The effect of substitution on the cytotoxicity of molybdenum(II) and tungsten(II) compounds

Article abstract of DOI:10.1016/j.jorganchem.2012.07.011

A series of allyl molybdenum [(η³-C₃H ₅)Mo(CO)₂L₂Cl], [(η³-C ₃H₄COOMe)Mo(CO)₂L₂Br], cyclopentadienyl molybdenum [(η⁵-C₅H

Full text of DOI:10.1016/j.jorganchem.2012.07.011

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Journal of Organometallic Chemistry 716 (2012) 258e268
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Journal of Organometallic Chemistry
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The effect of substitution on the cytotoxicity of molybdenum(II) and tungsten(II)
compounds
a
,
b
b
c
d
ꢀ
*
ꢀ
ꢀ
ꢀ
ꢀ
Jan Honzícek , Jaromír Vinklárek , Zdenka Padelková , Lucie Sebestová , Karolína Foltánová ,
d
ꢀ
Martina Rezácová
a Institute of Chemistry and Technology of Macromolecular Materials, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
b Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
c Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
d
ꢀ
Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University in Prague, Simkova 870, 500 01 Hradec Králové, Czech Republic
a r t i c l e i n f o
a b s t r a c t
A series of allyl molybdenum [(h h
3-C3H5)Mo(CO)2L2Cl], [( 3-C3H4COOMe)Mo(CO)2L2Br], cyclopentadienyl
Article history:
molybdenum [(
molybdenum [(
compounds [(
h
5-C5H4R)Mo(CO)2L2][BF4] (R
¼
H, 4-MeOC6H4CH2, 3,4,5-(MeO)3C6H2CH2), indenyl
Received 18 May 2012
Received in revised form
6 July 2012
h
5-C9H6R)Mo(CO)2L2][BF4] (R ¼ H, 4-MeOC6H4CH2) and cyclopentadienyl tungsten
h
5-C5H5)W(CO)2L2][BF4], where L2 is N,N0-chelating ligand, were synthesized and charac-
Accepted 10 July 2012
terized. The in vitro assay on human leukemia cells MOLT-4 has shown that the substitution in the
p
-ligand has lower effect of on cytotoxicity than exchange of the N,N0-chelating ligand. Nevertheless,
Keywords:
even this modification can lead to considerable enhance of cytotoxicity as was evidenced on the series of
the indenyl molybdenum(II) compounds.
Molybdenum
Cyclopentadienyl
Indenyl
Ó 2012 Elsevier B.V. All rights reserved.
X-ray diffraction
Cytotoxicity
Leukemia therapy
1. Introduction
In 2005, the molybdenum(II) compounds [(
Mo(CO)2L2Br], [(
5-Cp)Mo(CO)2L2][BF4] and [( 5-Ind)Mo(CO)2L2]
h
3-C3H5)
h
h
Cyclopentadienyl complexes of early transition metals have
[BF4] (Cp ¼ C5H5; Ind ¼ C9H7; L2 ¼ N,N-, S,S- and P,P-chelating
ligands) were established as new class of the cytotoxic active
compounds against several tumor cell lines [18]. Following studies
have extended the series of cytotoxic active compounds and
brought an early insight into the mechanism of the action [19e21].
The aim of this work is to describe effect of substitution on the
cytotoxicity of the molybdenum(II) and tungsten(II) compounds. It
covers several structural types, N,N0-chelating ligands and substit-
uents in the allyl, cyclopentadienyl and indenyl ligands. The cyto-
toxicity of the compounds under study was established on human
leukemia cells MOLT-4. This cell line is derived from human
T-lymphoblastic leukemia and shows specific surface signs: CD1þ
(49%), CD4þ (55%), CD5þ (72%) and CD7þ (77%). MOLT-4 contains
wild type of protein p53, which is crucial in the cell response to
cytostatic therapy and radiotherapy of p53wt tumors. Intact p53
pathway predicts them to be an excellent model for study of
molecular mechanism responding mainly to DNA damage [22,23].
The current study follows our previous interest in chemistry of
cyclopentadienyl compounds substituted in the cyclopentadienyl
rings with functional groups [24,25].
received great attention due to their biological properties [1e4].
The bis-cyclopentadienyl complexes [(
h
5-Cp)2MCl2] (Cp ¼ C5H5;
M ¼ group IV, V, VI metal) and their congeners are under
comprehensive scrutiny since the antitumor activity of [(h5
-
Cp)2TiCl2] was discovered in 1979 [5]. It is known that the bis-
cyclopentadienyl compounds of Ti(IV) [6], V(IV) [7], Nb(IV) [8],
Nb(V) [9], Mo(IV) [10] and Mo(VI) [9] are active toward Ehrlich
ascites tumor. The complexes of other metals from group IV, V and
VI are much less active or inactive [11]. Later studies on cis-platin
resistant tumor cell lines have proved that the cytotoxicity could be
enhanced through the substitution in the cyclopentadienyl ring.
Promising results were obtained mainly for the aminoalkyl
[12e14], methoxycarbonyl [15], and methoxybenzyl functionalized
compounds [16,17].
* Corresponding author. Fax: þ420 46603 7068.
ꢀ
E-mail address: jan.honzicek@upce.cz (J. Honzícek).
0022-328X/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2012.07.011

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259
Table 1
1H NMR data of coordinated bypiridine in molybdenum(II) compounds.a
Doublet
Doublet
Multiplet
Multiplet
3
6
8.80
8.63, 8.52
9.36
9.02
9.34
9.38
9.36, 9.26
9.25
8.28
8.31b
8.89
8.56
8.91
8.31
8.33
8.61
8.06
8.07
8.36
8.19
8.38
8.09
8.11
8.21
7.53
7.51
7.73
7.59
7.79
7.58
7.61
7.56
12
14
16
22
24
28
Scheme 1. Preparation of allyl complexes 3e5.
2. Results and discussion
a
Chemical shifts are given in ppm.
Multiplet.
2.1. Synthesis of the allyl molybdenum complexes
b
Literature procedure was used for the synthesis of the allyl
reacts with lithium cyclopentadienides to give allyl complexes [(h3
-
molybdenum complexes [(
h
3-C3H5)Mo(CO)2L2Cl] (3: L2 ¼ bpy, 4:
C3H5)(
h
5-C5H4R)Mo(CO)2] (R ¼ 4-MeOC6H4CH2, 3,4,5-(MeO)3C6H2CH2).
L2 phen) [26]. [(h
¼
3-C3H5)Mo(CO)2(5-NO2-phen)Cl] (5) was
These intermediates were not isolated. They react with tetra-
fluoroboric acid in presence of acetonitrile to give cationic
cyclopentadienyl complexes 10 and 11, respectively.
prepared according to this procedure starting from [(
Mo(CO)2(NCMe)2Cl] and 5-nitrophenantroline (Scheme 1). 1H NMR
spectrum of compound 5 shows the signals of
3-allyl ligand at 3.35
h
3-C3H5)
h
1H NMR spectra of the compounds 10 and 11 show two triplets
of the cyclopentadienyl protons at w5.5 and w5.7 ppm, singlet of
the coordinated acetonitrile at w2.5 ppm and the signals of the
substituents attached to the cyclopentadienyl ring. The infrared
spectra show the CeH stretching band at w3103 cmꢀ1 that was
assigned to the cyclopentadienyl ligand. Stretching bands of the
(1H), 3.29 (2H) and 1.37 ppm (2H). Coordinated 5-
nitrophenathroline shows the signals at considerably lower field
than the free ligand. The infrared spectrum of the compound 5
shows the bands in the region of terminal carbonyls stretching at
1930 (vs) and 1842 cmꢀ1 (vs).
Methoxycarbonylallyl molybdenum compounds [(
COOMe)Mo(CO)2L2Br] (6: L2 ¼ bpy, 7: L2 ¼ phen, 8: L2 ¼ 5-NO2-phen)
were synthesized from [{( -Br)}2]
3-C3H4COOMe)Mo(CO)2(NCMe)(
(2) and appropriate N,N0-chelating ligand, see Scheme 2. The h3
h
3-C3H4-
carbonyl ligands were observed at 1977e1980
1886e1887 cmꢀ1
ns(CO)]. The coordinated acetonitrile ligands give
two band of weak intensity at 2312e2322 na(CN)] and
[na(CO)] and
[
h
m
[
-
2285e2289 cmꢀ1
[ns(CN)]. The broad band of the BeF stretching at
coordinated substituted allyl ligand gives characteristic pattern in the
1H NMR spectra with one multiplet at w3.9 ppm (1H), one singlet at
w3.5 ppm (3H), three doublets at w3.3 (1H), w2.1 (1H) and
w1.7 ppm (1H). Coordinated N,N0-chelating ligands give the signalsin
the range 9.4e7.5 ppm, see Tables 1 and 2. Spectrum of compound
7$CH2Cl2 displays the singlet of uncoordinated dichloromethane at
5.45ppm. Infrared spectra of the compounds6e8 showcharacteristic
C]O stretching of the ester group at 1695e1698 cmꢀ1. The stretching
bands of the coordinated carbonyl ligands were found at considerably
higher wavenumbers than in the case of the analogs with the
unsubstituted allyl group (Table 3). It suggests a lower electron
density at the metal that correlates with the electron-withdrawing
properties of the substituent in the allyl ligand. Structures of the
compounds 6$0.5MeCN and 7$CH2Cl2 were determined by single
crystal X-ray diffraction analysis (Figs. 1 and 2).
1032 cmꢀ1 proves the presence of the BF4 anion.
The 1H NMR spectra of the compounds 12e17 show signals of
the coordinated N,N-chelating ligands and the signals of the
cyclopentadienyl ligand. The coordinated 2,20-bipyridine gives two
doublets at 9.02e9.36 (2H) and 8.56e8.91 ppm (2H) and two
multiplets at 8.19e8.38 (2H) and 7.59e7.79 ppm (2H), see Table 1.
In the case of the 1,10-phenathroline complexes one singlet at
8.18e8.40 ppm and doublets of doublets at 9.41e9.74, 8.75e9.01
and 7.91e8.18 ppm were observed (Table 2). The infrared spectra
of the compounds 12e17 show the CO stretching bands at
considerably lower wavenumbers
[ ,
na(CO): 1965e1975 cmꢀ1
ns(CO): 1884e1901 cmꢀ1] than the acetonitrile analogs (Table 3).
The cationic character of the compounds 12e17 is evident from the
BeF stretching of the BF4 anion that was observed at w1050 cmꢀ1
.
Structures of the complexes 14 and 16 were determined by X-ray
diffraction analysis (Figs. 3 and 4).
2.2. Synthesis of the cyclopentadienyl molybdenum complexes
2.3. Synthesis of the indenyl molybdenum complexes
The complexes 12e17 were prepared from cationic acetonitrile
complexes [(
h
5-C5H4R)Mo(CO)2(NCMe)2][BF4] (9: R ¼ H, 10: R ¼ 4-
Indenyl molybdenum compounds 22e25 were prepared simi-
MeOC6H4CH2, 11: R ¼ 3,4,5-(MeO)3C6H2CH2) using reaction with
the appropriate N,N-chelating ligand, see Scheme 3.
larly to their cyclopentadienyl analogs, see Scheme 5. The starting
indenyl compound [(h
5-Ind)Mo(CO)2(NCMe)2][BF4] (18) is available
Starting cyclopentadienyl complex [(h
5-Cp)Mo(CO)2(NCMe)2]
through the literature procedure [28].
[BF4] (9) was prepared by literature procedure [27]. The ring-
substituted analogs were synthesized using modified procedure
Table 2
1H NMR data of coordinated phenanthroline in molybdenum(II) compounds.a
(Scheme 4). The allyl complex [(h
3-C3H5)Mo(CO)2(NCMe)2Cl] (1)
Multiplet
Multiplet
Singlet
Multiplet
4
9.18b
8.63b
8.63
8.06
8.10
8.18
8.21
8.40
8.08
8.09
8.40
7.87b
7.85
7$CH2Cl2
9.03, 8.89
13
15
17
23
25
29
9.43b
8.75b
8.77b
9.01c
8.66b
8.68c
8.98b
7.91b
7.97b
8.18
9.41b
9.74c
9.74b
7.95b
7.98
9.71, 9.64
9.90b
8.12b
a
Chemical shifts are given in ppm.
Doublet of doublet.
Doublet.
b
c
Scheme 2. Preparation of methoxycarbonylallyl complexes 6e8.

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260
J. Honzícek et al. / Journal of Organometallic Chemistry 716 (2012) 258e268
Table 3
Summary of the infrared data.a
na(CO)
ns(CO)
na(CO)
ns(CO)
3
4
5
6
1929
1934
1930
1957
1950
1970
1985
1977
1980
1973
1965
1975
1971
1835
1848
1842
1867
1865
1873
1888
1887
1886
1901
1884
1888
1888
16
17
18
20
21
22
23
24
25
27
28
29
1970
1970
1976
1937
1964
1974
1968
1962
1964
2045
2046
2045
1890
1890
1886
1863
1895
1978
1874
1885
1886
1959
1973
1969
7$CH2Cl2
8
9
10
11
12
13
14
15
Fig. 2. ORTEP drawing of the molecule [(h
3-C3H4COOMe)Mo(CO)2(phen)Br] present in
the crystal structure of 7$CH2Cl2. The labeling scheme for all non-hydrogen atoms is
a
Wavenumbers of the CO stretching bands are given in cmꢀ1
.
shown. Thermal ellipsoids are drawn at the 30% probability level.
Substituted indenyl compound [(
OMe)Mo(CO)2] (20), necessary for the synthesis of [(
h
3-C3H5)(
h
5-C9H6CH2C6H4-
5-C9H6CH2-
9.4 (1H), 3.3 (1H), 8.3 (2H), 8.1 (2H), 7.6 ppm (2H). Signals at 9.7
(1H), 9.6 (1H), 8.7 (2H), 8.1 (2H), 8.0 ppm (2H) were observed for
the coordinated 1,10-phenanthroline in compound 25. Infrared
spectra of compounds 24 and 25 have the CO stretching band at
h
C6H4OMe)Mo(CO)2(NCMe)2][BF4] (21), was prepared using the
fulvene protocol (Scheme 6). Condensation of indene with
4-methoxybenzaldehyde in the presence of pyrrolidine gives ben-
zofulvene 19. Subsequent reaction with lithium triethylborohy-
dride gives appropriate substituted lithium indenide that reacts
1962 and 1885 cmꢀ1
.
2.4. Synthesis of the cyclopentadienyl tungsten complexes
with [(
h
3-C3H5)Mo(CO)2(NCMe)2Cl] (1) to give ring-substituted
3-C3H5)( 5-C9H6CH2C6H4-
h
Cyclopentadienyl tungsten compounds [(
h
5-Cp)W(CO)2L2][BF4]
indenyl molybdenum compound [(
h
(28: L2 ¼ bpy, 29: L2 ¼ phen) were prepared from [(
3-C3H5)( 5-Cp)
W(CO)2] (26). Protonation with tetrafluoroboric acid in presence of
acetonitrile gives [(
5-Cp)W(CO)2(NCMe)2][BF4] (27). Subsequent
reaction with 2,20-bipyridine and 1,10-phenanthroline gives [(h5
h
h
OMe)Mo(CO)2] (20). This intermediate was isolated. It forms
mixture of exo and endo isomers in solution as was evidenced by
NMR spectroscopy. At room temperature, the molar ratio between
exo and endo isomers was found to be 3:1. Infrared spectrum of the
solid sample shows two bands in the region of CO stretching at 1937
h
-
Cp)W(CO)2(bpy)][BF4] (28) and [(h
5-Cp)W(CO)2(phen)][BF4] (29),
[
na(CO)] and 1863 cmꢀ1
obtained from X-ray diffraction analysis is shown in Fig. 5.
Protonation of [(
3-C3H5)( 5-C9H6CH2C6H4OMe)Mo(CO)2] (20)
with tetrafluoroboric acid in presence of acetonitrile gives cationic
complex [(
5-C9H6CH2C6H4OMe)Mo(CO)2(NCMe)2][BF4] (21). The
[ns(CO)]. The structure of the compound 20
respectively (Scheme 7).
1H NMR spectra of the compounds 28 and 29 prove the presence
of
h
5-bonded cyclopentadienyl ligand and coordinated N,N-
h
h
chelating ligand. The infrared spectra of these compounds have the
CO stretching bands at considerably higher wavenumbers [na(CO)
w2045; ns(CO) w1970 cmꢀ1] than the molybdenum analogs 12 and
13 [na(CO) w1980; ns(CO) w1886 cmꢀ1]. Structure of the compound
28 was determined by X-ray analysis (Fig. 6).
h
product was characterized with 1H NMR and infrared spectroscopy.
The spectroscopic characterization of the indenyl complexes
with the N,N-chelating ligands 22 and 23 was reported previously
[18,29]. The complexes 24 and 25 give the 1H NMR spectra with the
pattern of the substituted indenyl ligand that has the signals of
indenyl at w7.1 (1H), w6.8 (1H), w6.6 (2H), w6.4 (1H) and
w5.7 ppm (1H). The 4-methoxybenzyl group gives two doublets of
the CH2 group at 4.5 and 4.0 ppm, two doublets of benzene at 7.3
and 6.8 ppm and singlet of the methoxy group at 3.7 ppm. The
coordinated 2,20-bipyridine in the compound 24 gives multiplets at
2.5. X-ray structures
Structures of the compounds 6$0.5MeCN, 7$CH2Cl2, 14, 16, 18,
20, 22$CH2Cl2 and 28 were determined by single crystal X-ray
diffraction analysis. Molecular structures of the complexes are
shown in Figs. 1e8. Selected bond lengths and bond angles are
listed in Tables 4 and 5. The unit cells of the compounds 6$0.5MeCN,
14, 18 and 22$CH2Cl2 contain two crystallographically independent
but essentially the same molecules of the complex. They are
denoted A and B. In the structures of the following crystals, 14, 18
and 22$CH2Cl2, there are positionally disordered fluorine atoms in
anionic parts (BFꢀ4 fragments). Attempts to treat these disorders
were made but the results do not differ significantly from the
starting structures.
The allyl complexes 6$0.5MeCN and 7$CH2Cl2 have distorted an
octahedral structure around molybdenum(II). The
h
3-bonded
Fig. 1. ORTEP drawing of the molecule [(h
3-C3H4COOMe)Mo(CO)2(bpy)Br] present in
the crystal structure of 6$0.5MeCN. The labeling scheme for all non-hydrogen atoms is
shown. Thermal ellipsoids are drawn at the 30% probability level.
Scheme 3. Preparation of cyclopentadienyl complexes 12e17.

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261
Scheme 4. Preparation of starting cyclopentadienyl complexes 10 and 11. a) [(
Mo(CO)2(NCMe)2Cl] (1) in THF; b) HBF4 in the mixture of CH2Cl2 and MeCN.
h
3-C3H5)
methoxycarbonylallyl and bromide occupy the axial positions while
two terminal carbonyls and donor atoms of the N,N-chelating ligand
are in the equatorial positions, see Figs. 1 and 2. In both structures,
the allyl ligand adopts the usual conformation with the open side
eclipsing the carbonyl ligands. This arrangement was previously
observed in the solid-state structure of the analogs with the
unsubstituted allyl ligand [(
h
3-C3H5)Mo(CO)2L2Br] (L2 ¼ bpy, phen)
[30] as well as in the octahedral complexes containing fac-[(h3
-
C3H4COOMe)Mo(CO)2] fragment [31]. The small angle between
plane of the COO group (PlC4O1O2) and allyl (PlC1C2C3) [6$0.5MeCN A:
3.7(7) deg, B: 5.1(7) deg; 7$CH2Cl2: 0.8(4) deg] suggests full conju-
gation of the ester group with h
3-allyl.
The cations of the compounds 14, 16, 18, 22$CH2Cl2 and 28 form
a distorted squareepyramid around central metal. The cis-coordi-
nated carbonyl groups and two nitrogen atoms form the basal
Fig. 4. ORTEP drawing of cation [{
the crystal structure of 16. The labeling scheme for all non-hydrogen atoms is shown.
Thermal ellipsoids are drawn at the 30% probability level.
h
5-C5H4CH2C6H2(OMe)3}Mo(CO)2(bpy)]þ present in
plane. The apical position is occupied by the
h
5-coordinated
moiety. The bond distances MoeN in the bipyridine complexes
14, 16 and 22$CH2Cl2 are systematically shorter [2.175(3)e
cyclopentadienyl (Figs. 4 and 5) or indenyl (Figs. 7 and 8). Both
indenyl complexes (18 and 22$CH2Cl2) adopt similar conformation
of the indenyl ligand with the benzene ring above the NeMoeN
ꢁ
2.189(4) A] than in octahedral complexes containing bipyridine in
ꢁ
equatorial position such as 6$0.5MeCN [2.227(4)e2.343(4) A] and
[(h3-C3H5)Mo(CO)2(bpy)Br] [2.233(5) A] [30]. This shortening is
ꢁ
a result of weaker trans-effect of the carbonyl ligands in the
squareepyramidal complexes [31,32].
The molecule of the compound 20 has pseudotetrahedral
coordination around the molybdenum(II) with h h
3-allyl, 5-bonded
substituted indenyl and two carbonyl ligands (Fig. 6). The allyl
ligand is in exo orientation. The structural data of compound 20
ꢁ
ꢁ
[MoeC(CO) ¼ 1.938(2), 1.947(2) A; MoeCg(allyl) ¼ 2.043(2) A;
ꢁ
MoeCg(Cp) 2.026(1) A; C(CO)eMoeC(CO) ¼ 80.5(1) deg; Cg(Cp)e
MoeCg(allyl) 128.0(1) deg] are in line with those previously
reported for several allyleindenyl compounds [(
h
3-C3H5)(h5-Ind0)
Mo(CO)2] (Ind0 ¼ substituted indenyl) [33e35].
2.6. Cytotoxicity
The cytotoxic activity of the molybdenum(II) and tungsten(II)
compounds was evaluated on human T-lymphocytic leukemia cells
MOLT-4 in exponential grow phase, 24 h after the incubation with
the drugs. The effect of the drug was examined by standard WST-1
viability assays [36].
It was observed that activity of the allyl complexes is strongly
dependent on the coordinated N,N0-chelating ligand and the
substituent in allyl ligand. The complexes containing 1,10-
phenanthroline (4 and 7) show considerably higher cytotoxicity
Fig. 3. ORTEP drawing of cation [(h
5-C5H4CH2C6H4OMe)Mo(CO)2(bpy)]þ present in the
crystal structure of 14. The labeling scheme for all non-hydrogen atoms is shown.
Thermal ellipsoids are drawn at the 30% probability level.
Scheme 5. Preparation of indenyl complexes 22e25.