Synthesis, characterization and cytotoxicity of novel mixed-ligand butyl-hexyltin(IV) complexes with N-hydroxybenzamides

Article abstract of DOI:10.1016/j.poly.2012.08.055

Five new mononuclear butyl-hexyltin(IV) complexes with para-position substituents of N-hydroxybenzamide anions [para-position substituent = H (1), F (2), Cl (3), Br (4), I (5)], formulated as the [ⁿBu ⁿHexSnL₂] (Bu = butyl

Full text of DOI:10.1016/j.poly.2012.08.055

Polyhedron 52 (2013) 429–434
Contents lists available at SciVerse ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis, characterization and cytotoxicity of novel mixed-ligand
butyl-hexyltin(IV) complexes with N-hydroxybenzamides
b
a
a
Xianmei Shang a, , Shaozhong Wei , Jia Yan , Jianping Wang
⇑
a Tongji School of Pharmacy, Huazhong University of Science and Technology, 13 Hangkong Road, 430030 Wuhan, PR China
b Cancer Biology Research Center, Hubei Cancer Hospital, 430079 Wuhan, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 29 August 2012
Five new mononuclear butyl-hexyltin(IV) complexes with para-position substituents of N-hydroxyben-
zamide anions [para-position substituent = H (1), F (2), Cl (3), Br (4), I (5)], formulated as the [nBunHex-
SnL2] (Bu = butyl, Hex = hexyl, HL = substituted N-hydroxybenzamide), were prepared and characterized
by elemental analyses, FT-IR, 1H, 13C, 119Sn NMR spectroscopies. Crystal structure of complex 2 was deter-
mined by X-ray diffraction analysis. The cytotoxicity was tested by SRB assay. The results indicate that
the complex 5 with iodine atoms has the best cytotoxicity against KB cells, even being better than that
of cisplatin. It suggests that both halogens and alkyl groups around tin have important effects on
cytotoxicity.
Dedicated to Alfred Werner on the 100th
Anniversary of his Nobel Prize in Chemistry
in 1913.
Keywords:
Butyl-hexyltin(IV)
Synthesis
Ó 2012 Elsevier Ltd. All rights reserved.
Cytotoxicity
1. Introduction
and if two butyl groups in butyltin(IV) complexes are really neces-
sary for the good antitumour activity.
Organotin(IV) compounds are a widely studied class of metal-
based antitumour drugs [1–10]. In the structure–activity relation-
ships for organotin(IV) derivatives RnSn(L)m, it can be concluded
that dialkyltin(IV) compounds generally exhibit higher antitumour
activity than those of the corresponding mono-, tri- and tetraorg-
anotin(IV) or the inorganic tin derivatives, and within the diorgano-
tin(IV) class (e.g. dimethyltin(IV), diethyltin(IV), di-n-butyltin(IV)
and diphenyltin(IV) complexes), neither dimethyltin(IV) nor dieth-
yltin(IV) complexes exhibit good antitumour activity [2,11,16,18].
The highest activity is exerted by the di-n-butyltin(IV) complexes,
and the nature of the organic group R is the primary factor.
According to the literature, those dialkyltin(IV) complexes hav-
ing been investigated their antitumour activity almost contained
the homoleptic di-n-butyltin(IV) varieties. Furthermore, changing
the organic radicals in the homoleptic species di-n-butyltin(IV)
may result in altering the target species in terms of antitumour
activity. So far, only a limited number of heteroleptic mixed
methyl-heptyltin(IV) [12] or methyl-aryltin(IV) systems [13–15]
are known, and most of which are triorganotin(IV) and tetraorg-
anotin(IV) compounds. As an extension of the research as above,
we are interested in the activities about the diorganotin(IV) com-
plexes with different carbon chain lengths. We are wondering if
much longer carbon chain can increase the antitumour activity
No more information has been given on this type of mixed al-
kyl-alkyltin(IV) complexes with N-hydroxybenzamides, and their
antitumour activities have not yet been investigated. As part of
our ongoing work, in this paper, five new butyl-hexyltin(IV) com-
plexes, [nBunHexSnL2] (Bu = butyl, Hex = hexyl, HL = substituted
N-hydroxybenzamide), have been prepared (Scheme 1) and char-
acterized by elemental analyses, FT-IR, 1H, 13C, 119Sn NMR spec-
troscopies and X-ray diffraction analysis. Here, we also report
their in vitro cytotoxicity in human nasopharyngeal carcinoma
(KB) cell lines. The IC50 values for the butyl-hexyltin(IV) complexes
are comparable to both dibutyltin(IV) complexes and cisplatin, and
some preliminary structure–activity relationships are discussed.
2. Results and discussion
2.1. Syntheses
Butyl-hexyltin(IV) compounds of the type [nBunHexSnL2] can be
prepared by reacting butyl-hexyltin(IV) oxide [nBunHexSnO] with
4-fluoro-N-hydroxybenzamide
(4-chloro-N-hydroxybenzamide,
4-bromo-N-hydroxybenzamide or 4-iodo-N-hydroxybenzamide)
under reflux condition. The detailed methodologies for the prepa-
ration of [nBunHexSnO] and 1–5 are reported in Sections 4.1.2–
4.1.7. These complexes are all white crystalline solids and stable
for months. Complexes 1–5 are not soluble in water, but soluble
in chloroform, dichloromethane, ethanol, benzene, toluene and
DMSO, and only partly soluble in methanol.
⇑
Corresponding author. Tel.: +86 27 83650537.
E-mail address: shang430030@hotmail.com (X. Shang).
0277-5387/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.poly.2012.08.055

430
X. Shang et al. / Polyhedron 52 (2013) 429–434
nBuSnCl3
UV
Et2O
-20
NH3.H2O
nHexLi + nBuSnCl3
nBunHexSnO +
nBunHex3Sn
nBunHexSnCl2
nBunHexSnO
°
H
N
O
C
X
OH
HN
O
O
Methanol-Benzene
Reflux
Sn
O
C
O
X
HN
X
X = H(1), F(2), Cl (3), Br (4), I (5).
Scheme 1. Synthesis of the butyl-hexyltin(IV) complexes of substituted N-hydroxybenzamides (1–5).
2.2. Spectroscopy
di-n-butyltin(IV) derivatives [2–5,16–18], which is consistent with
the presence of hexyl group. Due to the n-butyl protons overlap
with the signal of n-hexyl groups ligated to the tin atom, what
hampers the identification of the individual protons of the ligand
moieties and the measurement of the JSn–H coupling constants.
In the range of alkyl carbon (13.8–30.4 ppm), 13C NMR spectra
of complexes 1–5 give ten peaks distinctly, which well correspond
to every carbon atom (butyl and hexyl groups). Besides this,
another fourteen carbons also can find every peak value in the aro-
matic carbon part and carbonyl part. Similarly, due to the n-butyl
carbons overlap with the signal of n-hexyl groups ligated to the
tin atom, what hampers the identification of the individual carbons
of the ligand moieties and the measurement of the JSn–C coupling
constants.
In the infrared spectra, the important absorption bands
are strong
N-hydroxybenzamides (4-fluoro-N-hydroxybenzamide, 4-chloro-
N-hydroxybenzamide, 4-bromo-N-hydroxybenzamide and
4-iodo-N-hydroxybenzamide) [9]. These peaks disappear for the
complexes (1–5), indicating that the reaction had taken place
through the replacement of the N–OH hydrogen by the organotin
moiety. The IR spectra of all the five compounds show evidence
for the coordination of the 4-halo-N-hydroxybenzamide anions
by both oxygen atoms of the CONHO– group. In fact, the ligation
m
(O–H) in the region 3230–3020 cmꢀ1 in 4-halo-
through the carbonyl oxygen is indicated by the m(C@O) shift to a
lower frequency, i.e. from ca. 1630 cmꢀ1 in the free species to
1600 cmꢀ1 in the chelated one. The bands in the range 493–
119Sn NMR spectra in CDCl3 solution of 1–5 display only one res-
onance (the chemical shifts are from ꢀ350 to ꢀ400 ppm), indicat-
ing one type of tin site. The chemical shifts are agreement with the
hexa-coordinated tin atoms [19–21], which shows that the struc-
ture and the type of tin atom in the solid state are still retained
in solution. One of them will be further confirmed by single-crystal
X-ray analysis as below.
437 cmꢀ1 and 596–503 cmꢀ1 are assigned as
m
sym(Sn–C) and
asym(Sn–C), respectively. These absorption bands indicate the
presence of Sn–C bonds and are compatible with literature values
[16]. Similarly, the existence of (C–H) bending frequencies in CH2
m
m
and CH3, confirming the presence of n-alkyl groups of all the syn-
thesized compounds.
The proton chemical shift assignments of the butyl-hexyltin(IV)
moiety are readily deducible from the multiplicity patterns and
resonance intensities. The assignments of the signals for com-
pounds 1–5 are reported in Sections 4.1.3–4.1.7. The N–H signals
in 1–5 appeared as two separate singlets in the region of 14.83–
9.93 ppm, indicating the different surroundings of two N-hydroxy-
benzamide anions. The integration values are consistent with the
structures. In the 1H NMR spectra of complex 1–5, the complication
of peak shape in the region of 1.9–0.9 ppm is different from those
2.3. X-ray crystallography
A view of the molecular structure and atomic numbering
scheme for 2 is shown in Fig. 1. The selected bond lengths and an-
gles of the complex are given in Table 2. A summary of these data
by single-crystal X-ray diffraction analysis and selected experi-
mental information are given in Table 1.
Fig. 1. Molecular structure and atomic numbering scheme for complex 2 (hydrogen atoms are omitted for clarity).

X. Shang et al. / Polyhedron 52 (2013) 429–434
431
Table 1
Table 3
Experimental data for crystallographic analysis for complex 2.
Hydrogen bond geometry of complex 2.
2
D–H. . .A
D–H (Å)
H. . .A (Å)
D. . .A (Å)
\D–H. . .A (°)
Chemical formula
C
24H32F2N2O4Sn
N(1)–H(1). . .O(6)#1
N(3)–H(3A). . .O(3)#2
C(10)–H(10). . .F(2)#3
C(12)–H(12). . .O(6)#1
C(19)–H(19A). . .N(4)#1
C(30)–H(30). . .O(3)#2
C(43)–H(43A). . .N(2)#2
C(40)–H(40B). . .O(5)
0.86
0.86
0.93
0.93
0.97
0.93
0.97
0.97
1.92
1.95
2.51
2.45
2.03
2.51
2.07
2.94
2.729(5)
2.748(5)
3.292(6)
3.276(6)
2.780(5)
3.369(6)
2.731(5)
3.409(16)
156.8
154.8
141.7
148.1
132.2
154.5
123.8
110.6
M (g molꢀ1
)
569.21
tetragonal
I4(1)/a
27.6757(10)
27.676
26.5129(10)
90
Crystal system
Space group
a (Å)
b (Å)
c (Å)
a
(°)
b (°)
90
90
Symmetry codes for 2: (i) x + 1/2, y, ꢀz + 1/2; (ii) ꢀx + 3/2, ꢀy + 3/2, ꢀz + 1/2;
(iii) y + 1/4, ꢀx + 7/4, ꢀz ꢀ 1/4.
c
(°)
V (Å3)
20307.4(11)
32
1.489
1.052
116992
12027
Z
qcalc (g cmꢀ3
)
l
(mmꢀ1
)
and much shorter than those found in five-coordinated diorgano-
tin(IV) complexes [18,28,29], e.g. 2.321(4) [18]. Meanwhile, the
bond length of Sn–C19 (tin-hexyl) [2.049(4) Å] is slightly shorter
than that of Sn–C15 (tin-butyl) [2.129(6) Å], showing better stabil-
ization of Sn–hexyl bond than Sn–butyl bond.
Reflections collected
Individual reflections
Rint
h completeness [%]
Data/restraints/parameters
GOF on F2
0.0368
27.49° [99.2]
12027/118/595
1.085
In the molecular structure, the two five-member rings around
Sn are oriented at big dihedral angle degrees of 85.32° (between
the planes of Sn1/O1/O2 and Sn1/O3/O4). While in the structures
of other mononuclear organotin(IV) N-hydroxybenzamides
[17,18], such as [Bu2Sn{4-ClC6H4C(O)NHO}(4-ClC6H4COO)] and
[Me2Sn{3,4-F2C6H3C(O)NHO}2], the values of the corresponding
dihedral angle are 6.64° and 8.99°, respectively, being much less
than that of complex 2. So, the environment of the tin atoms
reported here for [nBunHexSnL2] (2) is different from those mono-
nuclear diorganotin(IV) N-hydroxybenzamides found in previous
derivatives published [17,18,22].
Final indices [I >
r
(I)]
R1 = 0.0642
wR2 = 0.1872
R1 = 0.0975
wR2 = 0.2463
Final indices (all data)
Table 2
Summary of the most relevant bond distances (Å) and angles (°) of 2.
Sn(1)–O(2)
Sn(1)–O(1)
Sn(1)–O(4)
Sn(1)–O(3)
Sn(1)–C(15)
Sn(1)–C(19)
C(7)–O(2)
C(7)–N(2)
C(14)–O(4)
2.116(3)
2.125(3)
2.174(3)
2.136(3)
2.129(6)
2.049(4)
1.285(5)
1.279(6)
1.271(5)
1.318(6)
104.07(19)
86.41(15)
156.15(15)
75.77(13)
85.73(13)
Sn(2)–O(8)
Sn(2)–O(7)
Sn(2)–O(6)
Sn(2)–O(5)
Sn(2)–C(43)
Sn(2)–C(39)
C(38)–O(7)
C(38)–N(4)
2.126(3)
2.125(3)
2.153(3)
2.172(3)
2.060(4)
2.126(6)
1.287(5)
1.293(6)
1.270(5)
1.316(6)
In complex 2, there are four sets of hydrogen bonds [N–Hꢁ ꢁ ꢁO,
C–Hꢁ ꢁ ꢁF, C–Hꢁ ꢁ ꢁO and C–Hꢁ ꢁ ꢁN] (see Table 3), which stabilize the
complex 2 into a three-dimensional structure as illustrated in
Fig. 2. Moreover,
benzene rings plays an important role in constructing the supra-
p p stacking interaction between two associate
ꢁ ꢁ ꢁ
molecular network.
C(31)–O(5)
C(31)–N(3)
C(14)–N(1)
C(19)–Sn(1)–C(15)
C(19)–Sn(1)–O(2)
C(19)–Sn(1)–O(1)
O(2)–Sn(1)–O(1)
O(2)–Sn(1)–O(3)
C(43)–Sn(2)–C(39)
C(43)–Sn(2)–O(8)
C(43)–Sn(2)–O(7)
O(7)–Sn(2)–O(8)
O(7)–Sn(2)–O(6)
104.3(3)
155.04(14)
86.14(15)
76.05(13)
85.76(12)
The crystal structure of 2 consists of two independent com-
plexes in the asymmetric unit with closely comparable geometries.
The coordination polyhedron consists of one butyl group, one hexyl
group and two oxygen atoms (one oxygen derived from C@O, the
other oxygen stemmed from –OH) from asymmetric N-hydroxy-
benzamide moieties, leading to a highly distorted octahedral
geometry [22–24]. Each tin centre is hexa-coordinated in cis
coordination geometry [25], with angles of 104.07(19)° for
C19–Sn1–C15 and 104.3(3)° for C43–Sn2–C39, being much smaller
than those reported dialkyltin(IV) complexes with N-hydroxyben-
zamides [26,27]. For example, the tin centers of [Me2Sn{4-ClC6H4-
C(O)NHO}2] with angles of 142.7(2)° C–Sn–C and [Me2Sn{4-
OCH3C6H4C(O)NHO}2] with angles of 140.8(2)° [16].
In the structure the two N-hydroxybenzamide residues are
functioning as bidentate ligands, but not equivalent. One group
of Sn–O bond lengths in 2 [Sn1–O2, 2.116(3) Å and Sn1–O1,
2.125(3) Å] are very close to that in [Me2Sn{4-ClC6H4C(O)NHO}2]
and [Me2Sn{4-OCH3C6H4C(O)NHO}2] [16], forming one short cova-
lent bond and one longer coordinate oxygen–tin bond (Table 2).
However, the other group of Sn–O bond lengths in 2 [Sn1–O3,
2.136(3) Å and Sn1–O4, 2.174(3) Å] are shorter than those in
[Me2Sn{4-ClC6H4C(O)NHO}2] and [Me2Sn{4-OCH3C6H4C(O)NHO}2]
Fig. 2. Packing diagram of the complex 2 viewed along c-axis.

432
X. Shang et al. / Polyhedron 52 (2013) 429–434
Table 4
suggests a close correlation between activity and electronic prop-
erties of halogens, which may be beneficial in the design of new
metal-based antitumour agents.
The cytotoxicity of compounds 1–5 against KB human tumor cells.
Compounds
IC50 (lM)
1
2
3
4
24.12 1.27
38.40 2.92
21.03 1.02
2.54 0.30
2.02 0.37
1.30 0.10
0.85 0.05
0.01 0.00
1.25 0.12
0.78 0.05
2.65 0.33
4. Experimental
4.1. Chemistry
5
[Bu2Sn{C6H5C(O)NHO}2]
[Bu2Sn{4-FC6H4C(O)NHO}2]
[Bu2Sn{4-ClC6H4C(O)NHO}2]
[Bu2Sn{4-BrC6H4C(O)NHO}2]
[Bu2Sn{4-IC6H4C(O)NHO}2]
Cisplatin
4.1.1. Materials and methods
Methyl 4-fluorobenzoate, methyl 4-chlorobenzoate, methyl
4-bromobenzoate, methyl 4-iodobenzoate, N-hydroxybenzamide,
n-hexyllithium and nBuSnCl3 were purchased from Aldrich and used
as received. (nButyl)(nhexyl)tin(IV) oxide was prepared as below
according to the literature methods (see Section 4.1.2) [30–32].
The other reagents were of analytical grade. 4-Fluoro-N-hydroxy-
benzamide, 4-chloro-N-hydroxybenzamide, 4-bromo-N-hydroxy-
benzamide and 4-iodo-N-hydroxybenzamide were prepared
according to a known general procedure [10]. Five di-n-butyltin(IV)
analogs [Bu2Sn{C6H5C(O)NHO}2], [Bu2Sn{4-FC6H4C(O)NHO}2], [Bu2-
Sn{4-ClC6H4C(O)NHO}2], [Bu2Sn{4-BrC6H4C(O)NHO}2] and [Bu2-
Sn{4-IC6H4C(O)NHO}2] were synthesized by reported methods [18].
Elemental analyses were performed on a PE-2400-II elemental
analyzer. IR spectra in the range 4000–400 cmꢀ1 were recorded
on a Perkin Elmer FT-IR spectrophotometer in KBr discs. 1H, 13C,
119Sn NMR spectra were recorded on a Varian INOVA 600 spec-
trometer (600.0 MHz for 1H, 150.8 MHz for 13C and 223.6 MHz
for 119Sn) at ambient temperature [d values in ppm relative to Me4-
Si (1H, 13C) or Me4Sn (119Sn)].
2.4. Cytotoxicity of compounds
According to the previous results [29], diorganotin(IV) com-
plexes is very sensitive to human cancer KB cell lines, so in this
experiment we select KB cell as model to check cytotoxicity. In
order to examine whether the introduced chemical modifications
improve their in vitro antitumour properties, the five butyl-hexyl-
tin(IV) complexes with N-hydroxybenzamides, the five dibutyl-
tin(IV) analogs and cisplatin have been screened at identical
conditions for the preliminary cytotoxicity against human naso-
pharyngeal carcinoma (KB) cell lines at five different concentra-
tions. The IC50 values obtained are listed in Table 4.
The following structure–activity relationships could be recog-
nized: (i) Among the complexes 1–5, the complexes 1, 2 and 3
exhibited lower in vitro cytotoxic activities towards the KB tumor
cell lines, while the complexes 4 and 5 exhibited stronger activities
Suitable single crystal of the complex 2 was mounted in glass
capillaries for X-ray structural analysis. Diffraction data were col-
lected on a Bruker SMART CCD diffractometer with Mo K
a
against the same cell lines with lower IC50 values (<3 lM). (ii) For
(k = 0.71073 Å) radiation at room temperature. During the inten-
sity data collection, no significant decay was observed. The inten-
sities were collected for Lorentz-polarization effects and
empirical absorption with the SADABS program. The structure was
solved by direct methods using the SHELXL-97 program. All non-
hydrogen atoms were found from the difference Fourier syntheses.
The H atoms were included in calculated positions with isotropic
thermal parameters related to those of the supporting carbon
atoms but were not included in the refinement. All calculations
were performed using the Bruker Smart program [33].
the series of butyl-hexyltin(IV) derivatives, the data show gradu-
ally increased cytotoxicity against human tumor KB cell lines with
a decrease of electron-withdrawing properties of X substituents,
following the orders: I > Br > Cl > F (5 > 4 > 3 > 2). The trend sug-
gests these X substituents of the substituted N-hydroxybenzamide
anions have important effects on cytotoxicity. (iii) Among 1–5
compounds, the complex 5 containing iodine atoms exhibit the
greatest cytotoxic properties, being even more active than ‘‘cis-
platin’’, the clinically used drug. (iv) Comparison of the IC50 values
suggests that dibutyltin(IV) complexes [11,16] of substituted N-
hydroxybenzamides with two butyl groups are better than the bu-
tyl-hexyltin(IV) analogs with one hexyl and one butyl groups, indi-
cating that the hexyl group led to a huge decrease in biological
activity.
4.1.2. Synthesis of (nBu)(nHex)SnO
Reaction of n-hexyllithium (nHexLi) with nBuSnCl3 in Et2O at
ꢀ20 °C gave nBunHex3Sn. Keeping 2 mol nBuSnCl3 and 1 mol
nBunHex3Sn in UV light 3 h gave 90% nBunHexSnCl2. nBunHexSnO
was precipitated from an aqueous solution of nBunHexSnCl2 by
the addition of aqueous ammonia. The precipitate was washed
with water until it was free of chloride ion and dried overnight
in a vacuum oven at 70 °C. Yield: 85%, m.p. > 300 °C. Elemental
Anal. Calc. for C10H22OSn: C, 43.36; H, 8.01. Found: C, 42.59; H,
7.87%.
3. Conclusions
In conclusion, for the first time, we have successfully prepared
five new butyl-hexyltin(IV) complexes with N-hydroxybenza-
mides, which were fully characterized by elemental analyses, IR,
1H, 13C, 119Sn NMR and, for 2, X-ray single-crystal diffraction anal-
ysis. These compounds exhibit in vitro antitumor activity towards
human tumor KB cell lines to some extent. According to our exper-
imental results, organic group R plays an important role indeed,
and butyl groups in di-n-butyltin(IV) complexes are necessary for
the good antitumour activity. The contribution of much longer car-
bon chain (e.g. hexyl group ligated to the tin atom) to antitumour
activity might be limited. On the other hand, the electronic effect of
oxygen-ligands (N-hydroxybenzamides) also has an important ef-
fect on cytotoxic activity. The case of complex 5 containing I
groups is the most active one and the type of the X substituents
in the 4-halo-N-hydroxybenzamide affects the cytotoxic activity,
following the orders: I > Br > Cl > F (5 > 4 > 3 > 2). Therefore, for
the butyl-hexyltin(IV) complexes, the order of antitumour activity
4.1.3. Synthesis of [(nBu)(nHex)Sn{C6H5C(O)NHO}2] (1)
A solution of 0.249 g (1.0 mmol) butyl-hexyltin(IV) oxide was
added to a solution of 2.0 mmol N-hydroxybenzamide in dry etha-
nol–toluene (1:3 v/v, 120 mL). The mixture was refluxed under
nitrogen atmosphere for 6 h, and the solvent was evaporated to
5 mL under reduced pressure. The precipitate thus formed was fil-
tered off, recrystallized from n-hexane and dried to constant
weight. Yield: 59%. Elemental Anal. Calc. for C24H34N2O4Sn: C,
54.06; H, 6.43; N, 5.25. Found: C, 54.26; H, 6.49; N, 5.28%. IR:
3427m (N–H), 3130, 1595s (C@O)/(N–C), 990s, 930w (N–O),
576m (Sn–C), 480s (Sn–O) cmꢀ1
1H, N–H), 9.72 (s, 1H, N–H), 7.38 [t, JHH = 8.1, 4H]; 7.75 [dd,
.
1H NMR (CDCl3): d = 10.30 (s,
3

X. Shang et al. / Polyhedron 52 (2013) 429–434
433
3
3JHH = 8.1, 4H]; 1.83–1.03 [m, 16H, 8CH2]; 0.83 [t, 3H, JHH = 5.4,
4.2. Pharmacology
CH3], 0.81 [t, 3H, JHH = 6.0, C0H3] ppm; 13C NMR (CDCl3):
3
d = 163.4, 162.9 (C@O), 116.3, 128.7, 114.4, 28.0–13.3 [Sn–R]
In order to compare with our previous experimental results, the
human nasopharyngeal carcinoma (KB) cell lines were used for
screening. They were grown and maintained in RPMI-1640 med-
ium supplemented with 10% fetal bovine serum, penicillin
ppm. 119Sn (CDCl3): d = ꢀ 356.9 ppm.
4.1.4. Synthesis of [(nBu)(nHex)Sn{4-FC6H4C(O)NHO}2] (2)
(100 U/mL), and streptomycin (100 lg/mL) at 37 °C in humidified
A solution of 0.249 g (1.0 mmol) butyl-hexyltin(IV) oxide was
added to a solution of 2.0 mmol 4-fluoro-N-hydroxybenzamide in
dry ethanol–toluene (1:3 v/v, 120 mL). The mixture was refluxed
under nitrogen atmosphere for 6 h, and the solvent was evaporated
to 5 mL under reduced pressure, the residue drying slowly by
exposure to the air. 15 mL n-hexane was then added to soak the so-
lid at room temperature for 24 h, filtrating. The filtrate lay in the air
for 1 week, and many long sheer prismy crystals thus formed.
Yield: 56%. Elemental Anal. Calc. for C24H32F2N2O4Sn: C, 50.64; H,
5.67; N, 4.92. Found: C, 50.68; H, 5.65; N, 4.89%. IR: 3423m (N–
H), 3163, 1606s (C@O)/(N–C), 917s (N–O), 509m (Sn–C), 418s
incubators in an atmosphere of 5% CO2.
The complexes were dissolved in DMSO at a concentration of
5 mM as stock solution, and diluted in culture medium at concen-
trations of 1.0, 10, 100, and 500 lM as working-solution. To avoid
DMSO toxicity, the concentration of DMSO was less than 0.1% (v/v)
in all experiments.
The cells harvested from the exponential phase were seeded
equivalently into a 96-well plate, and then the complexes were
added to the wells to achieve final concentrations. Control wells
were prepared by addition of culture medium. Wells containing
culture medium without cells were used as blanks. All experiments
were performed in quintuplicate. The SRB assay was performed as
previously described in KB cells [34]. Upon completion of the incu-
bation for 48 h, the cells were fixed in 10% trichloroacetic acid
(Sn–O) cmꢀ1 1H NMR (CDCl3): d = 14.83 (s, 1H, N–H), 13.38 (s,
.
3
3
1H, N–H), 7.26 [t, JHH = 3JHF = 8.4, 4H]; 7.55 [dd, JHH = 9.0,
4JHF = 4.8, 4H]; 1.90–1.88, 1.77–1.61, 1.50–1.37 [m, 16H, 8CH2];
3
3
0.97 [t, 3H, JHH = 5.4, CH3], 0.94 [t, 3H, JHH = 7.8, C0H3] ppm; 13C
NMR (CDCl3): d = 165.6, 165.0 (C@O), 163.9, 163.3 (C–F), 161.0,
160.5 (C1, C10); 129.1, 129.0, 128.2, 128.1, 122.8, 122.1, 114.7,
114.6 [C2, C20, C3, C30, C5, C50, C6, C60]; 30.4, 29.6, 27.4, 26.2,
21.5, 19.5, 19.1, 14.1 [(CH2)3 and (CH2)5], 13.9 (CH3), 13.8 (CH3)
ppm. 119Sn (CDCl3): d = ꢀ390.6 ppm.
(100
0.1% SRB in 1% acetic acid (100
washed four times in 1% acetic acid and air-dried. The stain was
solubilized in 10 mM unbuffered Tris base (100 l) and the OD
ll) for 30 min at 4 °C, washed five times and stained with
ll) for 15 min. The cells were
l
was measured at 540 nm as above. The IC50 value was determined
from plots of % viability against doses of compounds added.
4.1.5. Synthesis of [(nBu)(nHex)Sn{4-ClC6H4C(O)NHO}2] (3)
Acknowledgments
Similarly prepared employing 2.0 mmol 4-chloro-N-hydroxy-
benzamide. Yield: 45%. Elemental Anal. Calc. for C24H32Cl2N2O4Sn:
C, 47,87; H, 5.36; N, 4.65. Found: C, 47.92; H, 5.45; N, 4.57%. IR:
3431m (N–H), 3189, 1598 (C@O)/(N–C), 914s (N–O), 571m (Sn–
This work has been partially supported by the National Natural
Science Foundation of China (No.: 81102311), the National Natural
Science Foundation of Hubei Province of China (No.: 2008CDB242),
the Fundamental Research Funds for the Central Universities
and Huazhong University of Science and Technology (No.:
2011QN242).
C), 498s (Sn–O) cmꢀ1 1H NMR (CDCl3): d = 12.17 (s, 1H, N–H),
.
11.02 (s, 1H, N–H), 7.38 (m, 8H, 2C6H4), 1.68–1.61, 1.44–1.28 (m,
3
br, 16H, 8CH2), 0.959 (t, 3H, JHH = 7.2, C0H3), 0.907 (t, 3H,
3JHH = 7.2, CH3) ppm. 13C NMR (CDCl3): d = 161.6 (C@O), 145.9,
128.9, 128.3, 127.8 (aryl-C), 31.7, 29.6, 28.3, 27.3, 26.6, 25.1, 22.7,
19.1 [(CH2)3 and (CH2)5], 13.9 (CH3), 13.8 (CH3) ppm. 119Sn (CDCl3):
d = ꢀ389.3 ppm.
Appendix A. Supplementary data
CCDC 661105 contains the supplementary crystallographic data
for 2. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
4.1.6. Synthesis of [(nBu)(nHex)Sn{4-BrC6H4C(O)NHO}2] (4)
Prepared accordingly using 2.0 mmol 4-bromo-N-hydroxyben-
zamide. Yield: 41%. Elemental Anal. Calc. for C24H32Br2N2O4Sn: C,
47,71; H, 4.67; N, 4.05. Found: C, 47.88; H, 4.72; N, 3.99%. IR:
3429m (N–H), 3182, 1593 (C@O)/(N–C), 912s (N–O), 565m (Sn–
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