Cyclometalated Platinum(II) Complexes Bearing Bidentate O,O′-Di(alkyl)dithiophosphate Ligands: Photoluminescence and Cytotoxic Properties

Article abstract of DOI:10.1021/acs.organomet.7b00054

Mononuclear complexes [Pt(ppy)(S^∧S)] (1a, S^∧S = O,O′-di(cyclohexyl)dithiophosphate (ctp); 2a, S^∧S = O,O′-di(butyl)dithiophosphate (btp)) and [Pt(bzq)(S^∧S)] (1b, S^∧S = ctp; 2b, S^∧S = btp) have been prepared by the reaction of precursor complexes [Pt(C^∧N)Cl(dmso)], C^∧N = deprotonated form of 2-phenylpyrdine (ppy) and 7,8-benzoquinoline (bzq), and potassium salt of S^∧S ligands. All complexes were characterized by NMR spectroscopy, and the structure of 2b was further identified by single crystal X-ray determination. Although the complexes are not luminescent in solution at ambient temperature, they become strong emissive materials (bright green) in solid state (at room temperature) with high quantum yields and long lifetimes in the microsecond domain. In frozen glass state or at low temperature (solid state), these complexes become better emissive in relation to room temperature. UV-vis spectra, supported by TD-DFT calculations, indicate that ¹ILCT (intraligand charge transfer) predominates over the other transitions (L = C^∧N cyclometalated ligand). Accordingly, 1 and 2 exhibit structured emission bands which display a large involvement of ³LCCT (ligand-centered charge transfer) with lower contribution of ³MLCT (metal to ligand charge transfer) transition in the excited states. Also, biological activities of 1 and 2 were evaluated against three human cancer cell lines including A549 (human lung cancer), SKOV3 (human ovarian cancer), and MCF-7 (human breast cancer). 2a presented an effective potent cytotoxic activity regarding to the cell lines. The cellular localization of 1a and 2a in MCF-7 human cells was investigated by fluorescence microscopy.

Full text of DOI:10.1021/acs.organomet.7b00054

Article
pubs.acs.org/Organometallics
Cyclometalated Platinum(II) Complexes Bearing Bidentate
O,O′‑Di(alkyl)dithiophosphate Ligands: Photoluminescence and
Cytotoxic Properties
Masood Fereidoonnezhad,†,‡ Babak Kaboudin,§ Tabassom Mirzaee,† Reza Babadi Aghakhanpour,§
Mohsen Golbon Haghighi,∥ Zeinab Faghih,⊥ Zahra Faghih,# Zohreh Ahmadipour,† Behrouz Notash,∥
and Hamid R. Shahsavari*,§
‡
†Department of Medicinal Chemistry, School of Pharmacy and Cancer, Environmental and Petroleum Pollutants Research Center,
Ahvaz Jundishapur University of Medical Sciences, Ahvaz 61357-15794, Iran
§Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Yousef Sobouti Boulevard, Zanjan 45137-6731,
Iran
∥Department of Chemistry, Shahid Beheshti University, Evin, Tehran 19839-69411, Iran
#
⊥Pharmaceutical Sciences Research Center and Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of
Medical Sciences, Shiraz 71348-14336, Iran
S
* Supporting Information
ABSTRACT: Mononuclear complexes [Pt(ppy)(S∧S)] (1a,
S∧S = O,O′-di(cyclohexyl)dithiophosphate (ctp); 2a, S∧S =
O,O′-di(butyl)dithiophosphate (btp)) and [Pt(bzq)(S∧S)]
(1b, S∧S = ctp; 2b, S∧S = btp) have been prepared by the
reaction of precursor complexes [Pt(C∧N)Cl(dmso)], C∧N =
deprotonated form of 2-phenylpyrdine (ppy) and 7,8-
benzoquinoline (bzq), and potassium salt of S∧S ligands. All
complexes were characterized by NMR spectroscopy, and the
structure of 2b was further identified by single crystal X-ray
determination. Although the complexes are not luminescent in
solution at ambient temperature, they become strong emissive
materials (bright green) in solid state (at room temperature)
with high quantum yields and long lifetimes in the micro-
second domain. In frozen glass state or at low temperature (solid state), these complexes become better emissive in relation to
1
room temperature. UV−vis spectra, supported by TD-DFT calculations, indicate that ILCT (intraligand charge transfer)
predominates over the other transitions (L = C∧N cyclometalated ligand). Accordingly, 1 and 2 exhibit structured emission
bands which display a large involvement of 3LCCT (ligand-centered charge transfer) with lower contribution of 3MLCT (metal
to ligand charge transfer) transition in the excited states. Also, biological activities of 1 and 2 were evaluated against three human
cancer cell lines including A549 (human lung cancer), SKOV3 (human ovarian cancer), and MCF-7 (human breast cancer). 2a
presented an effective potent cytotoxic activity regarding to the cell lines. The cellular localization of 1a and 2a in MCF-7 human
cells was investigated by fluorescence microscopy.
is the combination of a neutral L ligand and an anionic X head.
Some anionic O∧O, N∧N, and N∧O chelates have been
employed as the successful examples of L∧X ancillary ligands
toward the cyclometalated complexes.16,18−23 Phosphino
alcohols can also give a special puckered P∧O ancillary ligand
in which the phosphorus head can play role of a strong-field
ligand with π-accepting character.24 Although the use of L∧X
ancillary ligands in the structure of cycloplatinated(II)
complexes is widespread in the literature,2,6,16,25,26 such
complexes bearing S∧S chelating systems27,28 like dithiocarba-
INTRODUCTION
■
Heteroleptic cycloplatinated(II) complexes incorporating ap-
propriate ancillary ligands represent impressive photophysical
properties.1−9 Also, they have wide range of applications
regarding these properties such as light-emitting devices,9,10
photocatalytic processes and hydrogen generation,11 dye-
sensitized solar cells,12 biosensors, and photoswitches.13−15
A
key step in the design of such emissive complexes can be
picking out suitable ancillary ligands.16 In recent years, the
ancillary chelating L∧X systems have been developed in order
to tune and enhance the emission properties of the
cycloplatinated(II) complexes; they are also able to impose
an extra structural rigidity on the complex.17 This kind of ligand
Received: January 22, 2017
© XXXX American Chemical Society
A
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mates29 or dithiophosphates30,31 ligands are scarce in the
published resources.
a
Scheme 3. Synthetic Route for Preparation of 1 and 2
In contrast, O,O′-di(alkyl)dithiophosphate ligands32 (S∧S)
represent a relatively new class of potentially L∧X chelating
systems (in cycloplatinated complexes)30,31 which can be easily
obtained by deprotonation of O,O′-di(alkyl)dithiophosphoric
acid organic compounds.32 Deprotonation reaction from the
acidic species gives the corresponding anion that they can be
defined by two resonance forms (Scheme 1). Furthermore, they
Scheme 1. Two Resonance Forms of Deprotonated O,O′-
Di(alkyl)dithiophosphoric Acid Compounds
a
All reactions were carried out under inert atmosphere at room
temperature.
their integrity in solid and solution were investigated by IR and
NMR spectroscopy, respectively. The details are given in the
Experimental Section. The ESI(+) mass spectra (Figure S1−
S4) of these complexes reveal the molecular peaks related to
[M]+ fragments, which obviously establish 1 and 2 in the gas
phase.
exhibit various coordination patterns toward a wide range of
metal ions33 while some binding modes are typically shown in
Scheme 2.32 For instance, the soft metals such as platinum
prefer to bind the structure “b” for producing isobidentate
coordination pattern (4).30−33
IR spectra of 1 and 2 (Figures S5−S8) displayed a strong
band due to υPS in the region 683−737 cm−1 while it shifted
to lower frequency ∼30 cm−1 with respect to salt ligands. Also,
the bands observed in the region of 459−540 cm−1 are
attributed to υP−S as symmetric and asymmetric vibrations.
NMR (1H, 31P{H}) spectroscopy was employed to precisely
identify the new structures in solution. The Experimental
Section provides the numerical NMR data, while the spectra are
embedded in Figures S9−S16. 2a was typically selected to
interpret NMR spectra. In the 1H NMR spectrum of 2a, at δ =
0.94 ppm a triplet signal is observed for the terminal methyl of
the butyl chains (Hd). Two multiplet signals appearing at δ =
1.44 and 1.74 ppm are related to Hc and Hb protons of the
butyl chains, respectively. Also, the signals for two diaster-
eotopic protons of CH2 groups adjacent to oxygen atoms (Ha)
are significantly deshielded and appeared as two triplet signals
at δ = 4.21 and 4.23 ppm. In the aromatic region, a distinctive
doublet signal being flanked by platinum satellites is observed at
δ = 8.79 ppm which corresponded to the H2 of ppy ligand
Scheme 2. Diversity of Coordination Patterns of O,O′-
Di(alkyl)dithiophosphate Ligands toward Different Metal
Ions
In the present study, a new series of cyclometalated
platinum(II) complexes containing O,O′-di(alkyl)dithiophos-
phates (alkyl = cyclohexyl and n-butyl) were synthesized and
characterized spectroscopically. Due to the lack of perfect
investigations on the cycloplatinated(II) complexes containing
S∧S ligands, we have decided to study the effect of such
ancillary ligands on the luminescence and biological properties
of these Pt(II) complexes. Additionally, the obtained photo-
luminescence data was supported by density functional theory
(DFT) and time-dependent DFT (TD-DFT) calculations.
Also, the cytotoxic activities of platinum complexes comprising
S∧S ligands have been evaluated against three cancer cell lines,
i.e., A549 (human lung cancer), SKOV3 (human ovarian
cancer), and MCF-7 (human breast cancer). Moreover, as these
complexes are intensely emissive, their cellular localization was
studied by fluorescence microscopy.
3
(3JHH = 5.7 Hz, JPtH = 43.4 Hz). Moreover, the 31P{H}NMR
spectrum of 2a includes a singlet with platinum satellites at δ =
2
100.8 ppm with JPtP = 320 Hz. This coupling constant is
relevant to the chelating binding mode of O,O′-di(alkyl)-
dithiophosphate ligands.30,36
Using slow layer diffusion of n-hexane into the acetone
solution of 2b, yellow crystals were obtained and provided a
good quality for single crystal X-ray crystallography. This
complex crystallizes in the monoclinic crystal system with the
P21/n space group. An ORTEP view of 2b is given in Figure 1
(possessing atom numbering for the important atoms). In this
structure, one of the butyl chains is located perpendicular to the
molecule plane, while another one is almost parallel to the
molecule plan (Figure 1). The four-membered “PtSPS” ring
exhibits a puckered structure with an almost tetrahedral
geometry at the phosphorus atom center.30,31 On the basis of
the previous experiences, the C∧N bite angle is considerably
smaller than 90° (83.7°) which proves that the C∧N chelate is
under a strain.37,38
RESULTS AND DISCUSSIONS
■
Synthesis and Characterization of Complexes. The
new chemistry is depicted in Scheme 3. The well-known
precursor complexes [Pt(C∧N) (Cl) (dmso)],34,35 where C∧N
= deprotonated form of 2-phenylpyridine (ppy) and 7,8-
benzoquinoline (bzq), were treated with 1 equiv of different
potassium O,O′-di(alkyl)dithiophosphate salts (O,O′-di-
(cyclohexyl)dithiophosphate (ctp) and O,O′-di(butyl)-
dithiophosphate (btp)) and gave corresponding complexes
[Pt(ppy)(S∧S)] (1a, S∧S = ctp; 2a, S∧S = btp) or [Pt(bzq)-
(S∧S)] (1b, S∧S = ctp; 2b, S∧S = btp).
Complexes 1 and 2 were deduced from common analytical
methods such as elemental analyses and mass spectroscopy, and
Photophysical Properties. The UV−vis spectra of 1 and 2
in CH2Cl2 solutions at room temperature are represented in
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Figure 1. ORTEP plot of the structure of 2b. Selected geometrical parameters (Å, deg): Pt1−C1 1.980(11); Pt1−N1 2.038(8); Pt1−S1 2.436 (3);
Pt1−S2 2.311(3); P1−S1 1.994(4); P1−S2 2.006(4); P1−O1 1.566(8); P1−O2 1.573(8); C1−Pt1−N1 83.7(4); C1−Pt1−S2 94.4(4); N1−Pt1−
S2 176.8(3); C1−Pt1−S1 177.8(4); N1−Pt1−S1 98.3(3); S2−Pt1−S1 83.64(10); S(1)−P(1)−S(2) 104.70(17). Ellipsoids are drawn at the 40%
probability level, and hydrogen atoms are omitted for clarity.
Figure 2. (a) Absorption spectra for 1 and 2 in CH2Cl2 solutions. (b) Normalized diffuse reflectance UV−vis spectra of 1 and 2 in solid state at
room temperature.
Figure 2a, while their corresponding normalized diffuse
reflectance UV−vis spectra are depicted in Figure 2b. The
numerical data are listed in Table 1. The UV−vis spectra of
complexes in solution bearing the same C∧N cyclometalated
ligands are almost identical. It indicates that the absorptions do
not depend on the nature of alkyl groups in the structure of
O,O′-di(alkyl)dithiophosphate ligands. On the basis of reported
assignments for the Pt(II) complexes incorporating C∧N
aromatic rings,9,39−41 it is rational to assign the high-energy
absorption bands below 350 nm to the ligand-centered (1LC
π−π*) transitions which are perturbed by the metal center.
This results in the free ppyH and bzqH compounds showing a
1LC transition lower than 300 nm under the same
conditions.6,42 However, the less intense bands (λ > 350 nm)
are normally related to the spin-allowed metal to ligand charge
Table 1. Numerical Absorption Data for 1 and 2 in Their
CH2Cl2 Solutions (5 × 10−5 M) and Solid State at Room
1
transfer transitions (1MLCT) or the mixture of MLCT and
a
Temperature
1LC. The bzq complexes (1b and 2b) exhibiting a more
extended aromaticity have a redshift in the 1MLCT/1LC region
with respect to those of ppy complexes (1a and 1b) which is
due to lowering the π* energy level.43,44 In the diffuse
reflectance spectra of complexes, an overall redshift is observed
for the bzq complexes in comparison to the ppy complexes,
mirroring the obtained spectra in solution. Almost, there is no
observable change between the solid state diffuse reflectance
UV−vis spectra and the spectra obtained in solution state
which is due to the lack of Pt−Pt or excimeric π−π
interactions.44 For 2b, in the low-energy bands, a weak
absorption is observed at approximately 580 nm, probably
not enough to change the color of this complex.
complex
absorption (nm (104 ε/M−1 cm−1))
407 (0.062), 362 (0.351), 313 (0.365), 287 (0.864); CH2Cl2
413, 362, 285, 254; solid
1a
430 (0.068), 377 (0.287), 322 (0.408), 294 (0.470), 271 (0.438);
CH2Cl2
1b
2a
2b
437, 388, 321, 253; solid
407 (0.062), 362 (0.372), 313 (0.413), 287 (0.984); CH2Cl2
411, 365, 309, 253; solid
423 (0.112), 374 (0.389), 319 (0.587), 294 (0.649), 271 (0.533);
CH2Cl2
425, 375, 310, 254; solid
a
Data at high concentration (10−3 M) are similar to those at low
concentration.
C
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All complexes exhibit poor and negligible emissions in their
CH2Cl2 solutions at room temperature because of molecular
motions in solution. Conversely, with the exception of 2b, they
are strong green emitters in solid state at room temperature
under irradiation of UV light (365 nm) as evidenced by high
measured quantum efficiencies (Figure 3 for the corresponding
near yellow region. Neither aggregation nor accordingly
excimeric emission is observed in the spectra probably because
of the presence of bulky R groups of the S∧S ancillary ligands.
In solid state at 298 K, the bright green powders of 1a and 2a,
having the same ppy cyclometalated ligand, give structured
emission bands with the same wavelengths. It indicates that R
substituents on the S∧S ligand do not affect the emission
wavelength or color. However, they have a relatively
considerable influence on the luminescence quantum yield
values for which the complexes bearing cyclohexyl exhibit
quantum yield values higher than those containing n-butyl (1a
> 2a). It arises from the higher structural rigidity of cyclohexyl
in relation to that of n-butyl which results in the higher
quantum yield.
The complexes with ppy ligand (1a and 2a) include a peak at
490 nm with a vibronic progression at 520 nm (maximum) and
a shoulder almost at 555 nm. Because of extending π-
conjugation system, bzq complexes 1b and 2b are slightly
red-shifted in relation to ppy complexes, in good agreement
with the UV−vis spectra.44 They exhibit relatively structured
emission bands at 510 and 504 nm (for 1b and 2b respectively)
with both vibronic progressions at 530 nm and shoulders at
570−580 nm region. The observed structured emission bands
in the complexes indicate the superiority of the ligand-centered
transitions (3LC) rather than other available transitions with
Figure 3. Photographic images of 1 and 2 under UV light in solid and
glass states.
44,45
3
photographic images). Expectedly, low temperature (77 K)
makes these complexes to display much brighter green
luminescence rather than room temperature, even including
2b which is a relatively poor luminescent at room temperature.
Also, the frozen CH2Cl2 solutions of complexes demonstrate
very shiny strong emissions under UV light exposure (Figure
3). The characters of emissions are definitely phosphorescence
due to the large amount of lifetime values in the microsecond
range which were obtained using the emission bands maxima of
complexes (Table 2).
The normalized emission spectra for the complexes under
different circumstances arising from the excitation wavelength
between 340 and 500 nm are demonstrated in Figure 4; the
numerical data are summarized in Table 2. For all the
complexes, the bands occur in green region with tails to the
lower contribution of MLCT transition.
Upon cooling to 77 K, complexes become clearly structured
and better emitters, exhibiting higher quantum yields, due to
the imposition of extra rigidity. The low temperature bands all
have blue-shifted compared with those of 298 K; therefore, no
change in emission color is observed. This blueshift could be
related to the improved rigidity in the freezing state, which has
frequently defined as rigidochromism.44,46 As mentioned above,
complexes display a very strong luminescence in their frozen
glassy states for which the corresponding emission bands
almost match up with those observed for the solid state at 77 K
showing the same types of transitions. However, the highest
energy bands for bzq complexes 1b and 2b are intensified in
comparison to their bands in solid state at 77 K, whereas those
of ppy complexes remain almost unchanged.
DFT Calculations. The structure of 2b was typically
optimized in CH2Cl2 solution and solid state, including singlet
(S0) and triplet (T1) states, by DFT calculations (see Figure 5
for the optimized structure of 2b in CH2Cl2 solution and Table
S1 for the geometrical parameters for all states). The crystal
structure of this complex was used as the input file for the
software. Besides, for 2b, the energy levels of the important
frontier molecular orbitals with their compositions were
obtained for singlet and triplet states. Figure 6 represents the
important MO plots of 2b while the corresponding
compositions are listed in Table 3.
For 2b the HOMO−LUMO energy gap is found to be 3.766
eV. In HOMO, the maximum contribution coefficient belongs
to dyz and dxy atomic orbitals of Pt1 center, while the py atomic
orbitals of S1 and carbons and nitrogen of bzq ligand occupy
the lower ranks. HOMO−1 almost resembles HOMO with the
effective contribution of py of S2 atom whereas the HOMO−2
energy level is almost completely located on Pt1 atom. LUMO
and LUMO+1 are predominantly localized on the py atomic
orbitals of carbons and nitrogen of aromatic rings in bzq ligand;
however, the major contribution of dxy of Pt1 in LUMO+2 is
followed by the considerable presence of s, px, and pz atomic
orbitals of the S1 and S2 atoms of btp ligand.
Table 2. Numerical Data for the Emission Wavelengths of 1
and 2
b
b
complex
λem (nm)/λex (nm)
τ (μs)
Φ
490, 520max, 555sh (340−500), solid (298 K)
8.2
0.721
0.837
488, 520max, 556sh (340−500), solid (77 K)
31.1
1a
488max, 517, 555sh (340−500),
a
5 × 10−5 M (77 K)
510, 530max, 581sh (340−500), solid (298 K)
503, 530max, 570sh (340−500), solid (77 K)
6.3
0.677
0.809
27.7
1b
2a
2b
496max, 533, 577sh (340−500),
a
5 × 10−5 M (77 K)
490, 520max, 555sh (340−500), solid (298 K)
488, 520max, 556sh (340−500), solid (77 K)
9.4
0.518
0.677
17.5
488max, 517, 555sh (340−500),
a
5 × 10−5 M (77 K)
504,530max, 570sh (340−500), solid (298 K)
493, 520max, 555sh (340−500), solid (77 K)
3.7
6.8
0.211
0.593
496max, 533, 577sh (340−500),
a
5 × 10−5 M (77 K)
a
Data at high concentration (10−3 M) are similar to those at low
b
concentration. Lifetime and quantum yield were measured as a neat
powder.
D
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Figure 4. Normalized emission (solid lines) and excitation spectra (dashed lines) for 1 and 2 in (a) solid state at 298 K, (b) solid state at 77 K, and
(c) CH2Cl2 glassy state.
and HOMO−1 → LUMO transitions that can be assigned as
1
1
1ILCT transitions with some mixing of MLCT and L′LCT
1
characters. At 353 nm, L′LCT transition dominates, but the
ILCT and MLCT transitions are still present. At higher
energies, the role of btp ligand becomes more important;
however, the ILCT predominates over the other transitions.
The greatest contribution for the bands around 292 nm is
related to the HOMO−4 → LUMO transition which has a
mixed 1ILCT/1MLCT/1L′LCT character. The main transitions
for 256 nm are similar to those observed for previous ones;
however, the intra btp ligand transitions are also observed at
this wavelength.
The calculated emission of 2b was also obtained by the
optimization of the geometry of the lowest-energy triplet state
T1 in solid state. The theoretical phosphorescence wavelength,
as the energy gap between the lowest optimized T1 and S0 in
solid state, was calculated and found to be 475 nm for 2b,
which is qualitatively close to that of experimental spectrum
with a relatively slight blue shift.
Biological Activity Studies. The in vitro cytotoxicity
effects of 1 and 2 were evaluated against a panel of three cancer
cell lines (lung carcinoma (A549), ovarian carcinoma
(SKOV3), and breast carcinoma (MCF-7)). The most active
complex of the series, 2a, exhibited higher antiproliferative
activity than cis-platin against SKOV3 and MCF-7 cells lines
(Figures S17−S20 and Table 5). It displayed a strong
Figure 5. View of the DFT optimized structure of 2b with the atom
numbering. Hydrogen atoms are omitted for clarity.
In order to have a better picture for the available transitions
in 2b, TD-DFT calculations were employed using the
optimized structure of this complex in CH2Cl2 solution. Figure
7 depicts the overlaid experimental absorbance spectrum and
calculated TD-DFT bars for 2b, of which an acceptable
matching is observed between the experimental spectrum and
calculated bars. Also, Table 4 summarizes the calculated
transitions with their assignments. As can be seen in Figure
7, the absorptions around 405 nm include HOMO → LUMO
E
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Figure 6. Important MO plot for 2b.
than did 1a against A549 and MCF-7 cancer cells lines. In
contrast, 1a showed a higher cytotoxic effect on SKOV3 cells
line than did 2b.
Table 3. Energies of the Selected MOs of 2b and Their
Compositions
components (%)
In general, it can be inferred that the presence of btp ligand
(in 2a and 2b) has higher cytotoxicity activity than that of ctp
ligand. Part of these data can be obtained from their interaction
with DNA as their target. For example, molecular modeling
studies revealed that 2b has the best docking binding energies
with DNA. This compound may exert its cytotoxic effect
through different mechanism from cis-platin. We currently
continue our study on these compounds to reveal its DNA
binding activity (experimentally), effect on cell cycle, and other
biological pathways.
DNA groove binding (in the major or minor groove of the
DNA) and DNA intercalation are two of the most commonly
observed modes of interaction of platinum anticancer agents
with the DNA. In groove binding mode, the ligand is typically
flexible, comprises rotatable bonds, and has the capability to
orient itself along the major or minor groove of the DNA, as a
result inhibiting regular function of DNA. However, DNA
intercalators are typically inflexible planar molecules that stack
in-between the DNA base pairs causing an intercalation gap to
appear in the DNA helical structure.47,48 As it was shown in
Figure 8, the docked model suggests that the most favorable
energetically conformation of the docked pose of 2b interacts
with the minor groove of 1BNA. The bzq group of 2b fits into
the minor groove of the DNA, and the btp group placed away
from the gap. It interacts via its sulfur groups with C11, A5, and
G4 base pairs and via the butyl moiety with C3 and G10 base
pairs in the minor groove of DNA.
MO
energy (eV)
bzq
Pt
btp
LUMO+5
LUMO+4
LUMO+3
LUMO+2
LUMO+1
LUMO
+0.386
−0.229
−0.335
−0.910
−1.316
−1.931
−5.697
−6.037
−6.286
−6.639
−6.726
−7.080
23
2
28
3
49
95
2
93
25
95
95
48
17
7
5
38
4
37
1
4
1
HOMO
40
46
89
11
29
10
12
37
4
HOMO−1
HOMO−2
HOMO−3
HOMO−4
HOMO−5
78
34
38
12
37
52
Fluorescence Microscopy Cellular Localization. Fluo-
rescence emission properties of 1a and 2a were assessed using
fluorescent microscopy imaging. For this purpose, the MCF-7
cells were incubated with two concentrations of these
compounds: 40 μM for 30 min and IC50 concentration (75
and 10 μM for 1a and 2a, respectively), alone (as control) and
in combination with propidium iodide (PI) as a DNA binding
agent. Live and fixed cells were examined with a fluorescence
microscope with different emission filters. According to our
observation, both compounds show green light emission. As
shown in Figure 9, both 1a and 2a penetrated into the cells and
dispersed in the cytoplasm of the MCF-7 cells; however, we
could not find any evidence of their presence in the nucleus
(Figure 9, unfixed cells). We repeated the experiment again to
Figure 7. Overlaid experimental absorbance spectrum and calculated
TD-DFT bars for 2b.
antitumor activities with IC50’s of 8.49 and 8.38 μM, compared
with that measured for cis-platin which were 13.94 and 13.17
μM against SKOV3 and MCF-7 cell lines, respectively. It had
also a moderate antitumor effect against A549 cell line activity
with an IC50 of 12.35 μM. Among the three investigated
complexes, 1b revealed weak cytotoxicity against the studied
cancer cells lines. 2b presented higher antiproliferative activity
F
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a
Table 4. Wavelengths and Corresponding Nature of Transitions for 2b
calculated λ (nm) (f)
transitions (contribution)
assignment
HOMO → LUMO (0.68)
ILCT/MLCT/L′LCT
L′LCT/ILCT/MLCT
L′LCT/ILCT/MLCT
ILCT/MLCT/L′LCT
L′LCT/ILCT/MLCT
ILCT/L′LCT
ILCT/MLCT/L′LCT
L′LCT/MLCT/ILCT
ILCT/L′LCT
405 (0.026)
HOMO−1 → LUMO (0.14)
HOMO−1 → LUMO (0.59)
HOMO → LUMO+1 (0.21)
HOMO−1 → LUMO (0.25)
HOMO−3 → LUMO (0.17)
HOMO−4 → LUMO (0.48)
HOMO−1 → LUMO+1 (0.32)
HOMO−3 → LUMO (0.30)
HOMO−4 → LUMO+1 (0.65)
HOMO → LUMO+4 (0.12)
HOMO−5 → LUMO+2 (0.11)
353 (0.090)
292 (0.175)
ILCT/MLCT/L′LCT
ILCT/MLCT/L′LCT
IL′CT/L′MCT/MLCT
256 (0.053)
a
Where M = Pt center, L = bzq, and L′ = btp ligands.
unfixed cells, Figure 9) 2a preferably localizes in the cytoplasm
in the perinuclear area. Perinuclear cytoplasm as well as nuclear
localization of some platinum(II) complexes was also observed
by Berenguer et al.49 They show that these complexes, similar
to our compounds, could be seen in the cytoplasm, especially in
perinuclear region and/or penetrate into the nucleus.
Table 5. In Vitro Cytotoxicity against Cancer Cell Lines
IC50 (μM SEM)
complex
A549
SKOV3
MCF-7
1a
69.58 2.47
>100
46.38 2.69
>100
74.67 1.74
>100
1b
2a
12.35 1.26
45.48 2.48
1.63 0.49
8.49 1.37
48.29 2.17
13.94 1.61
8.38 1.83
62.27 3.38
13.17 2.06
2b
CONCLUSION
■
cis-platin
Herein, a series of closely related heteroleptic cycloplatinated-
(II) complexes have been prepared featuring O,O′-di(alkyl)-
dithiophosphate as a bidentate anionic ancillary ligand (S∧S).
The new complexes exhibit strong green emissions at room
temperature because of high intrinsic rigidity imposed by C∧N
and S∧S chelates. Also, both bite angles of the chelates are
considerably smaller than 90°, indicating the chelates are under
strain and the molecule cannot undergo the molecular motions.
For these ancillary ligands, it was found that the nature of R
groups does not have any influence on the absorbance or
emission of the molecules. Conversely, the C∧N cyclomtalated
ligand has a determining role in the emission properties of the
provide enough time for our compounds to diffuse through the
cells, 48 h. As evident in Figure 9, the same pattern of cell
staining could be also observed after a long incubation time,
though both complexes show brighter cell staining than at 30
min staining time which could be due to increasing in their
differential fluorescence emission as result of their interactions
with a particular molecular microenvironment in the cell. In
addition, our results indicated that contrary to 1a which more
homogeneously stains cytoplasm (in fixed cells) or localizes in
some special intracellular compartments (white arrows in
Figure 8. Molecular docking simulation studies of the interaction between 2b and DNA (PDB ID: 1BNA).
G
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Figure 9. Intracellular tracking of compounds 1a and 2a in MCF-7 cells. MCF-7 cells were treated with 1a and 2a at 2 concentrations and 2 time
points (labeled appropriately) and investigated immediately by a fluorescent microscope with or without fixation in the presence of propidium iodide
(PI) as a DNA staining agent. 1a (top) stains the cells’ cytoplasm more homogeneously in the fixed cells (green color) or localized in special
compartment in the cytoplasm (shiny spots, white arrows in unfixed cells), while 2a (bottom) preferably localizes in perinuclear areas (white
arrows).
mass spectrum (ESI-MS) was recorded by a HP-5989B spectrometer
using methanol−water as the mobile phase. Fourier transform infrared
spectroscopy on KBr pellets was performed on a FT IR Bruker Vector
22 instrument. Multinuclear (1H,13C and 31P) NMR spectra were
recorded on a Bruker Avance DPX 400 MHz spectrometer at 298 K.
All chemical shifts are reported in ppm (part per million) relative to
molecules. As expected, the complexes possessing bzq ligand
(1b and 2b) have a redshift with respect to their ppy analogous
(1a and 2a) in both absorbance and emission spectra which is
due to extending the π-conjugation system in bzq in
comparison to ppy.44
The emission band shape and wavelength do not depend on
the excitation wavelength over the wide range of 340−500 nm
for excitation. The appearance of structured emission bands is
1
their corresponding external standards (SiMe4 for H,13C and 85%
H3PO4 for 31P{H}), and all the coupling constants (J values) are given
in Hz. UV−vis spectra were recorded using a PerkinElmer Lambda 25
spectrophotometer. Photoluminescence spectra were recorded on a
PerkinElmer LS45 fluorescence spectrometer at room and low
temperatures, and the lifetimes were measured in phosphorimeter
mode. The quantum yields of the complexes were measured using an
integrating sphere. Also, the quantum yields at 77 K were obtained by
indirect method based on the intensity change versus temperature by
calculation concerning relative peak area changes in comparison with
corresponding peak at ambient temperature. Complexes [Pt(C∧N)
(Cl) (dmso)], C∧N = ppy34 and bzq,35 were prepared as reported in
literature. The NMR labeling for the ligands are shown in Scheme 4
for clarifying the chemical shift assignments.
3
indicative of the presence of a large amount of LC (ligand
centered) with a lower contribution of 3MLCT transition in the
emissive states. This is confirmed by the TD-DFT calculations
which demonstrate that the transitions in the cyclometalated
moieties are the predominant electronic transitions in the
region between 295 and 500 nm; this region was employed for
excitation wavelength to yield emission bands. Furthermore, at
low temperatures (77 K), these bands become more intense
and more structured without any considerable change in the
wavelength. There is no any aggregation or excimeric
interactions in the emission bands of complexes.
Potassium O,O′-di(cyclohexyl)dithiophosphate (Kctp) and potas-
sium O,O′-di(butyl)dithiophosphate (Kbtp) were prepared in
quantitative yield by published method with slight modification.50−54
The cytotoxic activities of 1 and 2 were evaluated against
different cancerous cell lines. The results illustrated that 2a has
satisfactory cytotoxic activity and the highest potency, while
other complexes exhibited less cytotoxic activity. 2a displayed
significantly higher in vitro cytotoxicity than that of cis-platin
against SKOV3 and MCF-7 cells lines. Fluorescence micros-
copy presented effective localization of 1a and 2a on MCF-7
human cells.
Scheme 4. Representative Ligands with Position Labeling
EXPERIMENTAL SECTION
■
General Procedures and Materials. All the reactions were
carried out in common solvents, and all solvents were purified and
dried according to standard procedures. The microanalyses were
performed using a vario EL CHNS elemental analyzer and also all the
melting point values were measured by a Buchi 510. Electrospray ion
H
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3
Potassium carbonate (10 mmol, 1.38 g) was added to a mixture of
phosphorus pentasulfide (2.5 mmol, 1.11 g) in desired alcohol (5 mL,
excess) at 60 °C. The reaction mixture was stirred for 2 h at 80 °C.
The reaction mixture was filtered while hot to remove unreacted
potassium carbonate. The filtrate was allowed to cool, and pure
potassium O,O′-di(alkyl)dithiophosphate was crystallized in quantita-
tive yield as a white solid that could be recrystallized in ethanol.
Potassium O,O′-Di(butyl)dithiophosphate (Kbtp). White solid;
mp: 147−149 °C. NMR data in D2O: δ(1H) 0.81 (6H, t, J = 7.2 Hz),
1.28 (4H, sxt, J = 8.0 Hz), 1.53 (4H, qui, J = 6.8 Hz), 3.80−3.90 (4H,
m); δ(13C) 13.0, 18.4, 31.5 (d, JCP = 9 Hz), 66.6 (d, JCP = 8 Hz);
δ(31P) 111.2.
Potassium O,O′-Di(cyclohexyl)dithiophosphate (Kctp). White
solid; mp: 262−264 °C. NMR data in D2O: δ(1H) 1.09−1.28 (6H,
m), 1.32−1.45 (6H, m), 1.61−1.65 (4H, m), 1.88−1.92 (4H, m),
4.26−4.37 (2H, m); δ(13C) 23.7, 24.8, 33.3 (d, JCP = 4 Hz), 77.4 (d,
JCP = 9 Hz); δ(31P) 107.5.
(d, JHH = 8.8 Hz, 1H, H6), 7.59−7.76 (m, 2H, H9 and H7), 7.79 (d,
3JHH = 8.7 Hz, 1H, H5), 8.36 (dd, JHH = 8.1 Hz, JHH = 0.9 Hz, 1H,
H4), 9.02 (dd, 3JHH = 5.4 Hz, 4JHH = 0.9 Hz, 3JPtH = 44.2 Hz, 1H, H2);
3 4
δ(31P) 102.1 (s, JPH = 341.9 Hz, 1P of btp).
2
Computational Details. The geometries of complexes were fully
optimized by employing the density functional theory without
imposing any symmetry constraints. Density functional calculations
were performed with the program suite Gaussian0355 using the B3LYP
level of theory.56−58 The effective core potential of Hay and Wadt
basis set (LANL2DZ) basis set was chosen to describe Pt and I
atoms.59,60 The 6-31G(d) basis set was used for the other atoms.
X-ray Structure Determinations. The X-ray diffraction measure-
ments were carried out on STOE IPDS-2/2T diffractometer with
graphite-monochromated Mo Kα radiation. All single crystals were
mounted on a glass fiber and used for data collection. Cell constants
and an orientation matrix for data collection were obtained by least-
squares refinement of the diffraction data. Diffraction data were
collected in a series of ω scans in 1° oscillations and integrated using
the Stoe X-AREA61 software package. A numerical absorption
correction was applied using X-RED62 and X-SHAAPE63 software.
The data were corrected for Lorentz and polarizing effects. The
structures were solved by direct methods64 and subsequent difference
Fourier maps and then refined on F2 by a full-matrix least-squares
procedure using anisotropic displacement parameters.65 Atomic factors
are from International Tables for X-ray Crystallography.66 All non-
hydrogen atoms were refined with anisotropic displacement
parameters. Hydrogen atoms were placed in ideal positions and
refined as riding atoms with relative isotropic displacement parameters.
All refinements were performed using the X-STEP32 crystallographic
software package.67 Crystallographic and structure refinement data are
collected in Table S2.
Biological Assay. Cell Lines and Cell Culture. Human cancer cell
lines, A549 (nonsmall cell lung cancer), SKOV3 (ovarian cancer), and
MCF-7 (breast cancer), were obtained from National Cell Bank of
Iran (NCBI, Pasteur Institute, Tehran, Iran). All cells were cultured in
DMEM medium (Biosera, UK), except MCF-7 cells which were
cultured in RPMI 1640, supplemented with 10% fetal bovine serum
(FBS; Gibco, USA) and pencilin−streptomycin and were incubated at
37 °C in humidified CO2 incubator.
Cytotoxic activities of 1 and 2 were assessed by using a standard 3-
(4,5-dimethylthiazol-yl)-2,5-diphenyl-tetrazolium bromide (MTT)
assay. Briefly, the assay was performed according to a known
protocol.47,48,68 The cells were harvested and plated in 96-well
microplates at a density of 1 × 104 cells per well in 180 μL of complete
culture media. After 24 h of incubation, each cell was treated with five
different concentrations of the compounds ranging from 1 × 10−4 to 1
× 10−7 M. Each compound was dissolved in DMSO, and the final
concentration of DMSO was maintained at about 0.1% to avoid its
bystander cytotoxic effect. After 48 h of incubation at 37 °C in
humidified CO2 incubator, media were completely removed and
replaced with 150 μL of media containing 0.5 mg/mL MTT solution
and the plate were incubated for 3 h at room temperature. The media
containing MTT was then discarded, and 150 μL of DMSO was added
to each well to dissolve the formazan crystals. The solutions were
incubated overnight. The absorbance in individual wells was obtained
at 570 nm using Bio-Rad microplate reader (Model 680). Data was
analyzed and expressed as the 50% inhibitory concentrations (IC50),
which were tested four times for each complex in triplicate manner.
Data are presented as mean SEM.
[Pt(ppy)(ctp)], 1a. A solution of Kctp (36 mg, 0.11 mmol) in
ethanol (15 mL) was added to a solution of [Pt(ppy) (Cl) (dmso)]
(50 mg, 0.11 mmol) in acetone (5 mL) under an Ar atmosphere. After
stirring for 3 h at room temperature, a yellow solution was formed.
Then, the solvent was evaporated, and the residue was treated with
CH2Cl2. The obtained solution was filtered through Celite to remove
KCl. After evaporation of the solvent under reduced pressure, the
residue was washed with n-hexane (2 × 3 mL). The precipitate as a
yellow solid was dried under vacuum. Yield: 61 mg, 86%; mp = 220
°C. MS ESI(+): m/z 643.11 [M]+. Elem. Anal. Calcd for
C23H30NO2PPtS2 (642.7): C, 42.98; H, 4.71; N, 2.18. Found: C,
43.13; H, 4.65; N, 2.21. IR: 683 cm−1 (PS), 540 cm−1 (P−S). NMR
data in CDCl3: δ(1H) 1.26−1.74 (m, 16H, overlapping multiplets of
cyclohexyl groups), 2.03−2.06 (m, 4H, overlapping multiplets of
cyclohexyl groups), 4.61−4.68 (m, 2H, CH of cyclohexyl groups
3
adjacent to O atom), 7.07 (t, JHH = 6.1 Hz, 1H, H8), 7.11−7.19 (m,
2H, H7 and H3), 7.44 (d, 3JHH = 5.7 Hz, 3JPtH = 56.4 Hz, 1H, H9), 7.53
3
3
(m, 1H, H6), 7.74 (d, JHH = 7.8 Hz, 1H, H5) 7.86 (t, JHH= 7.7 Hz,
1H, H4), 8.78 (d, 3JHH = 5.5 Hz, 3JPtH = 43.1 Hz, 1H, H2); δ(31P) 96.8
(s, JPH = 323 Hz, 1P of ctp). The other complexes were made
2
similarly using the appropriate precursor complexes and ligands.
[Pt(bzq)(ctp)], 1b. Yield: 57 mg, 73%; mp = 246 °C. MS ESI(+):
m/z 667.11 [M]+. Elem. Anal. Calcd for C25H30NO2PPtS2 (666.7): C,
45.04; H, 4.54; N, 2.10. Found: C, 45.11; H, 4.48; N, 2.14. IR: 707
cm−1 (PS), 506 cm−1 (P−S). NMR data in CDCl3: δ(1H) 1.21−
1.77 (m, 16H, overlapping multiplets of cyclohexyl groups), 2.05−2.09
(m, 4H, overlapping multiplets of cyclohexyl groups), 4.65−4.74 (m,
3
2H, CH of cyclohexyl groups adjacent to O atom), 7.44 (dd, JHH
=
7.9 Hz, JPH = 5.4 Hz, 1H, H8), 7.53 (t, JHH = 7.5 Hz, 1H, H3), 7.57
(d, 3JHH = 8.7 Hz, 1H, H6), 7.66 (d, 3JHH = 8.1 Hz, 3JPtH = not resolved
Hz, 1H, H9), 7.69 (m, 1H, H7), 7.79 (d, 3JHH = 8.7 Hz, 1H, H5), 8.36
4
3
(dd, JHH = 8.1 Hz, JHH = 1.2 Hz, 1H, H4), 9.02 (dd, JHH = 5.4 Hz,
4JHH = 1.2 Hz, 3JPtH = 43.8 Hz, 1H, H2); δ(31P) 98.2 (s, 2JPH = 343 Hz,
1P of ctp).
3
4
3
[Pt(ppy)(btp)], 2a. Yield: 53 mg, 82%; mp = 226 °C. MS ESI(+):
m/z 591.08 [M]+. Elem. Anal. Calcd for C19H26NO2PPtS2 (590.6): C,
38.64; H, 4.44; N, 2.37. Found: C, 38.77; H, 4.51; N, 2.28. IR: 737
cm−1 (PS), 516 cm−1 (P−S). NMR data in CDCl3: δ(1H) 0.94 (t,
3JHH = 7.4 Hz, 6H, Hd), 1.38−1.49 (m, 4H, Hc), 1.71−1.78 (m, 4H,
Hb), 4.21 and 4.23 (t, 3JHH = 6.6 and 6.6 Hz, 4H, Ha), 7.09 (td, 3JHH
=
6.5 Hz,4JHH = 1.2 Hz, 1H, H8), 7.12−7.17 (m, 2H, H7 and H3), 7.44
3
4
(m, JPtH = not resolved, 1H, H9), 7.53 (dd,3JHH = 5.8 Hz, JHH = 3.4
Molecular Docking. The docking simulations were carried out by
means of AutoDock 4.2.69 The three-dimensional crystal structures of
DNA (Protein Databank ID: 1BNA) were retrieved from Protein
Databank (www.rcsb.org/pdb). All water molecules were removed,
missing hydrogens were added, and the Kollman united atom charges
were determined. Subsequently, the PDB were converted to PDBQT
using MGLTOOLS 1.5.6. In all experiments, Lamarchian genetic
algoritm search method was used to find the best pose of each ligand
in the active site of the DNA. The grid center on the DNA structures
was maintained by centering the grid box on the minor groove, major
groove, and the intercalation site to cover the full of DNA structure.
Hz, 1H, H6), 7.74 (d, 3JHH = 7.8 Hz, 1H, H5), 7.87 (td, 3JHH = 7.7 Hz,
4JHH = 1.5 Hz, 1H, H4), 8.79 (d, JHH = 5.7 Hz, JPtH = 43.4 Hz, 1H,
3
3
2
H2); δ(31P) 100.8 (s, JPH = 320 Hz, 1P of btp).
[Pt(bzq)(btp)], 2b. Yield: 59 mg, 87%; mp = 238 °C. MS ESI(+):
m/z 615.08 [M]+. Elem. Anal. Calcd for C21H26NO2PPtS2 (614.6): C,
41.04; H, 4.26; N, 2.28. Found: C, 41.13; H, 4.21; N, 2.35. IR: 711
cm−1 (PS), 459 cm−1 (P−S). NMR data in CDCl3: δ(1H) 0.95 (t,
3JHH = 7.4 Hz, 6H, Hd), 1.41−150 (m, 4H, Hc), 1.73−1.80 (m, 4H,
Hb), 4.25 and 4.27 (t, 3JHH = 6.6 and 6.6 Hz, 4H, Ha), 7.44 (dd, 3JHH
=
8.1 Hz, 4JPH = 5.34 Hz, 1H, H8), 7.53 (t, 3JHH = 7.7 Hz, 1H, H3), 7.57
I
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The grid maps had a spacing of 0.375 Å. All the other parameters were
kept at their default values. Parameters for docking with metal ions
such as platinum, used in the docking calculation, were added to gpf
and dpf files.
of Pharmacy, Ahvaz Jundishapur University of Medical
Sciences, in providing the required facilities for this work is
greatly acknowledged. The technical support of the Chemistry
Computational Center at Shahid Beheshti University is
gratefully acknowledged. This paper is extracted from Ms.
Tabassom Mirzaee’s thesis (B-94/061). Thanks are also due to
Mr. A. Biglari, the operator of Bruker NMR instrument at
IASBS, for recording the NMR spectra and Prof. M. T.
Moreno, Universidad de La Rioja, for ESI-MS measurements.
This paper is dedicated to the memory of Professor Mehdi
Rashidi who recently passed away. He was the founder of
organometallic field in Iran.
The structure of 2b was created by HyperChem Professional
(Version 8, Hypercube Inc., Gainesville, FL). 2b was optimized by
molecular mechanic methods (MM+) using HyperChem 8, followed
by energy minimization calculations at Hartree−Fock (HF) level using
Gaussian 09. The output structure was thereafter converted to
PDBQT using MGLtools 1.5.6. All calculations were run on a core i7
personal computer (CPU at 8 MB) with Windows 7 operating system.
With respect to the AutoDock scoring function, the lowest docking
binding energy conformation was chosen as the best binding mode.
Visualization of the docked pose has been performed by means of
AutoDock Tools 1.5.6 and PyMOL molecular graphics program.70
Crystallographic data (excluding structure factors) for the structural
analysis has been deposited with the Cambridge Crystallographic Data
Centre under Accession No. 1527164.
Localization in Cells. As mentioned, our compounds showed
fluorescence emission properties, and we used this to track two of our
effective compounds (1a and 2a) in the host cells. To do this, MCF7
cells were cultured over coverslips into a 6-well plate with 2 mL of
complete culture media per well for 24 h. The cells were then
separated into two groups: The first was incubated with 2 mL of new
medium containing 40 μM each compound (1a and 2a) at 37 °C for
30 min. The cells in second group, based on their IC50, were incubated
with 75 and 10 μM 1a and 2a, respectively, for 48 h at 37 °C. After
incubation, the cells were washed twice in 1× phosphate-buffered
saline (PBS, pH 7.2) and fixed with cold absolute methanol for 10 min
(Merck, Germany). The cells were then washed with PBS, dried at
room temperature, and stained with 0.25 μg/mL PI (BD Biosciences,
USA) prepared in glycerol. PI is a fluorescent molecule that
intercalates with DNA and can be used to stain cell nuclei. To
control the light emission interference between channels and to check
the presence of drugs in the nucleus, the cells were also incubated
separately with each compound and were visualized without fixation
and PI staining. The cells were finally washed twice with 1× PBS (pH
7.2). Coverslips were then removed, mounted on glass slides with
glycerol, and immediately examined under a fluorescence microscope
(BX61, Olympus, Japan). The images were taken at 100×
magnification and analyzed by the Olympus micro imaging software
cellSens (Olympus, Japan).
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ORCID
Hamid R. Shahsavari: 0000-0002-2579-2185
Notes
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ACKNOWLEDGMENTS
■
This work was supported by the Institute for Advanced Studies
in Basic Sciences (IASBS) Research Council and the Iran
National Science Foundation (grant no. 95822524 and
95834232). The collaboration of Medicinal Chemistry, Faculty
J
DOI: 10.1021/acs.organomet.7b00054
Organometallics XXXX, XXX, XXX−XXX

Organometallics
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DOI: 10.1021/acs.organomet.7b00054
Organometallics XXXX, XXX, XXX−XXX