Synthesis, characterization and biological activity of diorganotin complexes with ONO terdentate Schiff base

Article abstract of DOI:10.1016/j.ica.2013.04.036

Diorganotin(IV) complexes with general formula R₂SnL [H ₂L = (E)-N′-[1-(5-bromo-2-hydroxyphenyl) ethylidene]-3-hydroxy- 2-naphthohydrazide (H₂L1) and (E)-N′-[1-(5-chloro-2- hydroxyphenyl)ethyli-dene]-3-hydroxy-2-naphthohydrazide (H₂L ₂); R = Me, Bu, Ph, Cy, Bz, o-ClBz and p-ClBz (1-14)] have been synthesized and characterized by IR, ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopic techniques and single crystal X-ray diffractometry. The structure of the complexes, {[1-(5-bromo-2-oxidophenyl) ethylidene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV), 1, {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naph-thohydrazidato} dimethyltin(IV), 8 and {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naph- thohydrazidato}dicyclohexyltin(IV), 11 reveals a five-coordinated, trigonal-bipyramidal geometry, whereby the trigonal plane of the complexes consists of the imine nitrogen atom and alkyl groups from the diorganotin moieties. The complexes are stabilized by a strong intramolecular hydrogen bonding between N(2) and O(3)-H(3). The Schiff bases and their corresponding diorganotin(IV) complexes have been evaluated against three human carcinoma cell lines, namely HT29 (human colon carcinoma cell line), SKOV-3 (human ovarian cancer cell line) and MCF7 (hormone-dependent breast carcinoma cell line), for their cytotoxic activities. The dimethyltin derivatives and dibutyltin derivatives of the Schiff base ligands display good cytotoxic activities against the tested cell lines.

Full text of DOI:10.1016/j.ica.2013.04.036

Inorganica Chimica Acta 406 (2013) 272–278
Contents lists available at SciVerse ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Synthesis, characterization and biological activity of diorganotin
complexes with ONO terdentate Schiff base
a
b
b
a
See Mun Lee a, , Hapipah Mohd. Ali , Kae Shin Sim , Sri Nurestri Abdul Malek , Kong Mun Lo
⇑
a Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
b Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Diorganotin(IV) complexes with general formula R2SnL [H2L = (E)-N0-[1-(5-bromo-2-hydroxyphenyl)
ethylidene]-3-hydroxy-2-naphthohydrazide (H2L1) and (E)-N0-[1-(5-chloro-2-hydroxyphenyl)ethyli-
dene]-3-hydroxy-2-naphthohydrazide (H2L2); R = Me, Bu, Ph, Cy, Bz, o-ClBz and p-ClBz (1–14)] have been
synthesized and characterized by IR, 1H, 13C and 119Sn NMR spectroscopic techniques and single crystal X-
ray diffractometry. The structure of the complexes, {[1-(5-bromo-2-oxidophenyl)ethylidene]-3-hydroxy-
2-naphthohydrazidato}dimethyltin(IV), 1, {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naph-
Article history:
Received 25 January 2013
Received in revised form 16 April 2013
Accepted 23 April 2013
Available online 9 May 2013
Keywords:
Diorganotin
Schiff base
thohydrazidato}dimethyltin(IV),
8
and {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naph-
five-coordinated, trigonal–bipyramidal geometry,
thohydrazidato}dicyclohexyltin(IV), 11 reveals
a
whereby the trigonal plane of the complexes consists of the imine nitrogen atom and alkyl groups from
the diorganotin moieties. The complexes are stabilized by a strong intramolecular hydrogen bonding
between N(2) and O(3)–H(3). The Schiff bases and their corresponding diorganotin(IV) complexes have
been evaluated against three human carcinoma cell lines, namely HT29 (human colon carcinoma cell line),
SKOV-3 (human ovarian cancer cell line) and MCF7 (hormone-dependent breast carcinoma cell line), for
their cytotoxic activities. The dimethyltin derivatives and dibutyltin derivatives of the Schiff base ligands
display good cytotoxic activities against the tested cell lines.
Cytotoxic activity
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
naphthoylhydrazide with substituted 2-hydroxyacetophenone.
From literature, Schiff bases derived from 3-hydroxy-2-naph-
The studies of organotin(IV) compounds have gained interest
due to their various industrial and biocidal applications [1–5].
The organotin(IV) compounds have been actively studied because
of its versatile chemistry and its potential as biological active com-
pounds. Among these compounds, the chemistry of organotin(IV)
complexes of Schiff bases has been extensively studied due to its
structural diversity, thermal stability, and the compounds have
been proposed to possess mild-to-good antitumor [6–9], antimi-
crobial [10,11], antifungal [12–14], antibacterial [12–14], antioxi-
dant [15] or anti-inflammatory properties [15,16]. However, the
mode of biological activities of the organotin(IV) compounds is
not completely known. The structure of the organotin(IV) com-
plexes, its coordination number, the extent of alkylation and the
nature of the organic groups attached to the tin atom are the main
factors deciding the biological activities of the tin complexes
[10,17,18].
thoylhydrazide are reported to have good antimicrobial activities
[19]. The in vitro cytotoxicity of the Schiff bases and their diorgano-
tin(IV) complexes against three human carcinoma cell lines (HT29,
SKOV-3 and MCF7) is evaluated and discussed.
2. Experimental
2.1. Materials and methods
The reagents used are commercially available (Aldrich, Acros or
Merck) and used as supplied. Dibenzyltin dichloride, di(o-chloro-
benzyl)tin dichloride and di(p-chlorobenzyl)tin dichloride were
prepared according to the literature method [20]. All solvents used
in the reaction were procured commercially and used without
purification. The melting points of the ligands and complexes were
determined using an Electrothermal digital melting point appara-
tus and were uncorrected. Infrared spectra for the compounds
were recorded in KBr pellets on a Perkin–Elmer Spectrum RX1
FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded
on a JEOL JNM GX-270 FT NMR SYSTEM spectrometer while
In the current article, we report the synthesis and structural
studies of diorganotin(IV) complexes with terdentate ONO Schiff
bases prepared from the condensation reaction of 3-hydroxy-2-
⇑
Corresponding author. Tel.: +60 3 7967 7022x2141; fax: +60 3 7967 4193.
E-mail address: smlee@um.edu.my (S.M. Lee).
119Sn NMR spectra were recorded on
a JEOL ECA-400 MHz
0020-1693/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2013.04.036

S.M. Lee et al. / Inorganica Chimica Acta 406 (2013) 272–278
273
spectrometer and were referenced against Me4Sn. The chemical
shifts were recorded in ppm with reference to Me4Si for 1H NMR
and 13C NMR. Elemental analyses were carried out on a Perkin_El-
mer EA2400 CHNS Elemental Analyzer. Thermal analysis of the
complexes was carried out by heating in nitrogen gas at 10 °C
per minute on a Perkin–Elmer TGA-4000 thermobalance.
The precipitate was recrystallized from chloroform. Yellow crystals
suitable for X-ray crystallographic studies were obtained from the
slow evaporation of the filtrate. Yield: 0.44 g, 81%; m.p. 195–196oC.
Anal. Calc. for C21H19N2O3BrSn: C, 46.19; H, 3.51; N, 5.13. Found: C,
46.51; H, 3.48; N, 5.30%. IR (cmꢀ1): 3431
(–N@C–C@N), 1171 (C–O).
m(OH), 1638 m(C@N), 1578
m
m
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}dibutyltin(IV), Bu2SnL1, 2: Yield: 0.50 g, 79%; m.p. 138–
139 °C. Anal. Calc. for C27H31N2O3BrSn: C, 51.38; H, 5.11; N, 4.44.
2.1.1. Preparation of the ligands
(E)-N’-[1-(5-Bromo-2-hydroxyphenyl)ethylidene]-3-hydroxy-2-
naphthohydrazide [H2L1]: 2.03 g (0.01 mol) of 3-hydroxy-2-naph-
thoic hydrazide in 100 ml methanol was added to a 50 ml hot
stirring methanolic solution of 2.15 g (0.01 mol) of 5-bromo-2-
hydroxyacetophenone. The solution mixture was refluxed for 2 h.
A yellow solid was obtained upon cooling to room temperature
and was used without further purification.
Found: C, 51.46; H, 4.99; N, 4.63%. IR (cmꢀ1): 3400
m(OH), 1639
m(C@N), 1577 m(–N@C–C@N), 1171 m(C–O).
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}diphenyltin(IV), Ph2SnL1, 3: Yield: 0.49 g, 73%; m.p. 149–
150 °C. Anal. Calc. for C31H23N2O3BrSn: C, 55.56; H, 3.46; N, 4.18.
Found: C, 55.84; H, 3.23; N, 3.98%. IR (cmꢀ1): 3386
m(OH), 1639
Yield: 2.89 g, 72%; m.p. 214–216 °C. Anal. Calc. for C19H15N2O3-
Br: C, 57.16; H, 3.79; N, 7.02. Found: C, 56.96; H, 3.75; N, 6.98%. IR
m(C@N), 1581 m(–N@C–C@N), 1172 m(C–O).
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}dicyclohexyltin(IV), Cy2SnL1, 4: Yield: 0.53 g, 77%; m.p. 158–
160oC. Anal. Calc. for C31H35N2O3BrSn: C, 54.58; H, 5.17; N, 4.11.
(cmꢀ1): 3286
O).
m(O–H, N–H), 1656 m(C@O), 1649 m(–C@N), 1176 m(C–
1H NMR d (ppm): 2.43 (s, 3H, H-19), 6.80 (d, 1H, J = 8.2 Hz, H-3),
7.25–7.40 (m, 4H, H-4, H-11, H-14, H-15), 7.65–7.80 (m, 3H, H-6,
H-13, H-16), 8.39 (s, 1H, H-18), 11.35 (s, 2H, OH), 12.92 (s, 1H,
NH) [s = singlet, d = doublet, m = multiplet].
Found: C, 54.48; H, 5.34; N, 4.07%. IR (cmꢀ1): 3386
m(OH), 1639
m(C@N), 1581 m(–N@C–C@N), 1172 m(C–O).
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}dibenzyltin(IV), Bz2SnL1, 5: 0.40 g (1.0 mmol) of (E)-N0-[1-(5-
bromo-2-hydroxyphenyl)ethylidene]-3-hydroxy-2-naphthohydraz-
ide, H2L1 and 0.32 ml of triethylamine (1.0 mmol) were added to
50 ml of absolute ethanol and the mixture was refluxed for 2 h.
0.37 g (1.0 mmol) of dibenzyltin dichloride in 30 ml of absolute
ethanol was added and the mixture was further refluxed for 5 h
and filtered. The filtrate was evaporated until precipitation was ob-
tained. The precipitation was recrystallized from toluene and the
by-product, triethylammonium chloride, was removed through fil-
tration. The solid was recrystallized from a 1:1 mixture of chloro-
form and hexane.
13C NMR d (ppm): 22.6 (C-19), 110.6 (C-5), 119.0 (C-11), 120.1
(C-1), 121.4 (C-9), 123.3 (C-14), 125.8 (C-13), 126.4 (C-3), 127.9
(C-15), 128.3 (C-4), 128.9 (C-16), 130.5 (C-17), 131.6 (C-18),
132.6 (C-6), 134.3 (C-12), 155.0 (C-10), 161.0 (C-2), 166.5 (C-7),
170.5 (C-8).
(E)-N’-[1-(5-Chloro-2-hydroxyphenyl)ethylidene]-3-hydroxy-2-
naphthohydrazide [H2L2]: 2.03 g (0.01 mol) of 3-hydroxy-2-naph-
thoic hydrazide in 100 ml methanol was added to a 50 ml hot
stirring methanolic solution of 1.71 g (0.01 mol) of 5-chloro-2-
hydroxyacetophenone. The solution mixture was refluxed for 2 h.
A light yellow solid formed upon cooling to room temperature
and was used without further purification.
Yield: 0.50 g, 72%; m.p. 144–145 °C. Anal. Calc. for C33H28N2O3-
BrSn: C, 56.69; H, 4.04; N, 4.01. Found: C, 56.30; H, 3.91; N, 3.74%.
Yield: 2.62 g, 75%; m.p. 298–300 °C. Anal. Calc for C19H15N2O3Cl:
C, 64.32; H, 4.26; N, 7.90. Found: C, 64.02; H, 4.10; N, 7.70% IR
IR (cmꢀ1): 3400
(C–O).
m(OH), 1638 m(C@N), 1580 m(–N@C–C@N), 1171
m
(cmꢀ1): 3279
(C–O).
1H NMR d (ppm): 2.44 (s, 3H, H-19), 6.80 (d, 1H, J = 8.2 Hz, H-3),
m
(O–H, N–H), 1655
m
(C@O), 1648
m(–C@N), 1181
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}di(o-chlorobenzyl)tin(IV), (o-ClBz)2SnL1, 6: Yield: 0.57 g,
m
74%; m.p. 187–189 °C. Anal. Calc. for
51.60; H, 3.41; N, 3.65. Found: C, 51.96; H, 3.29; N, 3.53%. IR
(cmꢀ1): 3402
(OH), 1638 (C@N), 1578 (–N@C–C@N), 1171
(C–O).
C33H26N2O3BrCl2Sn: C,
7.25–7.44 (m, 4H, H-4, H-11, H-14, H-15), 7.70–7.90 (m, 3H, H-6,
H-13, H-16), 8.34 (s, 1H, H-18), 11.50 (s, 2H, OH), 12.30 (s, 1H,
NH) [s = singlet, d = doublet, m = multiplet],
m
m
m
m
13C NMR d (ppm): 25.2 (C-19), 110.9 (C-5), 118.6 (C-11), 120.6
(C-1), 121.2 (C-9), 124.0 (C-14), 126.0 (C-13), 126.9 (C-3), 128.5
(C-15), 129.0 (C-4), 129.5 (C-16), 130.6 (C-17), 131.1 (C-18),
132.5 (C-6), 134.4 (C-12), 154.9 (C-10), 162.2 (C-2), 164.1 (C-7),
170.9 (C-8).
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}di(p-chlorobenzyl)tin(IV), (p-ClBz)2SnL1, 7: Yield: 0.56 g,
73%; m.p. 188–190oC. Anal. Calc for C33H26N2O3BrCl2Sn: C, 51.60;
H, 3.41; N, 3.65. Found: C, 51.32; H, 3.32; N, 3.81%. IR (cmꢀ1):
3424 m(OH), 1639 m(C@N), 1578 m(–N@C–C@N), 1172 m(C–O)
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}dimethyltin(IV), Me2SnL2, 8: Yield: 0.41 g, 81%; m.p. 234–
235 °C. Anal. Calc. for C21H19N2O3ClSn: C, 50.29; H, 3.82; N, 5.59.
2.2. Preparation of the diorganotin complexes, 1–14
The preparation method used for compound 1 was repeated for
compounds 3, 4, 8, 10 and 11 with the appropriate diorganotin oxi-
des and Schiff base ligands. The preparation method used for com-
pound 5 was repeated for compounds 6, 7, 12, 13 and 14 with the
appropriate diorganotin chlorides and Schiff base ligands. The
preparation method for structurally known compounds 2 and 9
was in accordance to literature method [21,22].
Found: C, 50.19; H, 3.85; N, 5.80%. IR (cmꢀ1): 3400
m(OH), 1638
m(C@N), 1597 m(–N@C–C@N), 1172 m(C–O).
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}dibutyltin(IV), Bu2SnL2, 9: Yield: 0.49 g, 83%; m.p. 135–
136 °C. Anal. Calc for C27H31N2O3ClSn: C, 55.37; H, 5.34; N, 4.78.
Found: C, 55.51; H, 5.40; N, 4.59%. IR (cmꢀ1): 3400
m(OH), 1639
m(C@N), 1596 m(–N@C–C@N), 1172 m(C–O).
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naph-
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}diphenyltin(IV), Ph2SnL2, 10: Yield: 0.49 g, 79%; m.p. 169–
170 °C. Anal. Calc. for C31H23N2O3ClSn: C, 59.51; H, 3.71; N, 4.48.
thohydrazidato}dimethyltin(IV), Me2SnL1, 1: 0.40 g (1.0 mmol) of
(E)-N0-[1-(5-bromo-2-hydroxyphenyl)ethylidene]-3-hydroxy-2-
naphthohydrazide, H2L1 in 20 ml dry toluene was added to a sus-
pension of 0.17 g (1.0 mmol) of dimethyltin(IV) oxide in 40 ml of
dry toluene. The mixture was refluxed under azeotropic removal
of water using a Dean–Stark trap. The solvent was gradually re-
moved by evaporation under vacuum to give a yellow precipitate.
Found: C, 59.80; H, 3.66; N, 4.32%. IR (cmꢀ1): 3405
m(OH), 1638
m(C@N), 1598 m(–N@C–C@N), 1172 m(C–O).
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}dicyclohexyltin(IV), Cy2SnL2, 11: Yield: 0.50 g, 78%; m.p.
159–160 °C. Anal. Calc. for C31H35N2O3ClSn: C, 58.38; H, 5.53; N,

274
S.M. Lee et al. / Inorganica Chimica Acta 406 (2013) 272–278
4.39. Found: C, 58.70; H, 5.81; N, 4.11%. IR (cmꢀ1): 3424
1639 (C@N), 1598 (–N@C–C@N), 1170 (C–O).
m(OH),
3. Results and discussion
m
m
m
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}dibenzyltin(IV), Bz2SnL2, 12: Yield: 0.49 g, 75%; m.p. 140–
141 °C. Anal. Calc. for C33H27N2O3ClSn: C, 60.63; H, 4.16; N, 4.29.
3.1. Synthesis
The Schiff base ligands were prepared from stoichiometric reac-
tions of 3-hydroxy-2-napthoic hydrazide with substituted 2-
hydroxyacetophenone. The Schiff base ligands provided three
acidic protons which enabled it to readily react with diorganotin
oxides and diorganotin dichlorides as shown in Fig. 1. The diorga-
notin complexes were obtained in good yield and stable towards
air and moisture.
Found: C, 60.38; H, 3.91; N, 4.58%. IR (cmꢀ1): 3387
m(OH), 1639
m(C@N), 1593 m(–N@C–C@N), 1172 m(C–O).
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydraz-
idato}di(o-chlorobenzyl)tin(IV), (o-ClBz)2SnL2, 13: Yield: 0.55 g, 76%;
m.p. 159–160 °C. Anal. Calc. for C33H25N2O3Cl3Sn: C, 54.85; H, 3.49;
N, 3.88. Found: C, 55.08; H, 3.26; N, 3.74%. IR (cmꢀ1): 3387
m(OH),
1637 m(C@O), 1594 m(–N@C–C@N), 1170 m(C–O).
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}di(p-chlorobenzyl)tin(IV), (p-ClBz)2SnL2, 14: Yield: 0.56 g,
78%; m.p. 190–191 °C. Anal. Calc. for C33H25N2O3Cl3Sn: C, 54.85; H,
3.49; N, 3.88. Found: C, 55.09; H, 3.24; N, 3.54%. IR (cmꢀ1): 3400
3.2. IR Spectra
The IR data for the ligands and diorganotin complexes are pre-
sented in the Experimental section. Two sharp bands around 1600–
m(OH), 1639
m(C@O), 1596 m(N@C–C@N), 1172 m(C–O).
1660 cmꢀ1 region are attributed to
m(C@O) and m(C@N), and are
comparable to values reported for Schiff base ligands. In the com-
plexes, the involvement of the azomethine nitrogen in coordina-
tion with tin atom weakens the C@N bond and leads to the
2.3. X-ray structural studies
All measurements were performed on a Bruker SMART APEX2
lowering of the
[25–29]. The absence of the
m
(C@N) to be in the region of 1590–1640 cmꢀ1
CCD diffractometer at 100 K with graphite-monochromated Mo
0
m
(C@O) band suggests the deprotona-
Ka (k = 0.71073 ÅA). The structures were solved using direct method
tion of the enolic oxygens. In the spectra of ligands H2L1 and H2L2,
and refined by full-matrix least-squares procedure based on F2
using the SHELXL-97 programme [23]. Non-hydrogen atoms were re-
fined with anisotropic displacement parameters. The positions of
hydrogen atoms were calculated, and were included in the struc-
ture factor calculations.
a strong broad peak is observed at 3286 and 3279 cmꢀ1 which can
be attributed to the overlapping of m(NH) and m(OH). While, for the
complexes, a smaller band around 3300–3450 cmꢀ1 is observed,
suggesting the presence of a hydroxyl functional group in its
molecular structure.
2.4. Neutral Red cytotoxicity assay
3.3. NMR spectra
HT29 (human colon carcinoma cell line), SKOV-3 (human ovar-
ian cancer cell line) and MCF7 (hormone-dependent breast carci-
noma cell line) were purchased from American Type Culture
Collection (ATCC, USA). The HT29 and MCF7 cells were maintained
in RPMI 1640 medium (Sigma) while SKOV-3 cells in Dulbecco’s
Modified Eagle’s Medium (DMEM; Sigma), supplemented with
In the 1H NMR spectral, the signals at 6.60–8.00 and 8.20–
8.60 ppm are assigned to the aromatic protons of the ligands and
diorganotin complexes. For the Schiff base ligands, a singlet signal
around 12.30–12.90 ppm is assigned to the –NH– group and the
disappearance of the signal in the spectral of the complexes indi-
cates the engagement of the imine nitrogen atoms in complexa-
tion. Meanwhile, the strong sharp singlet at 11.35–11.50 ppm is
assigned to the hydroxy protons [30,31]. The presence of a small
signal in the region 11.40–12.10 ppm in the diorganotin complexes
suggests that the phenoxy proton on the naphthalene ring does not
participate in the coordination to the tin atom. The 1H NMR chem-
ical shifts of the methyl substituents on the azomethine carbon are
found in around 2.44 ppm, while for the complexes, the chemical
shifts are slightly downfield in the 2.50–2.90 ppm region.
10% fetal bovine serum (FBS; PAA Lab, Austria), 100
l
g mlꢀ1 peni-
cillin or streptomycin (PAA Lab, Austria) and 50
l
g mlꢀ1 of fungi-
zone (PAA Lab, Austria). The cells were maintained in a 5% CO2
incubator (Shel Lab water-jacketed) at 37 °C in humidified
atmosphere.
The cytotoxicity of the ligands and diorganotin complexes were
determined by the Neutral Red cytotoxicity assay [24]. Firstly, the
cultured cells were seeded in 96-well micro titer plate (Nunc) and
allowed to adhere for 24 h before addition of the test samples. The
cells were then treated with test samples at six different concen-
The 13C NMR spectra for the complexes show a significant
downfield shift for the carbon resonances in comparison to the free
Schiff base ligands. The signals of the azomethine carbons for the
Schiff base ligands and the diorganotin complexes appear in the
160–170 ppm region [32–34] while the chemical shift for the
methyl carbon appears in the 18–20 ppm region. The aromatic car-
bon resonances are assigned by two-dimensional proton-detected
heteronuclear single bond chemical shift correlation (HSBC) using
trations (0.1–100
bator at 37 °C. After incubation, the media was replaced with
medium containing 50 g/ml of Neutral Red and further incubated
lg/ml) and incubated for 72 h in a 5% CO2 incu-
l
for three hours to allow for uptake of the vital dye into lysosomes
of viable cells. The media was then removed and cells were washed
with Neutral Red washing solution. The dye was eluted from the
cells by adding 200 lg/ml of Neutral Red resorb solution and incu-
2
3
bated for another 30 min with rapid agitation on a micro titer plate
shaker (LT BioMax 500) at room temperature. The optical density
(OD) was measured at 540 nm using a micro titer plate reader
(Emax, Molecular Devices) at room temperature.
The assay was conducted in triplicate for all test samples. Cis-
platin was used as positive control while wells without addition
of any test sample were regarded as negative control. Cytotoxicity
of each test sample is expressed as IC50, which is the concentration
of test sample that caused 50% inhibition or cell death averaged
from three experiments. The IC50 values were obtained by non-
linear regression using GraphPad Prism statistical software. The
data are presented as mean SEM.
values corresponding to J(C,H) or J(C,H) between the carbons and
protons, and DEPT (distortionless enhancement by polarization
transfer) spectra.
The satellite signals due to the hydrogen-tin coupling and car-
bon-tin coupling are observed in most of the complexes except
in diphenyltin, dibenzyltin, di(o-chlorobenzyl)tin and di(p-chloro-
benzyl)tin derivatives. The calculated C–Sn–C angles of the diorga-
notin complexes are based on the Lockhart and Manders equation:
h(C–Sn–C) = 0.0161|2J(119Sn–1H)|2 ꢀ1.32 |2J(119Sn–1H)| + 133.4
[35,36], whereby the 2J(119Sn–1H) value is obtained from the 1H
NMR spectra. Alternatively, the 1J(119Sn–13C) coupling constants
from the 13C NMR spectra can be used to estimate the C–Sn–C an-

S.M. Lee et al. / Inorganica Chimica Acta 406 (2013) 272–278
275
Fig. 1. Reaction scheme for the synthesis of Schiff base ligands with diorganotin dichlorides and diorganotin oxides.
gles of the complexes using the Lockhart’s equation; h(C-Sn-C) =
[|1J(119Sn–13C)| + 875]/11.4 [36]. Overall, the estimated C-Sn-C an-
gles show slight deviation from the values obtained by X-ray crys-
tallographic diffraction [21,22] but they correspond to the values
reported for five-coordinate diorganotin complexes .
1, 8 and 11 with the corresponding atomic numbering schemes
are given in Figs. 2, 3 and 4.
The molecular structures showthat both ligands, (E)-N0-[1-(5-bro-
mo-2-hydroxyphenyl)-ethylidene]-3-hydroxy-2-naphthohydrazide
(H2L1) and (E)-N0-[1-(5-chloro-2-hydroxyphenyl)-ethylidene]-3-hy-
droxy-2-naphthohydrazide (H2L2), are tridentate dibasic coordinat-
ing agent via its phenolic oxygen, imino nitrogen and enolic
oxygens. The ligand is non-planar due to the steric requirements of
the five and six-membered rings. The indices of the trigonality of
The presence of a single signal in the 119Sn NMR spectral of the
complexes confirms the formation of a single species [37,38]. The
119Sn NMR chemical shifts of the dimethyltin complexes 1 and 8
are found around ꢀ176 ppm, dibutyltin complexes 2 and 9 at
ꢀ216 ppm, and dicyclohexyltin complexes
4
and 11 at
the plane can be determined from the
= (b- )/60, whereby and b are the two largest donor-metal-donor
angles in the five-coordinated environment. The -value for com-
s-value which is defined as
ꢀ283 ppm. The 119Sn NMR chemical shifts for the dibenzyltin
and substituted dibenzyltin complexes are found between ꢀ230
and ꢀ300 ppm while the 119Sn NMR chemical shifts for the diphe-
s
a
a
s
plexes 1 and 8 is 0.44, whereby the coordination should be nearly
half-way between a trigonal–bipyramidal and square-pyramidal
geometry. For complex 11, the s-value (0.26) indicates a distorted
square-pyramidal geometry, whereby the equatorial position con-
sists of two enolic oxygens and two cyclohexyl carbons with the azo-
methine nitrogen in the apical position [42–44]. The distortion from
the ideal trigonal–bipyramidal or square pyramidal geometry of the
complexes can also be observed from the deviation of the O(1)–Sn–
O(2) angles (154.86°, 154.29° and 153.64°) from 180°.
nyltin complexes
3
and 10 are found between ꢀ344 and
ꢀ355 ppm. The 119Sn NMR chemical shifts for dibenzyltin and
substituted dibenzyltin complexes are found in the range of
ꢀ230 to ꢀ297 ppm. The 119Sn NMR chemical shifts 1J(119Sn–1H)
and 1J(119Sn–13C) coupling values are in accordance with five-coor-
dination tin center [39–41].
3.4. X-ray crystallography
The chelating planes O(2)–Sn(1)–N(1)–N(2)–C(8) and O(1)–
Sn(1)–N(1)–C(7)–C(1)–C(2) in compound 11 are not planar and
have an RMS deviation from planarity of 0.15 and 0.20 Å,
respectively. The two rings form a dihedral angle of 17.9°. On the
other hand, the O(2)–Sn(1)–N(1)–N(2)–C(8) and O(1)–Sn(1)–
N(1)–C(7)–C(1)–C(2) planes in compounds 1 and 8 are rather pla-
nar, with a smaller dihedral angle of 4.0° and 4.2°, respectively.
The Ci–Sn(1)–Ci0 angle increases along with the increase in
size of the alkyl groups of the diorganotin moieties. For 1 and 8,
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
azidato}dimethyltin(IV), Me2SnL1, 1, {[1-(5-chloro-2-oxidophe-
nyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}-dimethyltin(IV),
Me2SnL2, 8 and {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydro-
xy-2-naphthohydrazidato}dicyclohexyltin(IV), Cy2SnL2, 11.
The crystallographic data and refinement details of compounds
1, 8 and 11 are shown in Table 1 while the selected bond lengths
and bond angles are given in Table 2. The molecular structures of
Table 1
Crystallographic data of {[1-(5-bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV), 1, {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-
naphthohydrazidato}dimethyltin(IV), 8 and {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dicyclohexyltin(IV), 11.
Compound
1
8
11
Empirical formula
Formula weight
Crystal system
space group
a (Å)
C
21H19BrN2O3Sn
C21H19ClN2O3Sn
501.52
C31H35ClN2O3Sn
637.75
monoclinic
P21/n
8.0138(1)
11.6732(1)
29.5049(3)
90
545.98
triclinic
P1
7.6760(1)
10.8469(1)
12.0039(1)
85.419(1)
triclinic
ꢀ
ꢀ
P1
7.6725(1)
b (Å)
c (Å)
10.7337(2)
12.0195(2)
85.095(1)
a
(°)
b (°)
78.538(1)
79.196(1)
961.216(17)
2
1.886
78.769(1)
78.944(1)
951.69(3)
2
1.750
1.508
91.393(1)
90
2759.27(5)
4
1.535
1.059
c
(°)
V (Å3)
Z
Calculated density (mg mꢀ3
)
l
(mmꢀ1
)
3.433
F(000)
536
500
1304
h (°)
1.73–27.50
9184/4388 (0.015)
0.795 and 0.481
4388/1/255
1.06
1.73–27.50
8957/4340 (0.020)
0.927 and 0.886
4340/0/257
1.09
1.38–27.50
26129/6348 (0.033)
0.949 and 0.770
6348/1/345
1.03
Reflections collected/unique (Rint
)
Maximum and minimum transmission
Data/restraints/parameters
Goodness-of-fit on F
Final R indices [I > 2
R indices (all data)
r
(I)]
R1 = 0.018, wR2 = 0.047
R1 = 0.020, wR2 = 0.048
0.52 and ꢀ0.42
R1 = 0.025, wR2 = 0.058
R1 = 0.030, wR2 = 0.060
0.62 and ꢀ0.58
R1 = 0.024, wR2 = 0.052
R1 = 0.030, wR2 = 0.054
0.43 and ꢀ0.33
Dq / )
max Dqmin (e Åꢀ3

276
S.M. Lee et al. / Inorganica Chimica Acta 406 (2013) 272–278
10 °C minꢀ1. All the diorganotin complexes are stable until after
120 °C. At temperatures above 120 °C, the TG curves show three
steps of weight loss. The first decomposition in the temperature
range of 120–250 °C involves the removal of the alkyl or aryl
groups of the diorganotin moieties. Next, there is a rapid weight
loss in the temperature range of 250–350 °C, followed by a gradual
weight loss in the temperature range of 350–800 °C. The total
decomposition of both the second and third weight losses may
be due to the dissociation of the Schiff base ligands from the tin
metal core [50,51]. Thermal decomposition continues until the fi-
nal residue, SnO2, is left.
Table 2
Selected bond lengths (Å) and angles (°) for {[1-(5-bromo-2-oxidophenyl)ethylidene]-3-
hydroxy-2-naphthohydrazidato}dimethyltin(IV), 1, {[1-(5-chloro-2-oxidophenyl)ethyli-
dene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV),
8 and {[1-(5-chloro-2-oxid-
ophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dicyclohexyltin(IV), 11.
1
8
11
Bond lengths
Sn(1)–O(1)
Sn(1)–O(2)
Sn(1)–N(1)
Sn(1)–Ci
2.054(1)
2.132(1)
2.204(2)
2.111(2)
2.111(2)
1.322(2)
1.291(2)
1.311(2)
1.320(2)
2.586(2)
2.059(3)
2.138(3)
2.201(4)
2.122(4)
2.114(4)
1.320(6)
1.288(6)
1.326(6)
1.338(6)
2.560(7)
2.088(1)
2.200(1)
2.183(2)
2.144(2)
2.156(2)
1.331(2)
1.289(2)
1.302(2)
1.326(2)
2.563(2)
Sn(1)–Ci0
C(2)–O(1)
C(8)–O(2)
C(7)–N(1)
C(8)–N(2)
N(2)–O(3)
3.6. Cytotoxic activity
The efficiency of the diorganotin compounds as anticancer drug
has been tested in vitro on three human carcinoma cell lines, which
were HT29, SKOV-3 and MCF7. The results of IC50 values of the
Schiff base ligands and the diorganotin complexes are summarized
in Table 3.
Bond angles
O(1)–Sn(1)–O(2)
154.86(6)
128.67(8)
122.94(7)
108.07(7)
154.29(13)
127.66(19)
108.18(17)
123.82(16)
153.64(5)
137.94(7)
107.95(6)
113.23(7)
Ci–Sn(1)–Ci0
N(1)–Sn(1)–Ci
N(1)–Sn(1)–Ci0
Ci refers to Cipso
.
Generally, Schiff base ligands were found to display good cyto-
toxic activities towards all the cell lines, with IC50 below 8 lg/ml.
The dimethyltin derivative of H2L1, 1 possesses the highest cyto-
Ci and Ci0 for compounds 1 and 8 is C20 and C21 while Ci and Ci’ for compound 11 is
C20 and C26.
toxic activity among the tested diorganotins, with IC50 values rang-
ing from 0.6 to 1.0 lg/ml against all the tested cell lines. The IC50
the Ci–Sn(1)–Ci0 angles are 128.67(19)° and 127.66(19)° while for
11, it is 137.94(7)°. The C–Sn–C angle of each complex shows a
small degree of deviation from the values estimated using the cou-
pling constants obtained from the NMR spectra.
values obtained by the dimethyltin derivative, 1 are even better than
the cytotoxicity of cis-platin, which is the positive reference standard
in this study. The trend of the cytotoxic activities decreases in the
following order: dibutyltin > dicyclohexyltin > dibenzyltin > di(p-
chlorobenzyl)tin > di(o-chlorobenzyl)tin > diphenyltin derivatives. The
diphenyltin, di(o-chlorobenzyl)tin and di(p-chlorobenzyl)tin deriv-
atives show mild cytotoxic activities against HT29 cells. The diphe-
nyltin derivative, 3 displays selectivity against SKOV-3 cells while
the di(o-chlorobenzyl)tin and di(p-chlorobenzyl)tin derivatives, 6
and 7 show selectivity against MCF7 and SKOV-3 cells.
The Sn(1)–O(1) and Sn(1)–O(2) bond lengths are in the range of
2.05–2.20 Å, which are lower than the sum of the van der Waals ra-
dii (3.69 Å). Whereas, the Sn(1)–N(1) bond length (2.204, 2.201
and 2.183 Å) is lower than the sum of the van der Waals radii
(3.75 Å) indicating the presence of stable coordinative Sn–N bonds
in the complexes. The Sn–C, Sn–O and Sn–N bond distances for the
complexes are comparable to the values reported for similar five-
coordinated diorganotin complexes. The complexes are stabilized
by a strong intramolecular hydrogen bonding interactions between
O(3)–H(3) and N(2) [1: O–Hꢁ ꢁ ꢁN 2.586(2) Å, 8: O–Hꢁ ꢁ ꢁN 2.560(7) Å,
and 11: O–Hꢁ ꢁ ꢁN 2.563(2) Å] and the values are comparable to
those reported in literature [45–49].
Among the H2L2 complexes, the dicyclohexyltin derivative 11
has very good cytotoxic activities in all the tested cell lines, with
IC50 values below 1 l
g mlꢀ1. Similarly, the dibutyltin derivative 9
shows good cytotoxic activities too, with IC50 values lower than
the Schiff base ligands. The IC50 values of the two complexes are
even better than the cytotoxicity of cis-platin, which is the positive
reference standard in this study. However, the di(o-chloroben-
zyl)tin derivative 13 hardly killed any cells in all the tested cell
lines while the diphenyltin derivative 10 displays moderate activ-
ities only against the HT29 cell line. The di(p-chlorobenzyl)tin
3.5. Thermal properties
The thermogravimetric analysis of the complexes was carried
out in the temperature range of 50–900 °C with a heating rate of
Fig. 2. Molecular structure and crystallographic numbering scheme for {[1-(5-bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV), 1.

S.M. Lee et al. / Inorganica Chimica Acta 406 (2013) 272–278
277
Fig. 3. Molecular structure and crystallographic numbering scheme for {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV), 8.
Fig. 4. Molecular structure and crystallographic numbering scheme for {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dicyclohexyltin(IV), 11.
derivative, 14 displays selectivity against MCF7 cells. The dimeth-
yltin and dibenzyltin derivatives, 8 and 12 exhibit moderate activ-
ities against all the tested cell-lines.
Overall, the dimethyltin, dibutyltin and dicyclohexyltin deriva-
tives show remarkable cytotoxic activities with IC50 values that are
lower than those of the Schiff base ligands.
the tested cell lines. Thus, the above complexes can be considered
as agents with potential anticancer activities, and can therefore be
investigated for further stages of in vitro or in vivo anticancer
studies.
Acknowledgements
The authors wish to acknowledge University of Malaya for its
financial assistance through grants PS348/2009C and RG020-
09AFR. The authors are grateful to Prof. Datin Dr. Norhanom Abdul
Wahab for the use of her laboratory space.
4. Conclusion
Several diorganotin complexes have been synthesized and charac-
terized by various spectroscopic techniques. The diorganotin com-
plexes are five-coordinated, as shown by the spectroscopic data and
X-ray crystallographic diffraction. The results of the cytotoxic activities
of the complexes are promising, whereby, {[1-(5-bromo-2-oxidophe-
Appendix A. Supplementary material
nyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV),
is most active among the diorganotin complexes of H2L1 ligand. For
the diorganotin complexes of H2L2 ligand, {[1-(5-chloro-2-oxidophe-
nyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dibutyltin(IV),
and {[1-(5-chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydr-
1
CCDC 838875, CCDC 838874 and CCDC 838873 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.ica.2013.04.036.
9
azidato}dicyclohexyltin(IV), 11 show good cytotoxic activities against all

278
S.M. Lee et al. / Inorganica Chimica Acta 406 (2013) 272–278
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Cytotoxic activity (IC50 values) of Schiff base ligands and its diorganotin complexes
against HT29, MCF7 and SKOV-3 cells.
Compounds
Cytotoxicity (IC50) in
HT29
l
g/ml
MCF7
SKOV-3
8.0 0.3
H2L1
1
2
3
4
5
6
7
H2L2
8
9
10
11
12
13
5.5
0.9 0.1
6.0
28.5 0.5
4.3 0.3
5.8 0.3
41.7 1.5
27.7 3.1
7.3 1.5
5.8 0.3
0
1.0
0.6
0
0
1.0
0.5
0
0
0
4.3 0.3
29.3 1.2
5.3 0.6
8.8 0.3
6.4 0.1
5.0
3.2 0.1
8.0
0.5
5.7 0.4
0.7
4.7 0.6
3.3
3.3
0
0
8.8 0.3
5.0
6.4 1.2
6.0
0
0
0
0
0
3.0
0
0.6 0.1
1.8 0.3
19.0
0.7
6.0
0
0
0
0
0.3
0
6.7 0.2
82.0 1.7
13.0
>100
0
100.0
0
14
6.0
5.0
0
0
0.5
2.4 0.6
0
4.3 0.3
1.4
Cis-platina
0
a
Cis-platin was used as positive control.
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