Beruflich Dokumente
Kultur Dokumente
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Department of Chemistry, Hanoi University of Science, 19 Le Thanh Tong, Hanoi, Viet Nam
Freie Universitt Berlin, Institute of Chemistry and Biochemistry, Fabeckstr. 34-36, D-14195 Berlin, Germany
a r t i c l e
i n f o
Article history:
Received 5 March 2015
Accepted 21 April 2015
Available online 27 April 2015
Keywords:
Transition metals
Benzamidines
Thiosemicarbazones
X-ray structure
Cytotoxicity
a b s t r a c t
The potentially tetradentate benzamidine/thiosemicarbazone ligand, Et2N(C@S)NH-C(Ph) = N(oC4H6)C(Me) = NNH(C@S)NHMe (H2L) readily reacts with Ni(CH3COO)2, [PdCl2(CH3CN)2],
[PtCl2(PPh3)2] and (NBu4)[ReOCl4] under formation of complexes of the compositions [M(L)] (M = Ni
(1), Pd (2), Pt (3)) and [ReO(L)(OMe)] (4). In all complexes, H2L is doubly deprotonated and bonded to
the central metal ion via its N2S2 donor set. Complexes 1, 2 and 3 have distorted square-planar coordination spheres, while the rhenium compound 4 is an octahedral trans oxido/methoxido complex. The H2L
proligand shows a medium cytotoxicity with an IC50 value of 21.1 lM. While the rhenium complex 4
exhibits a stronger antiproliferative effect (IC50 = 5.52 lM), the nickel, palladium and platinum complexes
are almost inactive.
2015 Elsevier Ltd. All rights reserved.
1. Introduction
Thiosemicarbazones, which form stable complexes with many
main group and transition metals [1,2], constantly attract the
interest of chemists and pharmacists due to their remarkable biological and pharmacological properties such as antibacterial,
antiviral, antineoplastic, or antimalarial activity [35].
Modications of the thiosemicarbazone framework, in order to nd
new compounds with higher activity and/or to tune their biological
activity, have been extensively studied, and relationships between
the biological activity and chelate formation are evident in a number of cases [68].
Recently we reported the synthesis and structural characterization of a series of tridentate benzamidine/thiosemicarbazide
ligands (H2L0 ), which were prepared by reactions of N-[N0 ,N0 -dialkylamino(thiocarbonyl)]benzimidoyl chlorides (Bzm-Cl) and
thiosemicarbazides [9,10]. They form stable complexes with various transition metals [912]. Additionally, the organic ligands as
well as their oxorhenium(V) and gold(III) complexes show a
promising cytotoxicity on breast cancer cell lines [1012]. The
reaction
of
2-aminoacetophenone-N-(4-methylthiosemicarbazone) with Bzm-Cl results in the formation of a tetradentate
hybrid thiosemicarbazone/benzamidine ligand, H2L [13]. This
ligand has hitherto only been used for reactions with
Corresponding authors.
E-mail addresses: ulrich.abram@fu-berlin.de (U. Abram), nguyenhunghuy@hus.edu.vn (H.H. Nguyen).
http://dx.doi.org/10.1016/j.poly.2015.04.026
0277-5387/ 2015 Elsevier Ltd. All rights reserved.
67
Ni(CH 3COO) 2
H 2L
[Pd(MeCN) 2Cl 2]
[Pt(PPh 3) 2Cl2]
Table 1
Selected bond lengths () and angles () in 1 and 2.
1
MS1
MS11
MN5
MN8
S1C2
C2N3
2.154(1)
2.157(1)
1.878(1)
1.909(1)
1.723(1)
1.355(2)
2.252(1)
2.270(1)
2.017(1)
2.033(1)
1.729(2)
1.348(2)
S1MN5
S1MN8
S1MS11
95.56(4)
166.46(4)
85.49(1)
94.85(4)
173.03(4)
88.64(2)
N3C4
C4N5
S11C10
C10N9
N9N8
N8C6
1.316(2)
1.357(2)
1.739(1)
1.300(2)
1.404(2)
1.313(2)
1.318(2)
1.348(2)
1.748(2)
1.296(2)
1.397(2)
1.308(2)
N5MN8
N5MS11
N8MS11
93.49(5)
167.64(4)
87.83(4)
91.70(6)
172.40(4)
85.14(4)
magnetically nonequivalent with respect to their axial and equatorial positions [9,10].
Single crystals suitable for X-ray studies were obtained by slow
evaporation of CH2Cl2/MeOH mixtures for the nickel and palladium
compounds. Fig. 1 illustrates the molecular structure of 1 as a
representative for this class of compounds. The structure of the
analogous palladium compound 2 is virtually identical and, thus,
no extra gure is shown. Selected bond lengths and angles of 1
and 2 are compared in Table 1. The atomic labeling scheme of
the palladium complex has been adopted from that of the nickel
complex. Both metal ions are coordinated by the S2N2 donor set
of the organic ligand in a distorted square-planar coordination
environment. The molecular planes dened by the metal atoms
MeOH, Et 3N
N
- 2 Et 3NHCH 3COO
CH 2Cl 2 / MeOH, Et 3N
S
M
- 2 Et 3NHCl, - 2 MeCN
CH 2Cl 2 / MeOH, Et 3N
S
N
- 2 Et 3NHCl, - 2 PPh 3
HN
1: M = Ni, 2: M = Pd; 3: M = Pt
Scheme 1. Synthesis of the [M(L)] complexes.
68
N
NH
(NBu 4)[ReOCl 4]
+
N
N
S
S
MeOH, Et 3N
- NBu 4Cl, HNEt 3Cl
N
S
Re
N
HN
HN
H 2L
OMe S
N
HN
4
Scheme 2. Synthesis of [ReO(OMe)(L)].
Table 2
Selected bond lengths () and angles () in 4.
ReS1
ReS11
ReN5
ReN8
ReO10
O10ReS1
O10ReN5
O10ReN8
O10ReS11
O10ReO20
S1ReN5
S1ReN8
S1ReS11
2.358(1)
2.379(1)
2.095(4)
2.127(4)
1.707(4)
ReO20
S1C2
C2N3
N3C4
C4N5
97.2(1)
91.2(2)
90.8(2)
96.0(1)
172.1(2)
93.7(1)
171.2(1)
93.5(4)
1.917(4)
1.753(5)
1.336(7)
1.311(7)
1.347(6)
S11C10
C10N9
N9N8
N8C6
S1ReO20
N5ReN8
N5ReS11
N5ReO20
N8ReS11
N8ReO20
S11ReO20
1.753(5)
1.309(7)
1.393(6)
1.311(7)
89.5(1)
89.8(2)
169.1(1)
84.2(2)
82.0(1)
82.8(2)
87.7(1)
and the four donor atoms S1, N5, N8 and S11 are slightly distorted
with maximum deviations from the mean least-squares planes of
0.215(1) for N8 (in 1) and of 0.098(1) for N5 (in 2).
2.2. Synthesis and structures of the oxidorhenium(V) complex
H2L reacts with (NBu4)[ReOCl4] in MeOH in the presence of the
supporting base Et3N under formation of a red crystalline solid of
the composition [ReO(OMe)(L)] (4) in high yields (Scheme 2). The
reaction can be carried out at room temperature or under reux
without signicant change in the yield.
The IR spectrum of 4 is similar to those discussed for the complexes 13 with a sharp medium absorption band of the NH
stretch at 3387 cm1 and a strong bathochromic shift of the mC@N
band with respect to the corresponding vibration in the spectrum
of H2L. The strong absorption at 941 cm1 is assigned to the
mRe@O vibration. This wavenumber is slightly lower than those,
which are normally reported for common six-coordinate
oxidorhenium(V) complexes [14], but within the typical range for
octahedral trans oxido/alkoxido rhenium(V) complexes [15,16].
The 1H NMR spectrum of 4 shows the same features as those of
the nickel, palladium and platinum compounds: the absence of
two NH resonances and a high eld shift of the NH signal of
the CSNHMe moiety to 5.26 ppm. The chelate formation also
leads to a strong downeld shift of about 1.1 ppm of the Me
C@N signal. The presence of a methoxy group in 4 is clearly indicated by an additional singlet at 3.04 ppm. The +ESI mass spectrum
of 4 shows no molecular ion peak, but an intense peak at
m/z = 641.11, which can be assigned to the fragment [MOMe]+.
The X-ray diffraction data of 4 are in a good agreement with the
spectroscopic results. Fig. 2 shows the molecular structure of the
complex. Selected bond lengths and angles are given in (Table 2).
The environment of the rhenium atom is best described as a distorted octahedron with an oxido and a methoxido ligand arranged
in trans positions to each other. The L2 ligand is expectedly coordinated to the metal via its N2S2 donor set. The Re atom is located
only 0.151(2) above the mean least-square plane formed by the
four donor atoms of L2 towards the oxido ligand. The ReO20
bond length of 1.917(4) is shorter than a typical rheniumoxygen single bond and reects some double bond character. The
required electron density is transferred from the double bond of
the oxido ligand. Consequently, the ReO10 bond length of
1.707(4) is slightly longer than those in ve-coordinate or other
octahedral oxidorhenium(V) complexes. This is in a good agreement with the relatively low wavenumber of the mRe@O absorption
in the IR spectrum of 4.
2.3. In vitro cell tests
We investigated the antiproliferative effects of the ligand H2L
and its complexes on human MCF-7 breast cancer cells in a concentration response assay. This allows the determination of their IC50
values. The uncoordinated H2L shows an IC50 value of 21.1(9) lM
reecting a medium antiproliferative effect. The complexation of
H2L with Ni2+, Pd2+ and Pt2+ ions dramatically decreases the cytotoxicity of the compound. Thus, complex 1 only causes a very weak
reduction of the growth of human MCF-7 breast cancer cells
(IC50 = 258(10) lM), while complexes 2 and 3 show almost no
antiproliferative effect. The low cytotoxicity of the square-planar
complexes reects their limited dissociation inside the cell and
the stable metal chelates themselves exhibit no antiproliferative
effects. This can be understood by the rigid tetradentate N2S2 coordination of the ligand, which is expected to form stable complexes
with Ni2+, Pd2+ and Pt2+. Additionally, no labile coordination site is
available, as they are present in all metal complexes of the previously studied tridentate thiosemicarbazone/benzamidine hybrid
ligands, for which promising antiproliferative effects have been
found [1012]. Such a potentially labile ligand is present in the
69
70
Table 3
X-ray structure data collection and renement parameter.
Formula
Mw
Crystal system
a ()
b ()
c ()
a ()
b ()
c ()
V (3)
Space group
Z
Dcalc (g cm3)
l (mm1)
Tmin
Tmax
Abs. Corr.
No. of reections
No. of indep.
No. parameters
R1/wR2
Goodness-of-t (GOF) on F2
C22H26N6S2Ni
497.32
orthorhombic
13.0699(3)
17.3185(5)
20.1027(5)
90
90
90
4550.3(2)
Pbca
8
1.452
1.059
0.5457
0.7457
multiscan
85,358
5422
284
0.0266/0.0638
1.056
C22H26N6S2Pd
545.01
orthorhombic
13.3416(3)
16.8770(5)
20.6174(5)
90
90
90
4642.3(2)
Pbca
8
1.560
1.001
0.6958
0.7457
multiscan
76,416
5774
284
0.0239/0.0539
1.081
C23H29N6O2S2Re
671.84
triclinic
9.927(1)
10.623(1)
13.863(1)
79.89(1)
79.07(1)
64.31(1)
1286.3(2)
P1
2
1.735
4.918
0.3537
0.7682
integration
23,666
6895
323
0.0377/0.0790
1.047
[15]
[16]
[17]
[18]
[19]