of the 1H–13C HSQC and 1H–13C HMBC techni-
ques allows the connection of the proton and carbon-13 spins across
the molecule. Practically, the 2D 1H–13C HSQC experiment allows the
observation of protons that are directly connected to carbons via one
bond; the 1H–13C HMBC experiment connects protons to carbons via
two- or three-bond couplings and, therefore, it can be used to connect
proton spin systems that are interrupted by quaternary carbon atoms.
The HMBC experiment is particularly useful for locating the
Fig. 2. A view of the extended network of [Ph3Sn(dcpa)(DMSO)] along the b-axis.

200
V. Dokorou et al. / Journal of Inorganic Biochemistry 105 (2011) 195–201
quaternary carbons by identifying the various protons interacting
with them through two-bond (2JCH), three-bond (3JCH), and occasion-
ally four-bond (4JCH) interactions.
activity against T-24 cancer cell line. Selectivity was observed for
complex 6 against A-549 and MCF-7 cell lines; also complex
8 exhibited an excellent selectivity against T-24 cell line.
The existence of the HN resonance in the 1H NMR spectra of
complexes indicates that the nitrogen atom remains protonated in 2
and 4. Deshielding of proton H(3) is observed for 2 and 4 (0.04 ppm,
0.02 ppm respectively), which should be related to the electrophilicity
of the tin. An σ-charge donation from the COO-donor to the tin
center removes electron density from the ligand and produces this
deshielding which will attenuate at positions remote from the metal.
All shifts are downfield except for that due to H(5) for complexes 2
and 4 which are shifted upfield (0.14 ppm, 0.09 ppm respectively).
The upfield shift observed for H(5) and its corresponding carbon atom
C5 (1.6 ppm) and (1.0 ppm) for complexes 2 and 4 respectively, para
to the tin center, could be due to the flow of charge from the tin into
the aromatic ring.
The cytotoxic activity shown by these compounds against all these
cancer cell lines indicates that coupling of 6 and 8 with R3Sn(IV) metal
center results in metallic complexes with important biological
properties and remarkable cytotoxic activity, since they display IC50
values in a μM range better to that of the antitumor drug cis-platin.
Compounds 6 and 8 are considered as agents with potential anti-
tumor activity, and can therefore be candidates for further stages of
screening in vitro and/or in vivo.
4. Summary
The compounds [Ph3Sn(flu)] (2), Hflu (1) and [Ph3Sn(dcpa)] (4)
and Hdcpa (3) have been synthesized and characterized by
spectroscopic and X-ray structural studies. The crystal and molec-
13C NMR spectra for 2 and 3 showed the expected signals for the
phenyl groups, as well as the signals corresponding to the different
carboxylate ligands. A typical signal at low field (ca. 170 ppm) was
observed in all the spectra assigned to the carbon atom of the
carboxylate group. The remaining resonances due to the aromatic
carbon do not shift significantly on binding to Sn [7–14,28,29].
ular structures of [SnPh3(dcpa)(DMSO)] 4a reveal
a distorted
trigonal bipyramidal coordination geometry with equatorial phenyl
groups and the carboxylate and dimethylsulfoxide oxygen atoms O
(1) and O(3) respectively occupying axial positions. The 1–4 and
the related NSAIDs from the carboxylic acid family, derivatives of
N-phenylanthranilic acid, Hdmpa (5), [Ph3Sn(dmpa)] (6), Hmef (7)
and [Ph3Sn(mef)] (8) have been evaluated against four cancer cell
lines. The IC50 values of all triphenyltin(IV) esters are ranged from
0.2–60 to 0.4–7 μΜ against A-549 and L-929 cancer cell lines
respectively and from 0.3–5 to 0.2–27 μΜ against T-24 and MCF-7
3.4. Pharmacology
3.4.1. Antiproliferative activity in vitro
The NSAIDs Hflu (1), Hmef (7) and the related NSAIDs carboxylic
acids Hdcpa (3) and Hdmpa (5) and the triphenyltin(IV) complexes 2,
4, 6 and 8 were tested for their antiproliferative activity in vitro
against the cells of three human cancer cell lines: MCF-7 (human
breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-
small cell lung carcinoma) and a mouse fibroblast L-929 cell line. The
results of cytotoxic activity in vitro are expressed as IC50—the
concentration of compound (in μM) that inhibits a proliferation rate
of the tumor cells by 50% as compared to control untreated cells,
Table 4. Meclofenamic (9) and the triphenyltin(IV) ester of meclofe-
namic (10) have been evaluated for antiproliferative activity in vitro
[12] and the results are compared with the present data, Table 4.
Complexes 6 and 10 exhibit high activity against all four cancer cell
lines. The IC50 values of these two complexes against all cancer cell
lines are in a micromolar range similar or better to that of the
antitumor drug cis-platin and of the starting material Ph3SnOH. Also,
the IC50 values of these two complexes against A-549, L-929 and MCF-
7 cancer cell lines are in a micromolar range better to that of the
starting material Phe3SnOH. Complex 6 exhibits the highest activity
against A-549 and MCF-7 cancer cell lines and complex 8 the highest
cancer cell lines respectively. Complex
6 exhibits the highest
activity and selectivity against A-549 and MCF-7 cancer cell lines
and complex 8 the highest activity and selectivity against T-24
cancer cell line. The dihedral angle between the planes of the
phenyl rings of dmpa in [Ph3Sn(dmpa)] (6) is 68.6° [14], for [Ph3Sn
(meclo)] (10) is 65.9(9)° [12] and for [Ph3Sn(mef)] (8) is 62.6(2)°
[13]. Adjacent to the imino group in meclofenamic acid and Hdmpa,
in 2,6 position, there are two equivalent Cl-atoms and two Me
groups, respectively, and in mefenamic, in 2,3 position, there are
two Me groups. The molecules are in a conformation where the
two phenyl rings try to minimize steric interactions. It seems that
the structural and electronic effect of the triphenyltin(IV) ester and
fenamate derivative plays an important role in the activity and
selectivity.
Compounds 6 and 8 are considered as agents with potential anti-
tumor activity, and can therefore be candidates for further stages of
screening in vitro and/or in vivo. [Ph3Sn(dmpa)] (6) and [Ph3Sn(mef)]
(8) are considered as excellent antitumor compounds and the results
of this study represent the discovery of triphenyltin(IV)esters as a
potential novel class of anticancer agents.
Table 4
The antiproliferative activity in vitro of fenamates and triphenyl esters of fenamates
(expressed as IC50 (μM))a against MCF-7, T-24, A-549 and L-929 cancer cell lines.
Appendix A. Supplementary data
Compounds
A549
L929
MCF7
T24
99.60 8.14
4.78 0.41
68.24 4.8
3.49 0.22
147.82 10.3
3.27 0.26
Supplementary data to this article can be found online at
doi:10.1016/j.jinorgbio.2010.10.008.
Hflu (1)
[Ph3Sn(flu)] (2)
Hdcpa (3)
[Ph3Sn(dcpa)] (4)
Hdmpa (5)
[Ph3Sn(dmpa)]
(6)
171.87 8.20 192.03 12.20 120.90 9.30
60.44 4.80
141.79 9.4
10.28 0.91
184.43 10.2 273.53 5.9
0.22 0.01
5.85 0.4
163.06 9.5
5.4 0.41
1.26 0.05
88.62 5.2
2.01 0.34
62.17 3.2
0.17 0.01
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