Self-Assembly of Novel Thiophene-Based BODIPY RuII Rectangles: Potential Antiproliferative Agents Selective Against Cancer Cells

Article abstract of DOI:10.1002/chem.201704368

Novel Ru (2+2) rectangles were designed and synthesized by self-assembly of a new thiophene-functionalized dipyridyl BODIPY ligand, BDPS, and ruthenium(II) precursors. The complexes exhibited dose-dependent antiproliferative activities against cancer cells, in which some compounds selectively kill cancer cells. The net fluorescence due to BODIPY allowed us to visualize their location inside cancer cells. Moreover, the metalla-rectangles displayed substantial propensity to bind with biomolecules.

Full text of DOI:10.1002/chem.201704368

A Journal of
Accepted Article
Title: Self-assembly of novel thiophene-based BODIPY Ru(II)
rectangles: Potential antiproliferative agents selective against
cancer cells
Authors: Gajendra Gupta, Abhishek Das, Sourav Panja, Ji Yeon Ryu,
Junseong Lee, Nripendranath Mandal, and Chang Yeon Lee
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To be cited as: Chem. Eur. J. 10.1002/chem.201704368
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Self-assembly of novel thiophene-based BODIPY Ru(II)
rectangles: Potential antiproliferative agents selective against
cancer cells
Gajendra Gupta,*+[a] Abhishek Das,+[b] Sourav Panja,[b] Ji Yeon Ryu,[c] Junseong Lee,[c] Nripendranath
Mandal,*[b] and Chang Yeon Lee*[a,d]
Dedication ((optional))
Abstract: Novel Ru (2+2) rectangles were designed and synthesized
by self-assembly of a new thiophene-functionalized dipyridyl BODIPY
ligand, BDPS, and ruthenium (II) precursors. The complexes exhibited
dose-dependent antiproliferative activities against cancer cells, where
some compounds selectively kill cancer cells. The net fluorescence
due to BODIPY allowed us to visualize their location inside cancer
cells. Moreover, the metalla-rectangles displayed substantial
propensity to bind with biomolecules.
based drugs such as ruthenium complexes, which exhibit
ligand exchange kinetics akin to platinum drugs, are an
intriguing avenue of research. Moreover, tailoring these
drugs to increase cancer cell selectivity, minimize drug
resistance, and reduce side effects would greatly improve
drug efficacy and patients’ quality of life. Ruthenium-based
metal drugs are potential candidates owing to their low
toxicity to normal cells and a dissimilar mode of action.[3b] In
general, cationic metal complexes form crosslinks with DNA,
causing hydrolysis and redox or photoreactions in living
cells.[3c]
Coordination-driven self-assembly is one of the most
convenient and useful techniques to synthesize complex
supramolecules, owing to its simplicity.[1] The reactions are
easily performed using appropriate electron-donor ligands
with different electron-deficient metal-centred precursors.
Various metal-centred precursors are widely used to
synthesize a library of supramolecules such as triangles,
squares, rectangles, prisms, and cubes, among others.[2] In
particular, arene-linked ruthenium metal supramolecules
have been widely studied in the last decade owing to their
interesting structures and vital applications in catalysis, drug-
delivery, and host-guest chemistry.[1] Despite the popularity
of platinum-containing drugs such as Cisplatin, Carboplatin,
and Oxaliplatin, their use is highly restricted by their efficacy
against only a limited range of cancers, owing to drug
resistance and severe side effects, viz. nephrotoxicity,
nausea, and bone marrow suppression.[3a] Other metal-
Boron dipyrromethene (BODIPY) is a class of fluorescent
dyes used for many applications such as light harvesting,
photodynamic therapy, imaging, and in solar cells.[4]
Although a large number of BODIPY-based compounds
have been synthesized and studied, metal-conjugated
BODIPY supramolecules are understudied. Recently,
BODIPY-based palladium, platinum, iron, and zinc
supramolecules have been synthesized by self-assembly
and analysed for their host-guest chemistry and biological
properties.[5] Inspired by these properties of BODIPY-based
supramolecules, we recently designed, synthesized, and
studied the antiproliferative activities of new ruthenium and
iridium metalla-rectangles.[6] Drugs containing thiophene
moieties are quite popular among the practitioners due to
their wide range of pharmacological efficacies.[7] In the field
of anticancer drugs, medicines containing thiophene group
have also been reported.[7a] Therefore, in order to further
improve the biological activities of ruthenium based
[a]
[b]
Dr. G. Gupta,+ Prof. Dr. C. Y. Lee
Department of Energy and Chemical Engineering
Incheon National University
119 Academy-ro, Yeonsu-gu, Incheon 22012, Republic of Korea
E-mail: gjngupt@gmail.com; cylee@inu.ac.kr
Dr. A. Das,+ S. Panja, Prof. Dr. N. Mandal
Division of Molecular Medicine
complexes, herein, we designed
a
new thiophene-
functionalized BODIPY ligand, BDPS, and used this ligand to
synthesize four new Ru (2+2) rectangles by self-assembly.
To investigate their activities against cells in vitro, rectangles
1-4 were studied in different cell lines and the presence of
Bose Institute, P-1/12, CIT Scheme VIIM, Kolkata-700054, West
Bengal, India
E-mail: mandaln@rediffmail.com
J. Y. Ryu, Prof. Dr. Junseong Lee
Department of Chemistry
Chonnam National University, Gwangju 500-757, Republic of Korea
Prof. Dr. C. Y. Lee
Innovation Center for Chemical Engineering
Incheon National University
these rectangles inside cancer cells was further
demonstrated by confocal laser scanning microscopy.
The thiophene-functionalized dipyridine BODIPY ligand,
BDPS, was synthesized in five steps by the Suzuki-Miyaura
coupling reaction, which resulted in moderate yield (Scheme
S1). The starting dinuclear arene-ruthenium precursors
[c]
[d]
119 Academy-ro, Yeonsu-gu, Incheon 22012, Republic of Korea
[Ru2(p-cymene)2(L)Cl2] (L
=
oxalato, 2,5-diydroxy-1,4-
benzoquinone, 5,8-dihydroxy-1,4-naphthoquinone and 1,4-
dihydroxyanthraquinone) were mixed with AgCF3SO3 in
[+]
These authors contributed equally to this work
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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Scheme 1. Reaction scheme for the synthesis of metalla-rectangles 1-4.
isotopically resolved and matched well with its theoretical
distributions (Fig. S3).
methanol and stirred for 3 h. AgCl salt formed was removed
by filtration. BDPS ligand was then added and the mixture
stirred at room temperature for 24 h, yielding four new
Single crystals suitable for X-ray diffraction studies were
obtained for rectangles
1
and
2 by slow vapor diffusion of
cationic, tetranuclear, metalla-rectangles
1
-4
(scheme 1).
diethyl ether into
a nitromethane solution of these
The complexes were obtained as their triflate salts and are
soluble in common organic solvents. Spectroscopic analyses
confirmed the formation of the desired (2+2) metalla-
complexes. The single crystal structures of both these
complexes unequivocally confirmed the formation of (2+2)
tetranuclear rectangular architectures (Fig. 1). The overall
geometry around the ruthenium centre corresponds to the
characteristic piano-stool configuration where metals are
capped by p-cymene ligands. The BDPS ligands act as a
bridge between the metal centres to form the rectangular
structure. The phenyl groups of the BDPS ligands in these
structures were directed away from each other, likely due to
their steric bulkiness.
rectangles 1-4
. The 1H NMR spectra of the BDPS ligand and
the rectangles showed well-defined peaks displaying the
expected resonances for these complexes (Fig. S1 & S2).
The 1H NMR spectra of the free BDPS ligand indicated peaks
at 8.59 and 7.46 ppm, which belong to the Hα and Hβ protons
of the pyridine group of this ligand, respectively. However,
after metalation, the Hα protons had shifted upfield whereas
the Hβ protons shifted downfield in comparison to the free
ligand. These data confirm the coordination of the ligands to
the metal centres in these rectangles. Electrospray ionization
mass spectrometry (ESI-MS) were further used to study the
formation of these supramolecules
1-4. The MS spectra
confirmed the formation of these metalla-rectangles and
showed di, tri, and tetracationic peaks corresponding to the
loss of two, three, and four triflate anions: [M-2CF3SO3]2+, [M-
3CF3SO3]3+, and [M-4CF3SO3]4+, respectively (Fig. S3),
where rectangles maintained good stability. The peaks at
Figure 1. X-ray structures of metalla-rectangles (a)
1 and (b) 2 and their
m/z = 600.15, 850.19, 1350.04 for
1400.04 for ; 650.69, 917.03, 1450.11 for
the loss of two, three and four triflate anions for complexes
, respectively. The peak at m/z 1501.11 correspond to the
loss of four triflate anions for complex . The peaks were
1
; 625.56, 883.92,
space-filling model (c) and (d).
2
3
correspond to
The UV-Vis absorption and fluorescence spectroscopy of
BDPS and rectangles was studied using solvents of
different polarities (Fig. 2 & Fig. S5). Interestingly, a
1-3
1-4
4
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bathochromic effect of up to 20 nm was observed upon
insertion of the thiophene group in the BDPS ligand
compared to the thiophene free ligand.[6] The visible region
iridium rectangles, concluding that some complexes
displayed varying degrees of selectivity in killing cancer cells
over normal WI38 cells.[6] In this study, we incorporated a
thiophene group into the BODIPY ligand with the aim of
improving their selectivity. Our results are supported by the
of rectangles 1-4 was dominated by an intense peak around
525 nm, which corresponded to the vibration band of the π-
π* transition localised on the BDPS chromophores of these
complexes. A blue shift of up to 10 nm was observed in these
complexes compared to the free BDPS ligand. In addition,
two strong, high-energy absorption bands shouldered at
approximately 402 and 318 nm were observed and could be
assigned due to the combination of intra/intermolecular π-π*
transitions mixed with MLCT transitions. The emission
spectra of the BDPS ligand and the rectangles were also
measured in different solvents. The rectangles were highly
fluorescent with an emission peak at approximately 630 nm
low cytotoxicity observed for rectangles
1 and 2 in normal
WI38 cells (Table 1; Fig. S7). For same reason, such
selectivity was also evident in the BDPS ligand against all
cells although yielding high IC50 values in most cases. It may
be noted that every complex has two BDPS ligands and
therefore there is a fair possibility that the activity of BDPS
itself has a major role to play in the toxicities of the
complexes. Although, there is no sufficient evidence to
ensure whether this activity is cumulative or synergistic.
Additionally, we had tested the activities of L1-L4 on
corresponding
to
the
BDPS
chromophore.
In
proliferation of cancer cells (Table S1). Interestingly, Linker
L3 projected a comparatively higher IC50 value in all the cell
lines than the other linkers. In U87 L3 showed the highest
activity, though it was still nearly 2.5 times lesser than that of
dichloromethane, rectangles
1
and
2 showed an interesting
red shift of approximately 25 nm in its emission spectra (Fig.
2). This behaviour was not observed using solvents with
increased polarity. The absorption and emission spectra are
summarised in Fig. S5.
its associating complex
evident in MCF-7 as well, but not HeLa. This imparts the fact
that activity of complex
may be primarily attributed to L3 [1d]
3 (Table SI 1). Similar trend was
3
.
Table 1. IC50 (μM) values of 1-4, BDPS, and Cisplatin in different cell lines.
* IC50 values of complexes 1-4 are inclusive of the effects of two BDPS
molecules in each complex.
Figure 2. Absorption (left) and emission (right) spectra of BDPS and
rectangles 1-4 in CH2Cl2.
Propidium iodide (PI) binding to DNA can be used to
determine the amount of DNA in G1, S, and G2/M cell cycle
phases as well as post-apoptotic, fragmented nuclear DNA
(as a sub-G1 peak) when analysed by flow cytometry.[9] Cell
cycle-dependent distributions of only those compounds that
exhibited selectivity for U87 and MCF-7 cells were measured
using this technique and the same were considered for
The activities of complexes
1-4 against cancer cells were
determined using cell lines of different origins, including
breast (MCF-7), cervical (HeLa), and brain (U87) cancers,
and results were compared with those of non-malignant
WI38 cells. Complexes
MCF-7 cells while exhibiting relatively low toxicity in WI38
cells (Table 1; Fig. S7). Moreover, complexes and were
more effective than cisplatin. Complex showed selective
1-4 were found to selectively kill
3
4
further experiments.
1 and 2 were not considered for
3
analyses with U87 cells due to their comparatively many
folds higher IC50 values than those with MCF-7 cells (Table
1), even though they had showed selectivity. Although an
exception has been made in case of HeLa cells. We
speculated that, despite comparatively higher IC50 values, it
would have been interesting to observe the behaviour of the
complexes against HeLa cells, as previously a similar
ruthenium complex was found to be the only example with
which we had observed nuclear localization in these cells
under a confocal microscope.[6] Dose ranges for compounds
were determined based on their cytotoxicity results. At 30
toxicity at lower doses compared to the other compounds
against U87 cells (Fig. S7). Overall, HeLa cells exhibited
higher resistance against the compounds, although
complexes
1 and 2 had lower IC50 values compared to that
in WI38 cells. Thiophene compounds are activated chiefly by
cytochrome P450 mediated oxidation which result in various
electrophilic
intermediates.[7b]
Thiophene
containing
compounds have potent antioxidant activities.[8a] Now due to
the anomalous mitochondrial function in the cancer cells
owing to their increased production of reactive oxygen
species (ROS) compared to that in normal cells that leads to
oxidative stress,[8b] thiophene compounds further disrupt the
redox balance particularly in cancer cells, which may aid to
their selective action. Our previous studies measured the
antiproliferative activities of BODIPY-based ruthenium and
µM, complexes
1 and 2 substantially compromised the cell-
cycle distribution, and at 50 µM, 23.62% and 34.26% of cells
were observed in the sub-G1 population, respectively (Fig.
S8; A-D). Complex
3 exhibited a dose-dependent increase
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Figure 3. Intracellular localization of rectangles 1-4. Nuclei stained with DAPI in the presence or absence of compound treatment were observed using
confocal microscope (excited at 488 nm). MCF-7 cells were treated with rectangles (1 μM), (0.5 μM), (1 μM) and (3 μM); HeLa cells were treated
with 3 μM of rectangles and ; U87 cells treated with 1 μM of rectangle
1
2
3
4
1
2
3.
in mortality of U87 cells, with 16.68% cell death at the highest
concentration (Fig. S8, E-F). When compounds were
by confocal laser scanning microscopy by exploiting the
intrinsic, green fluorescent characteristic of the BODIPY
(excitation at 488 nm). Cells were also stained with DAPI to
determine nuclear morphology. Control cells had well-
defined nuclear regions and no green fluorescence
throughout (Fig. 3). All rectangles were found to localise
predominantly in the cytoplasmic region both uniformly as
well as in the form of nano-aggregates (arrows indicate both
forms in BODIPY panels). For comparison, the fate of BDPS
only, was also checked in all the cell lines. Despite showing
1-3
studied against the MCF-7 breast cancer cells, it was found
that the percentage of apoptotic cells increased in a dose-
dependent manner. Also, there was a gradual decrease in
the G1 peak, suggesting cell death was predominantly
occurring during G1 phase (Fig. S9) Cellular uptake of many
ruthenium complexes is mediated by transferrin, an 80-kDa
iron transport protein.[10] The localisation of these thiophene-
based, BDPS-ruthenium rectangles was easily determined
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some amounts of loss in cellular integrity in case of MCF-7
cells (DAPI panel of BDPS+MCF-7 in Fig. 3), no green
fluorescence or aggregation was observed in any of the
cancer cells. This proves that the green fluorescence results
only when the rectangles carrying BDPS enter the cells and
undergo aggregation under hypoxic conditions (Fig. 3).
Nuclear disintegration, an indicator for apoptosis, was largely
observed in MCF-7 and HeLa cells (specified with arrows in
the DAPI panels, Fig. 3). Additionally, many pyknotic cells
were observed, mostly in breast and brain cancer cells.
These observations further supported the substantial rise in
sub-G1 peak from the cell-cycle results. Unlike our
previously established rectangles that showed both nuclear
in a decrease in peak intensity. The largest changes in peak
intensity were observed for compounds
3 and 4. Compound
1
exhibited the least peak intensity change, possibly due to
the absence of aromatic rings between the two metal cores.
These results were further confirmed by UV spectrometry
(Fig. S11, F-I). Static quenching may be considered as one
of the methods of interaction as no significant shift from the
normal spectra was observed.
In conclusion, we report the synthesis of novel thiophene-
based BDPS Ru (II) rectangles 1-4, where introduction of the
thiophene group in the BODIPY ligand significantly improved
its selectivity for cancer cells. All compounds showed
selective antiproliferative activities against breast cancer
and cytoplasmic locations,[6] rectangles
1
-4
predominantly
cells,
1
and
2
exhibited activity against cervical cancer cells,
worked against glioblastoma
localised in the cytoplasm. On the basis of this, along with
observations like nuclear disintegration and occurrence of
pyknotic cells, we postulate that their mechanism of selective
anti-proliferative activities and induction of apoptosis may be
mainly governed extranuclearly. Although to state anything
affirmatively, in depth studies must follow.
and all except compound
4
cells. This dose-dependent inhibition of cell growth was
further confirmed by cell-cycle analyses. Confocal laser
scanning microscopy studies suggested that the compounds
use a cytoplasmic mechanism of action in causing cell death.
Additionally, binding studies revealed the ability of
The ability of ruthenium to bind biomolecules, similar to
iron, makes ruthenium-based metalla-rectangles a promising
avenue for developing novel anticancer strategies.
Anticancer drugs primarily target and damage DNA, leading
to an obstruction of cell division and subsequent cell
death.[11] Therefore, we further investigated the interaction
between these complexes and genomic DNA by UV
spectroscopy. A prominent peak typical of genomic DNA was
observed close to 260 nm, using Salmon sperm DNA (Fig.
S10). Addition of compounds (5-25 µM) resulted in dose-
compounds 1-4 to substantially interact with DNA and
protein. Therefore, these compounds could be useful for
further studies on the biological activity of BODIPY-based
metal supramolecules.
Acknowledgements
This research was supported by a Post-Doctoral Research
Program (2016) for GG through Incheon National University,
Incheon, Republic of Korea. We acknowledge Mr R. Dutta, Mr A.
Poddar and Mrs S. G. Chakraborty of Central Instrument Facility
(CIF), Bose Institute, India for their technical assistance.
dependent hyperchromicity, where complexes 2-4 exhibited
equal DNA-binding abilities (Fig. S10, A-E). BDPS alone
showed least activity, even at its highest concentration. No
hypochromicity or bathochromicity were observed in any of
the conditions. Ruthenium-complexes are known to be
mutagenic and induce SOS repair, inhibit DNA replication,
and inhibit RNA synthesis by binding genomic DNA. These
observations complement in vivo studies of ruthenium-
compounds binding with DNA.[3b] Moreover, they are also
known to intercalate mainly within the major grooves of
DNA.[12] To investigate the nature of the DNA-compound
interaction, mixtures were heated at 95°C for 15 min. Single-
stranded DNA (ssDNA) showed a slight hyperchromic shift
compared to its native double-stranded (dsDNA) form (Fig.
S10, F-I). However, none of the compounds exhibited any
substantial decrease in absorbance, excluding the possibility
of intercalation. We postulate that electrostatic interactions
between exposed bases of ssDNA as well as some non-
covalent interactions mediate DNA-compound binding.
Next, we investigated the interaction between our
metalla-rectangle drugs with the model protein, bovine
serum albumin (BSA), owing to its high homology with
human serum albumin.[13] A peak at 340 nm was observed
using a fluorimeter, consistent with that for free BSA.
Increasing concentrations of compound (5-25 µM) resulted
Keywords: self-assembly • metalla-rectangles • bodipy •
antiproliferative activities • anticancer • confocal microscopy
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Gajendra Gupta,* Abhishek Das,
Sourav Panja, Ji Yeon Ryu,
Junseong Lee, Nripendranath
Mandal* and Chang Yeon Lee*
A
new
thiophene-based
BODIPY ligand, BDPS, has
been designed and utilized to
successfully synthesize four
new Ru (2+2) rectangles. The
presence of thiophene group
in these rectangles has
Page No. – Page No.
Self-assembly
of
novel
thiophene-based BODIPY Ru(II)
rectangles:
antiproliferative
Potential
agents
significantly
improved
its
selective against cancer cells
biological activities.
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