Self-Assembled BODIPY-Based Iridium Metallarectangles: Cytotoxicity and Propensity to Bind Biomolecules

Article abstract of DOI:10.1002/cplu.201800035

A new 4-ethynylpyridine 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based ligand L, which was synthesized by means of the Sonogashira coupling method, was used to obtain two new [2+2] iridium-based metallarectangles, 3 and 4. Ligand L and metallar

Full text of DOI:10.1002/cplu.201800035

Accepted Article
Title: Self-Assembled BODIPY-based Iridium Metalla-rectangles:
Cytotoxicity and Propensity to Bind Biomolecules
Authors: Gajendra Gupta, Abhishek Das, Junseong Lee,
Nripendranath Mandal, and Chang Yeon Lee
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Self-Assembled BODIPY-based Iridium Metalla-rectangles:
Cytotoxicity and Propensity to Bind Biomolecules
Gajendra Gupta†,*[a] Abhishek Das†,[b] Junseong Lee,[c] Nripendranath Mandal,[b] and Chang Yeon
Lee*[a]
Dedication ((optional))
Abstract: A new 4-ethynylpyridine bodipy-based ligand L, was
synthesized using the Sonogashira coupling method, was used to
obtain two new (2+2) Ir-based metalla-rectangles 3 and 4. Ligand L
and metalla-rectangles 3 and 4 were fully characterized using different
analytical techniques. The structure of rectangle 4 was further
confirmed by single crystal X-ray diffractometry, which showed the
formation of an expected (2+2) supramolecule, where the Ir metal
centers were bridged with the bodipy ligand L to form the desired
metalla-rectangle 4. As part of growing biological interest of metalla-
rectangles, rectangle 4 was found to be highly active against two
types of cancer cells with IC50 values almost three-fold superior than
cisplatin. Both 3 and 4 showed dose-dependent abilities to bind BSA
and Salmon sperm DNA, indicating their tendency to interact with
such biomolecules as a potential mode of action.
In the last few years, synthesis and biological applications of
metalla-assemblies containing arene ruthenium units has gained
popularity.4-21 Several groups have utilized arene ruthenium
starting materials to develop new multi-cationic metalla-
assemblies with important functionalities.22-28 These type of
multinuclear cationic supramolecules are known to have better
solubility and precisely target tumor cells by exploiting the
enhanced permeability and retention (EPR) effect.29 Similarly,
gold complexes have also received considerable attention for
their favorable anticancer activities. In the last few years, several
gold complexes are reported to have good anticancer properties
against different cancer cell lines.30 An important example is
auranofin which was reported to display potent in vitro and in vivo
anticancer properties.30 Iridium-based complexes have not been
tested as potential drug candidates as extensively as their
ruthenium counterparts.31-43 Ir(III) is one of the most inert low-spin
d6 metal ions but its inertness also depends on the other ligands
used in complexation. The inertness and stability of the organo-
Ir(III) complexes further favor their application in drug delivery, as
they can reach the target without altering other biological
pathways.37 Similarly, the extended aromatic surfaces and low
cationic charges of the cyclometalated Ir(III) complexes may act
as potential functional substitutes of tryptophan residues in
anticancer peptides.44, 45
On the other hand, boron dipyrromethene (bodipy) is an
excellent fluorescent dye with various important applications. In
the recent years, several metal based bodipy complexes were
designed and used for many applications such as, host-guest
chemistry, photodynamic therapy, anticancer, light harvesting and
imaging among others.46 Based on the recent developments in
our ongoing project on Ir-based supramolecules as anticancer
agents, here we present two new iridium metal-based (2+2)
metalla-rectangles 3 and 4, synthesized from a new bidentate
pyridyl-bodipy ligand L. Cytotoxicity studies showed that complex
4 reasoned high mortality in cervical and brain cancer cells.
Presence of the highly fluorescent bodipy ligand in these
supramolecules permitted their intracellular localization observed
from confocal microscopy studies. In addition, the complexes
interacted strongly with biomolecules such as DNA and protein.
Introduction
Metal-based compounds offer a plethora of possibilities to
develop therapeutic strategies, which are usually difficult to
achieve using organic compounds. The versatile
physicochemical properties of metal-based compounds,
including their ability to manipulate redox states in biological
systems unlocks promising opportunities to combat various
new world ailments.1 Transition metal complexes offer
certain crucial advantages as DNA-binding agents over
natural compounds for biomolecular recognition.2 The metal
center efficiently holds the complicated three-dimensional
scaffold and links the recognition elements.2 Moreover, their
excellent photophysical and electrochemical properties
extend their application to a wide range of possibilities such
as constructing fluorescent markers and electrochemical
probes for biological studies or using them as potential
agents against non-communicable diseases.2, 3
[a]
Dr. G. Gupta, J. S. Oh, Prof. Dr. C. Y. Lee
Department of Energy and Chemical Engineering, Incheon National
University, Incheon-22012, Republic of Korea.
E-mail: gjngupt@gmail.com; cylee@inu.ac.kr
Dr. A. Das, Prof. Dr. N. Mandal
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme
VIIM, Kolkata-700054, West Bengal, India.
J. Y. Ryu, Prof. Dr. J. Lee
[b]
[c]
[†]
Department of Chemistry, Chonnan National University, Gwangju
61186, Republic of Korea
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Figure 1. Schematic representation of the formation of metalla-rectangles 3 and 4
Results and Discussion
Dinuclear cyclopentadienyl Ir(III) clip (Cp*Ir)2dbqCl2, 1
(dbq = 2,5-dihydroxy-1,4-benzoquinone), was reacted with
AgCF3SO3 for 3 h. Next, the solution was filtered to remove
Synthesis and characterization
The new 4-ethynylpyridine bodipy-based ligand
the AgCl salt formed, followed by the addition of ligand
room temperature, resulting in the formation of the desired
rectangle Similarly, reaction between dinuclear
L at
L
was
synthesized in three-steps using the Sonogashira coupling
method, as shown in Scheme 1. The diiodo bodipy was
obtained by reacting the bodipy core with excess N-
Iodosuccinimide (NIS) in anhydrous dichloromethane by
stirring at room temperature to yield a dark red product with
an excellent yield.47 A subsequent Sonogashira reaction of
the diiodo bodipy with 4-ethnylpyridine hydrochloride formed
3
.
a
cyclopentadienyl Ir(III) clip (Cp*Ir)2dhnqCl2,
dihydroxy-1,4-naphthoquinone), with ligand
2
(dhnq = 5,8-
L
resulted in the
formation of rectangle
were obtained in high yield. Rectangle
dark brown solid while was obtained as a dark pink solid,
4
.
(Figure 1). Both the rectangles
3
was obtained as a
4
and were fully characterized using different analytical
techniques. They were highly soluble in common organic
solvents, such as dichloromethane, chloroform, acetone,
methanol, acetonitrile and dimethylsulfoxide, but insoluble in
the target ligand
L
as a dark red solid with a good yield.
was confirmed using 1H NMR, 13C
Formation of ligand
L
NMR, and Electron-spray ionization mass spectrometry
1
(ESI-MS) spectroscopy. The H NMR spectra of
L
in CDCl3
ether and hexane. The 1H NMR spectra of
3 was recorded in
showed one doublet and two multiplets in the aromatic region
between 8.56 and 7.29 ppm, corresponding to pyridine and
phenyl groups of the ligand. Two singlets at 2.72 ppm and
acetone-d6, and the spectroscopic data are summarized in
the experimental section. The spectra showed two doublets
at 8.42 ppm and 7.65 ppm, corresponding to the α-protons
1.53 ppm correspond to the methyl groups of ligand
L
. The
which
and β-protons of the pyridyl group of bodipy ligand L,
ESI-MS also confirmed the formation of ligand
showed a peak at m/z 527.20.
L
respectively. These α-protons were slightly shifted upfield,
whereas the β-protons shifted downfield, as compared to the
protons of free ligand
the phenyl group also shifted downfield after the formation of
rectangle . These shifts in the positions of the signals might
L (Figure 2). The protons belonging to
3
result from changes in the electron density around the metal
atom due to chelation of the bodipy ligand through its
nitrogen atoms after the formation of the target rectangle. A
singlet at 5.88 ppm corresponding to protons of the dbq
ligand, was also observed. In addition to these aromatic
peaks, three singlets at 2.59 and 1.53 ppm and 1.67 ppm
were observed, corresponding to two methyl groups of ligand
L
and the pentamethylcyclopentadienyl groups respectively.
The overall spectra of the proton peaks confirmed the
Scheme 1.
1
formation of rectangle
complex displayed
corresponding to the pyridyl protons, showing significant
3
.
Similarly, the H NMR spectra of
4
characteristic
resonances
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Figure 2.
shifts as compared to free ligand
L (Figure 2). The doublets
at 8.52 ppm and 7.50 ppm can be assigned to the pyridyl
protons of the bodipy ligand. The α-protons shifted slightly
upfield whereas, the β-protons showed
a significant
downfield shift. Peaks at 2.59 ppm and 1.50 ppm belonged
to methyl protons of the bodipy ligand, which showed an
upfield shift as compared to free ligand
L. The singlet
resonance at 7.41 ppm can be attributed to protons of the
dhnq bridges. The overall display of the characteristic
resonances confirmed the formation of pure rectangle 4.
The ESI-MS experiment was also performed to further confirm
the formation of rectangles 3 and 4. ESI-MS spectra measured in
acetonitrile showed di- and tetracationic peaks corresponding to
the loss of two and four triflate ions centered at m/z 1469.35 and
659.35 for complex 3 and at m/z 1518.70 and 684.79 for complex
4 respectively. These peaks were consistent with their theoretical
isotopic distribution. The peaks for [M-2CF3SO3]2+ together with
its theoretical isotopic distribution are shown in Figure 3.
for rectangle 3 by vapor deposition of diethyl ether into a
nitromethane solution of complex 3. As shown in Figure 4,
complex 3 possessed a rectangular structure, which is connected
by two dbq ligands and two bodipy molecules. The dbq ligands
were coordinated to the Ir metal center through its oxygen atoms.
The two bodipy ligands served as a linker by forming a bridge with
the Ir metals to form the target rectangular structure. The average
Ir-N and Ir-O bond distances were 2.102 Å and 2.101 Å ,
respectively, similar to those of other iridium metal-bridged
48
rectangles.33,
The Ir-Ir distances were 7.942 × 24.395 Å 2,
indicating dimensions of the rectangular pocket. The phenyl
substituents of the bodipy moiety in the structure were directed
away from each other. This could be due to the steric hindrance
generated due to the bulkiness of the phenyl groups. No solvent
or counter anions were found to be encapsulated within the cavity
of the rectangle.
Figure 3. ESI-MS spectra of metalla-rectangles 3 (left) and 4
The UV-Vis absorption and emission spectroscopy
experiments of ligand L and rectangles 3 and 4 were performed
in an acetonitrile solution at ambient temperature. The free bodipy
ligand L showed a major absorption peak at around 556 nm,
which can be assigned to the electronic transition π-π* with
(right) along with their theoretical mass distribution (blue).
Although 1H NMR and ESI-MS studies indicated the formation
of the desired rectangles, the rectangular architecture was
unequivocally confirmed by single crystal XRD studies (Figure 4).
Single crystals suitable for X-ray diffraction studies were obtained
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Figure 6. Intracellular localization of bodipy ligand L and rectangle 4 in HeLa and U87 cells. Cells with nuclei stained with DAPI in the
presence or absence of 48 h compound treatments (1 μM of 4 and 5 μM of L) were observed under a confocal microscope. White
arrows indicate localization of miniature fluorescent aggregates in the cytoplasm (see BODIPY slides), showing loss of cellular integrity
and pyknosis (see DAPI slides) of the treated cells.
vibrational progression, localized on the bodipy chromophore.
This peak showed a significant red shift of around 45 nm, as
compared to the parent bodipy core.47 The visible region of
rectangles 3 and 4 was also dominated by the intense peaks due
to the π-π* transition centered at 552 nm, showing a slight blue
shift as compared to free ligand L. In addition, low intensity peaks
shouldered between 400 nm and 320 nm were also observed and
assigned to the combination of the intra/intermolecular π-π*
transitions mixed with MLCT transitions.9 The emission spectra of
bodipy ligand L and supramolecules 3 and 4 are also measured
in an acetonitrile solution. Both the rectangles were highly
fluorescent with emission peaks at approximately 577 nm,
corresponding to the bodipy chromophore L present in these
complexes. The absorption and emission spectra are presented
in figure 5. The fluorescence quantum yields (ɸ) of the bodipy
ligand L and supramolecules 3 and 4 are found to be 0.22, 0.25
and 0.26 respectively.
Complex
lines, whereas
toxicity in any of the cases (Table 1; Figure S5).
4
was found to be highly toxic against both the cell
was unable to induce an equally effective
projected
3
L
a very high IC50 value, rendering it ineffective against cancer
cell proliferation (Table 1; Figure S5). The probable reason
behind the augmented toxicity of
of aromatic groups from linker
4
may be the higher number
in its structure.9,
18
2
This
hypothesis was further consolidated from the IC50 value of
linker . Moreover, activities of both the linkers were
2
evidently enhanced when they formed the metalla-
rectangles. The overall structure of the complex resulting in
increased hydrophobicity encouraged better interaction with
biomolecules, thus manipulating the cellular mechanisms.
Additionally, complex
4 was found to be more effective in
killing cancer cells than the standard drug cisplatin (Table 1;
Figure S5). However, the complexes did not show any
selectivity on normal WI-38 cells.
Biological Activities
When a fluorescent complex induces cancer cell death,
visualizing its fate inside a cancer cell using its fluorescent
properties is essential to understand its route of action.51-56
The characteristic green fluorescence of the bodipy ligand in
Iridium complexes have recently gained popularity
because of their antiproliferative activities against cancer cell
lines of different origins.32-44,49,50 Human cervical cancer
(HeLa) and glioblastoma (U87) cells were incubated with
4
makes it extremely simple to visualize the intracellular
regions of treated cells under a confocal microscope, where
the complex could possibly localize.33, 57 HeLa and U87 cells
increasing doses (0–50 µM) of
3
and
4
. For comparison, the
were also studied.
activities of linkers and and ligand L
1
2
were thus treated with non-toxic doses of
4, which was
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chosen over
3 due to its comparatively much better
antiproliferative activity. To ensure whether the resulting
fluorescence is due to free BODIPY or not, cells were also
treated with 5 μM doses of ligand
L alone. Samples were
counterstained with DAPI to demarcate the nuclear region
from rest of the cell. Fixed slides were visualized under a
DAPI specific filter (358–461 nm) and compared with the
bodipy specific filter at a custom wavelength range of 530–
600 nm. The cells devoid of any treatment (control) displayed
negligible green fluorescence and a clearly demarcated
nuclear region due to blue fluorescence of DAPI. Upon
treating HeLa cells with 1 µM of 4, the complex was found to
predominantly localize in the cytoplasmic region (Figure 6) in
the form of brilliant green fluorescent tiny granules. Similar
results were observed in case of U87 cells, where in addition
to cytoplasmic localization, these nanoaggregates showed a
tendency to accumulate near the nuclear membrane
(indicated by white arrows). A similar activity was also
witnessed previously with a Pd-complex in U87 cells.57 The
polar functional groups residing in the fluorophores are
known to improve the overall solubility of the compound in
water. Although the intrinsic hydrophobicity of its aromatic
groups (e.g., phenyl rings) may have resulted the formation
of nanoaggregates that made them visible under
a
microscope.56 Non-toxic doses were used in both the cancer
cells; however, both cell types (Figure 6) showed certain
degrees of pyknosis and loss in the cellular integrity (shown
by white arrows in DAPI images), indicating the onset of
programmed cell death. Complex
4 is speculated to be
envisages the extent of DNA–compound interaction58
through external electrostatic binding59, and thus may also
depict partial uncoiling of the double stranded helix of B-DNA
(dsDNA), exposing more nitrogen bases for subsequent
interactions.60 To test the nature and affinity of binding of our
internalized through endocytosis. However, to investigate
these hypotheses, further in-depth studies of the molecular
mechanisms need to be performed. Both cell lines showed
negligible green fluorescence and an intact nucleus, similar
to the control cells, when treated with ligand L. This proves
metal complexes, increasing doses (5–25 µM) of
were added to 200 nM Salmon sperm DNA in KBPES buffer
at 25°C following a previously reported protocol.33
3, 4 and L
that the ligand alone could neither project any self-
fluorescence under the hypoxic condition inside a cancer cell,
nor could it cause any visible damage to the cell.
A
wavelength scan of 200–350 nm revealed a characteristic
peak of double stranded B-DNA (dsDNA) near 260 nm,
which experienced a dose-dependent hyperchromicity upon
Table 1 IC50 values of complexes 1-4, L and cisplatin
addition of
similar degrees of interaction with dsDNA, whereas addition
of showed no such interaction (Figure S6). Hyperchromic
3 and 4 (Figure S6). Both complexes showed
L
shift is a spectral feature resulting from conformational
damage to dsDNA on intercalation of a compound between
two nucleotide pairs.61 Hyperchromicity, observed in
3 and 4,
supports the aforementioned perception, which may be
ascribed to the inter-ligand π-π* transitions of the
coordinated groups. Metal-intercalators are substitutionally
inert and coordinatively saturated discouraging any direct
coordination with the DNA bases. However, their rich
photochemistry and photophysics allow understanding of the
various aspects of their interactive role in nucleic acid
chemistry.2 To understand their interaction with single
stranded DNA (ssDNA), we further denatured dsDNA by
heating the dsDNA–compound mixtures at 95°C. The
It is vital to understand the mode of interaction between
a metal complex and DNA, to comprehend the underlying
mechanism for its bioactivity. Metal complexes are found to
interact with B-DNA through groove binding, intercalation, or
insertion.2 Moreover, occurrence of a hyperchromic shift
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resultant spectra (Figure S6) showed comparatively reduced
hyperchromicities in both the complexes (indicated by short
green arrows), which is usually seen when compounds
intercalated within dsDNA are released upon denaturation to
its ssDNA form. The enhanced hydrophobicity projected by
cancer cell lines. Complex 4 did not seem to break the nuclear
membrane after 48 h of incubation, indicating a cytoplasmic route
of action for its bioactivity in both the cancer cell types.
Additionally, both the complexes showed excellent dose
dependent interaction with DNA and protein.
the structures of
3 and 4 that show similar degrees of
lipophilicity as their co-ligands facilitates the complexes to
cross the cell membrane, bind the DNA, and damage it,
thereby killing the cancer cells.
Experimental Section
Analyzing the interaction of compounds with standard
proteins is very important while studying the mechanisms of
their bioactivities. Due to its structural homology with human
serum albumin, bovine serum albumin (BSA) is widely used
as a target protein for studying drug–protein interactions.62
BSA binds diverse exogenous and endogenous ligands.
Intrinsic fluorescence of BSA results from two tryptophan
residues, Trp134 (located on the protein surface) and Trp213
(located in a hydrophobic binding pocket). Interaction with
certain compounds quenches the intrinsic fluorescence of
BSA due to the occurrence of excited-state reactions,
molecular rearrangements, energy transfer, and collisions.63
As evident from the emission spectra (Figure 7), addition of
The new dipyridine-functionalized bodipy ligand
by the procedure described in the SI. The starting materials
Cp*Ir)2(dbq)Cl2 and
(η5-Cp*Ir)2(dhnq)Cl2 were prepared according
L
was synthesized
1
(η5-
2
to reported methods.64 The di-iodo bodipy was synthesized by
following previously reported method.47 All other reagents were
commercially available and used without further purification. The 1H
and 13C{1H}-NMR spectra were recorded on an Agilent 400-MR
spectrometer using the residual protonated solvent as internal
standard. Infrared spectra were recorded on a Bruker/Hyperion 2000
FTIR spectrometer using KBr pellets. UV-visible absorption spectra
were recorded on a Thermo Scientific Genesys 10S UV-Vis
Spectrophotometer. Fluorescence spectra were recorded on a
Scinco FluoroMate FS-2 fluorescence spectrometer. HRESI-MS
were recorded on a Waters SynaptG2Si spectrometer at KBSI, South
Korea. Elemental analysis was recorded on an Elemental Analyzer
(Elementar Analysensysteme GmbH, Germany) at KBSI, Busan
increasing doses of
3 and 4 showed a concentration
dependent decline in the fluorescence intensities of BSA at
341 nm, indicating significant drug–protein interactions. This
high protein binding affinity of both the complexes may be
attributed to the hydrophobicity conferred by the aromatic
Synthetic procedures:
Synthesis of supramolecule 3: A mixture of 1
(η5-Cp*Ir)2(µ4-dbq)Cl2
rings of
3 and 4. We further studied BSA-complex
(33 mg, 0.038 mmol) and AgCF3SO3 (24 mg, 0.093 mmol) in
nitromethane:methanol mixture (10+10 mL) was stirred at room
temperature for 4 h and then filtered to remove AgCl. To the dark
interactions in the UV range, where similar dose-dependent
activities of both the compounds were observed. At the
highest dose of 25 µM, a slightly greater absorbance value
brown filtrate, bodipy ligand
L (20.2 mg, 0.038 mmol) was added and
at 280 nm was observed with complex
(1.271 a.u.), indicating its better protein–binding efficacy,
sparsely supporting the better antiproliferative activity of
4 (1.452 a.u.) than 3
the solution was stirred at room temperature for 15 h, then the solvent
was removed under vacuum. The residue was dissolved in
dichloromethane (3 mL), and hexane was slowly added to precipitate
the dark solid. The solid was removed by centrifugation, recrystalized
in chloroform/dichloromethane solution and dried under vacuum.
Yield 45 mg (72%). ESI MS (CH3CN): m/z = 659.35 [M-4CF3SO3]4+,
4
against the cancer cells. From the above results, we
interpreted that static quenching could be one of the
mechanisms of interaction for
3 and 4 because, unlike
dynamic quenching, static quenching results in a shift in the
normal protein spectrum after the protein–compound
interaction.
1469.35
[M-2CF3SO3]2+.
Calculated
(%)
for
C122H114B2F16N8O20Ir4S4·CHCl3: C, 44.04; H, 3.46, N, 3.34: Found: C,
43.96; H, 3.63; N, 3.56. IR (KBr pellets): ν = 2206 (s, C≡Cbodipy), 1603
1
(s, C–Caromatic), 1519 (s, C–Ooxalate), 1256 (s, C–F of CF3). H NMR
(400 MHz, Acetone-d6): δ = 8.4 (d, 8H, J = 8 Hz, HPy), 7.7 (t, 6H, J =
4 Hz, HPh), 7.6 (d, 8H, J = 8 Hz, HPy), 7.6-7.5 (m, 4H, HPh), 5.9 (s, 4H,
Hdbq), 2.6 (s, 12H, CH3), 1.7 (s, 60H, Cp*), 1.5 (s, 12H, CH3). 13C{1H}-
NMR (100 MHz, Acetone-d6): δ = 86.5, 160.3, 153.1, 147.8, 146.3,
136.0, 134.7, 132.7, 131.2, 130.9, 129.5, 128.9, 102.7, 94.4, 92.5,
88.6, 14.0, 13.9, 9.1. 19F NMR (376 MHz, Acetone-d6): δ = -78.76 (d,
12F, FC-F), -145.70 (m, 4F, FB-F).
Conclusions
In conclusion, we have synthesized and utilized a new dipyridyl
bodipy ligand L for the synthesis of two novel (2+2) iridium-based
metalla-rectangles 3 and 4. The new complexes were fully
characterized using different analytical techniques, including a
crystal structure for complex 3. The biological activities of these
complexes were further explored in cancer cell lines of two
different origins. Complex 4, unlike complex 3, showed high
toxicity against both the cell lines. The reason behind these
differential activities was speculated to be the different number of
aromatic rings present in their component linker molecules,
evident from the low IC50 values of linker 2. Moreover, complex 4
showed more anticancer activity than cisplatin against the tested
Synthesis of supramolecule 4: A mixture of 2
(η5-Cp*Ir)2(µ4-dhnq)Cl2
(35 mg, 0.038 mmol) and AgCF3SO3 (24 mg, 0.093 mmol) in
nitromethane:methanol mixture (10+10 mL) was stirred at room
temperature for 4 h and then filtered to remove AgCl. To the dark
brown filtrate, bodipy ligand
L (20.2 mg, 0.038 mmol) was added and
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standard drug cisplatin (Sigma Aldrich, St. Louis, USA) were prepared in
DMSO:water in such a manner that the final amount of DMSO exposed to
the cell at the highest concentration of treatment remains non-toxic for the
cells. Cell proliferation and cell viability were quantified using the WST-1
Cell Proliferation Reagent (Roche diagnostics, Mannheim, Germany),
according to the manufacturer’s instructions. Principle of this assay is
based on cleavage of the water soluble tetrazolium (WST-1) salt to a
the solution was stirred at room temperature for 15 h, then the solvent
was removed under vacuum. The residue was dissolved in
dichloromethane (3 mL), and hexane was slowly added to precipitate
the dark solid. The solid was removed by centrifugation, recrystalized
in chloroform/dichloromethane solution and dried under vacuum.
Yield 47 mg (73%). ESI MS (CH3CN): m/z = 684.79 [M-4CF3SO3]4+,
1518.70
[M-2CF3SO3]2+.
Calculated
(%)
for
C130H118B2F16N8O20Ir4S4·2CHCl3: C, 44.36; H, 3.40; 3.14: Found: C,
44.00; H, 3.69; N, 3.59. IR (KBr pellets): ν = 2206 (s, C≡Cbodipy), 1608
(s, C–Caromatic), 1525 (s, C–Ooxalate), 1262 (s, C–F of CF3). 1H NMR
(400 MHz, Acetone-d6): δ = 8.5 (d, 8H, J = 8 Hz, HPy), 7.7 (br, 6H,
HPh), 7.6 (d, 8H, J = 4 Hz, HPy), 7.5 (br, 4H, HPh), 7.4 (s, 8H, Hdhnq),
2.6 (s, 12H, CH3), 1.7 (s, 60H, Cp*), 1.4 (s, 12H, CH3). 13C{1H}-NMR
(100 MHz, Acetone-d6): δ = 168.2, 159.1, 150.3, 146.4, 138.9, 134.8,
130.0, 129.7, 128.0, 127.6, 114.2, 113.4, 93.2, 90.7, 87.1, 83.5, 12.6,
12.7, 7.4. 19F NMR (376 MHz, Acetone-d6): δ = -78.77 (s, 12F, FC-F),
-145.40 (m, 4F, FB-F).
formazan
by
cellular
enzymes,
especially
mitochondrial
dehydrogenases.67 The number of metabolically active cells correlates
directly to the amount of formazan generated. HeLa was seeded at a
density 1 x 104 cells/well and U87 cells at a density of 2.5 X 103 cells/well
in 96-well culture plates followed by a 16 h incubation facilitating the cells
to attach to the substratum. Cells were then treated with the compounds
at increasing doses (0-50 µM for 1, 2, 3 & L and 0-20 µM for 4 and
Cisplatin) for 48 h. After treatment, 10 µl of WST-1 cell proliferation reagent
was added to each well followed by 3–4 h of incubation at 37°C. Cell
proliferation and viability were quantified by measuring the absorbance of
the formazan at 460 nm using a microplate ELISA reader MULTISKAN EX
(Thermo Electron Corporation, Waltham, MA, USA).
Single-crystal X-ray structure analysis
Reflection data for 3 was collected using a Bruker APEX-II CCD-based
diffractometer with graphite-monochromated Mo Kα radiation (λ = 0.7107
Å). Hemispheres of reflection data were collected as ω scan frames with
0.5/frame and an exposure time of 5 s/frame. Cell parameters were
determined and refined using the SMART program.65 Data reduction was
performed using SAINT software. The data were corrected for Lorentz and
polarization effects. An empirical absorption correction was applied using
the SADABS program. The structures of the compounds were solved using
direct methods and refined by full-matrix least-squares methods using the
SHELXTL program package with anisotropic thermal parameters for all
non-hydrogen atoms.66 Geometrical restraints, i.e., DFIX, SADI, SIMU,
and AFIX 66, on part of the hexagonal aromatic rings were used in the
refinements. Crystallographic details for 3 are summarized in Table S1.
Figures of molecular structures were drawn with MERCURY program.
CCDC 1562827 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: (internat.) +44-1223/336-033; Email: deposit@ccdc.cam.ac.uk].
The IC50 values were calculated by the formula,
Y = 100 × A1/(X + A1)
where A1 = IC50, Y = response (Y = 100% when X = 0) and X = inhibitory
concentration. The IC50 values were compared by paired t-test. P < 0.05
was considered significant.
Intracellular localization of complexes using confocal microscopy
DAPI (4', 6-diamidino-2-phenylindole) counter staining was done using the
method described earlier with some minor modifications.33 U87 and HeLa
cells were seeded at a density of 2 × 105 cells/well in 6-well culture plates
containing 22 mm2 glass coverslips, and allowed to adhere for 16 h. Cells
were incubated with 3 μM of 3, 1 μM of 4 and 5 μM of L for 48 h. Post
treatment, samples were fixed with 4% paraformaldehyde followed by
permeabilization with 0.1% Triton X-100. Cells were stained with 10 µg/ml
DAPI for 40 min at room temperature followed by washing to remove any
unbound dye. The control and treated cells were observed and imaged
from ten fields of view at 1070X magnifications with DAPI and BODIPY
specific wavelengths under a Leica TCSSP8 laser scanning confocal
microscope (Leica Microsystems, Illinois, USA) and the data was analyzed
using Leica Application Suite X software.
Cell culture
Human cervical cancer (HeLa) and glioblastoma (U87) cell lines were
purchased from the National Centre for Cell Science (NCCS, Pune, India)
and maintained in the laboratory. Both the cell lines were grown in DMEM,
supplemented with 10 % (v/v) fetal bovine serum (FBS), 100 U/ml Penicillin
G, 50 µg/ml Gentamycin sulphate, 100 µg/ml Streptomycin and 2.5 µg/ml
Amphotericin B. The cell lines were maintained at 37°C in a humidified
atmosphere containing 5% CO2 in an incubator.
Protein binding study
Measurements of UV–vis Absorption Spectra
A method previously illustrated33 was followed. Solutions of 100 µM Bovine
serum albumin (BSA) (MP Biomedicals, Ohio, USA) and 300 µM
complexes were prepared in Tris–buffer (pH 7.2). Concentration
dependent studies were conducted by mixing increasing amounts of
complexes 3, 4 and L (5–25 µM) each with 20 µM BSA in 1:1 (v/v)
proportions. Samples were scanned at 25°C (range 200-350 nm) using 1
cm path length 1 ml quartz cuvettes in a Shimadzu UV-2401 PC UV-VIS
WST-1 cell proliferation assay
For cell culture experiments the stock solutions of the complexes and
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10.1002/cplu.201800035
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Measurements of Fluorescence Spectra
The fluorescence spectra of the compounds were measured according to
the method previously described.57 Solutions of 20 µM Bovine serum
albumin (BSA) (MP Biomedicals, Ohio, USA) and 300 µM complexes were
prepared in Tris-buffer (pH 7.2). Increasing concentrations of 3, 4 and L
(5–25 µM) each were added to 1 µM BSA in 1:1 (v/v) proportions in Tris-
buffer and successive spectrum of each sample was acquired within the
wavelength range of 310-400 nm.
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Entry for the Table of Contents (Please choose one layout)
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New BODIPY based iridium metal
(2+2) supramolecules were designed
and synthesized by self-assembly.
G. Gupta,* A. Das, J. Lee, N. Mandal, C.
Y. Lee*,
Self-Assembled BODIPY-based Novel
Iridium Metalla-rectangles:
Cytotoxicity and Propensity to Bind
Biomolecules
Upon
biological
studies,
the
supramolecules were found to be
highly cytotoxic and showed excellent
tendency to bind with proteins and
DNA.
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Title
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