A Diorganotin(IV) Complex of 2,6-Diacetylpyridine Bis(N 4- Cyclohexylthiosemicarbazone): Synthesis, Crystal Structure, and Cytotoxicity

Article abstract of DOI:10.1080/15533174.2013.867878

A diorganotin(IV) complex formulated as [(Me)₂Sn(L)] (1) (H2L = 2,6-diacetylpyridine bis(N⁴-cyclohexylthiosemicarbazone) has been synthesized and structurally characterized by elemental analysis, IR, UV, and NMR spectroscopy, and sin

Full text of DOI:10.1080/15533174.2013.867878

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A Diorganotin(IV) Complex of 2,6-Diacetylpyridine
Bis(N4- Cyclohexylthiosemicarbazone): Synthesis,
Crystal Structure, and Cytotoxicity
Han Yua, Gaofeng Zhangb, Mingxue Lia, Yanli Lua & Hechen Wua
a Henan Key Laboratory of Polyoxometalates, Institute of Molecular and Crystal Engineering,
College of Chemistry and Chemical Engineering, Henan University, Kaifeng, P. R. China
b Yancheng Experimental High School, Luohe, P. R. China
Accepted author version posted online: 29 Jun 2015.
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To cite this article: Han Yu, Gaofeng Zhang, Mingxue Li, Yanli Lu & Hechen Wu (2015) A Diorganotin(IV) Complex of 2,6-
Diacetylpyridine Bis(N4- Cyclohexylthiosemicarbazone): Synthesis, Crystal Structure, and Cytotoxicity, Synthesis and Reactivity
in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 45:12, 1864-1869, DOI: 10.1080/15533174.2013.867878
To link to this article: http://dx.doi.org/10.1080/15533174.2013.867878
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry (2015) 45, 1864–1869
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2013.867878
A Diorganotin(IV) Complex of 2,6-Diacetylpyridine
Bis(N4- Cyclohexylthiosemicarbazone): Synthesis, Crystal
Structure, and Cytotoxicity
HAN YU1, GAOFENG ZHANG2, MINGXUE LI1, YANLI LU1, HECHEN WU1
1Henan Key Laboratory of Polyoxometalates, Institute of Molecular and Crystal Engineering, College of Chemistry and Chemical
Engineering, Henan University, Kaifeng, P. R. China
2Yancheng Experimental High School, Luohe, P. R. China
Received 14 October 2013; accepted 10 November 2013
A diorganotin(IV) complex formulated as [(Me)2Sn(L)] (1) (H2L D 2,6-diacetylpyridine bis(N4-cyclohexylthiosemicarbazone) has
been synthesized and structurally characterized by elemental analysis, IR, UV, and NMR spectroscopy, and single-crystal X-ray
diffraction. Complex 1 contains mononuclear neutral molecules composed of one N3S2 pentadentate anionic thiosemicarbazone
ligand and one (Me)2Sn(IV) group with a seven-coordinated tin ion. In vitro biological studies have indicated that complex 1
exhibited enhanced cytotoxicity compared to the thiosemicarbazone alone against human hepatocellular carcinoma HepG2 cells and
could slightly distinguish HepG2 cells from normal hepatocyte QSG7701 cells.
Keywords: thiosemicarbazone, diorganotin(IV), crystal structure, cytotoxic activity
Introduction
them increase the biological activity by forming chelates
with specific metal ions.[12,13] In some cases, the highest in
The search for new antitumor agents has immense impor- vivo activity is associated with a metal complex rather than
tance for drug development. Considerable attention has the parent ligand and some side effects may decrease upon
been focused on heterocyclic thiosemicarbazones due to complexation.[4,13–15]
their coordination chemistry and biological activity.[1–6]
Tin complexes are known for their multiple applications as
The best known member of this family, 3-aminopyridine antimicrobials and biocides.[16] Moreover, diorganotin(IV)
carboxaldehyde thiosemicarbazone (3-AP), is a potent compounds are known to exhibit important cytotoxic effects
ribonucleotide reductase inhibitor that is currently in phase against tumor cells,[17–19] but are often very toxic.[20,21] There-
II clinical trials for the treatment of a number of forms of fore, the syntheses of tin complexes with thiosemicarbazones
cancer, including non–small-cell lung cancer and renal car- could be a strategy of preparation of new drug candidates in
cinoma.[7] This compound shows therapeutic activity over which the metal and ligand could act synergistically.
a certain range of dosages in preclinical tumor models
In recent years we have been working on the structural
without imposing intolerable host toxicity[8] and has led to and biological properties of heterocyclic thiosemicarba-
a renewed interest in this class of compounds. The studies zones and their metal complexes.[22] Our chemical strategy
indicate that the biological activities of thiosemicarbazones focuses on modifications to the ligand substitutions and
often show a high dependence on their substituents. Minor the types of metal ions with the aim of enhancing biologi-
modifications in thiosemicarbazones can lead to significant cal activities and reducing the potential toxicity of these
changes in biological activity.[9–11] Moreover, the biologi- compounds. These results have revealed that thiosemicar-
cal properties of thiosemicarbazones are often related to bazones derived from 2-acetylpyridine and their transi-
metal ion coordination in different ways since some of tion-metal complexes show significant cytotoxicity. After
a careful literature search, N3S2 pentadentate 2,6-diacetyl-
pyridine bis(N4-cyclohexylthiosemicarbazone) and its
metal complexes are not well documented. It is envisaged
Address correspondence to Mingxue Li, Henan Key Labora-
that they are likely to exhibit interesting properties both
tory of Polyoxometalates, Institute of Molecular and Crystal
structurally and biologically.
Engineering, College of Chemistry and Chemical Engineer-
ing, Henan University, Kaifeng 475004, P. R. China. E-mail:
limingxue@henu.edu.cn
Color versions of one or more of the figures in the article can be
As a part of our ongoing studies, we have synthesized and
characterized 2,6-diacetylpyridine bis(N4-cyclohexylthiosemi-
carbazone) and its tin(IV) complex [(Me)2Sn(L)] (1)
(Scheme 1). We have studied their in vitro cytotoxicity
found online at www.tandfonline.com/lsrt.

Diorganotin(IV) Complex
1865
Sch. 1. The reaction scheme for the synthesis of 1.
against human hepatocellular carcinoma HepG2 cells. In were recorded from KBr discs on a Nicolet 170 FT infrared
addition, toxicity studies, on normal hepatocyte QSG7701 spectrophotometer. Electronic spectra were obtained with a
cells, have been carried out as an attempt to provide an Hitachi U4100 spectrometer. 1H NMR spectra were
insight into the pharmacological properties of the title recorded using a Bruker AV-400 spectrometer.
compounds.
Synthesis of H2L
Experimental
A methanol solution of 4-cyclohexyl-3-thiosemicarbazide
(2.08 g, 12 mmol) was refluxed with 2,6-diacetylpyridine
(0.978 g, 6 mmol) in 30 mL methanol continuously for
Materials and Physical Measurements
All solvents and reagents used in this study were reagent 4 h after adding a few drops of acetic acid. The mixture
grade and used without further purification. Human hepato- was allowed to cool to room temperature and kept for
cellular carcinoma HepG2 cells and normal hepatocyte 12 h. The yellow precipitate was filtered off, washed with
QSG7701 cells were purchased from the Shanghai Institute methanol and dried over P4O10 in vacuo. Yield, 82 %.
for Biological Science, Chinese Academy of Science (Shang- Elemental Anal. Calcd. (%) for C23H35N7S2: C, 58.32; H,
hai, China). Elemental analysis of C, H, and N was per- 7.45; N, 20.70. Found: C, 58.48; H, 7.39; N, 20.57. -IR
formed on a Perkin Elmer 240 analyzer. The infrared spectra [KBr, n (cm¡1)]: 3335, 3298 and 3157 (N—H), 2930 and
Table 1. Summary of crystal data and refinement results for 1
Empirical formula
Formula weight
T (K)
C25H39N7S2Sn
620.44
296(2) K
Crystal size (mm)
Crystal system
0.45 £ 0.39 £ 0.28
Monoclinic
Space group
P21/c
ꢀ
a (A)
33.339 (3),
ꢀ
b (A)
9.8003(10),
ꢀ
c (A)
18.1785(17)
99.216(2)
5862.8(10)
1.406
b (ꢀ)
ꢀ
V (A3)
Dc (g cm¡3
)
Z
8
m (mm¡1
)
1.040
u range for data collections
F (000)
0.62–26ꢀ
2560
Limiting indices
¡40 ꢀ h ꢀ 44, ¡13ꢀ k ꢀ 12, ¡24ꢀ l ꢀ15
Reflections collected
Independent reflections
R1, wR2 [I ꢁ 2s (I)]
R1, wR2 (all date)
Goodness-of-fit on F2
14280
7941 (Rint D 0.0624)
0.0520, 0.1284
0.1121, 0.1758
0.885

1866
Yu et al.
ꢀ
Table 2. Selected bond lengths (A) and angles (ꢀ) for 1
Sn(1)–C(25)
Sn(1)–C(24)
Sn(1)–N(4)
Sn(1)–N(5)
Sn(1)–N(3)
Sn(1)–S(1)
Sn(1)–S(2)
Sn(2)–C(49)
Sn(2)–C(50)
Sn(2)–N(11)
Sn(2)–N(12)
C(25)–Sn(1)–C(24)
C(25)–Sn(1)–N(4)
N(4)–Sn(1)–N(5)
N(3)–Sn(1)–S(1)
N(5)–Sn(1)–S(2)
S(1)–Sn(1)–S(2)
N(4)–Sn(1)–N(3)
2.127(6)
2.141(6)
2.371(5)
2.438(4)
2.442(5)
2.658(2)
2.689(2)
2.119(6)
2.130(6)
2.390(4)
2.432(5)
172.0(3)
85.6(2)
Sn(2)–N(10)
Sn(2)–S(4)
Sn(2)–S(3)
S(1)–C(7)
S(2)–C(17)
N(2)–N(3)
N(3)–C(8)
N(5)–C(15)
N(5)–N(6)
N(6)–C(17)
2.433(4)
2.647(2)
2.702(2)
1.752(5)
1.725(6)
1.373(6)
1.265(7)
1.293(7)
1.356(6)
1.340(7)
N(12)–Sn(2)–S(4)
N(10)–Sn(2)–S(3)
N(11)–Sn(2)–N(10)
C(49)–Sn(2)–C(50)
S(4)–Sn(2)–S(3)
71.91(11)
71.37(11)
66.93(15)
173.8(2)
83.52(5)
66.50(15)
88.0(2)
67.29(16)
71.46(11)
71.46(12)
82.99(5)
67.05(15)
N(11)–Sn(2)–N(12)
C(49)–Sn(2)–N(11)
2854 (cyclohexyl), 1635 (CDN), 1154 (N—N), 782 (CDS). X-Ray Crystallographic Determination
-UV/Vis (MeOH, λ(nm)): 235, 314. -1H NMR (CDCl3,
A high-quality single-crystal was carefully selected under an
optical microscope. The intensity data for 1 were collected at
ppm): 14.20 (s, 2H, NH), 8.72 (s, 2H, NH), 8.65 (s, 2H,
py), 7.77 (t, J D 7.8 Hz, 1H, py), 2.44 (s, 6H, Me), 2.42 (s,
2H, C6H11), 2.17–2.14 (m, 8H, C6H11), 1.79–1.76 (m, 8H,
C6H11), 1.70–1.66 (m, 4H, C6H11).
296(2) K on a Bruker APEX–II CCD detector with Mo Ka
ꢀ
radiation (λ D 0.71073 A). Corrections for Lorentz and polar-
ization effects and empirical absorption were applied. The
structure was solved by direct methods and refined by full-
matrix least-squares techniques on F2. All calculations were
performed using the SHELXTL–97 software.[23,24] The non-
Synthesis of [(Me)2Sn(L)] (1)
A
methanol solution containing (Me)2SnCl2 (0.044 g, hydrogen atoms were refined anisotropically. Hydrogen
0.2 mmol) was added dropwise to a methanol solution (20 mL) atoms attached to carbon and nitrogen atoms were geometri-
of 2,6-diacetylpyridine bis(N4- cyclohexylthiosemicarbazone) cally placed in the idealized positions and refined with a rid-
(0.068 g, 0.2 mmol) and NaOAc (0.032 g, 0.4 mmol). ing model using default SHELXL parameters. The
After refluxing for 1 h with stirring, the resulting mixture crystallographic data are listed in Table 1. The selected bond
was filtered. Yellow crystals suitable for X-ray studies lengths and angles are given in Table 2. Hydrogen bond
were obtained by the slow evaporation of an ethanol solu- lengths and bond angles are listed in Table 3.
tion of 1. The complex was recrystallized from methanol
and dried over P4O10 in vacuo. Yield, 79 %. Elemental
Anal. Calcd. (%) for C25H39N7S2Sn: C, 48.39; H, 6.34; N,
In Vitro Cytotoxicity Assay
15.80. Found: C, 48.26; H, 6.48; N, 15.62. -IR [KBr, n
(cm¡1)]: 3390 and 3368 (N—H), 2930 and 2854 (cyclo- 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bro-
hexyl), 1563 (CDN), 1161 (N—N), 756 (CDS). ¡UV/Vis mide (MTT) assay was carried out to evaluate cytotoxicity.
(MeOH, λ(nm)): 359, 416. -1H NMR(DMSO-d6, ppm): Cells were plated into 96-well plates at a cell density of 1 £
8.27 (s, 2H, NH), 8.18 (t, J D 8.0 Hz, 1H, py), 8.08 (d, J 104 cells per well and allowed to grow in a CO2 incubator.
D 8.0 Hz, 1H, py), 7.90 (d, J D 8.0 Hz, 1H, py), 2.51 (s, After 24 h, the medium was removed and replaced by fresh
6H, Me), 1.94–1.00 (m, 22H, C6H11), 0.51 (s, 6H, Sn-Me). medium containing the tested compounds which were
ꢀ
Table 3. Hydrogen bond lengths (A) and bond angles (ꢀ) for complex 1
D–H¢¢¢A
d(H¢¢¢A)
d(D¢¢¢A)
ff(D–H¢¢¢A)
N(1)–H(1A)–S(1)#1
N(7)–H(7A)–N(9)#2
N(8)–H(8A)–N(6)#3
N(14)–H(14A)–S(4)#4
2.97
2.32
2.40
2.99
3.637(5)
3.117(7)
3.145(7)
3.568(6)
135.5
153.4
145.4
126.9
Symmetry codes: #1: ¡x, ¡y, ¡z C 1; #2: x, y C 1, z; #3: x, y¡1, z; #4: ¡x C 1, ¡y ¡ 1, ¡z C 1.

Diorganotin(IV) Complex
1867
Fig. 1. Molecular structure of complex 1 with atomic numbering scheme.
dissolved in DMSO at 0.01 M and diluted to various concen- 72ꢀ. Therefore, the distortion from pentagonal bipyramidal
trations with phosphate-buffered saline (PBS) before the geometry is evident from the bond angles N(4)–Sn(1)–N(5)
experiment, and the final concentration of DMSO is lower 67.29(16), N(4)–Sn(1)–N(3) 67.05(15), N(3)–Sn(1)–S(1) 71.46
than 1 %. After 24 h incubation, cultures were incubated in (11), N(5)–Sn(1)–S(2) 71.46(12), S(1)–Sn(1)–S(2) 82.99(5),
100 mL of medium with 10 mL of 5 mg/mL MTT solution N(11)–Sn(2)–N(12) 66.50(15), N(10)–Sn(2)–N(11) 66.93(15),
for 4 h at 37ꢀC. The medium with MTT was removed, and N(10)–Sn(2)–S(3) 71.37(11), N(12)–Sn(2)–S(4) 71.91(11), S
100 mL of DMSO was added to each well to dissolve the for- (3)–Sn(2)–S(4) 83.52(5), respectively. Although the azome-
mazan. The absorbance at 570 nm was measured with micro- thine nitrogen atoms are typically stronger donors than pyri-
plate reader (Bio-Tek ELX800, USA). The inhibitory dine, the Sn¡Nimine bond distances in the present complex
percentage of each compound at various concentrations was are longer than the Sn¡Npyridine distance. While M¡Nimine
calculated, and the IC50 value was determined.
bond distances in complexes of tridentate NNS thiosemicar-
bazone derived from heterocyclic aldehydes and ketones are
invariably shorter than the M¡Npyridine distances, the reverse
appears to be true for metal complexes of pentadentate thio-
semicarbazone ligands.[25] This is probably due to the geo-
metrical requirements of the pentadentate N3S2 ligand and
the fact that the pyridine nitrogen donor occupies the central
position of the pentadentate ligand and is forced into a
shorter than normal interaction with the metal because of the
Results and Discussion
X-Ray Crystallography Diffraction Analysis
As shown in Figure 1, X-ray single-crystal structure analysis
reveals that the asymmetric unit of the crystal of complex 1
consists of two slightly different crystallographically indepen-
dent molecules with bond lengths and angles, which agree
with each other and are within normal ranges (see Table 2).
Each tin(IV) ion adopts a seven-coordinated distorted pen-
tagonal bipyramidal geometry with the pentagonal plane
defined by the pentadentate N3S2 thiosemicarbazone,
whereas the axial positions are occupied by the two methyl
groups. For an ideal pentagonal bipyramidal complex, each
of the five angles subtended at the equatorial plane should be
restraints of the two chelating arms. ꢀThe measured C(7)–S(1)
ꢀ
(ꢀ1.752(5) A), C(17)–S(2) (1.725(6) A), C(32)–S(3) (1.714(5)
ꢀ
A) and C(42)–S(4) (1.735(6) A) bond distances are longer
ꢀ
than the typical thione double bond distance (1.56 A) indicat-
ing that the ligand adopted a thiol tautomeric form and acted
as a negative ligand.[26]
Since the thiosemicarbazone moieties have both the hydro-
gen bond donors and the hydrogen bond acceptors, the species
provide the possibility of forming hydrogen bonds in the crys-
Fig. 2. Hydrogen bonds (dashed lines ) in crystals of 1.

1868
Yu et al.
structurally characterized. It exhibited enhanced cytotox-
icity compared to the thiosemicarbazone alone against
human hepatoblastoma HepG2 cells and could slightly
distinguish HepG2 cells from normal hepatocyte
QSG7701 cells.
Funding
This work was financially supported by the National Natural
Science Foundation of China (21071043), the Natural Sci-
ence Foundation of Henan Province (132300410146), and
Students’ Innovation Training Program of Henan University
(13NB052).
Fig. 3. The cytotoxicity of the title compounds against HepG2
cells and QSG7701 cells.
Supplementary Material
tal. The molecules of 1 are held together in the crystal packing
through an extended network of intermolecular hydrogen Crystallographic data for the structural analyses reported in
bonds involving the terminal nitrogen atoms N(1), N(7), N(8), this article have been deposited with the Cambridge Crystal-
and N(14), the hydrazine nitrogen atoms N(6), N(9) and the lographic Data Centre with CCDC 889493. Copies of this
coordinated sulfur atoms S(1), S(4), respectively (Figure 2). information may be obtained free of charge from The Direc-
The separations for N(1)¢¢¢S(1) (symmetry code: ¡x, ¡y, ¡z tor, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
ꢀ
C 1) is 3.637(5) A, with the N(1)¡H(1A)¢¢¢S(1) angle being (Fax: t44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
135.5ꢀ, the separations for N(7)¢¢¢N(9) (symmetry code: x, y C
ꢀ
1, z) is 3.117(7) A, with the N(7)¡H(7A)¢¢¢N(9) angle being
153.4ꢀ, the separation for N(8)¢¢¢N(6) (symmetry code: x, y ¡
ꢀ
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(N4-cyclohexylthiosemicarbazone was synthesized and

Diorganotin(IV) Complex
1869
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