Biologically active [Pd2L4]4+ quadruply-stranded helicates: stability and cytotoxicity

Article abstract of DOI:10.1039/c5dt01259g

There is emerging interest in the anti-proliferative effects of metallosupramolecular systems due to the different size and shape of these metallo-architectures compared to traditional small molecule drugs. Palladium(ii)-containing systems are the most ab

Full text of DOI:10.1039/c5dt01259g

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Journal Name
RSCPublishing
ARTICLE
Biologically active [Pd2L4]4+ quadruply-stranded
helicates: stability and cytotoxicity
Cite this: DOI: 10.1039/x0xx00000x
Samantha M. McNeill,a Dan Preston,b James E. M. Lewis,b Anja Robert,a Katrin
KnerrꢀRupp,a Danyon O. Graham,a James R. Wright,b Gregory. I. Giles,a,* and
James D. Crowleyb,*
Received 00th January 2012,
Accepted 00th January 2012
There is emerging interest in the antiꢀproliferative effects of metallosupramolecular systems
due to the different size and shape of these metalloꢀarchitectures compared to traditional
small molecule drugs. Palladium(II)ꢀcontaining systems are the most abundant class of
metallosupramolecular complexes, yet their biological activity has hardly been examined.
Here a small series of [Pd2(L)4](BF4)4 quadruplyꢀstranded, dipalladium(II) architectures
were screened for their cytotoxic effects against three cancer cell lines and one nonꢀ
malignant line. The helicates exhibited a range of cytotoxic properties, with the most
cytotoxic complex [Pd2(hextrz)4](BF4)4 possessing low micromolar IC50 values against all
of the cell lines tested, while the other helicates displayed moderate or no cytotoxicity.
Against the MDAꢀMBꢀ231 cell line, which is resistant to platinumꢀbased drugs,
[Pd2(hextrz)4](BF4)4 was 7ꢀfold more active than cisplatin. Additionally, preliminary
mechanistic studies indicate that the [Pd2(hextrz)4](BF4)4 helicate does not induce cell death
in the same way as clinically used metal complexes such as cisplatin. Rather than
binding/interacting with DNA, the helicate appears to disrupt the cell membrane. These
studies represent the first biological characterisation of quadruplyꢀstranded helicate
architectures, and provide insight into the design requirements for the development of
biologically active and stable palladium(II)ꢀcontaining metallosupramolecular architectures.
DOI: 10.1039/x0xx00000x
www.rsc.org/
nonꢀcovalent complexation at the center of threeꢀway (Yꢀ
shaped) DNA12 and RNA13 junctions. The binding of [Fe2L3]4+
Introduction
Spurred on by the success of small molecular inorganic drugs1
such as cisplatin2 (cisꢀ[Pt(NH3)2Cl2], CDDP)3 there has been an
upsurge of interest in the biological properties4 of
metallosupramolecular architectures.5 This is driven by the
hope that the different size and shape of these
metallosupramolecular systems, compared to small molecule
drugs, will lead to cytotoxic agents with novel biological
mechanisms of action. The biological properties of a range of
selfꢀassembled architectures including metalloꢀmacrocycles,6
cages/prisms7 and helicates have been examined. It is the
metalloꢀhelicates,8 however, that have received particular
attention. Building on early work from Lehn and coꢀworkers,9
which had shown that cationic doubleꢀhelical copper(I)
complexes interact strongly with DNA, Hannon and coꢀworkers
carried out a series of pioneering studies on the biological
to DNA has also been shown to induce coiling of the nucleic
acid structure.14 Additionally, Hannon and coꢀworkers found
that these tetracationic iron(II) cylinders and related
ruthenium(II) systems display both antiꢀcancer15 and antiꢀ
bacterial16 properties. The biological properties of other related
triplyꢀstranded helicate systems have also been examined.
These molecules have been shown to bind Gꢀquadruplex
DNA,17 inhibit Aβ amyloid aggregation18 and also display
cytotoxic (antiꢀcancer19 and antiꢀbacterial19b) properties. While
it is clear from these studies that cationic helicate architectures
can strongly interact with DNA, a recent report from Scott and
coꢀworkers20 has suggested that DNA binding is not always
responsible for the observed biological activity.
Palladium(II) containing systems21 represent the most
common class of metallosupramolecular architectures.
However, despite considerable interest in small palladium(II)
complexes,22 the biological properties of palladiumꢀcontaining
metallosupramolecular architectures have hardly been
examined.6i, 23
properties of the
(methanediyldibenzeneꢀ4,1ꢀdiyl)bis[1ꢀ(pyridinꢀ2ꢀ
yl)methanimine]) helicate.10 This tetracationic cylinder interacts
strongly with duplex DNA, binding in the major groove,11 but
interestingly it can display alternative binding modes including
triplyꢀstranded [Fe2L3]4+ (L = N,N'ꢀ
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Herein, as part of our interests in metallosupramolecular Solutions (d6ꢀDMSO/D2O, 3:2, 2.5 mM) of the [Pd2(
architectures24 and the biological applications of metal architectures were treated with 8 equivalents of one of the
complexes,25
we screened four quadruplyꢀstranded, nucleophiles and the course of the reaction monitored, using
dipalladium(II) architectures for their antiproliferative effects timeꢀcourse H NMR spectroscopy, for a period of 20 hours
again three different cancer cell lines, and compared this (Table and ESI†). Under these conditions the
L)4](BF4)4
1
1
activity against nonꢀmalignant cells. It is shown that the most [Pd2(tripy)4](BF4)4 cage rapidly decomposed. The halfꢀlife for
stable dipalladium(II) helicate displays low micromolar IC50 the decomposition of the palladium(II)ꢀtripyridyl complex with
values against all the tested cell lines. Furthermore, mechanistic histidine was 5 minutes. The halfꢀlives for the corresponding
studies indicate that the helicate does not cause cell death by reactions with the chloride (Clꢀ) and cysteine nucleophiles were
interacting with DNA, rather it seems to disrupt the cell less than one minute. This rapid decomposition behaviour is
membrane. To the best of our knowledge this is the first consistent with previous experiments using chloride and 4ꢀ
reported cytotoxic study of quadruplyꢀstranded helicate dimethylaminopyridine in acetonitrile (CH3CN) solutions.26
architectures.
Compared to the [Pd2(tripy)4](BF4)4 system the triazoleꢀ
based helicates [Pd2(bntrz)4](BF4)4, [Pd2(hextrz)4](BF4)4 and
[Pd2(pegtrz)4](BF4)4 were all considerably more stable. All of
the triazoleꢀbased helicates displayed good stability against
chloride (Clꢀ) nucleophiles, with the halfꢀlives for the
decomposition reactions all over 20 hours. The
[Pd2(bntrz)4](BF4)4 and [Pd2(pegtrz)4](BF4)4 helicates were
less stable in the presence of histidine and cysteine. The halfꢀ
lives for the helicate decomposition reactions with histidine
were both approximately 12 hours, while a much more rapid
disassembly
of
the
[Pd2(bntrz)4](BF4)4
and
[Pd2(pegtrz)4](BF4)4 helicates occurred with the sulphurꢀ
containing cysteine nucleophile (t1/2 = 30 and 20 minutes,
respectively). Interestingly, the [Pd2(hextrz)4](BF4)4 helicate
was longꢀlived in the presence of all the nucleophiles tested ( 1/2
t
= >20 hours for all the nucleophiles). No cage decomposition
was observed in the presence of chloride (Clꢀ), and only 13% of
the [Pd2(hextrz)4](BF4)4 cage was broken down when exposed
either to histidine or cysteine.
Table 1. Halfꢀlives
(t1/2) for the decomposition of the Pd2L4
architectures against 8 equivalents of selected biologically relevant
nucleophiles (3:2 d6-DMSO/D2O, 298 K, 500 MHz).
Nucleophile
Figure 1 a) Chemical structures of the pyridineꢀ (tripy) and triazoleꢀ
[Pd2(L)4](BF4)4
13C δ*
(
bntrz, hextrz and pegtrz) based ligands; the molecular structures of b)
2
6
2
4
h
architecture
[Pd2(tripy)4](BF4)4
and c) [Pd2(bntrz)4](BF4)4
architectures.
Chloride
Histidine
Cysteine
Anions, solvent molecules and hydrogen atoms have been omitted for
clarity.
[Pd2(tripy)4](BF4)4
[Pd2(bntrz)4](BF4)4
[Pd2(hextrz)4](BF4)4
[Pd2(pegtrz)4](BF4)4
<1 min
>20 hr
>20 hr
>20 hr
5 min
12 hr
>20 hr
12 hr
<1 min
30 min
>20 hr
20 min
158.7
161.3
161.4
161.4
Results and Discussion
Synthesis and Stability
The ligands (tripy 27
,
bntrz24g and hextrz24e) and complexes
[Pd2(bntrz)4](BF4)4,24h
([Pd2(tripy)4](BF4)4,26
24e
*
chemical shift of Pd(II) probe complex carbene carbon (ESI†)
[Pd2(hextrz)4](BF4)4
)
were generated using previously
reported procedures (Fig. 1 and ESI†). The new bistriazole
ligand (pegtrz) and its corresponding dipalladium helicate
[Pd2(pegtrz)4](BF4)4 were synthesised using the conditions24e
previously exploited to generate the hextrz ligand and helicate
(Fig. 1 and ESI†).
It appears that both electronic and steric factors are
responsible for the observed differences in the stability of the
[Pd2( )4](BF4)4 architectures. The electron donor strength of
the pyridyl and triazolyl ligands was determined using the
palladium(II) probe complexes reported by Huynh and coꢀ
workers (ESI†).28 The 13C carbene carbon chemical shift of
these probe complexes suggested that the triazolyl ligands are
all more electronꢀrich and therefore “better” ligands than the
L
Before carrying out cytotoxicity measurements the stability
of the [Pd2(L)4](BF4)4 architectures in the presence of common
biological nucleophiles (chloride (Clꢀ), histidine and cysteine)
was determined using 1H NMR competition experiments.
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pyridyl system (Table 1 and ESI†). The observed higher ligand cytotoxicities were due to the helicate, rather than palladium(II)
ꢀ
donor strength of the triazole ligands relative to the pyridyl or BF4 administration.
system undoubtedly contributes to the greater stability of the
triazole based helicates relative to the pyridyl cage. Inspection cell line; for example [Pd2(tripy)4](BF4)4 was almost twice as
of the molecular structures (Fig. 1) of the [Pd2( )4](BF4)4 potent against the A549 cell line compared to DUꢀ145, while
There was no correlation between helicate cytotoxicity and
L
architectures indicates that steric factors also potentially help [Pd2(bntrz)4](BF4)4 was more potent against the DUꢀ145 line
stabilize the triazoleꢀbased helicates. The [Pd2(tripy)4](BF4)4 than A549. None of the compounds displayed any selectivity
adopts a lantern shape that contains an open/accessible internal towards cancerous phenotypes, with all of the helicates
cavity. This allows the nucleophiles access to the square planar exhibiting approximately similar IC50 values against nonꢀ
palladium(II) ions of the cage either from the “outside” face of malignant MCF 10A cells as towards the tumourꢀderived cell
the cage or through the central cavity of the architecture. lines. When compared, under identical conditions, to the
Conversely, the helical twist of the triazoleꢀbased architectures clinically used platinum complex cisplatin (CDDP,
means that there is no open central cavity in these systems. As experimentally derived IC50 of 41.2
± 3.9 µM against the
such the nucleophiles can only attack the palladium(II) ions of MDAꢀMBꢀ231 cell line) [Pd2(tripy)4](BF4)4 was less potent,
the helicates from the “outside” face of the architectures. This while [Pd2(bntrz)4](BF4)4 and [Pd2(hextrz)4](BF4)4 were 2.3
steric effect in combination with the greater ligand donor and 6.8 fold more potent, respectively.
strength of the triazole ligands leads to the higher stability of
the helicates relative to the tripyridyl cage system.
Table 2. Halfꢀmaximal inhibitory concentrations (IC50) of ligands
bntrz hextrz and pegtrz and their respective [Pd( )4](BF4)4
The difference in the stabilities of the three triazole based tripy
,
,
L
helicates is more subtle. Each system has the same helicate architectures at 24 h.
structure and the 13C carbene chemistry shift of the probe
complexes suggested that donor strength of all the triazolyl
ligands was very similar (Table 1 and ESI†). Despite these
IC50 (µM)
Compound
structural and electronic similarities, the stability testing
showed that the [Pd2(hextrz)4](BF4)4 complex was
considerably more stable than the [Pd2(bntrz)4](BF4)4 and
MDA
A549
DU145
MCF10A
MB231
[Pd2(pegtrz)4](BF4)4 helicates against the amino acid
[Pd2(tripy)4](BF4)4
41.4 ±
3.9
56.7 ±
2.2
70.1 ±
13.8
71.4 ± 3.9
51.9 ± 0.7
nucleophiles histidine and cysteine. We postulate that this
enhanced stability is connected to the presence of the
55.5 ±
1.2
18.1 ±
2.7
34.1 ±
0.9
hydrophobic hexyl substituents in the [Pd2(hextrz)4](BF4)4
[Pd2(bntrz)4](BF4)4
complex.
Presumably
these
hydrophobic
chains
clump/aggregate together in the polar d6ꢀDMSO/D2O solvent
mixture used for stability studies and reduce the nucleophile’s
access to the palladium(II) ions of the helicate, thereby
increasing the kinetic stability of this system relative to the
other helicates.
6.9 ±
0.9
3.4 ±
0.4
[Pd2(hextrz)4](BF4)4
[Pd2(pegtrz)4](BF4)4
tripy
6.0 ± 0.6
-
8.1 ± 1.2
>100
-
-
95.3 ±
9.7
>100
>100
>100
>100
>100
Helicate Cytotoxicity
To assess biological activity the cytotoxicities (as halfꢀ
maximal inhibitory concentrations (IC50)) of the individual
ligands tripy, bntrz, hextrz and pegtrz, along with their
bntrz
>100
88.6 ± 5.4
18.1 ± 3.1
-
28.5 ±
2.6
89.8 ±
10.7
28.5 ±
1.3
hextrz
respective [Pd(L)4](BF4)4 architectures, were determined
against four different cell lines: A549 (lung cancer), CDDP
resistant MDAꢀMBꢀ231 (breast cancer),29 DUꢀ145 (prostate
cancer), and MCF10A (immortalized nonꢀmalignant breast
tissue) (Table 2).
pegtrz
>100
-
-
“ – “ signifies not determined.
The ligands tripy, bntrz and pegtrz and the
[Pd2(pegtrz)4](BF4)4 helicate exhibited minimal cytotoxicity
under the conditions studied (IC50 > 80 µM). The ligand hextrz
and both [Pd2(tripy)4](BF4)4 and [Pd2(bntrz)4](BF4)4 helicates
displayed increased cytotoxicity, with IC50 values ranging from
70 to 18 µM against all of the cell lines, while the
[Pd2(hextrz)4](BF4)4 helicate displayed high cytotoxicity (IC50
As [Pd2(hextrz)4](BF4)4 displayed the lowest IC50 value
(Table 2) and also the highest stability (Table 1), it was possible
that an intact [Pd2(L)4](BF4)4 helicate structure was required for
high cytotoxicity. A comparison of the ligand hextrz and
[Pd2(hextrz)4](BF4)4 cytotoxicity data supported this
hypothesis. As the palladium(II) metallocenters are coordinated
by four ligands, if ligand dissociation was required for
cytotoxicity then the helicate IC50 would be fourꢀfold less than
=
3ꢀ8 µM against all cell lines studied
).
The
[Pd(CH3CN)4](BF4)4 complex alone did not display any
cytotoxicity (IC50 > 100 µM), indicating that the observed
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the IC50 of the individual ligands (Fig 2). While that by 2 hours the administration of the helicate had resulted in
[Pd2(hextrz)4](BF4)4 was consistently more toxic than hextrz, the rapid onset of cell death; however, after 2 hours the helicate
a
fourꢀfold ratio was only observed against A549 cells (Fig. 2). induced no further toxicity to the surviving cells. This cytotoxic
Additionally, the ratio of ligand to helicate toxicity varied mode of cell death is distinct from classical metal complexes
substantially between cell lines, from approximately 2 for the such as CDDP, which display increasing cytotoxicity over
MCF10A cells to 15 for the MDAꢀMBꢀ231’s (Fig. 2), time.30 CDDP toxicity is a result of the drug’s ability to bind to
demonstrating that there was no correlation between ligand and DNA, causing errors in the cell replication process which
helicate cytotoxicity.
results in the initiation of programmed cell death via apoptosis.
As CDDP toxicity is dependent upon the replication status of
individual cells, it selectively kills cells as they undergo cell
division, resulting in a staggered cell death over several days.31
In contrast, the rapid onset of cell death with
[Pd2(hextrz)4](BF4)4 provides evidence that the helicate is
killing cells by a mechanism unrelated to DNA damage.
[Pd2(hextrz)4](BF4)4 Treatment Causes a Rapid Loss of Cell
Membrane Integrity
We next aimed to identify the potential biological targets of
the [Pd2(hextrz)4](BF4)4 helicate. As rapid cell death is often
associated with a compromised membrane integrity, we
evaluated whether helicate induced cell death was attributable
to membrane damage. For these studies we measured the
release of the intracellular enzyme lactate dehydrogenase
(LDH) into the extracellular medium. Extracellular levels of
LDH are usually present at low concentrations, attributable to a
small population of cells undergoing spontaneous death in
culture systems.32 However these extracellular LDH levels
rapidly increase if the cell membrane is disrupted, due to the
release of intracellular enzyme into the extracellular space. The
assay therefore provides a convenient method for rapidly
assessing membrane integrity.32
Figure 2. [Pd2(hextrz)4](BF4)4 cytotoxicity is not due to helicate
decomposition. Cells were treated with [Pd2(hextrz)4](BF4)4 or hextrz
for 24 hours before cell viability analysis. (A) Against DUꢀ145 cells the
IC50 for the ligand (28.5 µM) was 8 fold higher than for the helicate
(3.4 µM); if helicate toxicity was due to rapid decomposition to release
the ligand, then the stoichiometry of the complex would predict a 4ꢀfold
ratio in IC50. (B) A comparison of the IC50 ratio between ligand and
helicate across the four cell lines demonstrated no correlation between
helicate and ligand toxicity. Data points are expressed as means ± SEM
where n=6.
Figure 3. Cell death caused by [Pd2(hextrz)4](BF4)4 occurs within 2 hours
post administration. A549 cells were treated with 0ꢀ50 µM
[Pd2(hextrz)4](BF4)4 for 2, 24 or 48 hours, and cell viability assessed. There
was no significant difference in IC50 between time points. Data are expressed
as means ± SEM (n=6).
Time Course of Helicate Action – A Comparison with CDDP
To further identify the mechanistic basis of the high
cytotoxicity displayed by [Pd2(hextrz)4](BF4)4, a time course
analysis was performed to determine the time required for the
onset of cytotoxicity (Fig. 3). No further difference in
cytotoxicity was observed between 2 and 48 hours, indicating
Consistent with a mechanism involving membrane damage,
a time and concentration dependent increase in extracellular
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LDH levels was observed immediately following mechanism underlying this remarkably rapid switch in activity
[Pd2(hextrz)4](BF4)4 administration (Fig. 4). At a relatively is currently unknown. In comparison, administration of the
high concentration of 50 µM (7 fold above the IC50), a rapid hextrz ligand alone, even at 100 µM (4ꢀfold higher than the 24
elevation in LDH activity was observed, which peaked at 10 hour IC50), resulted in no cell death at 10 min, confirming that
minutes. However, at lower concentrations of 5 and 10 µM, the helicate and its cognate ligandꢀinduced cytotoxicity via
continuous increases in LDH release were observable at 10, 30 distinct molecular mechanisms (Fig. 5).
and 60 minutes, indicating that around the IC50 concentration
membrane damage was a continual process that occurred over a
sustained time period (Fig. 4).
Conclusions
H erein the biological activities of four quadruplyꢀstranded
dipalladium architectures were studied. The palladium(II)ꢀ
based helicates exhibited a range of cytotoxic properties, with
the most cytotoxic complex [Pd2(hextrz)4](BF4)4 possessing
low micromolar IC50 values against all of the cell lines tested,
while the other helicates displayed moderate or no cytotoxicity.
Stability studies indicated that the cytotoxic effect of the
dipalladium architectures correlated well with the stability of
these systems in the presence of biological nucleophiles,
suggesting that it is intact helicate that is responsible for the
biological activity.
Disappointingly, the [Pd2(hextrz)4](BF4)4 helicate displayed
no selectivity towards cancerous phenotypes, the compound
exhibited approximately similar IC50 values against nonꢀ
malignant MCF 10A cells as towards the tumourꢀderived cell
lines. Against the MDAꢀMBꢀ231 cell line, which is resistant to
platinumꢀbased drugs, [Pd2(hextrz)4](BF4)4 was 7ꢀfold more
Figure 4. [Pd2(hextrz)4(BF4)4 causes rapid disruption of the cell
membrane. A549 cells were treated with [Pd2(hextrz)4](BF4)4 and the active than cisplatin and, when compared to the IC50 values
change in extracellular LDH levels calculated by measuring enzyme activity.
Data represents extracellular LDH activity at each time point and are
expressed as means ± SEM (n=3). *=p<0.05.
against the other cell lines, there was no evidence of resistance.
This suggests that the helicate does not induce cell death in the
same way as clinically used metal complexes such as cisplatin.
Preliminary
mechanistic
investigations
with
the
To investigate the extent to which LDH release was a
diagnostic indicator of the viability of the entire cell population,
we next conducted double labelling experiments with the dyes
Hoechst 33342 and propidium iodide. Hoechst 33342 is a
membrane permeable dye used for cell counting as it
effectively labels all cells. In contrast, propidium iodide is a cell
membrane impermeable dye, which is only taken up by nonꢀ
viable cells with compromised cell membrane integrity. In
combination with Hoechst 33342 it can therefore be used to
distinguish between dead and viable cells within a heterogenous
population.33 In A549 cells this double label analysis confirmed
[Pd2(hextrz)4](BF4)4 helicate revealed that it induced cell death
within minutes, accompanied by a loss of cellular membrane
integrity. While these observations are consistent with the
helicate acting as a metalloꢀdetergent,35 there are several
potential alternative mechanisms of membrane damage,
including pore formation36 and changes to the fluidity of the
lipid bilayer.37 With the current data the exact cause of the
membrane damage is not clear. Because the cyctotoxic
mechanism of the helicate was loss of cellular membrane
integrity, the compound exhibited no selectivity towards cancer
cells compared to nonꢀmalignant cells. This lack of specificity
towards cancer cells prevents the immediate application of this
complex as an antiꢀcancer agent.
that, by 10 minutes,
a
10 µM concentration of
[Pd2(hextrz)4](BF4)4 (slightly above the 24 hour IC50 of 7 µM)
was sufficient to have killed > 85% of the cell population, while
a 50 µM concentration induced 100% cell death (Fig 5). The
phase contrast image demonstrated that [Pd2(hextrz)4](BF4)4
induced cell death was accompanied by a rounding of the cells,
a characteristic feature of cell damage that can accompany
necrosis34 (Fig. 5). In contrast 5 µM [Pd2(hextrz)4](BF4)4
(slightly below the 24 hour IC50) only induced 1.5% cell death
at 10 min, although rounding of the cell population was
observable in the phase contrast image, indicating that cell
death processes had potentially been initiated in a greater
However, the current work suggests that suitably designed
stable
palladium(II)ꢀcontaining
metallosupramolecular
architectures (especially quadruplyꢀstranded helicates) can
display biological activity. As such we are now examining
other palladium (II)ꢀcontaining architectures and quadruplyꢀ
stranded helicates containing other metals ions in search of
more selective antiꢀcancer agents.
Acknowledgements
This work was supported by an Otago Medical Research
Foundation Laurenson Award (LA307). The authors thank the
Department of Pharmacology and Toxicology and the
number of cells. Therefore
a small switch in helicate
concentration, from slightly below to slightly above the IC50
value, could result in the sudden onset of cell death. The
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ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5DT01259G
Department of Chemistry, University of Otago for additional
funding. DP and JEML thank the University of Otago for PhD
scholarships. DP thanks Otago Medical Research Foundation
for a McQueen Summer Studentship.
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Figure 5. [Pd2(hextrz)4](BF4)4 induces rapid membrane damage. A549 cells were treated with helicate or ligand for 10 min and then double
stained with Hoechst 33342 and propidium iodide. ( ) Control cells (0.15% DMSO) (B) Cells treated with 5ꢀ50 µM of [Pd2(hextrz)4](BF4)4 (C)
A
.
Cells treated with hextrz. The representative images were acquired with a 20× objective, scale bars (white) indicate 50 µm. (D) The percentage of
propidium iodide (PI) positive cells were calculated from fluorescence images obtained for each treatment condition (n=3), data is expressed as
means ± SEM. *=p<0.05 as compared to control.
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Notes and references
a
Department of Pharmacology and Toxicology, University of Otago, P.O.
Box 913, Dunedin, New Zealand . E-mail: gregory.giles@otago.ac.nz
b
Department of Chemistry, University of Otago, PO Box 56, Dunedin, New
Zealand. Fax: +64
3 479 7906; Tel: +64 3 479 7731; E-mail:
jcrowley@chemistry.otago.ac.nz
†Electronic Supplementary Information (ESI) available: the
supplementary information contains the experimental
procedures, 1H, 13C and DOSY NMR, ESMS, and
crystallographic data. CCDC reference numbers 1045884ꢀ
1045889. See DOI: 10.1039/b000000x/
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A quadruply-stranded dipalladium(II) helicate exhibits low micromolar IC50 values against are range of
different cancer cell lines. Additionally, preliminary mechanistic studies indicate that the helicate does
not induce cell death in the same was as cisplatin, rather it appears to disrupt the cell membrane.