Structure and properties of binuclear nitrosyl iron complex with benzimidazole-2-thiolyl

Article abstract of DOI:10.1039/b818443g

The single crystals of a new chemotherapeutic agent, binuclear nitrosyl iron complex with benzimidazole-2-thiolyl, [Fe₂(SC₇H ₅N₂)₂(NO)₄]·2C ₃H₆O (1), have been synthes

Full text of DOI:10.1039/b818443g

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Structure and properties of binuclear nitrosyl iron complex with
benzimidazole-2-thiolyl†
Nataliya Sanina,* Tatyana Roudneva,* Gennady Shilov, Roman Morgunov, Nikolay Ovanesyan and
Sergey Aldoshin
Received 20th October 2008, Accepted 8th January 2009
First published as an Advance Article on the web 23rd January 2009
DOI: 10.1039/b818443g
The single crystals of a new chemotherapeutic agent, bin-
uclear nitrosyl iron complex with benzimidazole-2-thiolyl,
[Fe2(SC7H5N2)2(NO)4]·2C3H6O (1), have been synthesized.
The structure of 1 and its properties have been studied by
the methods of X-ray, Mo¨ssbauer, IR-, mass-spectroscopy
and SQUID-magnetometry.
with 2-mercaptoimidazole according to a previously published
procedure,17 with the further crystallization from dry acetone.
Heterocyclic ligand 2-mercaptobenzimidazole, belonging to a
structural class of N–C–S ligands,19 is a potential ambidental
ligand characterized by thioketo–thiol tautomery. In the solid
state, a thione tautomer
|
–NH–C=S
In modern medical studies, the search for hybrid substances
containing two medicinal pharmacophores in the molecule and
able to act as a double drug is one of the approaches to the
improvement of drug effectiveness.1 Some hybrid drugs are able
to interact with multiple targets as a unified molecule, while
others should be destroyed, with active individual components
attacking the target. The hybrid molecules can be potentially used
in chemotherapy. For example, hybrids containing aspirin and a
nitrate group (–ONO2) generating NO act as inhibitors for colon
cancer in vitro and in vivo.2–4
We propose to consider nitrosyl [2Fe2S] complexes, which are
synthetic models of natural NO reservoirs in cells,5 as hybrid
medicines, provided that functional azaheterocyclic thiolyls (for
example, 2-mercaptobenzimidazole and its derivatives) will be
used as sulfur-containing ligands.6,7 2-Mercaptobenzimidazole has
been known as a reversible inhibitor for synthesis of cellular
DNA and RNA since the nineteen sixties, and together with
its derivatives (benzoxazole, benzthiazole) it is widely used in
biochemical and medical experiments for inhibiting the growth
of malignant tumors of different genesis8 and for the protection of
the cell genome.9 On the other hand, NO groups act as the second
pharmacological component of such hybrids, because binuclear
nitrosyl iron complexes with azaheterocyclic ligands of m-N–C–
S type are able to spontaneously generate NO,10 a key signal
molecule controlling neoplasm formation.11–15
(C–S bond 1.671(8) A) predominates,20,21 while in the solution the
˚
nitrogen and sulfur atoms become free because of deprotonation
and formation of
|
–N=C–S-
anion. As follows from the literature, for mercaptobenzimidazole
derivatives, the metal atom coordination in complexes occurs
either by a monodentate way through exocyclic sulfur atom or
by a chelate way through the sulfur and nitrogen atoms of the
imidazole ring,22 the latter being the most common.
As shown in theoretical studies of similar complexes with 2-
mercaptoimidazole derivatives, this type of coordination is more
energetically beneficial, as the basicity of nitrogen atoms in the
cycle approaches that for aliphatic amines23
As follows from X-ray data,‡ in 1 sulfur-containing ligands
coordinate the iron atoms in the thiol form (Fig. 1): bond length
C(1)–S(3) in 1 (1.736(2) A) is longer than the length of double
bond C S in non-coordinated ligand by 0.065 A. Bond C(1)–N(3)
(1.338(3) A) is shorter than C(1)–N(4) (1.354(3) A), and bond
˚
˚
=
˚
˚
˚
˚
C(3)–N(3) (1.409(3) A) is longer than C(2)–N(4) (1.375(3) A). The
bonds lengths in the heterocycle are similar, within the limits of
experimental error (1.39 A), this being due to strong delocalization
˚
of p-electrons in the ring.
Complex 1 has a centrosymmetric dimeric binuclear structure
(Fig. 1). In the dimer, the iron atoms are coordinated by two
NO groups and two benzimidazole thiolyls in a tetrahedral
way, and linked to each other by m-S–C–N bridge, similar to
nitrosyl iron complexes with 5-amino-1,2,4-triazole-3-yl6 and 2-
mercaptoimidazole derivatives18 we have obtained earlier.
The structural equivalency of iron atoms has been confirmed
by Mo¨ssbauer spectroscopy data.§ At 290 K the spectrum of 1 is a
single doublet, with the values of isomer shift dFe (0.202(1) mm s-1),
quadrupole splitting DEQ (0.954(1) mm s-1) and line width C
(0.27(1) mm s-1) being close to those for the complex with
In this work, the structure of tetranitrosyl iron complex
with benzimidazole-2-thiolyl, [Fe2(SC7H5N2)2(NO)4]·2C3H6O (1),
having a high antiproliferative effect on the cells of human ovarian
carcinoma (SCOV3 line),16 has been studied, this being aimed
at designing new nitrosyl hybrid iron complexes with sulfur-
containing ligands as structural analogs of antimetabolites.
The single crystal of binuclear tetranitrosyl iron complex 1 was
obtained in the reaction of thiosulfate tetranitrosyl iron complex
Institute of Problems of Chemical Physics, Russian Academy of Science,
142432, Chernogolovka, Moscow region, Russia. E-mail: ruta@icp.ac.ru,
sanina@icp.ac.ru
† Electronic supplementary information (ESI) available. CCDC reference
number 665846. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b818443g
5-amino-1,2,4-triazole-3-thiolyl (dFe = 0.216(1) mm s-1; DEQ
=
0.997(2) mm s-1) and exceeding dFe and DEQ for the complexes
with imidazole-2-yl (0.196(1) mm s-1; 1.109(2) mm s-1), 1-methyl-
imidazole-2-yl (0.180(1) mm s-1; 0.928(4) mm s-1) and
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2-mercaptobenzimidazole upon decomposition more readily than
complexes with 2-mercaptoimidazole derivatives.24
In structural fragment {Fe(NO)2} of 1, N(1)–O(1) and N(2)–
O(2) bond lengths do not differ, as well as Fe(1)–N(1) and Fe(1)–
N(2), as compared to earlier studied complexes.6,18 However,
valence angles Fe(1)N(1)O(1) and Fe(1)N(2)O(2) are essentially
similar and deviate from the linear one by 17◦ on average. It
is known25 that the closer is the Fe–N–O angle to linear and
the shorter is the Fe–NO bond, the more positive is the NO
group. Taking into account Mo¨ssbauer spectroscopy data and
that frequencies of valence vibrations of the nitrosyl groups in IR
spectra¶ of 1 are in the region typical for neutral NO groups, the
oxidation number of the iron atom is +1, this being consistent with
a high-spin electron configuration d7 and spin S = 3/2.26
The crystalline structure of 1 (see Fig. 2) consists of the
layers parallel to ac plane, which are formed by the complex
and the solvent molecules. The adjacent layers are connected by
translations along b axis. Within the layer, the complex molecules
are linked via two bridges of the solvent molecules: atom O3 of
the acetone molecule participates in the hydrogen bond with atom
˚
N4 of the heterocyclic ligand of one molecule (N4 ◊ ◊ ◊ O3 2.839 A,
˚
O3 ◊ ◊ ◊ H 2.042 A), while C8 participates in the intermolecular van
˚
der Waals short contact (3.011 A) with the oxygen atom of the
˚
Fig. 1 Molecular structure of complex 1. Selected bond lengths (A):
nitrosyl group of the neighboring molecule, thus forming a cyclic
structure of the associate with the inversion center (see Fig. 2b). At
the same time, each solvent molecule of one layer also participates
Fe(1) ◊ ◊ ◊ Fe(1A) 4.057, Fe(1)–N(1) 1.682(2), Fe(1)–N(2) 1.687(2),
N(1)–O(1) 1.165(3), N(2)–O(2) 1.172(3), Fe(1)–S(3) 2.3029(7),
Fe(1)–N(3A) 2.0215(18), S(3)–C(1) 1.736(2). Selected bond angles (◦):
O(1)–N(1)–Fe(1) 164.7(2), O(2)–N(2)–Fe(1) 161.6(2), N(2)–Fe(1)–S(3)
107.52(7), N(3A)–Fe(1)–S(3) 109.73(6), N(1)–Fe(1)–N(2) 111.05(10),
C(1)–S(3)–Fe(1) 102.48(7), N(1)–Fe(1)–N(3A) 117.32(9), C(1)–N(3)–
Fe(1A) 126.14(14), N(2)–Fe(1)–N(3A) 106.94(9), N(1)–Fe(1)–S(3)
103.92(7), N(3)–C(1)–S(3) 126.47(16).
˚
in van der Waals contacts O3 ◊ ◊ ◊ C8 3.113 A with the solvent
molecule of the neighboring layer. Thus, the acetone molecules and
the molecules of the complex coalesce into a three-dimensional
framework via the system of van der Waals and hydrogen bonds.
This specific feature of the crystalline structure determines thermal
instability of the crystals at room temperature (see Experimental‡).
Based on Fe1+ configuration and Fe ◊ ◊ ◊ Fe distance (4.057 A),
imidazolidine-2-yl (0.155(4) mm s-1, 1.015(2) mm s-1). The increase
of dFe value is evidence of the reduction of 4s electron density
on the iron nuclei. It results in the increase of the Fe–S length
in 1 (confirmed by X-ray data), and its higher ability to the
rupture. It can be assumed that complex 1 will generate NO and
˚
the complex can be expected to be a paramagnetic. Magnetic
susceptibility c vs T (Fig. 3) is a non-monotonic curve.ꢀ Effective
magnetic moment calculated from equation meff = (8cT)1/2 is al-
most constant at high temperatures and tends to 2.45 mB, this being
Fig. 2 (a) Projection of the crystalline packing on plane ac displaying the molecules layers in the crystals of 1. (b) Layer fragment. Dotted lines show
the van der Waals contacts and hydrogen bonds.
1704 | Dalton Trans., 2009, 1703–1706
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Fig. 3 Magnetic susceptibility c and effective magnetic moment meff vs T
in constant magnetic field 1 kOe. Circles: experimental data; solid curves:
approximation by the sum of Bleaney–Bowers and Curie–Weiss equations.
Fig. 4 Mass spectra of the gaseous phase above the crystalline sample of
1 at various temperatures.
consistent with the calculated value meff = g S(S +1) + S(S +1)
(g is g-factor) for two independent spins S = 1/2 in one
molecule. With the temperature decrease, meff diminishes, due to a
antiferromagnetic exchange interaction in dimers.
of [NO]+ being the most intensive. Therefore complex 1 can be
considered as a thermoactivated crystalline NO donor.
Fig. 5 shows concentration of NO generated by complex 1 in
water solution vs. time.†† The curve evidences that complex 1
generates NO immediately after dissolving in a protonic solvent
(without thermal, photo or fermentative activation), similar to
organic NONOates.29According to the data obtained in anaerobic
conditions within 1000 s from the reaction starting, 1 mol of the
complex isolates in average 0.2 mol of NO instead of expected
4 mol. Apparently, decomposition of the studied complex 1 in the
solution is accompanied by the formation of rather long-living
nitrosyl intermediates, their structure and properties being the
subject of our further investigations.
Each spin in the dimer pair is formed by Fe and NO spins. For
that reason, in our experiments the spin of the dimer fragment
containing one Fe+1 ion deviates from Fe+1 spin and equals 1/2.
This was determined additionally by the field dependence and
its analysis by Brillouin function. Thus, in the range of 2–300 K
two of three unpaired electrons of the metal ion are completely
paired with the unpaired electrons of two coordinated NO groups,
while the remaining unpaired electron in each Fe(NO)2 fragment
is linked by antiferromagnetic interaction with unpaired electron
of the similar fragment of the dimeric molecule.27
All possible excited states of the dimers with different spin values
are included in formula of Bleaney–Bowers.28 The difference in
energy between the states with S = 2 and 3 and the ground
state is very high. In the range of used temperatures 2–300 K
and magnetic fields up to 0.1 T these states do not contribute to
magnetic properties.
c(T), similar to meff(T), are approximated using eqn (1), with the
first term being the expression of Bleaney–Bowers28 for magnetic
susceptibility of dimers with a total spin S = 0 of ground state
and the second term being the equation of Curie–Weiss for
single paramagnetic particles (paramagnetic impurities), which
are responsible for a drastic increase of magnetic susceptibility
at temperatures below 15 K.
-1
2mB2g2
3kT
1
-2J
kT
C
È
˘
Ê
ˆ
(1)
c =
1 + exp
(1 - p) +
p
Í
Á
Ë
˜˙
¯
3
T - q
Î
˚
Fig. 5 Concentration of NO generated upon decomposition of sulfur–ni-
trosyl iron complexes 1 (0.4 ¥ 10-5 mol L-1) in 1% DMSO water solutions
at 25 ◦C vs. time.
In expression (1) exchange integral J = -33.1 cm-1 corresponds
to the interaction inside the dimers, Weiss constant q = -1.1 K,
and p = 0.01 is the fraction of the paramagnetic admixture (see
also the analogous complex with 2-mercaptoimidazole18c).
Mass-spectra of the gas phase** above the crystalline sample
of 1 confirm that the crystals are unstable at room temperature
because of the loss of acetone molecules, which are binding
elements of the three-dimensional structure (there are peaks with
m/z = 15, 43 and 58 (Fig. 4) corresponding to the fragments
of acetone molecules). Upon heating to 70 ◦C, the peaks with
m/z = 30, 28, 18, 14, 44 appear, which correspond to molecular
ions [NO]+, [CO]+, [H2O]+, [N]+, [CS]+, respectively, with the peak
Acknowledgements
The work has been performed with financial support of the
Program of the Presidium of RAS “Fundamental problems of
medicine”, RFBR grant No. 06-03-32381 and the grants of
“Russian Science Support Foundation”. We thank Dr Yuri Shulga
for IR spectroscopy experiment and Dr Vyacheslav Martynenko
for mass-spectroscopy research.
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D. Amadori, M. Bolla and W. Zoli, Apoptosis, 2006, 11, 1321–
1330.
5 For recent reviews of sulfur-nitrosyl iron complexes, see: (a) A. R.
Butler and I. L. Megson, Chem. Rev., 2002, 102, 1155–1165; (b) K.
Szacilowski, A. Chmura and Z. Stasicka, Coord. Chem. Rev., 2005,
249, 2408–2436.
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2003, 6, 145–148.
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53(11), 2428–2448.
Notes and references
‡ Crystallographic data of compound 1: C20H22Fe2N8O6S2, M = 646.28,
¯
˚
˚
˚
triclinic, space group P1, a = 8.737(1) A, b ◦= 9.072(1) A, c = 9.083(1) A,
◦
◦
3
˚
a = 74.82(1) , b = 73.10(1) , g = 86.62(1) , V = 664.70(13) A , Z = 1,
dc = 1.615 g cm-3, l = 13.00 cm-1, F(000) 330, q = 2.33 to 25.00◦, the total
number of reflections/the number of independent reflections = 2572/2080
[Rint = 0.0205], N/the number of parameters = 2080/174, GOF over F2
1.006, R-factor for reflections with [I >2(s)(I); R1 = 0.0274, wR2 = 0.0722,
R-factor for all reflections; R1 = 0.0315, wR2 = 0.0748. Reflection losses
are associated with the peculiarities of the temperature add-on, which does
not operate with some orientation angles of goniometer (diffractometer)
due to its design. However, these forced losses of reflections do not have
a significant impact on refining of the structure, as long as the number
of meaningful reflections (with the intensity ≥ 2s(I)) exceeds 10 for each
adjustable parameter. X-Ray diffraction analysis of the complex has been
performed on automatic four-circle diffractometer P-4 (Bruker) (graphite
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˚
monochromator, l(Mo-Ka) = 0.71073 A, at 200(2) K, q/2q-scanning).
The black parallelepiped-shaped single crystal with dimensions 0.25 ¥
0.20 ¥ 0.15 mm was used in the experiment. The crystals are unstable at
room temperature and decompose with rate 10% per hour. The structure
was solved by the direct methods. Positions and thermal parameters of
non-hydrogen atoms were refined first in isotropic and then in anisotropic
approximation by the full-matrix method of the least squares (MLS). The
hydrogen atoms were found from Fourier difference synthesis and refined
in isotropic approximation. All calculations were performed using program
package SHELXTL.30
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§ Mo¨ssbauer absorption spectra of Fe57 were recorded on WissEl GMBH
spectrometer operating in constant acceleration mode. Co57 in Rh matrix
was used as the source. At low temperatures, the spectra were measured
using a continuous flow helium cryostat CF-506 (Oxford Instruments) with
controllable temperature. Mo¨ssbauer spectra were processed by the least
square method assuming the Lorentzian form of the individual spectral
components.
¶ IR spectra of all samples were recorded on Fourier-spectrometer
SPECTRUM BX-II. The sample was prepared as pellets with KBr (1 mg
of the substance per 300 mg of KBr). IR spectrum (cm-1): 3207, 1787,
1738, 1515, 1467, 1428, 1384, 1272, 1218, 1183, 1002, 742, 713, 603. nNO
:
1787 and 1738 cm-1.
ꢀ Magnetic moment of the powder sample M was measured using SQUID
magnetometer Quantum Design MPMS 5XL in constant magnetic field
H = 1 kOe in the temperature range 2–300 K. Magnetic susceptibility of
the paramagnetic sample M was determined from equation c = M/H.
** Mass-spectra of emitted gases were registered using mass-spectrometer
MI 1201V. Ionization of the gases in the spectrometer ionic source was
performed by the electron beam with energy 70 eV. To get the gaseous
phase, the sample (80 mg) was placed in a quartz ampoule of the pyrolysis
reactor connected through a fine-regulation valve to bleeding system. The
quartz ampoule with the sample was pumped out over an hour to a pressure
2 ¥ 10-5 Pa to remove surface and loosely bound admixtures. After pumping
out, the ampoule was disconnected from the vacuum system and was left
at room temperature (19 ◦C) for a day. Then the fine-regulation valve was
opened, and mass-spectrometric analysis of the gas was performed. Then
the fine-regulation valve was closed, the sample was heated to 70 ◦C and
left at this temperature for 1 h. The collected gas was analyzed, with the
sample temperature being constant. The measurements were performed in
the range of 1 ≤ m/z ≤ 120, m: atomic weight, z: the ion charge.
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†† To measure concentration of NO produced by sulfur–nitrosyl iron
complexes 1 sensor electrode “amiNO-700” of “inNO Nitric Oxide
Measuring System” (Innovative Instruments, Inc., Tampa, FL, USA) was
used. NO concentrations were recorded over 1000 s (with 0.2 s steps)
in 1% aqueous solution of DMSO with NO donor concentration 0.4 ¥
10-5 mol L-1. DMSO was purified using the method from ref. 31. For
calibration of the electrochemical sensor, a standard aqueous solution of
NaNO2 (0.01 M) was used, which was added to the mixture of 0.12 M of
KI (Aldrich) and 2 ml of 1 M H2SO4 (chemical grade) in 18 ml of water.
All experiments were performed in anaerobic solutions at 25 ◦C.
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