Highly Water-Soluble Cyclopentadienyl and Indenyl Molybdenum(II) Complexes - Second Generation of Molybdenum-Based Cytotoxic Agents

Article abstract of DOI:10.1002/ejic.201501133

A series of the cyclopentadienyl and indenyl molybdenum compounds bearing alkylammonium functions [(η⁵-Cp′)Mo(CO)₂(^N,NL)][BF₄]₂ were synthesized and characterized by analytical and spectroscopic methods. The structures of [{η⁵-C₅H₄CH₂CH₂NH(CH₂)₅}Mo(CO)₂(4,7-Ph₂-phen)][BF₄]₂ (4,7-Ph₂-phen = 4,7-diphenyl-1,10-phenanthroline) and [(η⁵-C₉H₆CH₂CH₂NHMe₂)Mo(CO)₂(phen)][BF₄]₂ (phen = 1,10-phenanthroline) were determined by X-ray crystallography. All of the synthesized compounds exhibit high activity against the human leukemia cell lines MOLT-4 and HL-60. They are approximately one order of magnitude more active than cisplatin. This study has proven that the modification of the outer coordination sphere of molybdenum complexes has a strong impact on their activity and may be successfully used for the design of new highly cytotoxic active species. A series of highly cytotoxic molybdenum(II) complexes are synthesized, and their activity against MOLT-4 and HL-60 leukemia cells is established.

Full text of DOI:10.1002/ejic.201501133

DOI: 10.1002/ejic.201501133
Full Paper
Cytotoxic Agents
Highly Water-Soluble Cyclopentadienyl and Indenyl
Molybdenum(II) Complexes – Second Generation of
Molybdenum-Based Cytotoxic Agents
Ondřej Mrózek,[a] Lucie Šebestová,[b] Jaromír Vinklárek,*[a] Martina Řezáčová,[c]
Aleš Eisner,[b] Zdeňka Růžičková,[a] and Jan Honzíček[d]
Abstract: A series of the cyclopentadienyl and indenyl molyb- synthesized compounds exhibit high activity against the hu-
denum compounds bearing alkylammonium functions
[(η5-Cp′)Mo(CO)2(N,NL)][BF4]2 were synthesized and character-
ized by analytical and spectroscopic methods. The structures
of [{η5-C5H4CH2CH2NH(CH2)5}Mo(CO)2(4,7-Ph2-phen)][BF4]2 (4,7-
man leukemia cell lines MOLT-4 and HL-60. They are approxi-
mately one order of magnitude more active than cisplatin. This
study has proven that the modification of the outer coordina-
tion sphere of molybdenum complexes has a strong impact on
their activity and may be successfully used for the design of
new highly cytotoxic active species.
Ph2-phen
=
4,7-diphenyl-1,10-phenanthroline) and [(η5-
C9H6CH2CH2NHMe2)Mo(CO)2(phen)][BF4]2 (phen = 1,10-phenan-
throline) were determined by X-ray crystallography. All of the
Introduction
chemists since the cytostatic properties of cisplatin {cis-
[PtCl2(NH3)2]; DDP} were discovered by Rosenberg.[3] In recent
decades, various transition-metal compounds have been scruti-
nized, and many structural patterns with enhanced activity to-
ward cisplatin-resistant tumor cells have been found.[4]
Despite our constantly deepening knowledge about the patho-
biochemical mechanisms of various hematological malignan-
cies, many leukemias remain incurable and have very bad sur-
vival prognoses. Although targeted therapies, such as tyrosine
kinase inhibitors and specific monoclonal antibodies, were a
great revolution for the treatment of some types of leukemia,
others rely fully on classical chemotherapy.[1] For example, the
core of the treatment regimen for acute myeloid leukemia (vari-
ations on a theme of cytosine arabinoside combined with an
anthracycline or anthracenedione) has remained nearly un-
changed for 40 years, and the prognosis remains poor, espe-
cially for elderly patients.
Therefore, new cytostatic agents are constantly researched,
and they should be associated with fewer undesirable side-ef-
fects with potent antitumor activity maintained.[2] Transition-
metal complexes and organometallic compounds have at-
tracted considerable attention from biochemists and pharmaco-
Nevertheless, the quest for new highly active species with
reduced side-effects is still ongoing. Our investigation follows
the fundamental work of Romão et al., who established the
allyl, cyclopentadienyl (Cp), and indenyl (Ind) molybdenum
compounds [(η3-C3H5)Mo(CO)2L2Br] and [(η5-Cp′)Mo(CO)2L2]-
[BF4] (Cp′ = cyclopentadienyl, indenyl), in which L2 is a N,N-, S,S-
or P,P-chelating ligand, as a new class of highly cytotoxic species
against several tumor cell lines.[5] Subsequent studies have ex-
tended the series of cytotoxic compounds[6] and brought an
early insight into the mechanism of their action.[7] The cyto-
toxicity of the molybdenum compounds seems to correlate
mainly with the nature of the coordinated chelating ligand, and
the substitution pattern in the π-coordinated ligand plays only
a minor role.[8,9] High activity was observed mainly for com-
plexes bearing 1,10-phentanthroline (phen) and its 4,7-diphenyl
derivative (4,7-Ph2-phen). However, the main drawback of these
complexes is their poor water solubility, which hinders their
pharmaceutical application.
[a] Department of General and Inorganic Chemistry,
Faculty of Chemical Technology, University of Pardubice,
Studentská 573, 53210 Pardubice, Czech Republic
E-mail: jaromir.vinklarek@upce.cz
http://www.upce.cz/fcht/koanch.html
[b] Department of Analytical Chemistry, Faculty of Chemical Technology,
University of Pardubice,
Studentská 573, 53210 Pardubice, Czech Republic
[c] Department of Medical Biochemistry, Faculty of Medicine in Hradec
Králové, Charles University in Prague,
Šimkova 870, 50001 Hradec Králové, Czech Republic
[d] Institute of Chemistry and Technology of Macromolecular Materials,
Faculty of Chemical Technology, University of Pardubice,
Studentská 573, 53210 Pardubice, Czech Republic
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejic.201501133.
The aim of this study is to modify the outer coordination
sphere of molybdenum(II) compounds to improve their water
solubility. The functionalization of the cyclopentadienyl ligand
with hydrophilic functions seems to be a suitable approach for
this purpose as the coordination sphere of the metal center is
unchanged. This work describes the assembly of species bear-
ing ammonium salts of tertiary amines in cyclopentadienyl and
indenyl ligands. The cytotoxic properties of these derivatives
were examined in vitro against two human leukemia cell lines.
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Results and Discussion
Mo–CO moiety (exo) predominates in all compounds under
study. This observation is in line with the data reported for
unsubstituted analogues.[14] Compounds 11–13 show two
broadened signals at δ ≈ 5.15 ppm (2 × 2 H), which were as-
signed to the protons of the η5-coordinated cyclopentadienyl
Synthesis of Allyl Molybdenum Precursors
The tertiary-amine-functionalized cyclopentadienes C5H5CH2-
CH2NR2 [R = Me (6); NR2 = N(CH2)5 (7), N(CH2)4O (8)] and indene
C9H7CH2CH2NMe2 (9) were synthesized by the reaction of the
appropriate alkyl chloride (3–5) with sodium cyclopentadienide
(1) and sodium indenide (2), respectively (Scheme 1). This syn-
thetic strategy has been used several times,[10–13] but the use
of freshly distilled free amines (3–5) enhances the yields and
enables the synthesis of reasonable quantities of these ligand
precursors to facilitate the exploration of the corresponding co-
ordination chemistry.
1
ring. In the H NMR spectrum of 14, the protons from the C5
ring of the η5-coordinated indenyl ligand appeared as two sets
of doublets at δ ≈ 5.8 and 5.6 ppm (3JH,H = 2.7 Hz) and were
1
assigned to the given conformers. The patterns of the H NMR
spectra further prove that the pendant amine arms in 11–14
are not coordinated to the molybdenum centers, which satisfy
the 18e rule.
Table 1. Infrared data of molybdenum compounds 11–14.[a]
νa(CO)
νs(CO)
νa(CO)
νs(CO)
11
12
1920
1929
1827
1844
13
14
1930
1933
1839
1852
[a] Wavenumbers in cm–1
.
The crystal structure of 12 was determined by X-ray diffrac-
tion analysis (see Figure 1). The molecule has a distorted tetra-
hedral structure with an η3-allyl ligand, an η5-cyclopentadienyl
ligand, and two carbonyl ligands around the molybdenum cen-
ter in the formal oxidation state +II. The allyl ligand adopts the
exo conformation. The geometric parameters that describe the
molybdenum coordination sphere are given in the caption of
Figure 1. The large Cg(allyl)–Mo–Cg(Cp) bond angle [128.3(1)°]
and the small C(CO)–Mo–C(CO) bond angle [80.2(1)°] represent
the largest deviations from the ideal tetrahedron. Nevertheless,
these values are in line with the data reported for similar com-
plexes bearing a substituted cyclopentadienyl ring.[15]
Scheme 1. Synthesis of substituted cyclopentadienes 6–8 and indene 9.
The lithium cyclopentadienides 6-Li to 8-Li, prepared by the
deprotonation of cyclopentadienes 6–8 with nBuLi, react with
the chloride complex [(η3-C3H5)Mo(CO)2(NCMe)2Cl] (10) to give
the cyclopentadienyl complexes [(η3-C3H5)(η5-C5H4CH2CH2-
NR2)Mo(CO)2] [R = Me (11), NR2 = N(CH2)5 (12), N(CH2)4O (13);
see Scheme 2]. The indenyl complex [(η3-C3H5)(η5-
C9H6CH2CH2NMe2)Mo(CO)2] (14) was prepared accordingly
from indene 9.
Scheme 2. Synthesis of molybdenum compounds 11–14.
The infrared spectra of 11–14 show two CO stretching bands
in the range typical for terminal carbonyl ligands (see Table 1).
The higher wavenumbers observed for the indenyl derivative
14 [ν = 1933 (ν ), 1852 cm–1 (νs)] reflect the lower electron
˜
a
density of the metal center owing to the weaker donor proper-
1
Figure 1. ORTEP drawing of 12. The labeling scheme for all non-hydrogen
atoms is shown. Thermal ellipsoids are drawn at the 30 % probability level.
Selected bond lengths [Å] and angles [°]: Mo1–Cg(C1–C5) 2.019(1), Mo1–
Cg(C13–C15) 2.047(2), Mo1–C16 1.943(2), Mo1–C17 1.950(2), Cg(C1–C5)–
Mo1–Cg(C13–C15) 128.3(1), C16–Mo1–C17 80.2(1).
ties of the indenyl ligand. The H NMR spectra show two sets
of signals for the allyl ligand and, therefore, reveal the presence
of two conformations of this ligand in solution. At room tem-
perature, the conformer with the allyl ligand eclipsing the OC–
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Synthesis of Complexes with N,N-Chelating Ligands
The infrared spectra of 15–23 show two CO stretching bands
˜
at ν ≈ 1960 (νa) and 1890 cm–1 (νs); see Table 2. The considera-
The molybdenum complexes 15–23 bearing N,N-chelating li-
gands were prepared according to Scheme 3 by following the
route developed for the analogues with unfunctionalized Cp
ligands.[8,16] The treatment of the starting complexes 11–14
with HBF4 in the presence of a coordinating solvent leads to
the protonation of the allyl ligand. Subsequent ligand exchange
gives unstable acetonitrile intermediates. These species were
not isolated but only washed to remove the excess acid and the
boron-based impurities. The treatment with the N,N-chelating
ligands followed by the protonation of the pendant arm gives
the dicationic complexes 15–23.
bly higher carbonyl ligand stretching frequencies compared
with those of the neutral precursors 11–14 are due to de-
creased back-donation from the molybdenum centers to the
carbonyl ligands in the cationic complexes. The NMR spectro-
scopic measurements reveal that the cyclopentadienyl com-
plexes 15–20 have Cs-symmetric structure. The protons of the
η5-coordinated cyclopentadienyl ligands show typical AA′BB′-
type patterns, in which the signals appear as two pseudotriplets
at δ ≈ 5.9 and 5.8 ppm (3JH,H ≈ 4JH,H ≈ 2.2 Hz). The lower overall
symmetry of the indenyl complexes 21–23 results in more com-
plex NMR spectra. Nevertheless, the η5-coordination mode of
the indenyl ligands was evidenced from the signal of proton
H2, which appears at higher field (δ ≈ 5.7 ppm) than those of
the remaining protons of the indenyl framework (H3–H7).[17]
Table 2. Infrared data of complexes bearing N,N-chelating ligands.[a]
νa(CO)
νs(CO)
νa(CO)
νs(CO)
15
16
17
18
19
1968
1967
1974
1971
1959
1887
1887
1894
1903
1902
20
21
22
23
1971
1963
1966
1951
1900
1888
1891
1878
[a] Wavenumbers in cm–1
.
The assembly of complex cations 15–23 was further sup-
ported by ESI mass spectrometry. These compounds show
peaks for [M – H]+ in positive-ion mode. The absence of the
parent dicationic species [M]2+ is not surprising as the deproto-
nation of the ammonium group from the pendant arm is clearly
an acid–basic reaction. Nevertheless, some dications (15–18
and 21–23) were stabilized by acetonitrile, as evidenced by the
observed intense [M + MeCN]2+ peaks.
The solid-state structures of 18 and 21·phen were deter-
mined by X-ray diffraction analysis (Figures 2 and 3, respec-
tively). The molybdenum(II) centers in the dicationic complex
species have square-pyramidal coordination spheres with η5-
coordinated cyclopentadienyl (18) or indenyl ligands (21·phen)
at their apical positions. The basal planes are occupied by two
carbonyl ligands in a cis configuration and the nitrogen donor
atoms of the N,N-chelating ligand. The bond lengths and angles
of the molybdenum coordination sphere are very similar
to those of the related 2,2′-bipyridine (bpy) complexes
[(η5-C5H4CH2C6H4OMe)Mo(CO)2(bpy)][BF4], [{η5-C5H4CH2C6H2-
(OMe)3}Mo(CO)2(bpy)][BF4], and [(η5-Ind)Mo(CO)2(bpy)][BF4].[8]
Therefore, the modification of the cyclopentadienyl and indenyl
ligands with alkylammonium substituents has little effect on
the inner coordination.
Scheme 3. Synthesis of molybdenum compounds bearing N,N-chelating li-
gands: (a) HBF4·Et2O (2 equiv.)/MeCN, (b) N,NL/CH2Cl2, (c) HBF4·Et2O (1 equiv.)/
MeCN.
One could expect that the acidification after the treatment
with the N,N-chelating ligand would be unnecessary as the pen-
dant arm should be protonated in the first reaction step. How-
ever, our experiments on Me2NCH2CH2-functionalized com-
pounds 11 and 14 revealed the appearance of the products
without protonated arms (15a, 16a, 21a, and 22a; see
Scheme 4) if the last reaction step was omitted. These species
were recognized by 1H NMR spectroscopy owing to the absence
of the spin–spin interaction between the protons of the ammo-
nium group and the protons from the neighboring methyl (3JH,H
≈ 5.2 Hz) and methylene groups (3JH,H ≈ 5.5 Hz). The patterns
of the remaining NMR spectra were virtually the same. We sug-
gest that the appearance of the monocationic compounds 15a,
16a, 21a, and 22a could be clarified by the coordination of the
pendant arm in the acetonitrile intermediates, but these species
were not isolated or characterized satisfactorily owing to their
low stability.
The cation of 21 and a phenanthroline molecule are con-
nected through intermolecular hydrogen bonds between the
hydrogen atoms of the ammonium group and the nitrogen at-
oms of the phenanthroline molecule. The distances between
the nitrogen atoms were 3.012(3) and 2.909(3) Å for N1···N4
and N1···N5, respectively.
Scheme 4. Recognized monocationic intermediates.
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Cytotoxicity of Chelate Complexes
By procedures described previously,[18] molybdenum com-
pounds 15–23 were tested for their cytotoxic effects against
the human leukemia cell lines MOLT-4 and HL-60. The half maxi-
mal inhibitory concentration (IC50) values are listed in Table 3.
The cytotoxicity curves showing the effect on the cell viability
are given in the Supporting Information (Figures S1–S9).
Table 3. Cytotoxicity data of complexes bearing N,N-chelating ligands.[a]
MOLT-4
HL-60
MOLT-4
HL-60
15
16
17
18
19
2.4 0.1
6.6 0.6
3.7 0.7
1.2 0.1
4.6 0.5
6.9 0.7
8.3 0.5
6.1 0.5
3.4 0.2
5.4 0.4
20
21
22
2.2 0.1
2.0 0.1
1.4 0.1
1.2 0.1
15.8 1.9
2.3 0.3
6.1 0.9
1.5 0.2
2.6 0.3
11.3 2.5
23
DDP[b]
[a] The IC50 values are given in μmol/L. [b] Data reported elsewhere.[19]
All of the compounds under study (15–23) are highly active
against both cell lines. Their IC50 values are much lower than
that reported for DDP (see Table 3). The considerable increase
of the cytotoxicity is a result of the modification of the cyclo-
pentadienyl compounds, as the unsubstituted parent, [(η5-
Cp)Mo(CO)2(phen)][BF4], only shows medium activity against
MOLT-4 leukemic cells [IC50 = (19.9 0.7) μmol/L;[8] cf. with 15–
20 in Table 3]. The parent indenyl compound, [(η5-
Ind)Mo(CO)2(phen)][BF4], is more effective [IC50 (MOLT-4) =
(4.9 0.7) μmol/L],[8] but even here the modification leads to
species with approximately 2.5 times higher cytotoxicity (see
21–23 in Table 3). The very similar cytotoxic behavior of the
species under study suggests that the increased hydrophilicity
plays a very important role in the transport of the active species
into the diseased cells, and this seem to be crucial for effective
cytotoxic action of molybdenum compounds. The exchange of
1,10-phenanthroline with larger π systems [e.g., 4,7-Ph2-phen
or 2,2′-biquinoline (bq)] has a negligible effect on the activity;
this contrasts with the results from previous studies on species
without polar function groups in the cyclopentadienyl or inde-
nyl ligand,[8,9] probably as a result of a much smaller effect of
the chelating ligand on the physical properties of the com-
plexeswiththehighlypolarfunctiongroupsattachedtothecyclo-
pentadienyl or indenyl ligand.
Figure 2. ORTEP drawing of the dication [{η5-C5H4CH2CH2NH(CH2)5}-
Mo(CO)2(4,7-Ph2-phen)]2+ in the crystal structure of 18. The labeling scheme
for all non-hydrogen atoms is shown. Thermal ellipsoids are drawn at the
30 % probability level. Selected bond lengths [Å] and angles [°]: Mo1–Cg(C1–
C5) 1.993(2), Mo1–C37 1.976(4), Mo1–C38 1.975(3), Mo1–N2 2.178(2), Mo1–
N3 2.179(3), C37–Mo1–C38 75.7(2), N2–Mo1–N3 73.3(1).
The highly efficient compound 20 was subjected to deeper
biological investigations to reveal more information about the
mechanism of the cytotoxic effect. 1H NMR spectroscopy meas-
urements of 20 in D2O suggest that it has satisfactory stability
for application. The mechanism was studied by flow cytometry,
spectral methods, and western blotting in combination with
SDS-PAGE and the immunochemical detection of the MOLT-4
and HL-60 cell lines. The obtained IC50 values were used to
determine the optimal concentrations for the follow-up experi-
ments.
The flow cytometry measurements revealed that low con-
centrations of 20 (1 and 2 μmol/L) have a negligible effect on
the MOLT-4 cells over the whole experiment (see Figure 4, A
and B). A considerable cytotoxicity was observed for a concen-
tration 3 μmol/L after 48 h of incubation with 20, accompanied
by an increased percentage of dead cells. The increasing con-
centration of 20 and prolonged incubation time led to an in-
Figure 3. ORTEP drawing of the dication [(η5-C9H6CH2CH2NHMe2)-
Mo(CO)2(phen)]2+ present in the crystal structure of 21·phen. The labeling
scheme for all non-hydrogen atoms is shown. Thermal ellipsoids are drawn
at the 30 % probability level. Selected bond lengths [Å] and angles [°]: Mo1–
Cg(C1–C5) 1.992(1), Mo1–C26 1.967(2), Mo1–C27 1.973(2), Mo1–N2 2.200(2),
Mo1–N3 2.199(2), C26–Mo1–C27 76.8(1), N2–Mo1–N3 73.5(1).
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Figure 4. The effect of 20 on the proliferation and viability of leukemia cells over three days. Concentration of 20: 1 (brown line), 2 (green line), 3 (purple
line), 5 (blue line), and 7 μmol/L (orange line), control (dark blue line). (A) The proliferation of the MOLT-4 cells, (B) the viability of the MOLT-4 cells, (C) the
proliferation of the HL-60 cells, (D) the viability of the HL-60 cells. The results are taken from three independent experiments.
crease in the cytotoxicity. At concentrations of 5 and 7 μmol/L, its a higher cytotoxic effect toward the MOLT-4 cells than to-
the viability decreased shortly after the treatment with 20.
ward HL-60 cells.
The cytostatic behavior of 20 against the HL-60 leukemia
The measurement of the activity of caspases 3/7, 8, and 9
cells is shown in Figure 4, C and D. The effects on the viability confirmed that the apoptotic processes of the MOLT-4 (Figure 5,
and proliferation are similar to those described for the MOLT-4 A) and HL-60 cells (Figure 5, B) were induced by the treatment
cell line. Hence, the proliferation is inhibited at a concentration with 20. The application of the tested compound (2 and
of 3 μmol/L, and the number of dead cells increases with time. 4 μmol/L) on these leukemia cells caused significant dose-de-
The application of higher concentrations (5 and 7 μmol/L) led pendent increases in the activity of the effector caspase 3/7
to considerable decreases in proliferation and viability shortly and the initiator caspases 8 and 9. This behavior seems to be
after the application. On the basis of the WST-1 assay, 20 exhib- similar to that of DDP, for which the mechanism of action has
Figure 5. The activity of caspases 3/7 (black), caspase 8 (white), and caspase 9 (grey) determined 24 h after the application of 20 and DDP (2 and 4 μmol/L)
on the leukemia cells. (A) Cell line MOLT-4, (B) cell line HL-60. * Significantly different from control (P < 0.05). The results were taken from three independent
experiments.
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Figure 6. The effect of 20 and DDP on apoptosis induction in leukemia cells 24 h after treatment with the tested compound, as determined by flow cytometry.
The percentage of viable (black), early apoptotic (white), and late apoptotic cells (grey) is shown. (A) Cell line MOLT-4, (B) cell line HL-60. * Significantly
different from control (P < 0.05). The results were taken from three independent experiments.
been described previously.[20,21] After the purine bases of the 60 cell line produced similar results to those described for the
DNA are damaged by DDP, the inner pathway activation of MOLT-4 cells. Hence, DDP seems to be more active than 20 at
apoptosis in tumor cells is induced. In addition to the inner a concentration of 2 μmol/L. Nevertheless, at a concentration
induction (mitochondrial pathway), FasL mRNA expression is of 4 μmol/L, 20 induces a stronger apoptotic effect than that
induced. This starts the extrinsic pathway of apoptosis. The of DDP. The comparison of the apoptotic induction verified that
antitumor effect of DDP has also been ascribed to increased the HL-60 cell line is more resistant than the MOLT-4 cell line to
oxidative stress and calcium efflux from mitochondria.[20,21] Our the treatment with 20.
measurements reveal that the cytotoxic effect of 20 is more
powerful than that observed for DDP. Furthermore, the apop-
totic process is induced predominantly by the mitochondrial-
dependent apoptosis-inducing pathway (caspase 9) followed by
the activation of effector caspases 3 and 7 for both cell lines.
The apoptosis was further cross-verified by flow cytometry
detection with Annexin V and propidium iodide (PI) staining of
the MOLT-4 (Figure 6, A) and HL-60 cells (Figure 6, B). For the
MOLT-4 cell line, no significant change to the number of apop-
totic cells occurred after 24 h incubation with 20 at a concentra-
tion of 2 μmol/L. A noticeable decrease in the amount of viable
cells appeared at a concentration of 4 μmol/L, and the consider-
able growth of early and late apoptotic cells was observed. DDP
induces significant apoptotic changes to the MOLT-4 cells at a
concentration of 2 μmol/L after 24 h incubation. However, an
increase of concentration to 4 μmol/L does not cause further
considerable apoptotic changes. The experiments with the HL-
Follow-up experiments revealed that the response of the
MOLT-4 cells to the treatment with 20 and DDP includes
changes to the expression of the p53 protein and its form phos-
phorylated at serine 15 (p53_ser15); see Figure 7. The quantity
of ꢀ-actin was monitored as a verification of the equal protein
Figure 7. Induction and activation of p53 in the MOLT-4 cells exposed to the
tested compounds for 4 and 24 h. (1) Control, (2) 2 μmol/L of 20, (3) 4 μmol/
L of 20, (4) 2 μmol/L of DDP, (5) 4 μmol/L of DDP. p53_ser15: p53 phosphoryl-
ated at serine 15. To confirm equal protein loading, the membranes were
reincubated with ꢀ-actin. Representative results of one of three independent
experiments are shown.
Figure 8. The cell-cycle analysis of the apoptosis induction in the leukemia cells 24 h after treatment with 20 and DDP, as determined by flow cytometry with
propidium iodide. The percentages of cells in the G1 (black), G2 (white), and S phases (grey) are shown. The results were taken from three independent
experiments. (A) Cell line MOLT-4, (B) cell line HL-60. * Significantly different from control (P < 0.05).
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trometer equipped with a diamond smart orbit attenuated total
reflectance (ATR) accessory. The 1H NMR spectra were recorded at
300 K with a Bruker 400 Avance spectrometer. The chemical shifts
are given in ppm relative to the external standard [tetramethylsilane
(TMS)]. Deuterated solvents were used as obtained (Acros Organics).
Mass spectrometry was performed with a quadruple mass spec-
trometer (LCMS 2010, Shimadzu). The samples were injected into
the mass spectrometer in infusion mode at a constant flow rate of
10 μL/min. Electrospray ionization mass spectrometry (ESI-MS) was
used to identify the analyzed samples.
loading. A noticeable increase of the p53 level occurred 4 h
after the treatment with 20, and it increased with the concen-
tration of tested compound. The level of p53 remained elevated
during the whole experiment (24 h). Additionally, it was proved
that the p53 protein was phosphorylated at serine 15. This
modification is responsible for the stability and accumulation
of the p53 protein in the cell. The expression of p53_ser15 in-
creases with increasing concentration of 20 and with the length
of the experiment. The p53 protein is a transcription factor in-
volved in the response to DNA damage and in the subsequent
induction of DNA repair, cell-cycle arrest, and apoptosis. Its level
in the cell is regulated through post-translational modifications
that interfere with p53 degradation and translocation. The
phosphorylation of ser15 is a crucial function of p53. Hence,
it inhibits the interaction with the ubiquitin ligase Mdm2 and
protects protein p53 from ligation to ubiquitin, stabilizes it,[21]
and extends its half-life.[22]
ClCH2CH2NMe2 (3): Potassium hydroxide (15 g, 0.27 mol) was dis-
solved in distilled water (150 mL) and treated with
[ClCH2CH2NHMe2]Cl (18.7 g, 0.13 mol). The mixture was extracted
with pentane (4 × 75 mL). The combined organic phases were dried
with magnesium sulfate. The solvent was removed by distillation at
normal pressure, and the product was vacuum distilled at 40 °C
(60 Torr), yield 7.6 g (71 mmol, 54 %). Colorless liquid. The analytical
and spectroscopic data are in line with those reported elsewhere.[24]
Although 20 causes significant changes to the p53 protein
of the MOLT-4 cells, the cell cycle remains unchanged for both
leukemia cells under study (MOLT-4 and HL-60); see Figure 8.
The increase in the expression of the p53 protein and its phos-
phorylated form p53_ser15 was monitored for DDP as well.
However, the relevant changes in the cell cycle were not ob-
served with the same concentrations of DDP as those of 20 (2
and 4 μmol/L).
ClCH2CH2N(CH2)5 (4): Potassium hydroxide (15 g, 0.27 mol) was
dissolved in distilled water (150 mL) and treated with
[ClCH2CH2NH(CH2)5]Cl (24.0 g, 0.13 mol). The mixture was extracted
with hexane (4 × 75 mL). The combined organic phases were dried
with magnesium sulfate. The solvent was removed by distillation at
normal pressure, and the product was vacuum distilled at 65 °C
(15 Torr), yield 8.8 g (60 mmol, 46 %). Colorless liquid. The analytical
and spectroscopic data are in line with those reported elsewhere.[24]
ClCH2CH2N(CH2)4O (5): The reaction was performed as was de-
scribed for 4 but with [ClCH2CH2NH(CH2)4O]Cl (24.2 g, 0.13 mol).
The product was vacuum distilled at 80 °C (15 Torr), yield 11.5 g
(77 mmol, 59 %). Colorless liquid. The analytical and spectroscopic
data are in line with those reported elsewhere.[24]
Conclusions
Complexes 15–23 represent a second generation of molybde-
num-based cytotoxic agents with increased water solubility. The
synthetic part of this study describes the pathway toward func-
tionalized molybdenum compounds together with detailed
analytical and spectroscopic characterization. The structures of
one key intermediate (12) and two final products (18 and 21)
were elucidated by single-crystal X-ray diffraction analysis.
The functionalization of the outer coordination sphere of
C5H5CH2CH2NMe2 (6): Sodium cyclopentadienide (1; 4.4 g,
50 mmol) was dissolved in THF (150 mL), and the solution was
cooled to 0 °C. Compound 3 (4.95 g, 46 mmol) was added dropwise,
and the reaction mixture was stirred at room temperature over-
night. The mixture was poured into distilled water (75 mL), and the
crude product was extracted with CH2Cl2 and dried with magne-
sium sulfate. The volatiles were removed in vacuo, and the product
molybdenum(II) compounds with ammonium functions has a was vacuum distilled at 70 °C (20 Torr), yield 3.1 g (23 mmol, 49 %).
Pale yellow liquid. The analytical and spectroscopic data are in line
strong impact on their cytotoxicity. All of the studied com-
pounds are approximately one order magnitude more active
than DDP against MOLT-4 and HL-60 leukemia cells. The effect
of the highly efficient compound 20 on the leukemia cells was
studied in detail. This molybdenum(II) compound induces
apoptotic processes in cell lines MOLT-4 and HL-60. The apopto-
sis is activated by the inner apoptotic pathway through caspase
9 activation. Complex 20 causes an upregulation of the p53
with those reported elsewhere.[12]
C5H5CH2CH2N(CH2)5 (7): The reaction was performed as was de-
scribed for 6 but with 4 (6.8 g, 46 mmol). The product was vacuum
distilled at 60 °C (15 Torr), yield 4.3 g (24 mmol, 53 %). Pale yellow
liquid. The analytical and spectroscopic data are in line with those
reported elsewhere.[11]
C5H5CH2CH2N(CH2)4O (8): The reaction was performed as was de-
protein and its form phosphorylated at serine 15. This complex scribed for 6 but with 5 (6.9 g, 46 mmol). The product was vacuum
distilled at 60 °C (15 Torr), yield 3.7 g (21 mmol, 45 %). Pale yellow
liquid. The analytical and spectroscopic data are in line with those
reported elsewhere.[13]
seems to be more effective than DDP and should undergo fur-
ther scrutiny as a potential cytostatic agent.
C9H7CH2CH2NMe2 (9): The reaction was performed as was de-
scribed for 6 but with sodium indenide (2; 6.9 g, 50 mmol) and 3
(4.95 g, 46 mmol). The product was vacuum distilled at 75 °C
(12 Torr), yield 5.5 g (29 mmol, 64 %). Pale yellow liquid. The analyti-
cal and spectroscopic data are in line with those reported else-
where.[11]
Experimental Section
Methods and Materials: All operations were performed under
nitrogen by conventional Schlenk-line techniques. The solvents
were purified and dried by standard methods.[23] The starting mate-
rials were available commercially; [(η3-C3H5)Mo(CO)2(NCMe)2Cl] (10)
was prepared by literature procedures.[14]
[(η3-C3H5)(η5-C5H4CH2CH2NMe2)Mo(CO)2] (11): C5H5CH2CH2NMe2
(6; 0.69 g, 5 mmol) was diluted with THF (30 mL), cooled to 0 °C,
Measurements: Infrared spectra were recorded in the 4000–
400 cm–1 wavenumber region with a Nicolet Magna 6700 FTIR spec- and treated dropwise with nBuLi (1.6 mol L–1, 3.1 mL). The reaction
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525
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3
3
mixture was stirred for 2 h at room temperature and then added
0.17 (tt, JH,H = 11.2, JH,H = 7.4 Hz, 1 H of 14a, meso-C3H5), –0.81
3
3
dropwise to a THF solution of 10 (1.55 g, 5 mmol) precooled to (d, JH,H = 10.7 Hz, 1 H of 14b, anti-C3H5), –0.85 (d, JH,H = 10.7 Hz,
–80 °C. The reaction mixture was stirred at room temperature over-
night and then vacuum evaporated to dryness. The solid residue
was extracted with hexane, and vacuum evaporation afforded a
viscous yellow liquid. The product was purified by recrystallization
from a hexane/diethyl ether mixture at –80 °C and then vacuum
1 H of 14b, anti-C3H5) ppm. IR (ATR): ν = 1933 [vs, νa(CO)], 1852 [vs,
˜
νs(CO)] cm–1
.
[(η5-C5H4CH2CH2NHMe2)Mo(CO)2(phen)][BF4]2 (15): Complex 11
(0.23 g, 0.70 mmol) was dissolved in CH2Cl2 (5 mL), cooled to 0 °C,
and treated with acetonitrile (1 mL) and then with HBF4·Et2O
(192 μL, 1.40 mmol). The reaction mixture was stirred for 4 h at
room temperature, and the solvent was vacuum evaporated. The
intermediate was washed several times with ether, vacuum dried,
dissolved in CH2Cl2 (15 mL), and treated with 1,10-phenanthroline
(126 mg, 0.70 mmol). The solution was stirred at room temperature
overnight, vacuum evaporated, and washed with diethyl ether
(2 × 10 mL) and CH2Cl2 (2 × 5 mL); the solid was dissolved in MeCN
and treated with HBF4·Et2O (96 μL, 0.70 mmol). The reaction mix-
ture was stirred for 1 h at room temperature, and the solvent was
vacuum evaporated. The crude product was washed with diethyl
ether (2 × 10 mL) and CH2Cl2 (2 × 5 mL), recrystallized twice from a
MeCN/Et2O mixture, and vacuum dried, yield 0.26 g (4.0 mmol,
58 %). Red powder. C23H23B2F8MoN3O2 (643.00): calcd. C 42.96, H
3.61, N 6.54; found C 42.82, H 3.48, N 6.49. Positive-ion MS (MeCN):
dried, yield 0.78
g (2.4 mmol, 47 %). Viscous yellow oil.
C
14H19MoNO2 (329.25): calcd. C 51.07, H 5.82, N 4.25; found C 51.24,
H 5.60, N 4.51. 1H NMR [CDCl3, 400 MHz, 4:1 mixture of 11a (exo-
C3H5) and 11b (endo-C3H5)]: δ = 5.16 (br, 2 H of 11a and 2 H of
11b, C5H4), 5.14 (br, 2 H of 11a and 2 H of 11b, C5H4), 3.86 (tt,
3JH,H = 10.8, JH,H = 7.0 Hz, 1 H of 11a, meso-C3H5), 3.62 (br, 1 H of
3
11b, meso-C3H5), 2.79 (d, 3JH,H = 4.8 Hz, 2 H of b, syn-C3H5), 2.70 (d,
3JH,H = 7.0 Hz, 2 H of 11a, syn-C3H5), 2.45–2.35 (m, 4 H of 11a and
4 H of 11b, CH2), 2.26 (s, 6 H of 11a and 6 H of 11b, CH3), 1.59 (d,
3JH,H = 10.6 Hz, 2 H of 11b, anti-C3H5), 0.93 (d, JH,H = 10.8 Hz, 2 H
3
of 11a, anti-C3H5) ppm. IR (ATR): ν = 1920 [vs, νa(CO)], 1827 [vs,
˜
νs(CO)] cm–1
.
[(η3-C3H5){η5-C5H4CH2CH2N(CH2)5}Mo(CO)2] (12): The reaction
was performed as was described for 11 but with 7 (0.89 g, 5 mmol),
yield 0.71 g (1.9 mmol, 38 %). Yellow powder. C17H23MoNO2
(369.31): calcd. C 55.29, H 6.28, N 3.79; found C 55.42, H 6.23, N
3.86. 1H NMR [CDCl3, 400 MHz, 4:1 mixture of 12a (exo-C3H5) and
1
m/z (%) = 256 (100) [M + MeCN]2+, 470 [M – H]+. H NMR (CD3CN,
3
4
400 MHz): δ = 9.41 (dd, JH,H = 5.4, JH,H = 1.3 Hz, 2 H, C12H8N2,
4
H2,9), 8.80 (dd, 3JH,H = 8.1, JH,H = 1.3 Hz, 2 H, C12H8N2, H4,7), 8.23 (s,
12b (endo-C3H5)]: δ = 5.15 (br, 2 H of 12a and 2 H of 12b, C5H4),
2 H, C12H8N2, H5,6), 7.98 (dd, 3JH,H = 8.1, 3JH,H = 5.4 Hz, 2 H, C12H8N2,
3
3
5.13 (br, 2 H of 12a and 2 H of 12b, C5H4), 3.86 (tt, JH,H = 10.7, H3,8), 6.85 (br, 1 H, NH), 5.84 (t, JH,H = 2.2 Hz, 2 H, C5H4), 5.75 (t,
3JH,H = 7.0 Hz, 1 H of 12a, meso-C3H5), 3.62 (br, 1 H of 12b, meso- 3JH,H = 2.2 Hz, 2 H, C5H4), 3.09 (td, JH,H = 8.1, JH,H = 5.7 Hz, 2 H,
3
3
3
3
3
3
C3H5), 2.79 (d, JH,H = 5.0 Hz, 2 H of 12b, syn-C3H5), 2.69 (d, JH,H
=
CH2CH2NH), 2.69 (d, JH,H = 5.3 Hz, 6 H, CH3), 2.05 (t, JH,H = 8.1 Hz,
7.0 Hz, 2 H of 12a, syn-C3H5), 2.45–2.35 (m, 8 H of 12a and 8 H of
12b, CH2), 1.58 (m, 4 H of 12a and 4 H of 12b, CH2), 1.42 (m, 2 H
of 12a and 2 H of 12b, CH2), 0.92 (d, JH,H = 10.7 Hz, 2 H of
2 H, CH2CH2NH) ppm. IR (ATR): ν = 1968 [vs, νa(CO)], 1887 [vs,
˜
νs(CO)], 1030 [vs br, νa(BF)] cm–1
.
3
[(η5-C5H4CH2CH2NHMe2)Mo(CO)2(4,7-Ph2-phen)][BF4]2
(16):
12a, anti-C3H5) ppm. IR (ATR): ν = 1929 [vs, νa(CO)], 1844 [vs, νs(CO)]
˜
Complex 11 (0.23 g, 0.70 mmol) was dissolved in CH2Cl2 (5 mL),
and the solution was cooled to 0 °C, treated with acetonitrile (1 mL),
and then with HBF4·Et2O (192 μL, 1.40 mmol). The reaction mixture
was stirred for 4 h at room temperature, and the solvent was vac-
uum evaporated. The intermediate was washed several times with
ether, vacuum dried, dissolved in CH2Cl2 (15 mL), and treated with
4,7-diphenyl-1,10-phenanthroline (226 mg, 0.70 mmol). The solu-
tion was stirred at room temperature overnight, vacuum evapo-
rated, and washed with diethyl ether (2 × 10 mL). The solid was
dissolved in CH2Cl2 and treated with HBF4·Et2O (96 μL, 0.70 mmol).
cm–1. Single crystals suitable for X-ray diffraction analysis were pre-
pared by the slow evaporation of a hexane solution under an inert
atmosphere.
[(η3-C3H5){η5-C5H4CH2CH2N(CH2)4O}Mo(CO)2] (13): The reaction
was performed as was described for 11 but with 8 (0.90 g, 5 mmol).
Yellow powder. C16H21MoNO3 (371.29): calcd. C 51.76, H 5.70, N
3.77; found C 51.65, H 5.57, N 3.92. 1H NMR [CDCl3, 400 MHz, 4:1
mixture of 13a (exo-C3H5) and 13b (endo-C3H5)]: δ = 5.18 (br, 2 H
of 13a and 2 H of 13b, C5H4), 5.12 (br, 2 H of 13a and 2 H of 13b,
3
3
C5H4), 3.88 (tt, JH,H = 10.7, JH,H = 6.9 Hz, 1 H of 13a, meso-C3H5), The reaction mixture was stirred for 1 h at room temperature, and
3.72 (m, 4 H of 13a and 4 H of 13b, CH2), 3.62 (br, 1 H of 13b,
meso-C3H5), 2.78 (br, 2 H of 13b, syn-C3H5), 2.71 (d, JH,H = 6.9 Hz,
the solvent was vacuum evaporated. The crude product was
washed with diethyl ether (2 × 10 mL), recrystallized twice from a
MeCN/Et2O mixture, and vacuum dried, yield 0.29 g (0.36 mmol,
52 %). Red powder. C35H31B2F8MoN3O2 (795.19): calcd. C 52.87, H
3
2 H of 13a, syn-C3H5), 2.53–2.39 (m, 8 H of 13a and 8 H of 13b,
3
3
CH2), 1.60 (d, JH,H = 10.1 Hz, 2 H of 13b, anti-C3H5), 0.92 (d, JH,H
=
10.7 Hz, 2 H of 13a, anti-C3H5) ppm. IR (ATR): ν = 1930 [vs, νa(CO)], 3.93, N 5.28; found C 53.01, H 3.95, N 5.32. Positive-ion MS (MeCN):
˜
1
1839 [vs, νs(CO)] cm–1
.
m/z (%) = 332 (100) [M + MeCN]2+, 622 [M – H]+. H NMR (CD3CN,
400 MHz): δ = 9.44 (d, JH,H = 5.7 Hz, 2 H, C12H6N2, H2,9), 8.15 (s, 2
3
[(η3-C3H5)(η5-C9H6CH2CH2NMe2)Mo(CO)2] (14): The reaction was
performed as was described for 11 but with 9 (0.94 g, 5 mmol),
yield 0.64 g (1.7 mmol, 34 %). Yellow powder. C18H21MoNO2
(379.31): calcd. C 57.00, H 5.58, N 3.69; found C 56.88, H 5.71, N
3.63. H NMR [CDCl3, 400 MHz, 3.3:1 mixture of 14a (exo-C3H5) and
14b (endo-C3H5)]: δ = 7.46–6.89 (m, 4 H of 14a and 4 H of 14b,
C9H6), 5.85 (d, JH,H = 2.7 Hz, 1 H of 14a, C9H6), 5.78 (d, JH,H
2.7 Hz, 1 H of 14b, C9H6), 5.66 (d, JH,H = 2.7 Hz, 1 H of 14a, C9H6),
5.59 (d, JH,H = 2.7 Hz, 1 H of 14b, C9H6), 3.37 (d, JH,H = 6.4 Hz, 2
H of 14b, syn-C3H5), 3.29 (m, 1 H of 14b, meso-C3H5), 3.00–2.55 (m,
4 H of 14a and 4 H of 14b, CH2), 2.39 (s, 6 H of 14b, CH3), 2.33 (s,
H, C12H6N2, H5,6), 7.94 (d, 3JH,H = 5.7 Hz, 2 H, C12H6N2, H3,8), 7.67 (m,
10 H, C6H5), 6.95 (br, 1 H, NH) 5.90 (t, 3JH,H = 2.2 Hz, 2 H, C5H4), 5.80
(t, 3JH,H = 2.2 Hz, 2 H, C5H4), 3.15 (td, 3JH,H = 8.0, JH,H = 5.6 Hz, 2 H,
3
3
3
CH2CH2NH), 2.72 (d, JH,H = 5.2 Hz, 6 H, CH3), 2.11 (t, JH,H = 8.0 Hz,
2 H, CH2CH2NH) ppm. IR (ATR): ν = 1967 [vs, νa(CO)], 1887 [vs,
1
˜
νs(CO)], 1030 [vs br, νa(BF)] cm–1
.
3
3
=
[{η5-C5H4CH2CH2NH(CH2)5}Mo(CO)2(phen)][BF4]2 (17): The reac-
tion was performed as was described for 16 but with 12 (0.26 g,
0.70 mmol) and 1,10-phenanthroline (126 mg, 0.70 mmol). The
crude product was washed with diethyl ether (2 × 10 mL), recrystal-
lized twice from a MeCN/Et2O mixture, and vacuum dried, yield
0.29 g (0.42 mmol, 61 %). Red powder. C26H27B2F8MoN3O2 (683.06):
3
3
3
3
6 H of 14a, CH3), 2.21 (d, JH,H = 7.4 Hz, 1 H of 14a, syn-C3H5), 2.18
3
3
(d, JH,H = 7.4 Hz, 1 H of 14a, syn-C3H5), 0.92 (d, JH,H = 11.2 Hz, 1
H of 14a, anti-C3H5), 0.84 (d, 3JH,H = 11.2 Hz, 1 H of 14a, anti-C3H5), calcd. C 45.72, H 3.98, N 6.15; found C 45.78, H 4.06, N 6.21. Positive-
Eur. J. Inorg. Chem. 2016, 519–529
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526 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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ion MS (MeCN): m/z (%) = 276 (100) [M + MeCN]2+, 510 [M – H]+.
lized twice from a CH2Cl2/Et2O mixture, and vacuum dried, yield
0.30 g (0.43 mmol, 62 %). Red powder. C27H25B2F8MoN3O2 (693.06):
3
4
1H NMR (CD3CN, 400 MHz): δ = 9.41 (dd, JH,H = 5.4, JH,H = 1.3 Hz,
2 H, C12H8N2, H2,9), 8.80 (dd, 3JH,H = 8.2, 4JH,H = 1.3 Hz, 2 H, C12H8N2, calcd. C 46.79, H 3.64, N 6.06; found C 46.63, H 3.69, N 5.96. Positive-
3
H4,7), 8.23 (s, 2 H, C12H8N2, H5,6), 7.98 (dd, 3JH,H = 8.2, JH,H = 5.4 Hz,
ion MS (MeCN): m/z (%) = 281 (100) [M + MeCN]2+, 520 [M – H]+.
3
3
4
2 H, C12H8N2, H3,8), 6.70 (br, 1 H, NH), 5.84 (t, JH,H = 2.2 Hz, 2 H,
1H NMR (CD3CN, 400 MHz): δ = 9.71 (dd, JH,H = 5.4, JH,H = 1.3 Hz,
1 H, C12H8N2, H2,9), 9.54 (dd, 3JH,H = 5.4, 4JH,H = 1.3 Hz, 1 H, C12H8N2,
H2,9), 8.70 (m, 2 H, C12H8N2, H4,7), 8.10 (s, 2 H, C12H8N2, H5,6), 7.98
3
C5H4), 5.75 (t, JH,H = 2.2 Hz, 2 H, C5H4), 3.29 (m, 2 H, CH2), 3.03 (td,
3
3JH,H = 8.2, JH,H = 5.4 Hz, 2 H, C5H4CH2CH2NH), 2.73 (m, 2 H, CH2),
3
2.08 (t, JH,H = 8.2 Hz, 2 H, C5H4CH2CH2NH), 1.86–1.32 (m, 6 H, CH2)
(m, 2 H, C12H8N2, H3,8), 7.30 (br, 1 H, NH), 6.99 (dd, 3JH,H = 8.5, 4JH,H
=
3
4
ppm. IR (ATR): ν = 1974 [vs, νa(CO)], 1894 [vs, νs(CO)], 1025 [vs br,
0.9 Hz, 1 H, C9H6, H7), 6.79 (dt, JH,H = 8.5, JH,H = 0.9 Hz, 1 H, C9H6,
˜
νa(BF)] cm–1
.
H4), 6.62 (dd, JH,H = 2.8, JH,H = 0.8 Hz, 1 H, C9H6, H3), 6.41 (ddd,
3
4
3JH,H = 8.5, JH,H = 6.8, JH,H = 0.9 Hz, 1 H, C9H6, H5,6), 6.32 (ddd,
3
4
[{η5-C5H4CH2CH2NH(CH2)5}Mo(CO)2(4,7-Ph2-phen)][BF4]2 (18):
The reaction was performed as was described for 16 but with 12
(0.26 g, 0.70 mmol). The crude product was washed with diethyl
ether (2 × 10 mL), recrystallized twice from a CH2Cl2/Et2O mixture,
and vacuum dried, yield 0.32 g (0.38 mmol, 54 %). Red powder.
C38H35B2F8MoN3O2 (835.26): calcd. C 54.64, H 4.22, N 5.03; found C
54.52, H 4.17, N 5.14. Positive-ion MS (MeCN): m/z (%) = 352 (100)
[M + MeCN]2+, 662 [M – H]+. 1H NMR (CD3CN, 400 MHz): δ = 9.45
3JH,H = 8.5, 3JH,H = 6.8, 4JH,H = 0.9 Hz, 1 H, C9H6, H5,6), 5.65 (d, 3JH,H
=
2.8 Hz, 1 H, C9H6, H2), 3.62 (m, 1 H, CH2), 3.35 (m, 2 H, CH2), 3.15
(m, 1 H, CH2), 2.96 (d, 3JH,H = 5.2 Hz, 3 H, CH3), 2.93 (d, 3JH,H = 5.2 Hz,
3 H, CH ) ppm. IR (ATR): ν = 1963 [vs, ν (CO)], 1888 [vs, ν (CO)], 1030
˜
3
a
s
[vs br, νa(BF)] cm–1. Single crystals of 21·phen suitable for X-ray
diffraction analysis were prepared by layering an acetonitrile solu-
tion of the crude product with diethyl ether.
3
(d, JH,H = 5.7 Hz, 2 H, C12H6N2, H2,9), 8.16 (s, 2 H, C12H6N2, H5,6),
[(η5-C9H6CH2CH2NHMe2)Mo(CO)2(4,7-Ph2-phen)][BF4]2 (22): The
reaction was performed as was described for 16 but with 14 (0.27 g,
0.70 mmol). The crude product was washed with diethyl ether
(2 × 10 mL), recrystallized twice from a MeCN/Et2O mixture, and
vacuum dried, yield 0.33 g (0.39 mmol, 56 %). Red powder.
7.95 (d, 3JH,H = 5.7 Hz, 2 H, C12H6N2, H3,8), 7.67 (m, 10 H, C6H5), 6.65
(br, 1 H, NH), 5.91 (t, 3JH,H = 2.2 Hz, 2 H, C5H4), 5.81 (t, 3JH,H = 2.2 Hz,
3
3
2 H, C5H4), 3.32 (m, 2 H, CH2), 3.08 (td, JH,H = 8.2, JH,H = 5.4 Hz, 2
3
H, C5H4CH2CH2NH), 2.76 (m, 2 H, CH2), 2.15 (t, JH,H = 8.2 Hz, 2 H,
C5H4CH2CH2NH), 1.87–1.33 (m, 6 H, CH2) ppm. IR (ATR): ν = 1971 [vs,
˜
C39H33B2F8MoN3O2 (845.25): calcd. C 55.42, H 3.94, N 4.97; found C
νa(CO)], 1903 [vs, νs(CO)], 1050 [vs br, νa(BF)] cm–1. Single crystals
of 18 suitable for X-ray diffraction analysis were prepared by layer-
ing an acetonitrile solution with diethyl ether.
55.60, H 3.89, N 4.91. Positive-ion MS (MeCN): m/z (%) = 357 [M +
1
MeCN]2+, 672 (100) [M – H]+. H NMR (CD3CN, 400 MHz): δ = 9.75
3
3
(d, JH,H = 5.6 Hz, 1 H, C12H6N2, H2,9), 9.57 (d, JH,H = 5.6 Hz, 1 H,
C12H6N2, H2,9), 8.03 (s, 2 H, C12H6N2, H5,6), 7.93 (d, JH,H = 5.6 Hz, 2
3
[{η5-C5H4CH2CH2NH(CH2)4O}Mo(CO)2(phen)][BF4]2 (19): The reac-
tion was carried out as was described for 16 but with 13 (0.26 g,
0.70 mmol) and 1,10-phenanthroline (126 mg, 0.70 mmol). The
crude product was washed with diethyl ether (2 × 10 mL), recrystal-
lized twice from a MeCN/Et2O mixture, and vacuum dried, yield
0.16 g (0.23 mmol, 33 %). Red powder. C25H25B2F8MoN3O3 (685.03):
calcd. C 43.83, H 3.68, N 6.13; found C 43.91, H 3.61, N 6.10. Positive-
ion MS (MeCN): m/z (%) = 512 (100) [M – H]+. 1H NMR (CD3CN,
H, C12H6N2, H3,8), 7.65 (m, 10 H, C6H5), 7.33 (br, 1 H, NH), 7.06 (dd,
3JH,H = 8.5, 4JH,H = 0.9 Hz, 1 H, C9H6, H7), 6.88 (dt, 3JH,H = 8.5, 4JH,H
=
0.9 Hz, 1 H, C9H6, H4), 6.67 (dd, 3JH,H = 2.8, JH,H = 0.8 Hz, 1 H, C9H6,
H3), 6.53 (ddd, 3JH,H = 8.5, 3JH,H = 6.8, 4JH,H = 0.9 Hz, 1 H, C9H6, H5,6),
4
6.44 (ddd, JH,H = 8.5, JH,H = 6.8, JH,H = 0.9 Hz, 1 H, C9H6, H5,6),
3
3
4
5.70 (d, JH,H = 2.8 Hz, 1 H, C9H6, H2), 3.66 (m, 1 H, CH2), 3.38 (m, 2
3
H, CH2), 3.16 (m, 1 H, CH2), 2.98 (d, 3JH,H = 5.2 Hz, 3 H, CH3), 2.94 (d,
3JH,H = 5.2 Hz, 3 H, CH3) ppm. IR (ATR): ν = 1966 [vs, νa(CO)], 1891
3
400 MHz): δ = 9.41 (d, JH,H = 5.4 Hz, 2 H, C12H8N2, H2,9), 8.80 (d,
˜
[vs, νs(CO)], 1055 [vs br, νa(BF)] cm–1
.
3JH,H = 8.2 Hz, 2 H, C12H8N2, H4,7), 8.22 (s, 2 H, C12H8N2, H5,6), 7.99
(dd, 3JH,H = 8.2, 3JH,H = 5.4 Hz, 2 H, C12H8N2, H3,8), 7.30 (br, 1 H, NH),
[(η5-C9H6CH2CH2NHMe2)Mo(CO)2(bq)][BF4]2 (23): The reaction
was performed as was described for 16 but with 14 (0.27 g,
0.70 mmol) and 2,2′-biquinoline (179 mg, 0.70 mmol). The crude
product was washed with diethyl ether (2 × 10 mL), recrystallized
twice from a MeCN/Et2O mixture, and vacuum dried, yield 0.28 g
(0.36 mmol, 52 %). Red powder. C33H29B2F8MoN3O2 (769.16): calcd.
C 51.53, H 3.80, N 5.46; found C 51.69, H 3.74, N 5.24. Positive-ion
3
3
5.85 (t, JH,H = 2.1 Hz, 2 H, C5H4), 5.75 (t, JH,H = 2.1 Hz, 2 H, C5H4),
3.95 (m, 2 H, CH2), 3.64 (m, 2 H, CH2), 3.25 (m, 2 H, CH2), 3.13 (td,
3JH,H = 8.2, JH,H = 5.4 Hz, 2 H, C5H4CH2CH2NH), 2.94 (m, 2 H, CH2),
3
3
2.09 (t, JH,H = 8.2 Hz, 2 H, C5H4CH2CH2NH) ppm. IR (ATR): ν = 1959
˜
[vs, νa(CO)], 1902 [vs, νs(CO)], 1030 [vs br, νa(BF)] cm–1
.
[{η5-C5H4CH2CH2NH(CH2)4O}Mo(CO)2(4,7-Ph2-phen)][BF4]2 (20):
The reaction was performed as was described for 16 but with 13
(0.26 g, 0.70 mmol). The crude product was washed with diethyl
ether (2 × 10 mL), recrystallized twice from a CH2Cl2/Et2O mixture,
and vacuum dried, yield 0.18 g (0.21 mmol, 31 %). Red powder.
C37H33B2F8MoN3O3 (837.23): calcd. C 53.08, H 3.97, N 5.02; found C
53.17, H 3.91, N 4.95. Positive-ion MS (MeCN): m/z (%) = 664 (100)
MS (MeCN): m/z (%) = 319 (100) [M + MeCN]2+, 596 [M – H]+. 1H
3
NMR (CD3CN, 400 MHz): δ = 9.51 (d, JH,H = 8.9 Hz, 1 H, C18
H
12N2),
3
3
8.84 (d, JH,H = 8.9 Hz, 1 H, C18
H
12N2), 8.77 (d, JH,H = 8.9 Hz, 1 H,
12N2), 8.68 (d, JH,H = 8.9 Hz, 1 H, C18
3
3
C18
8.9 Hz, 1 H, C18
8.22 (m, 4 H, C18
H
H
12N2), 8.55 (d, JH,H
12N2), 8.36–
12N2), 7.24 (br, 1 H,
=
3
H
12N2), 8.51 (d, JH,H = 8.9 Hz, 1 H, C18
H
H
12N2), 8.06–8.00 (m, 2 H, C18
H
NH), 6.86 (d, JH,H = 2.9 Hz, 1 H, C9H6, H3), 6.62–6.48 (m, 3 H, C9H6,
3
1
3
[M – H]+. H NMR (CD3CN, 400 MHz): δ = 9.45 (d, JH,H = 5.6 Hz, 2
H4–7), 6.30 (d, JH,H = 8.7 Hz, 1 H, C9H6, H4,7), 5.85 (d, JH,H = 2.9 Hz,
3
3
H, C12H6N2, H2,9), 8.15 (s, 2 H, C12H6N2, H5,6), 7.95 (d, JH,H = 5.6 Hz,
3
1 H, C9H6, H2), 3.60–3.25 (m, 4 H, CH2), 2.97 (d, JH,H = 5.1 Hz, 3 H,
3
2 H, C12H6N2, H3,8), 7.67 (m, 10 H, C6H5), 7.30 (br, 1 H, NH), 5.93 (t,
3JH,H = 2.2 Hz, 2 H, C5H4), 5.82 (t, 3JH,H = 2.2 Hz, 2 H, C5H4), 3.96 (m,
2 H, CH2), 3.65 (m, 2 H, CH2), 3.29 (m, 2 H, CH2), 3.19 (td, 3JH,H = 8.2,
3JH,H = 5.4 Hz, 2 H, C5H4CH2CH2NH), 2.98 (m, 2 H, CH2), 2.16 (t,
3
CH3), 2.92 (d, JH,H = 5.1 Hz, 3 H, CH3) ppm. IR (ATR): ν = 1951 [vs,
˜
νa(CO)], 1878 [vs, νs(CO)], 1030 [vs br, νa(BF)] cm–1
.
X-ray Crystallography: The X-ray crystallography data for 12, 18,
and 21·phen were obtained at 150 K with an Oxford Cryostream
low-temperature device and a Nonius KappaCCD diffractometer
with Mo-Kα radiation (λ = 0.71073 Å) and a graphite monochroma-
tor. The data reductions were performed with DENZO-SMN.[25] The
3JH,H = 8.2 Hz, 2 H, C5H4CH2CH2NH) ppm. IR (ATR): ν = 1971 [vs,
˜
νa(CO)], 1900 [vs, νs(CO)], 1050 [vs br, νa(BF)] cm–1
.
[(η5-C9H6CH2CH2NHMe2)Mo(CO)2(phen)][BF4]2 (21): The reaction
was performed as was described for 16 but with 14 (0.27 g,
0.70 mmol) and 1,10-phenanthroline (126 mg, 0.70 mmol). The absorption was corrected by integration methods.[26] The structures
crude product was washed with diethyl ether (2 × 10 mL), recrystal-
were solved by direct methods (Sir92)[27] and refined by full-matrix
Eur. J. Inorg. Chem. 2016, 519–529
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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least-squares techniques on F2 (SHELXL97).[28] Hydrogen atoms
were mostly localized in the difference Fourier maps. However, to
ensure the uniformity of the treatment of the crystal, all hydrogen
atoms were recalculated in idealized positions (riding model) and
assigned temperature factors Uiso(H) = 1.2[Ueq(pivot atom)] or
1.5Ueq for the methyl moiety with C–H = 0.96, 0.97, and 0.93 Å for
methyl, methylene, and hydrogen atoms in aromatic rings or the
allyl moiety, respectively.
Keywords: Molybdenum · Medicinal chemistry · Antitumor
agents · Cytotoxicity
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CCDC 1401170 (for 21·phen), 1401171 (for 18), and 1401172 (for
12) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
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Biological Studies: The studies were performed with the human
T-lymphocytic leukemia cells MOLT-4 obtained from the American
Type Culture Collection and human promyelocytic leukemia cells
HL-60 obtained from the European Collection of Cell Cultures (Por-
ton Down). The cells were cultured in Iscove's modified Dulbecco's
medium (IMDM) supplemented with 20 % fetal calf serum and
0.05 % L-glutamine (all Sigma–Aldrich) in a humidified incubator at
37 °C and a controlled 5 % CO2 atmosphere. Cell lines in the maxi-
mal range of up to 20 passages were used for this study. The cyto-
toxicities of the compounds were evaluated by the WST-1 cell viabil-
ity test (Roche) according to the instructions from the manufacturer,
as described previously.[18] Briefly, the leukemia cells were seeded
in 96-well plates, incubated in solutions of the compounds for 24 h,
and then washed and incubated for 180 min in WST-1 solution. The
absorbance at λ = 440 nm corresponds to the cell viability and was
measured with a multiplate reader (Tecan Infinite 200). The inhibi-
tory effect of 20 was analyzed through the measurement of cell
proliferation and viability with propidium iodide (Sigma–Aldrich)
and a flow cytometer with a Coulter volume. Concentrations of 1,
2, 3, 5, and 7 μmol/L of 20 were selected to determine the cell
proliferation and viability after the incubation of MOLT-4 and HL-60
cells for 24, 48, and 72 h. The activity of caspases 3/7, 8, and 9 were
evaluated for 20 and DDP through Caspase-Glo Assays (Promega)
24 h after the treatment of the MOLT-4 and HL-60 cells. For the
determination of apoptosis, the Apoptest-FITC kit (Dako-Cytoma-
tion) was used. The incubation time for the tests of 20 and DDP
against the MOLT-4 and HL-60 cell lines was 24 h. The quantities of
the proteins p53 and p53-ser15 were determined by electrophoresis
and western blotting with immunochemical detection 4 and 24 h
after the treatment of the MOLT-4 cells with 20 and DDP. The cell
cycle was analyzed by flow cytometry of the MOLT-4 and HL-60 cell
lines with 20 and DDP. The cells were washed with cold phosphate-
buffered saline (PBS) and fixed with 70 % ethanol. For the detection
of DNA, the cells were incubated for 5 min at room temperature in
a buffer (192 mL, 0.2
M Na2HPO4, 8 mL of 0.1 M citric acid, pH 7.8)
and then labeled with propidium iodide in Vindelov solution for 1 h
at 37 °C. The DNA content was determined with a DakoCyAn flow
cytometer (Beckman Coulter). The data were analyzed with the Mul-
ticycle AV software (Phoenix Flow systems). All reagents were ob-
tained from Sigma–Aldrich. The concentrations of the tested com-
plexes (20 and DDP) were 2 and 4 μmol/L, and untreated cells (con-
trol) were evaluated together with the treated cells for all experi-
ments. The measurements were performed by a standard protocol
(out cell cycle).[29]
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This work was supported by Ministry of Education of the Czech
Republic (project number SG350004) and the Charles University
in Prague (program PRVOUK P37/01).
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