Photoswitching the Cytotoxic Properties of Platinum(II) Compounds

Article abstract of DOI:10.1002/anie.201412157

The photoactivation of potential anticancer metal complexes is a hot topic of current research as it may lead to the development of more selective drugs. Photoactivated chemotherapy (PACT) with coordination compounds is usually based on a (photo)chemical reaction taking place at the metal center. Herein, a new strategy is exploited that consists of "photomodifying" a ligand coordinated to metal ions. Platinum(II) complexes from photoswitchable 1,2-dithienylethene-containing ligands have been prepared, which exhibit two interconvertible photoisomeric forms that present distinct DNA-interacting properties and cytotoxic behaviors.

Full text of DOI:10.1002/anie.201412157

Angewandte
Chemie
DOI: 10.1002/anie.201412157
Drug Design
Photoswitching the Cytotoxic Properties of Platinum(II)
Compounds**
Andreu Presa, Rosa F. Brissos, Ana Belꢀn Caballero, Ivana Borilovic, Luꢁs Korrodi-Gregꢂrio,
Ricardo Pꢀrez-Tomꢃs,* Olivier Roubeau, and Patrick Gamez*
Abstract: The photoactivation of potential anticancer metal
complexes is a hot topic of current research as it may lead to the
development of more selective drugs. Photoactivated chemo-
therapy (PACT) with coordination compounds is usually
based on a (photo)chemical reaction taking place at the
metal center. Herein, a new strategy is exploited that consists of
“photomodifying” a ligand coordinated to metal ions. Plati-
num(II) complexes from photoswitchable 1,2-dithienylethene-
containing ligands have been prepared, which exhibit two
interconvertible photoisomeric forms that present distinct
DNA-interacting properties and cytotoxic behaviors.
better control of drug-action specificity through spatial and
temporal activation.[4,5] The photoactivation of metal-con-
taining compounds is fundamentally metal-centered,[5] with
various mechanisms of action.[6] To the best of our knowledge,
potential PACT based on the photochemical modification of
ligand(s) coordinated to a metal ion has not been reported so
far.
1,2-Dithienylethene derivatives are photochromic mole-
cules which can be converted into either their open or closed
forms upon exposure to visible or UV light.[7] These thermally
stable photoswitching moieties exhibit clear differences
regarding specific physical properties, for example, molecule
size, conformational flexibility, and electronic energy levels.[8]
Consequently, this remarkable category of molecular switches
has found numerous applications in several fields.[9]
Herein, we report on the preparation of two platinum(II)
complexes obtained from photoswitchable diarylethene
ligands, that is, LH[10] and LF[11] (Figure 1a), and the inves-
tigation of their DNA-binding abilities and cytotoxic proper-
ties. The studies reveal that the open/closed forms of the Pt/LH
and Pt/LF complexes display distinct behaviors.
T
ransition-metal complexes represent an attractive class of
compounds for medicinal or biological applications.[1] For
instance, cisplatin and its derivatives have proven successful
as metal-based anticancer drugs.[2] One major drawback of
chemotherapy is the development of unpleasant treatment-
related side effects, which are due to the poor selectivity of the
therapeutic agents.[3] In that context, photoactivated chemo-
therapy (PACT) constitutes an elegant approach towards
[*] Prof. P. Gamez
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluꢀs Companys 23, 08010 Barcelona (Spain)
E-mail: patrick.gamez@qi.ub.es
Homepage: http://www.bio-inorganic-chemistry-icrea-ub.com/
A. Presa, R. F. Brissos, A. B. Caballero, I. Borilovic, Prof. P. Gamez
Departament de Quꢀmica Inorgꢁnica, Universitat de Barcelona
Martꢀ i Franquꢂs 1-11, 08028 Barcelona (Spain)
Dr. L. Korrodi-Gregꢃrio, Prof. R. Pꢄrez-Tomꢅs
Department of Pathology and Experimental Therapeutics
Universitat de Barcelona, Campus Bellvitge
Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat (Spain)
Dr. L. Korrodi-Gregꢃrio
Figure 1. a) The light-driven switching process for 1,2-bis[2-methyl-5-
(4-pyridyl)-3-thienyl]-cyclopentene (LH) and 1,2-bis[2-methyl-5-(4-pyr-
idyl)-3-thienyl]-perfluorocyclopentene (LF). b) X-ray structure of the
open form of 2, with partial atom numbering. H atoms are omitted for
clarity.
Laboratory of Signal Transduction, Centre for Cell Biology
Biology Department and Health Sciences Department
University of Aveiro
Campus de Santiago, 3810-193, Aveiro (Portugal)
Dr. O. Roubeau
Instituto de Ciencia de Materiales de Aragꢃn (ICMA), CSIC and
Universidad de Zaragoza, 50009 Zaragoza (Spain)
The ligands LH and LF (which are not water soluble) were
synthesized by applying common procedures used to generate
such molecules (see the Supporting Information).[12]
The crystal structures of one coordination compound
from LH[13] and five coordination compounds from LF[10,14]
have been reported so far, but none of them with platinum as
metal. We have prepared platinum(II) complexes with each
ligand by reaction of two equivalents of cis-[PtCl2-
(DMSO)2][15] and one equivalent of either LH or LF, in
methanol at room temperature. The compounds, identified as
[**] P.G. acknowledges the Instituciꢃ Catalana de Recerca i Estudis
AvanÅats, the Ministerio de Economꢀa y Competitividad of Spain
(Project CTQ2011-27929-C02-01), and COST Action CM1105. This
work was partially supported by a grant from the Spanish govern-
ment, the EU (FEDER) (FIS PI13/00089), La Maratꢃ de TV3
Foundation (20132730), and an individual grant from Fundażo
para a CiÞncia e Tecnologia of the Portuguese Ministry of Science
and Higher Education to L.K.G. (SFRH/BPD/91766/2012).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412157.
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trans-[Pt2Cl4(DMSO)2(LR)] (R = H for 1, R = F for 2), were
fully characterized, and the structure of open 2 was obtained
by single-crystal X-ray diffraction (see the Supporting Infor-
mation).
observed, especially for the closed complexes. The data
obtained thus show that the coordination compounds do
interact with the biomolecule, and most importantly, that
their open/closed forms exhibit drastically distinct behaviors.
The affinity of the compounds for DNA has been
evaluated and compared using the Stern–Volmer quenching
constant, KSV, by applying Equation (1).
A representation of the molecular structure of 2 is
depicted in Figure 1b. Crystallographic data, and selected
bond lengths, and angles are summarized in Tables S1 and S2
in the Supporting Information. As expected, 2 is a dinuclear
platinum(II) compound with two symmetry-related metal
centers, which exhibit a slightly distorted square-planar
geometry. It is notable that while the platinum precursor
has a cis configuration, the two metal ions in 2 display
a trans configuration. Such cis-to-trans isomerization has been
observed, and is due to the trans effect of S-bonded dimethyl
sulfoxide ligands.[16] The Pt–N, Pt–Cl, and Pt–S bond lengths
(see Table S2) are in normal ranges.[17] The slight distortion of
the square plane likely arises from steric hindrance induced
by the DMSO methyl groups. The analytical data for 1 suggest
that its structure is analogous to that of 2.
I0
I
ð1Þ
¼ 1 þ KSV ½complexꢀ
Herein, I0 and I are the emission intensities without and with
complex, respectively. A plot of I0/I vs. [complex] will give
a straight line whose slope is equal to KSV. The corresponding
plots for 1 and 2 (open/closed forms) are depicted in
Figure S4. The compound 1 displays a slightly better DNA
affinity than 2, with KSV = 6.6 ꢀ 103 ꢁ 0.8mꢂ1 (logKSV = 3.82)
for 1, while it is 4.8 ꢀ 103 ꢁ 0.9mꢂ1 (logKSV = 3.68) for 2. This
difference may be due to the fluorinated cyclopentenyl ring of
LF, whose fluorine atoms may induce unfavorable electro-
static repulsion with the phosphate backbone of the double
helix.[20] The most striking and important feature is the
significantly different behaviors of the open and closed forms
of both complexes; the KSV value for closed 1* is 42.5 ꢀ 103 ꢁ
0.6mꢂ1 (logKSV = 4.63), which is 6.5 times higher than that for
The switching properties of LH and LF, and the platinum
complexes 1 and 2, have next been examined by UV/Vis
spectroscopy. The corresponding spectra are shown in Figur-
es S1 (LH and LF), S2 (1), and S3 (2). Before UV irradiation at
l = 365 nm, strong absorption bands are observed below l =
400 nm (l = 230, 285 and 323 nm for LH; and l = 265, 275 and
300 nm for LF), and are due to p–p* transitions of the open
form of the ligands. Upon irradiation with UV light, two new
absorption bands are observed at l = 378 and 550 nm for LH,
and l = 381 and 592 nm for LF. These are ascribed to p–p*
transitions of the closed form of the ligands.[18] Upon
coordination to platinum, the p–p* transitions of both ligands
are red shifted. The solution (in dichloromethane) UV/Vis
spectrum of closed 1, that is 1*, exhibits characteristic p–p*
transition bands at l = 412 and 622 nm (Figure S2), and that
of 2* at l = 404 and 627 nm (Figure S3). Upon irradiation with
visible light, the initial spectra are recovered for 1 and 2 (as
for LH and LF), therefore indicating that the photocyclization
process is reversible. The stability of the closed forms of the
two coordination compounds has been also evaluated by UV/
Vis spectroscopy. Thus, solutions of 1 and 2 in CH2Cl2 have
been kept both in daylight and in the dark for 24 hours. UV/
Vis spectra have been subsequently recorded (Figures S2 and
S3), and show that the closed complexes are stable in the
absence of light. In contrast, in daylight, a clear decrease of
the p–p* transition bands of the closed compounds is
observed as a result of the partial opening of the coordinated
ligands LH and LF. The stability of the closed metal complexes
in the dark is of paramount importance regarding the study of
their potential DNA-interacting and cytotoxicity properties.
The potential interactions between DNA and the open/
closed forms of 1 and 2 have been investigated by fluores-
cence spectroscopy. Competitive binding studies using ethid-
ium bromide (EB) bound to calf thymus DNA (ct-DNA) have
been carried out. Displacement of EB from the fluorescent
EB-DNA adduct by a DNA-interacting molecule will induce
fluorescence quenching.[19] Fluorescence spectra have been
recorded at constant [ct-DNA] and [EB] (15 and 75 mm,
respectively), and using increasing amounts of 1 and 2 (in the
range 1–-25 mm). A clear decrease in emission intensity is
open 1. An analogous behavior is observed for 2* with KSV
=
26.8 ꢀ 103 ꢁ 0.9mꢂ1 (logKSV = 4.43), which is about 5.5 times
the value obtained for 2.
The greater interaction of the closed complexes with
duplex DNA may be explained structurally. The X-ray
structure of 2* could not be obtained, however, the structures
of the open/closed forms of one of the simplest members of
the 1,2-dithienylethene family, namely 1,2-bis[2,5-dimethyl(3-
thienyl)]-perfluorocyclopentene have been reported (see
Figure S5).[21] The open form is distinctly more voluminous
than the closed one (about 12% longer and 25% wider), and
the molecule is clearly more planar upon ring closure, with
a greater p conjugation. Consequently, it may be reasonable
to expect that the 1* and 2* will have an increased proficiency
to expel EB, owing to a sterically favored interaction with
DNA. Furthermore, the electronic changes taking place upon
ring closure will modify the coordination properties of the
ligand, and therefore affect the metal center (which may
modulate its DNA-binding properties).
It should be mentioned here that analogous studies with
the free ligands LH and LF could not be performed, since they
are not soluble in aqueous media or even buffer solutions
containing up to 10% DMSO. Therefore, the involvement of
the metal ions is crucial and the mechanism of action (of the
DNA interaction) is currently being investigated.
The interaction of the photoisomeric forms of 1 and 2 with
DNA has then been studied by agarose gel electrophoresis.
Electrophoretic-mobility measurements with pBR322 plas-
mid DNA were carried out, after a 24 hour incubation of
increasing quantities of 1/1* and 2/2* with the biomolecule in
the dark. The corresponding gels are depicted in Figure 2. The
free plasmid DNA is principally composed of form I, that is,
the normal supercoiled form, and some form II or relaxed
circular form (Figure 2, lanes 1). As reported earlier,[22] the
electrophoretic mobility of form II increases after incubation
2
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Figure 3. Cell-viability assays of the open and closed forms of the
complexes with different cancer cell lines, that is, A549 (lung adeno-
carcinoma), A375 (melanoma), DMS53 (SCLC), GLC4 (SCLC), MCF7
(breast adenocarcinoma), and PC3 (prostate adenocarcinoma), using
[complex]=50 mm (single-point screening) and an incubation time of
48 hours (the results are given in % of cell viability; see Table S3).
Figure 2. Agarose gel electrophoresis images of pBR322 DNA incu-
bated for 24 h at 378C with increasing concentrations of a) 1 and b) 2
(open and closed* forms). Lane 1: pure plasmid DNA; lane 2: DNA +
cisplatin; lanes 3,4: 0.5 equiv complex (op./cl.*); lanes 5,6: 1 equiv
complex (op./cl.*); lanes 7,8: 1.5 equiv complex (op./cl.*); lanes 9,10:
2 equiv complex (op./cl.*); lanes 11,12: 2.5 equiv complex (op./cl.*).
Each sample contains [DNA]=15 mm.
DMS53 cells, using 1*. Furthermore, no important difference
is noticed between 1 and 1*. For 2, clear differences are
observed between the open and closed forms. While open 2
does not show any significant cytotoxicity properties for all
cancer cell lines tested, closed 2* is active against most of
them. The best result for 2 is obtained with SCLC DMS53,
with a cell viability of 74%. However, 2* displays very good
cytotoxic properties towards melanoma and SCLC DMS53,
and to a lesser extent for adenocarcinoma. In particular, a cell
viability of 16% is achieved with skin-cancer A375 cells
(melanoma), whereas it is 89% for 2. Significant disparities
between the open/closed photoisomers are also observed in
SCLC DMS53 (74% vs. 29%) and GLC4 (93% vs. 36%), and
in MCF7 (95% vs. 68%).
with cisplatin (lanes 2) because of a shortening effect.[23]
Incubation of 0.5 equivalents ([complex] = 7.5 mm) of either
1 or 2 with DNA appears to decrease the electrophoretic
mobility until the complex/DNA adduct co-migrates with
relaxed circular DNA (lanes 3). This phenomenon, ascribed
to the unwinding of the double helix,[24] seems to be slightly
more pronounced for 1. In contrast, 0.5 equivalents of either
1* or 2* has almost no effect on supercoiled DNA. Only
initiation of the reduction of the electrophoretic mobility is
noticed (lanes 4). When 1 equivalent of the complex is used,
clear disparities are observed between 1 and 2 (lanes 5).
Indeed, while 1 nearly does not affect the DNA form I, 2
induces the disappearance of form I in favor of form II.
Remarkably, when using 1 equivalent of 1* and 2*, opposite
results are achieved (lanes 6), that is, 1* leads to the exclusive
formation of form II, whereas 2* initiates the alteration of the
electrophoretic mobility of form I. Using 1.5 equivalents of
the complexes causes comparable features (lanes 7 and 8).
Open 1 and 2 mediate the reduction of the electrophoretic
mobility of form I, with 2 being slightly more efficient than 1.
Both 1* and 2* cause an unwinding of DNA form I (smears
are observed in lanes 8), thus decreasing its electrophoretic
mobility. For higher complex quantities, (2 and 2.5 equiva-
lents; lanes 9–12), the same behavior is observed for 1 and 1*,
that is, form I and II are observed for 1, while form I has
disappeared for 1*. Avanishing of the bands is also discerned,
and may originate from the initial precipitation of the DNA/
complex adduct. For 2 and 2*, the high concentration of
complex leads, in all cases, to a total conversion of form I into
form II. The open/closed forms of the complexes have
drastically distinct DNA-interacting behaviors, with the
closed ones modifying the DNA shape more efficiently. The
closed 2* performs better than 1*, which is reversed
compared to the competitive binding studies.
IC50 values have been determined for the SCLC DMS53
cell line, which is the most common and most virulent of
neuroendocrine (NE) cancers. The corresponding results,
after incubation times of 48 and 72 hours, are shown in
Figure S6, and listed in Table 1. The data obtained corrobo-
Table 1: IC50 values[a] (mm) of open/closed 1, 2 and cisplatin for the
DMS53 cell line (SCLC), after 48 h and 72 h of incubation. ꢁSD of three
independent experiments.
Compound[b]
48 h
72 h
1
1*
2
2*
77.37ꢁ3.27
76.40ꢁ5.26
75.87ꢁ5.42
34.40ꢁ3.74
8.53ꢁ1.59
75.00ꢁ5.39
73.59ꢁ4.22
55.00ꢁ6.34
30.46ꢁ4.38
3.97ꢁ0.31
cisplatin
[a] IC25 and IC75 have been determined as well, and are listed in Table S4.
[b] Closed complexes are indicated by an asterisk (*).
rate those achieved by single-point screening measurements.
The behavior of 1/1* is similar (identical IC50 values are
obtained, and the same trend is observed for the IC25 and IC75
values in Table S4). As previously observed, 2/2* exhibit
distinct cytotoxicity properties. After an incubation time of
48 hours, 2 displays an IC50 value analogous to those of 1/1*,
but 2* is more than twice as active, with IC50 = 34.40 mm versus
75.87 mm (Table 1). After an incubation time of 72 hours,
a marked difference between 2 and 2* is still noted, albeit it
somewhat less pronounced. Compounds 1/1* are weakly
cytotoxic, and this behavior is not altered by a longer
incubation time. Compared to cisplatin, 2* is about four to
eight times less active. It should be taken into account,
Cell-viability assays were carried out subsequently. First,
each compound (open/closed forms) was screened by means
of single-point assays, using [complex] = 50 mm, with six
cancer cell lines, that is A549 (lung adenocarcinoma), A375
(melanoma), DMS53 (small cell lung cancer, SCLC), GLC4
(SCLC), MCF7 (breast adenocarcinoma), and PC3 (prostate
adenocarcinoma). The corresponding results, obtained after
an incubation time of 48 hours, are shown in Figure 3 and
Table S3.
The compounds 1/1* exhibit very poor cytotoxicity
properties. At best, a cell viability of 72% is achieved with
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however, that contrary to cisplatin, 2 is a photoactivatable
molecule.
other. These first (unprecedented) results open up a new
perspective in the field of PACT. We are currently preparing
new members of this new category of molecules, and the study
of the effect of the photoswitching process inside cells is being
set up.
Finally, since these platinum(II) compounds show fluo-
rescence properties, their cellular uptake in affected (A375
and DMS53) and unaffected (PC3 and A549) cell lines has
been examined by confocal microscopy. The fluorescence
data obtained clearly indicate that all compounds are capable
of entering the cells. However, their behavior inside the cells
is not the same, and is apparently associated with their
cytotoxic activity. When the cell-viability assays reveal a poor
cytotoxicity, vesicular structures are detected (A549, DMS53
and PC3 cells; see Figures S7, S8 and S9, respectively). In
contrast, a diffuse cytoplasmic staining is observed when the
compound is cytotoxic, as seen in Figure 4 for 2* in A375.
Received: December 19, 2014
Revised: January 9, 2015
Published online: && &&, &&&&
Keywords: cancer · cytotoxicity · drug design · photochemistry ·
.
platinum
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Communications
Drug Design
Toxic switch: The photoswitchable open
and closed forms of 1,2-dithienylethene-
based platinum(II) compounds exhibit
distinct DNA-interacting and cytotoxic
properties, which may lead to a new class
of potential photoactivatable anticancer
agents.
A. Presa, R. F. Brissos, A. B. Caballero,
I. Borilovic, L. Korrodi-Gregꢁrio,
R. Pꢂrez-Tomꢃs,* O. Roubeau,
P. Gamez*
&&&& — &&&&
Photoswitching the Cytotoxic Properties
of Platinum(II) Compounds
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!