The cis-Diammineplatinum(II) Complex of Curcumin: A Dual Action DNA Crosslinking and Photochemotherapeutic Agent

Article abstract of DOI:10.1002/anie.201507281

[Pt(cur)(NH₃)₂](NO₃) (1), a curcumin-bound cis-diammineplatinum(II) complex, nicknamed Platicur, as a novel photoactivated chemotherapeutic agent releases photoactive curcumin and an active platinum(II) species upon irradiation with visible light. The hydrolytic instability of free curcumin reduces upon binding to platinum(II). Interactions of 1 with 5′-GMP and ct-DNA indicated formation of platinum-bound DNA adducts upon exposure to visible light (λ=400-700 nm). It showed apoptotic photocytotoxicity in cancer cells (IC₅₀≈15 μM), thus forming OH, while remaining passive in the darkness (IC₅₀>200 μM). A comet assay and platinum estimation suggest Pt-DNA crosslink formation. The fluorescence microscopic images showed cytosolic localization of curcumin, thus implying possibility of dual action as a chemo- and phototherapeutic agent.

Full text of DOI:10.1002/anie.201507281

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507281
German Edition: DOI: 10.1002/ange.201507281
Cell Imaging Hot Paper
The cis-Diammineplatinum(II) Complex of Curcumin: A Dual Action
DNA Crosslinking and Photochemotherapeutic Agent
Koushambi Mitra, Srishti Gautam, Paturu Kondaiah,* and Akhil R. Chakravarty*
Dedicated to Professor Animesh Chakravorty on the occasion of his 80th birthday
Abstract: [Pt(cur)(NH ) ](NO ) (1), a curcumin-bound cis-
no dark toxicity is photoactivated to generate cytotoxins
3
2
3
[
4]
diammineplatinum(II) complex, nicknamed Platicur, as
a novel photoactivated chemotherapeutic agent releases photo-
active curcumin and an active platinum(II) species upon
irradiation with visible light. The hydrolytic instability of free
curcumin reduces upon binding to platinum(II). Interactions
of 1 with 5’-GMP and ct-DNA indicated formation of
platinum-bound DNA adducts upon exposure to visible light
selectively within the cancerous tissues. The control of the
drug release and drug doses makes PDT more advantageous
[
5,6]
in contrast to the conventional anticancer therapies.
To circumvent two major predicaments associated with
cisplatin, that is 1) the nuclear excision repair mechanism and
2) rapid dissociation of the chlorides, one needs to consider
different sets of ligands instead of chloride. The use of O,O-
donor ligands, such as oxalic acid in oxaliplatin or a dicarbox-
ylic acid in carboplatin, has shown improvement in the
(
l = 400–700 nm). It showed apoptotic photocytotoxicity in
·
cancer cells (IC ꢀ 15 mm), thus forming OH, while remaining
5
0
[1]
passive in the darkness (IC > 200 mm). A comet assay and
efficacy of the drug. Another alternate and viable strategy
could be to direct the platinum(II) complex to mitochondrial
DNA instead of nuclear DNA. We put forward a new strategy
in this communication in which a different class of O,O-donor
ligand, well known for showing preferential cytosolic local-
ization than nuclear uptake, is used in designing a cisplatin
analogue. The O,O-donor ligand is curcumin (Hcur), which in
its enolic form binds to metals. Hcur is derived from yellow
turmeric and has diverse medicinal properties as a traditional
Indian and Chinese medicine. Curcumin itself has the ability
to inhibit various proinflammatory transcription factors (NF-
kB), thus leading to its remarkable anti-inflammatory and
50
platinum estimation suggest Pt–DNA crosslink formation. The
fluorescence microscopic images showed cytosolic localization
of curcumin, thus implying possibility of dual action as
a chemo- and phototherapeutic agent.
T
he therapeutic pathway of cisplatin involves dissociation of
the PtÀCl bonds to form a diaquadiammineplatinum(II)
species which acts as a transcription inhibitor by forming
platinum–nuclear DNA crosslinks and triggers apoptosis, thus
[
1]
eventually leading to cellular senescence. Modulation of the
kinetic processes involved has led to the introduction of
cisplatin analogues such as carboplatin and oxaliplatin. These
platinum(II) species together are considered the backbone of
cancer chemotherapy. The potency of platinum-based anti-
cancer agents is limited by several undesired side-effects, such
as nephrotoxicity, hepatotoxicity, neurotoxicity, and ototox-
[
7]
anticancer properties. Despite immense potency and safety
at high doses, it has failed to gain much approval as
a therapeutic agent because of its low aqueous solubility,
rapid metabolism leading to degradation, and reduced
bioavailability (only 1% of actual dose retained in plasma
[
1c]
[8]
icity, as well as the drug-resistance of cisplatin.
A new
of rats after 1 h of oral administration). Reports have shown
IV
strategy has emerged in which six-coordinate Pt complexes,
as inert prodrugs, are shown to release four-coordinate active
platinum(II) species upon reduction by cellular glutathione or
that the degradation of curcumin can be arrested upon its
[
9]
complexation with d- and f-block metal ions. Curcumin has
an intense absorption band in the visible region at about l =
430 nm and this imparts its photosensitizing abilities. The
triplet state of photoactivated curcumin reacts with molecular
oxygen and generates reactive oxygen species (ROS). More-
over, the green emissive band of the dye at about l = 520 nm
enables cellular imaging and tracking of its conjugates within
the cell.
[
2]
IV
upon photoactivation. The Pt diazido complexes in blue
[
3]
light show remarkable cytotoxicity. Photoactivated chemo-
therapy (PACT) as a complementary methodology to photo-
dynamic therapy (PDT) has emerged as a viable modality for
cancer treatment in which a prodrug showing lower or even
[
*] K. Mitra, Prof. A. R. Chakravarty
Department of Inorganic and Physical Chemistry
Indian Institute of Science
Bangalore 560012, Karnataka (India)
E-mail: arc@ipc.iisc.ernet.in
With an objective to achieve controlled cellular delivery
of curcumin, we have designed and synthesized a platinum(II)
complex of curcumin, [Pt(cur)(NH ) ](NO ) (1). The complex
3
2
3
1, called Platicur, is found to release curcumin and a cisplatin
analogue upon irradiation with visible light (l = 400–700 nm).
Light activation imparts controlled release of curcumin.
Though curcumin has earlier been used as an adjuvant and
S. Gautam, Prof. P. Kondaiah
Department of Molecular Reproduction, Development and Genetics,
Indian Institute of Science
Bangalore 560012, Karnataka (India)
E-mail: paturu@mrdg.iisc.ernet.in
[10]
in combination with cisplatin for cancer treatment,
no
previous attempt is documented involving the delivery of
both curcumin and a cisplatin analogue from a single prodrug.
The complex 1 and its acetylacetonate analogue [Pt(acac)-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507281.
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13989

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Communications
crystallography (Figure 1c; see Tables S2 and S3 and Fig-
[
11]
ure S6b).
The complex crystallized in the orthorhombic
II
Cmc2 space group and has the Pt center in a distorted
1
square-planar geometry with two ammine ligands and a che-
lating monoanionic acac. The PtÀO and PtÀN bond lengths
are 1.990(6) and 2.046(8) Š, respectively.
The stability of 1 and 2 were studied in 10% DMSO/
DPBS or DMEM (pH 7.2, 378C) by monitoring UV-visible
spectral changes with time. The complex 1 showed slow
À7
À1
hydrolysis (initial rate, khyd = 8.9 ” 10 min for 1). The dye
alone degraded rapidly and only about 10% remained intact
after 4 hours, while 1 was about 75% intact (see Figure S7).
This data indicates enhanced stability of the b-diketone
moiety upon complex formation. There was no noticeable
1
change in the H NMR spectra in 1:1 D O/[D ]MeOH, even
2
4
after 48 hours, and thus further suggested the stability of the
complexes. Platinum analogues having O,O-donor ligands are
known for slow release of the ligands in a cellular medium.
Photorelease of these ligands from the platinum(II) center is
Figure 1. a) Chemical structures of 1 and 2. b) UV-visible spectra of 1,
, and Hcur (100 mm) in 10% DMSO/DPBS (pH 7.2). c) ORTEP
drawing of 2a. Thermal ellipsoids shown 50% probability. H atoms
are omitted for clarity. d) Increase in emission intensity of 1 (50 mm in
2
[
11]
[12]
1
:1 DMSO/water), monitored at l=530 nm (lexc =430 nm), upon
photoirradiation (visible light, l=400–700 nm). Data recorded at
0 min time intervals. e) Energy-minimized structure of 1 using
B3LYP/LanL2DZ (for Pt)/6-31+G (for other atoms) level of theory.
known. The excellent photophysical properties of curcumin
II
and the 5d Pt heavy metal amplify the possibilities of such
1
phototriggered conversions of 1. Thus we studied the
possibility of release of the dye upon exposure to light
(Luzchem; l = 400–700 nm) and in the dark. The emission
intensity of free curcumin is dampened in the metal-bound
form (see Figure S6a). An increment in emission intensity
therefore will indicate the release of curcumin. We observed
this enhancement of emission intensity at l = 530 nm upon
photoexposure of 1 (Figure 1d). However, the intensity
remained unaltered in the darkness for 24 hours, thus
indicating the importance of light activation for metal–O,O-
donor ligand bond dissociation (see Figure S8).
(
7
NH ) ](NO ) (2), as a control, were synthesized in about
3 2 3
0% yield upon reacting cisplatin with AgNO , with subse-
3
quent addition of curcumin (Hcur) for 1 and acetylacetone
Hacac) for 2 in the presence of a base (Figure 1a; see
(
Scheme S1 in the Supporting Information). The complexes
are characterized by ESI-MS, NMR, HPLC, ICP-MS, IR,
CHN, redox, and electronic spectral data (see Figures S1–S6
and Table S1). The molar conductance value of about
The fluorescence lifetimes were measured to support our
hypothesis. The respective values in 1:1 aqueous DMSO in the
dark are 13.6 and 23 ps for 1 and curcumin. The solutions of
1 after 1 hour of light exposure gave a lifetime of 19.4 ps,
which is similar to that of free curcumin (see Table S4). It
remained unaltered for curcumin when exposed to light. The
absorption spectra of 1 showed a decrease in the intensity at
l = 460 and 435 nm upon light exposure with concomitant
increase at l = 385 nm and the appearance of a band at l =
400 nm (see Figure S8d). These bands are assignable to
2
À1
8
0 Scm mol in aq. DMF (1:1 v/v) at 258C suggests 1:1
electrolytic nature of the complexes. A single peak in the mass
+
spectra corresponding to [MÀNO ] species (m/z 596.13 for
3
1
and 328.05 for 2) indicated formation of the desired
complexes. The isotopic distribution further confirmed the
presence of platinum in the ionic form (see Figure S1). The
1
H NMR spectrum of 1 showed the g-proton of the diketone
moiety having an up-field shift of 0.1 ppm as compared to that
in Hcur. The IR spectra showed characteristic peaks at 3200
(
À1
[13]
nN-H), 1590 (nC
=
O), and 1495 (nC C
=
) cm . The complex
curcumin and its degraded products. The experiments in
1
(1 mm in DMF-0.1m TBAP) showed an irreversible
10% DMSO/DPBS showed a rapid loss of the emission and
response at À1.35 V versus SCE, and is characteristic of
absorption intensity (initial rate of photodegradation, k
=
photo
À6
À1
curcumin [E (Hcur) = À1.80 V] (see Figure S4c,d). The
2.8 ” 10 min ) upon photoexposure for 10 minutes (l =
400–700 nm), owing to the instability of the released curcumin
at pH 7.2 (see Figure S9). The mass spectral analysis of the
irradiated samples of 1 confirmed the presence of free
f
absence of any metal-based redox activity indicates the
electrochemical stability of the complex. The solution purity
of the complexes (ca. 95%) was ascertained using ICP-MS
and HPLC methods (see Figure S5), and in the solid state by
CHN analysis. The absorption spectra of 1 (100 mm) in 10%
DMSO/DPBS (pH 7.2) exhibited two equally intense bands
+
curcumin (m/z 369, [M+H] ) and its hydrolyzed products
(see Figure S10). Loss of curcumin from the platinum(II)
center is expected to form an aqua species capable of forming
crosslinks with DNA. To evaluate such a possibility, 1 was
mixed with guanosine monophosphate (5’-GMP, 1:10 ratio in
À1
À1
at l = 460 and 435 nm (e = 22500m cm ) with a shoulder at
À1
À1
l = 385 nm (e = 15000m cm ; Figure 1b). The acac com-
plex 2 (lmax = 308 nm) did not show such bands. The complex
1
1:1 D O/[D ]DMSO) and H NMR spectra were recorded
2
6
1
was emissive (lem = 530 nm) when excited at l = 430 nm,
thus giving a quantum yield (F) value of 0.02 in 1:1 aq. DMSO
F of curcumin, 0.04; see Figure S6a). The complex 2 as its
CF SO salt (2a) was structurally characterized by X-ray
after 8 hours of light exposure (l = 400–700 nm) and showed
the appearance of new peaks at d = 8.5 and 9.2 ppm (see
Figure S11). The H8 proton of uncoordinated 5’-GMP
appeared at d = 8.1 ppm. This proton experienced downfield
(
3
3
1
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shift upon coordination of 5’-GMP to Pt at N7, and is
[
14]
characteristic of the Pt–GMP adducts. The downfield shift
of d = 0.4 and 1.1 ppm can be respectively assigned to the bi-
and monofunctional adduct. The bifunctional adduct was
detected in the mass spectra (m/z = 477.08; see Figure S12a).
In contrast, 1 reacts with 5’-GMP in the dark only after
3
0 hours. The DNA crosslink formation was also evidenced
from the experiments using ct-DNA (300 mm) and ethidium
bromide (EB, 50 mm) in 5% DMSO/DPBS medium. EB, upon
intercalation within DNA, increases its emission intensity as
a result of entrapment in the hydrophobic core. Upon
treatment with the complex (50 mm) and light, the emission
intensity of DNA-intercalated EB decreased (ca. 13%) at l =
Figure 2. Cell viability plots of 1 for a) HaCaT and BT474 and
b) Hep3B and T47D. There was a 4 h pre-incubation followed by either
À2
light exposure (L, l=400–700 nm, 10 Jcm ) or without irradiation (D,
in the dark).
5
95 nm (lexc = 546 nm), thus suggesting formation of Pt–DNA
adducts (see Figure S12b). Thiourea (10 mm) treatment led to
a marginal increase in its emission intensity, thus indicating
that about 2% of adducts were monofunctional. Curcumin
alone did not alter the emission intensity of EB. To rule out
any displacement of EB by 1 with DNA, the DNA melting
studies were performed. The complex 1 and curcumin showed
that of free curcumin (10–13 mm). The acac complex 2 did not
show any PDTactivity. The complex 1 showed about a twofold
lower photocytotoxicity [IC (light) ꢀ 30 mm] in the immor-
50
talized nontransformed human peripheral lung epithelial
HPL1D cells as compared to the cancer cells (see Figure S15
and Table S8). Since PDT is applicable to superficially
exposed cells, we used HaCaT cells for further studies. The
DCFDA assay, a quantitative method to assess cellular ROS
formation, showed that about 90% of the HaCaT cells treated
with 1 caused DCF formation only upon light exposure
(Figure 3a; see Figure S16). AnnexinV/FITC-PI assay
no DNA intercalative property (DT ꢀ 08C) as compared to
m
EB (DT ꢀ 198C; see Figure S13a). Interestingly, 1, upon light
m
exposure, gave similar temperature shifts to those of cisplatin
in the dark (DT ꢀ 1.08C). The complex was stable at 1008C,
m
thus ensuring no thermal degradation of 1 during the DNA
melting studies. Viscosity studies revealed non-intercalative
nature of 1 (see Figure S13b). Furthermore, an increased
amount of Pt of about 170 ppb was detected by ICP-MS in
light-exposed samples of 1 (100 mm) and ct-DNA (200 mm)
[
5% DMSO/DPBS buffer, pH 7.2] compared to samples
incubated in the dark (see Figure S13c). The control complex
showed its photostability with no apparent formation of Pt–
2
DNA adducts (see Figure S7d).
Theoretical calculations (B3LYP functional with basis sets
LanL2DZ for Pt/6-31 + G* for C,H,N,O) were done to study
Figure 3. a) The percent cell positivity from a DCFDA assay for HaCaT
cells upon 4 h pre-treatment with the compounds [A: cells alone; B:
cells+DCFDA; C: 1 (18 mm); D: 2 (40 mm); E: curcumin (12 mm)] and
[15]
the photophysical properties of 1.
The l = 493 nm (f =
1
0
.833) transition is assigned to the dissociative LMCT:
HOMO (Hcur)!LUMO (PtÀO bond; Figure 1e; see
Tables S5 and S6). These are s* towards PtÀO bonds, thus
suggesting photocleavage. Pt promotes intersystem crossing
1
h light exposure (l=400–700 nm). b) AnnexinV-FITC/PI assay in
HaCaT cells with 1 (18 mm, 4 h incubation, 1 h light-exposure) showing
% apoptotic cell death [Quadrants: lower left=live cells, lower right=
early apoptotic cells, upper right=late apoptotic cells, upper left=
necrotic/dead cells].
(
ISC) by spin-orbit coupling resulting in long-lived triplet
states. The optimization of the triplet excited state geometry
revealed elongation of the PtÀO bonds by about 0.2 Š with
loss of planarity of the curcumin moiety (C1-C2-C3-C4
dihedral angle of 268), thus suggesting the possibility of
elimination of curcumin from the photoexcited state (see
Figure S14a and Table S7). Concomitant loss of respective
Mulliken charges on Pt and O was also observed in the
excited state.
revealed that about 83% of the total cell population of
HaCaT cells treated with 1 (18 mm) was early apoptotic on
light treatment while only 13% cell death was observed in the
dark (Figure 3b; see Figure S17). The PI (propidium iodide)
cell cycle analysis resulted in light-triggered arrest (ca. 58%)
in the sub-G1 phase of 1-treated HaCaT cells (see Fig-
ure S18). To understand the nature of ROS, we performed
DNA photocleavage experiments using an Ar-Kr mixed gas
ion laser (power= 50 mW) of l = 457 nm (see Figure S19).
The complex 1 (10 mm in buffer having 10% DMF) showed
photocleavage of pUC19 DNA, thus forming about 90% of
the nicked circular (NC) form. The presence of singlet-oxygen
The photorelease of curcumin leading to the formation of
a DNA crosslinking agent prompted us to assess the light-
activated anticancer potency of 1. The IC50 values were
determined from the MTT assay in HaCaT (immortalized
transformed skin keratinocytes), BT474 and T47D (breast
epithelial ductal carcinoma), and Hep3B (hepatocarcinoma)
cells (Figure 2; see Figure S15 and Table S8). The complex
quenchers like NaN and TEMP diminished the amount of
3
1
7
2
gave IC50 values of 12–18 mm (4 h pre-incubation, 400–
the NC form by about 10%. However, addition of KI and
DMSO as hydroxyl radical scavengers brought marked
reduction (ca. 50% NC) in the DNA photocleavage activity,
À2
00 nm, 10 Jcm ), and were nontoxic in the dark [IC >
50
00 mm]. The IC50 values of 1 in light were comparable to
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.
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thus suggesting that hydroxyl radicals are the major ROS. The
DNA cleavage was also reduced (ca. 20% NC) under an inert
cancer cells upon light activation. The curcumin dye alone
fails to reach the target tumour cells because of its hydrolytic
instability in a buffer medium and poor bioavailability, while
the nonspecific interaction of cisplatin results from its rapid
uncontrolled hydrolysis. These drawbacks limit the medicinal
applications of both curcumin and cisplatin. The observed
in vitro photodegradation of 1, from fluorescence studies and
platinum estimations, is unique and unprecedented, thus
permitting controlled generation of diammineplatinum(II)
species as a DNA crosslinking/transcription inhibitor agent
and the released curcumin as a PDT agent, in visible light, at
the site of action. The remarkable phototoxic behavior of 1 in
cancer cells (IC ꢀ 12–18 mm, 400–700 nm), along with the 15-
atmosphere, thereby implying the need for aerial O for its
2
photoactivity.
Fluorescence microscopic images show cytoplasmic local-
ization of 1 (20 mm) in HaCaT cells (Figure 4). This local-
5
0
fold lower toxicity in the dark, defines a new generation of
visible-light activated dual-action anticancer agents.
Acknowledgements
We thank the Department of Science and Technology (DST),
Government of India, for financial support (SR/S5/MBD-02/
2
015), and the Alexander von Humboldt Foundation (Ger-
many) for an electrochemical system. A.R.C. thanks DST for
a J. C. Bose Fellowship. We thank Dr. R. Chakrabarti, Center
of Earth Sciences, IISc for the ICP-MS facility.
Keywords: antitumor agents · cell imaging · curcumin · DNA ·
platinum
Figure 4. Fluorescence images of HaCaT cells upon 4 h incubation
with 1 (20 mm), thus showing co-localization in ER. Trackers in rows
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13989–13993
Angew. Chem. 2015, 127, 14195–14199
1
through 4: PI, MTR, ER-Tracker red, and lyso tracker red, respectively.
Scale bar=20 mm.
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