Synthesis, characterization, crystal structure, and cytotoxicity of a 7-coordinate diorganotin(IV) complex of 2-acetylpyrazine N4- methylthiosemicarbazone

Article abstract of DOI:10.1515/znb-2012-0206

The diorganotin(IV) complex [Ph₂Sn(L)(CH₃COO)] (1), where HL = 2-acetylpyrazine N₄-methyl thiosemicarbazone, has been synthesized and characterized by elemental analysis, IR, UV/Vis and NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. Complex 1 contains mononuclear neutral molecules composed of one N₂S tridentate anionic thiosemicarbazone ligand, one acetato group, and one Ph ₂Sn(IV) group with a seven-coordinated tin atom. In vitro biological studies have indicated that complex 1 shows effective cytotoxicity with IC ⁵⁰ = 5.4 μM against the K562 leukaemia cell line.

Full text of DOI:10.1515/znb-2012-0206

Synthesis, Characterization, Crystal Structure, and Cytotoxicity
of a 7-Coordinate Diorganotin(IV) Complex of 2-Acetylpyrazine
N4-Methylthiosemicarbazone
Xian Feng Zhub, Li Zhi Zhanga, Min Yanga, Yan Ke Lia, and Ming Xue Lia
a Institute of Molecular and Crystal Engineering, College of Chemistry and Chemical Engineering,
Henan University, Kaifeng 475004, P. R. China
b Bioengineering Institute and College of Life Science, Henan University, Kaifeng 475004,
P. R. China
Reprint requests to Prof. Ming Xue Li. Fax: +86-378-2853650. E-mail: limingxue@henu.edu.cn
Z. Naturforsch. 2012, 67b, 149 – 153; received December 27, 2011
The diorganotin(IV) complex [Ph2Sn(L)(CH3COO)] (1), where HL = 2-acetylpyrazine N4-meth-
yl thiosemicarbazone, has been synthesized and characterized by elemental analysis, IR, UV/Vis
and NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. Complex 1 contains
mononuclear neutral molecules composed of one N2S tridentate anionic thiosemicarbazone ligand,
one acetato group, and one Ph2Sn(IV) group with a seven-coordinated tin atom. In vitro biological
studies have indicated that complex 1 shows effective cytotoxicity with IC50 = 5.4 µM against the
K562 leukaemia cell line.
Key words: Thiosemicarbazone, Diorganotin(IV), Crystal Structure, Cytotoxic Activity
Introduction
Heterocyclic thiosemicarbazones and their metal
complexes have received considerable attention in
chemistry and biology, owing to their marked and vari-
able biological properties [1 – 6]. The biological activ-
ities of thiosemicarbazones often depend on the parent
aldehyde or ketone. On the other hand, the biological
properties of metal thiosemicarbazones can be modi-
fied and often differ from those of either the ligands or
the metal ions with changes in the metal ion coordina-
tion [7 – 9]. In some cases the highest in vivo activity is
associated with a metal complex rather than the parent
ligand, and some side effects may decrease upon com-
plexation [10, 11].
Tin complexes are known for their multiple ap-
plications as antimicrobials and biocides [12]. More-
over, diorganotin(IV) compounds are known to exhibit
important cytotoxic effects against tumor cell lines
[13 – 15].
In recent years we have been working on the
structural and biological properties of heterocyclic
thiosemicarbazones and their metal complexes [16].
The results have revealed that thiosemicarbazones de-
rived from 2-acetylpyrazine and their metal complexes
show significant antitumor activities. After a careful
Scheme 1. The reaction scheme for the synthesis of 1.
literature search, we can affirm that 2-acetylpyrazine
N4-substituted thiosemicarbazones and their diorgan-
otin(IV) complexes are scarce. Therefore, it seemed
important for us to obtain their tin complexes as a
strategy for the preparation of new drug candidates in
which the metal and ligand could act synergistically.
From the present study, we describe the synthesis,
characterization and cytotoxicity of the 7-coordinate
diorganotin(IV) complex 1 with 2-acetylpyrazine N4-
methylthiosemicarbazone as ligand (Scheme 1).
Experimental Section
General
Materials: All solvents and reagents were commercially
available and used without further purification. 2-acetylpyr-
azine N4-methylthiosemicarbazone was prepared according
to the literature method [17].
c
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X. F. Zhu et al. · A 7-Coordinate Diorganotin(IV) Complex of 2-Acetylpyrazine N4-Methylthiosemicarbazone
Table 1. Summary of crystal data and numbers pertinent to
data collection and structure refinement for complex 1.
Instrumentation
Elemental analysis of C, H and N was performed on
a Perkin-Elmer 240 analyzer. The infrared spectra were
recorded from KBr discs on a Nicolet 170 FT infrared spec-
trophotometer. Electronic spectra were obtained with a Hi-
tachi U4100 spectrometer. 1H NMR spectra were recorded
using a Bruker AV-400 spectrometer. The masss spectra were
taken on an Esquire 3000 LC-MS spectrometer.
Formula
Mr
C22H23SnN5SO2
540.200
0.47×0.21×0.03
monoclinic
C2/c
28.112(3)
10.282(1)
16.729(2)
4772.9(9)
8
1.50
1.2
2.39 – 23.39
2176
31, −11 → 12, 19
11979 / 1192 / 0.0696
0.0401 / 0.1087
0.0568 / 0.1155
0.956
Crystal size, mm3
Crystal system
Space group
˚
a, A
˚
b, A
˚
c, A
3
˚
V, A
Synthesis
Z
Dcalcd, g cm−3
An ethanol solution containing Ph2SnCl2 (0.068 g,
0.2 mmol) was added dropwise to an ethanol solution
(20 mL) of 2-acetylpyrazine N4-methylthiosemicarbazone
(0.042 g, 0.2 mmol) and NaOAc (0.016 g, 0.2 mmol).
After refluxing for 2 h with stirring, the resulting mix-
ture was filtered. Orange crystals suitable for X-ray studies
were obtained by slow evaporation of an ethanol solution. –
Elemental analysis for C22H23SnN5SO2: calcd. C 48.92,
H 4.29, N 12.96; found C 49.02, H 4.64, N 12.78. – UV/Vis
(C2H5OH): λmax = 320 nm. – 1H NMR(CDCl3, ppm): 9.21
(s, 1H, NH), 8.64 (s, 1H, Pz), 8.53 (d, J = 1.6 Hz, 1H, Pz),
8.50 (d, J = 2.4 Hz, 1H, Pz), 7.74 – 7.72 (m, 2H, Ph), 7.62
(t, J = 4 Hz, 4H, Ph), 7.46 – 7.44 (m, 4H, Ph), 3.29 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 2.09 (s 3H, CH3COO−). – MS ((+)-
ESI): m/z = 481.4 [(Ph)2Sn(L)]+. The complex is soluble in
CH3OH, C2H5OH, DMF, and DMSO.
µ(MoKα ), cm−1
θ range data collection, deg
F(000), e
hkl range
Refl. measured / unique / Rint
R1 / wR2 [I ≥ 2σ(I)]
R(F) / wR2 (F2) (all refl.)
GOF
−3
˚
∆ρfin (max / min), e A
1.37 / −0.64
˚
Table 2. Selected bond lengths (A) and angles (deg) for com-
plex 1.
Sn(1)-O(2)
Sn(1)-O(1)
Sn(1)-C(9)
Sn(1)-C(15)
Sn(1)-S(1)
N(4)-Sn(1)-N(3)
N(3)-Sn(1)-S(1)
C(9)-Sn(1)-C(15)
2.339(3)
2.454(3)
2.146(5)
2.149(5)
2.551(1)
68.00(1)
75.68(1)
167.7(2)
Sn(1)-N(4)
Sn(1)-N(3)
C(3)-N(3)
S(1)-C(2)
N(3)–N(2)
N(2)–C(2)
O(2)-Sn(1)-S(1)
O(1)-Sn(1)-N(4)
2.451(4)
2.345(4)
1.312(6)
1.730(5)
1.362(5)
1.331(6)
83.87(1)
78.30(1)
X-Ray crystallographic study
An orange crystal with approximate dimensions of
0.47×0.21×0.03 mm3 was mounted in random orientation
on a glass fiber. Intensity data were collected at T =
296(2) K on a Siemens SMART-CCD diffractometer with
˚
Table 3. Hydrogen bond lengths (A) and bond angles (deg)
for complex 1a.
D–H···A
d(H···A)
d(D···A)
∠(D–H···A)
N(1)-H(1A)···O(2)#1
2.43
3.191(6)
150.2
˚
graphite-monochromatized MoKα radiation (λ = 0.71073 A)
Symmetry operation: #1 −x+1/2, y+1/2, −z+1/2.
a
using the programs SMART and SAINT [18]. The structure
was solved by Direct Methods and refined by full-matrix
least-squares based on F2. All non-hydrogen atoms were
refined anisotropically. The positions of hydrogen atoms
were added in idealized geometrical positions. Details are
given in Table 1.
phosphate-buffered saline (PBS) before the experiment. The
final concentration of DMSO was lower than 1 %. After 24 h
incubation, cultures were incubated in 100 µL of a medium
with 10 µL of a 5 mg mL−1 MTT solution for 4 h at 37 ◦C.
The medium with MTT was removed, and 100 µL of DMSO
was added to each well to dissolve the formazan. The ab-
sorbance at 570 nm was measured with a microplate reader
(Bio-Tek ELX800, USA). The inhibitory percentage of each
compound at various concentrations was calculated, and the
IC50 value was determined.
CCDC 800548 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data request/cif.
Cytotoxicity assay
K562 leukaemia cells (purchased from Institute of Bio-
chemistry and Cell Biology, SIBS, CAS) were placed into
96-well plates at a density of 1 × 104 cells per well and
allowed to grow in a CO2 incubator. After 24 h, the
medium was removed and replaced by fresh medium con-
taining the tested compounds which were dissolved in
Results and Discussion
Crystal and molecular structure of 1
Table 1 summarizes crystal and refinement data for
complex 1. Selected bond lengths and angles are given
DMSO at 0.01 M and diluted to various concentrations with in Table 2. Hydrogen bond lengths and angles are
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X. F. Zhu et al. · A 7-Coordinate Diorganotin(IV) Complex of 2-Acetylpyrazine N4-Methylthiosemicarbazone
151
pseudo-macrocyclic coordination mode of the ligand
affords two five-membered chelate rings, which are
nearly planar, the dihedral angle between the chelate
◦
˚
rings being 4.5 . The C–S bond lengths of ca. 1.73 A
are within the normal range of C–S single bonds, in-
dicating that the thiosemicarbazone moiety adopts the
tautomeric thiol form and acts as a mononegative lig-
and [16a]. The C(3)–N(3) and N(3)–N(2) distances
˚
of 1.312(6) and 1.362(5) A, respectively, are interme-
diate between formal single and double bonds, point-
ing to an extensive electron delocalization over the en-
tire ligand skeleton. The shortening of the bond lengths
of Sn–N (imine) relative to Sn–N (pyridine) may be at-
tributed to the fact that the imine nitrogen is a stronger
base compared with the pyridine nitrogen [19].
The molecules of complex 1 are held together in the
crystal through intermolecular hydrogen bonds involv-
ing the terminal nitrogen atom N(1) of a thiosemicar-
bazone ligand and the oxygen atom O(2) of an acetato
group (Fig. 2). The separation for N(1)···O(2) (sym-
Fig. 1. Molecular structure of complex 1 with atomic num-
bering scheme adopted.
˚
metry code: −x+1/2, y+1/2, −z+1/2) is 3.191(6) A
with the N–H···O angle being 150.2◦.
IR spectra
The infrared spectral bands most useful for deter-
mining the mode of coordination of the ligand are
the ν(C=N), ν(N-N) and ν(C=S) vibrations. The IR
spectrum of HL does not display ν(C–SH) in the re-
gion 2500 – 2600 cm−1 indicating that in the solid
state these ligands remain in the thione form [20].
The ν(C=N) bands of HL at 1610 cm−1 are shifted
to 1541 cm−1 in the spectrum of complex 1, a clear
sign of coordination via the imine nitrogen atom [21].
The band at 861 cm−1 in HL is assigned to ν(C=S),
whereas in its complex the band is shifted to lower fre-
quency (847 cm−1), indicating the coordination of sul-
fur [22]. The increase in the frequency of the ν(N–N)
band of the thiosemicarbazone in the spectrum of the
complex is due to the increase in the bond strength,
again confirming the coordination via the imine nitro-
gen. These observations were also evident from the
above-described molecular structure determination.
Fig. 2. Hydrogen bonds (dashed lines) in crystals of com-
plex 1.
listed in Table 3. The molecular and crystal structures
along with the atom numbering scheme are depicted in
Figs. 1 and 2, respectively.
As shown in Fig. 1 the tin atom in 1 is seven-
coordinate and adopts a distorted pentagonal bipyra-
midal geometry with the pentagonal plane defined by
the tridentate N2S thiosemicarbazone and the bidentate
acetato group, whereas the axial positions are occupied
by the two phenyl groups. The distortion from pentag-
onal bipyramidal geometry is evident from the bond
In vitro cytotoxicity
In terms of the cytotoxic activity of thiosemicarb-
angles N(3)–Sn(1)–N(4) 68.00(1)◦, N(3)–Sn(1)–S(1) azones [23, 24], we have tested the ability of com-
75.68(1)◦, C(9)–Sn(1)–C(15) 167.7(2)◦, O(2)-Sn(1)- plex 1 as well as the starting compound Ph2SnCl2 to in-
S(1) 83.87(1)◦, and O(1)-Sn(1)-N(4) 78.30(1)◦. The hibit tumor cell growth against K562 leukaemia cells.
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X. F. Zhu et al. · A 7-Coordinate Diorganotin(IV) Complex of 2-Acetylpyrazine N4-Methylthiosemicarbazone
value (5.4 µM) than both HL (25.9 µM) [16c] and
Ph2SnCl2 (38.9 µM) indicating that coupling of HL
to Ph2Sn(IV) leads to an enhancement of the anti-
tumor activity of the free ligand. This confirms that
complexation with a metal has a synergetic effect
on the cytotoxicity [11, 16]. In particular, it should
be emphasized that 1 shows activity comparable to
that of cis-diamminedichloroplatinum(II) (cis-DDP)
(1.2 µM). Therefore, complex 1 merits further biolog-
ical screening as well as studies of the mechanism of
action.
Fig. 3. The cytotoxicity of the tested compounds against the
K562 leukaemia cell line [cis-DDP = cis-diamminedichloro-
platinum(II)].
Acknowledgement
IC50 values (compound concentration that pro-
duces 50 % of cell death) in micromolar units were
calculated (Fig. 3). The comparison of the cytotoxic
activities indicates that 1 shows a much lower IC50
This work was financially supported by the National Nat-
ural Science Foundation of China (21071043) and the Nat-
ural Science Foundation of the Educational Department of
Henan Province (2010B150003).
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