Multifunctional DNA interactions of Ru-Pt mixed metal supramolecular complexes with substituted terpyridine ligands

Article abstract of DOI:10.1021/ic900190a

The coupling of a light absorbing unit to a bloactive site allows for the development of supramolecules with multifunctional Interactions with DNA. A series of mixed metal supramolecular complexes that couple a DNA-bindlng cis-Pt^IICl₂

Full text of DOI:10.1021/ic900190a

Inorg. Chem. 2009, 48, 9077–9084 9077
DOI: 10.1021/ic900190a
Multifunctional DNA Interactions of Ru-Pt Mixed Metal Supramolecular
Complexes with Substituted Terpyridine Ligands
Avijita Jain,† Jing Wang,† Emily R. Mashack,† Brenda S. J. Winkel,‡ and Karen J. Brewer*,†
†Departments of Chemistry and, and ‡Biological Sciences, Virginia Polytechnic Institute and State University,
Blacksburg, Virginia 24061-0212
Received January 29, 2009
The coupling of a light absorbing unit to a bioactive site allows for the development of supramolecules with
multifunctional interactions with DNA. A series of mixed metal supramolecular complexes that couple a DNA-binding
cis-PtIICl2 center to a ruthenium chromophore via a polyazine bridging ligand have been prepared, and their
DNA interactions have been studied, [(TL)RuCl(dpp)PtCl2](PF6) (TL = tpy (2,20:60,200-terpyridine), MePhtpy (40-(4-
t
methylphenyl)-2,20:60,200-terpyridine), or Bu3tpy (4,40,400-tri-tert-butyl-2,20:60,200-terpyridine and dpp = 2,3-bis(2-
pyridyl)pyrazine). This series provides for unique tridentate coordinated Ru(II) systems to photocleave DNA with
preassociation with the DNA target via coordination of the Pt(II) center. Electronic absorption spectroscopy of the
complexes displays intense ligand-based πfπ* transitions in the UV region and metal to ligand charge transfer
(MLCT) transitions in the visible region. The Ru(dπ)fdpp(π*) MLCT transitions occur at 545 nm, red-shifted relative
to the 520 nm maxima for the monometallic synthons, [(TL)RuCl(dpp)](PF6). The title RuPt complexes display
t
reversible RuII/III oxidative couples at 1.10, 1.10, and 1.01 V vs Ag/AgCl for TL = tpy, MePhtpy, and Bu3tpy,
respectively. The TL0/- reduction occurred at -1.43, -1.44, and -1.59 V vs Ag/AgCl for TL = tpy, MePhtpy,
t
and Bu3tpy, respectively. These complexes display a dpp0/- couple (-0.50 -0.55, and -0.59 V) significantly
shifted to positive potential relative to their monometallic synthons (-1.15, -1.16, and -1.22 V), consistent with
the bridging coordination of the dpp ligand. Coupling of (TL)RuIICl(BL) subunit to a cis-PtIICl2 site provides for the
application of photochemically inactive RuII(tpy)-based chromophores in DNA photocleavage applications. The
[(TL)RuCl(dpp)PtCl2]+ complexes display covalent binding to DNA and photocleavage upon irradiation with visible
light modulated by TL identity. The redox, spectroscopic, DNA-binding, and photocleavage properties of a series of
supramolecular complexes are presented.
Introduction
analogs with reduced toxicity and improved clinical
efficacy.5,6
Cisplatin, cis-[Pt(NH3)2Cl2] (cis-diamminedichloroplatinum-
(II)), and its analogs are a class of widely used antitumor
drugs. The antitumor activity of cisplatin derives from its
binding to DNA and formation of covalent cross-links
that inhibit both DNA replication and transcription.1-4
Cisplatin is extensively used in the treatment of testicu-
lar, ovarian, bladder, lung, head, and neck carcinomas.
Significant side effects, including nephrotoxicity, gastro-
intestinal toxicity, neurotoxicity, and ototoxicity, low
water solubility, and drug resistance have limited the
clinical applications of this drug. There has been a
considerable interest in the development of cisplatin
Ruthenium polyazine complexes have attracted the
attention of researchers for decades.7 These complexes
possess highly versatile photophysical, photochemical,
and redox properties and play an important role in
electron and energy transfer processes. The prototypical
ruthenium polyazine complex, [Ru(bpy)3]2+ (bpy = 2,20-
bipyridine), is well studied due to its long excited-
state lifetime and interesting photophysical and redox
properties.7-9 Upon optical excitation at 450 nm, popula-
tion of the Ru(dπ)fbpy(π*) 1MLCT occurs which popu-
3
3
lates the MLCT state with unit efficiency. The MLCT
of [Ru(bpy)3]2+ is relatively long-lived and emissive
*To whom correspondence should be addressed. E-mail: kbrewer@vt.
edu.
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2009 American Chemical Society
Published on Web 09/09/2009
pubs.acs.org/IC

9078 Inorganic Chemistry, Vol. 48, No. 19, 2009
Jain et al.
emission quantum yield of [Ru(tpy)2]2+-type molecules upon
incorporation of a methylphenyl group at the 40 position of
the terpyridine ring.15 The 40-methyl-sulphonyl substituted
bis-terpyridine complexes have been shown to have length-
ened room temperature luminescence lifetimes ([Ru(MeSO2-
tpy)2](PF6)2, 25 ns; [(MeSO2-tpy)Ru(tpy-OH)](PF6)2, 50 ns)
due to the strong electron-withdrawing ability of the methyl-
sulfonyl group.19
Figure 1. Polyazine ligands used in the study (tpy = 2,20:60,200-terpyridine,
MePhtpy = 40-(4-methylphenyl)-2,20:60,200-terpyridine, tBu3tpy = 4,40,400-
tri-tert-butyl-2,20:60,200-terpyridine), dpp = 2,3-bis (2-pyridyl)pyrazine).
The DNA photocleavage activity of ruthenium polyazine
complexes is well known.24-26 These types of complexes have
been shown to photocleave DNA via singlet oxygen (1O2)
3
em
3
generation. The MLCT state of these complexes under-
(λmax = 605 nm, excited-state lifetime of the MLCT,
goes energy transfer to molecular oxygen (3O2) to generate
1O2, which reacts with DNA, cleaving the backbone.24-26
Thummel and co-workers have reported that the complex,
[Ru(bpy)2(DAP)]2+ (DAP = 1,12-diazaperylene), photo-
cleaves DNA upon irradiation with visible light due to the
τ = 860 ns in acetonitrile).10
Applications of ruthenium(II) bis-tridentate polyazine
light absorbers are more limited than the highly studied
ruthenium(II) tris-bidentate polyazine chromophores. The
complex, [Ru(tpy)2]2+ (tpy = 2,20:60,200-terpyridine), exhibits
1
formation of the O2 species.27 The lower excited-state life-
less favorable photophysical properties than [Ru(bpy)3]2+
,
time of [Ru(tpy)2]2+ prevents its application in DNA photo-
3
exhibiting a very short-lived MLCT (0.25 ns in aqueous
cleavage.28,29
solution) excited state due to the thermal population of the
3LF (ligand field) excited state.11-14 The thermal accessibility
of the ligand field state is due to the unfavorable bite angle for
octahedral coordination associated with tpy-type ligands,
lowering the energy of the ligand field state. The low-lying
3LF state deactivates the normally emissive 3MLCT state. The
use of terpyridine ligands (Figure 1) provides the distinct
advantage of allowing stereochemical control, eliminating
the Δ and Λ isomeric mixtures, characteristic of tris-bidentate
systems.
The photophysical properties of Ru(II) bis-tridentate poly-
azine metal complexes can be tuned by the introduction of
various substituents on the terpyridine ligand.15-22 Electron-
withdrawing groups stabilize the lowest unoccupied molecu-
lar orbital (LUMO), while electron-donating groups destabi-
lize the highest occupied molecular orbital (HOMO).19,23
Stabilization of the lowest 3MLCT state results in lower
thermal population of the 3LF state. Balzani and co-workers
have reported both an increased excited-state lifetime and an
Complexes incorporating a tpy ligand were reported to
interact with DNA through electrostatic interaction, intercala-
tion, and groove binding.30-32 Turro and co-workers have
recently reported the DNA photocleavage activity of
[Ru(tpy)(pydppz)]2+ (pydppz = 3-(pyrid-20-yl)dipyrido(3,2-
a:20,30-c]phenazine) in the presence of oxygen.28 Thorp and co-
workers have examined the DNA cleavage activity of
[Ru(tpy)(tmen)(OH2)]2+ (tmen =N,N,N0,N0-tetramethylethy-
lenediamine) by cyclic voltammetry.26 The heteroleptic com-
plexes, [Ru(tpy)(PHBI)]2+ (PHBI = 2-(2-benzimidazole)-
1,10-phenanthroline) and [Ru(tpy)(PHNI)]2+ (PHNI = 2-(2-
napthoimidazole)-1,10-phenanthroline), were reported to inter-
act with DNA via electrostatic interaction and intercalation,
respectively.26 Recently, the 1O2 generation and the DNA
photocleavage ability of an aryl modified [Ru(X-tpy)2]2+
(X = 2-naphthyl, 1-pyrenyl, or 9-anthracenyl) complex has
been reported.33
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absorbers and a cisplatin unit, represent an emerging class
of bioactive molecules of interest as anticancer agents. The
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(PF6)2 (where M = Ru and Os, dpb = 2,3-bis(2-pyri-
dyl)benzoquinoxaline, bpy = 2,20-bipyridine) bind with
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Article
Inorganic Chemistry, Vol. 48, No. 19, 2009 9079
central pyridine ring of the tpy or the chloride ligand. The
effect of subunit modification of the terminal tpy ligand upon
spectroscopic and redox properties, DNA-binding, and
DNA cleavage ability of the mixed metal supramolecular
complexes is explored.
Experimental Section
Figure 2. Mixed metal Ru(II)-Pt(II) complexes of the form
TL-LA-BL-BAS with hydrogens omitted for clarity (TL = terminal
ligand, LA= lightabsorber, BL= bridging ligand, BAS = bioactivesite,
tpy = 2,20:60,200-terpyridine, MePhtpy = 40-(4-methylphenyl)-2,20:60,200-
Materials. All reagents were used as received unless otherwise
noted. The ligands, 2,20:60,200-terpyridine, 40-(4-methylphenyl)-
2,20:60,200-terpyridine, 4,40,4000-tri-tert-butyl-2,20:60,200-terpyri-
dine, and 2,3-bis(2-pyridyl)pyrazine, were purchased from
Aldrich Chemical Co. Ruthenium trichloride hydrate was ob-
tained from Alfa Aesar. Adsorption alumina (80-200 mesh)
was obtained from Fisher Scientific. Spectral grade acetonitrile
was received from Burdick and Jackson. Circular plasmid
pUC18 DNA was purchased from Bayou Biolab. Lambda
DNA/HindIII molecular weight marker was obtained
from Promega. Electrophoresis grade boric acid, agarose,
and molecular biology grade glycerol were purchased
from Fisher Scientific. The supporting electrolyte for electro-
chemical studies, tetrabutylammonium hexafluorophosphate
(Bu4NPF6), was purchased from Fluka. The complexes,
[(tpy)RuCl3],41 [(tpy)RuCl(dpp)](PF6),42 [(MePhtpy)RuCl3],41
[(MePhtpy)RuCl(dpp)](PF6),29 and [(tBu3tpy)RuCl3]43 were
synthesized as previously reported.
t
terpyridine, Bu3tpy = 4,40,400-tri-tert-butyl-2,20:60,200-terpyridine), and
dpp = 2,3-bis(2-pyridyl)pyrazine; gray sphere = carbon, blue sphere =
nitrogen, green sphere = chlorine, gold sphere = ruthenium, and white
sphere = platinum).
DNA through a cis-PtIICl2 moiety.34 The positive charge
imparted by the Ru(II) or Os(II) affords greater water
solubility as well as increased electrostatic attraction toward
DNA as compared to cisplatin.34 The [(tpy)Ru(dtdeg)-
PtCl]Cl3 (dtdeg = bis[40-(2,20:6;200-terpyridyl)]diethylenegly-
col) complex has been reported to interact with DNA through
intercalation in addition to covalent and electrostatic interac-
tions.36 Similarly, DNA-DNA and DNA-protein cross-
linking interactions of the [(μ-NH2(CH2)4NH2){cis-Pt(NH3)2-
Cl2)}2] complex have been reported.37
The DNA-binding properties of the heteronuclear bime-
tallic complexes, [(tpy)RuCl(BL)PtCl2](PF6) (BL = 2,3-bis-
(2-pyridyl)pyrazine (dpp), 2,3-bis(2-pyridyl)quinoxaline
(dpq), or 2,3-bis(2-pyridyl)benzoquinoxaline (dpb)), have
been reported.38 The [(tpy)RuCl(dpp)PtCl2](PF6) complex
shows rapid binding to plasmid DNA with significant re-
tardation of migration of the DNA through agarose gels as
compared to that of cisplatin, though no photocleavage is
reported. Brewer and co-workers have reported the Ru-Pt
tetrametallic complex displaying covalent binding by a cis-
PtIICl2 unit and DNA photocleavage via ruthenium poly-
pyridyl moiety.39 Recently, antimicrobial properties of the
[(tpy)RuCl(dpp)PtCl2](PF6) complex have been reported.40
Herman and co-workers have reported that the mixed metal
supramolecular complex, consisting of a cisplatin moiety and
two NAMI subunits [(ImH)(trans-RuCl4(DMSO)-(Im))], is
capable of DNA binding and potent against both neoplastic
and metastatic cancer.6
Herein, we report the coupling of [(tpy)RuCl(BL)] sub-
units to a cis-PtIICl2 moiety, which provides for the applica-
tion of typically shorter lived chromophores in DNA
photocleavage applications. The impact of component modi-
fication on DNA-binding and photocleavage properties of
Ru-Pt mixed metal supramolecular complexes is explored.
With the proper choice of ligand, multifunctional supramo-
lecular assemblies (Figure 2) can be formed that can coordi-
nate to DNA through a cis-PtIICl2 moiety and can
photocleave DNA through a tpy-containing Ru polyazine
chromophore. These complexes exist as mixtures of two
stereoisomers with the pyrazine of the dpp BL trans to the
Methods
ESI Mass Spectroscopy. Electrospray ionization mass
spectral analysis was performed by M-Scan Inc., West
Chester, PA, on a VG analytical ZA\B 2-SE high
field mass spectrometer. The spectra observed for the
complexes are consistent with the proposed molecular
structure.
Electrochemistry. Cyclic and square wave voltam-
metric experiments were performed using a one compart-
ment three-electrode cell, Epsilon potentiostat from
Bioanalytical Systems (BAS). The three-electrode system
consisted of a platinum disk working electrode, a plati-
num wire auxiliary electrode, and a Ag/AgCl reference
electrode (0.21 V vs NHE). The reference electrode
+
was calibrated using the Fe(C5H5)2/Fe(C5H5)2 couple
(0.67 V vs NHE).44 The supporting electrolyte used was
0.1 M Bu4NPF6, and measurements were carried out in
spectral grade acetonitrile under argon.
Electronic Absorption Spectroscopy. Electronic absorp-
tion spectra were recorded at room temperature using a
Hewlett-Packard 8452 diode array spectrophotometer
with 2 nm resolution. Solutions were prepared gravime-
trically in spectral grade acetonitrile, and data were
collected at room temperature using 1 cm quartz cuvettes.
The extinction coefficients are the average of three mea-
surements on separate solutions.
DNA-Binding and Photocleavage Studies. The ability of
the metal complex to bind and photocleave pUC18
plasmid DNA was assayed using agarose gel electropho-
resis. All samples were prepared according to a standard
protocol.34 Master solutions of metal complexes were
(36) Schilden, K. V. D.; Garcia, F.; Kooijman, H.; Spek, A. L.; Haansoot,
J. G.; Reedijk, J. Angew. Chem., Int. Ed. 2004, 43, 5668–5670.
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11794–11801.
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2003, 42, 4394–4400.
(39) Miao, R.; Mongelli, M. T.; Zigler, D. F.; Winkel, B. S. J.; Brewer, K.
J. Inorg. Chem. 2006, 45, 10413–10415.
(40) Jain, A.; Winkel, B. S. J.; Brewer, K. J. J. Inorg. Biochem. 2007, 101,
1525–1528.
(41) Sullivan, B. P.; Calvert, J. M.; Meyer, T. J. Inorg. Chem. 1980, 19,
1404–1407.
(42) Vogler, L. M.; Franco, C.; Jones, S. W.; Brewer, K. J. Inorg. Chim.
Acta 1994, 221, 55–59.
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9080 Inorganic Chemistry, Vol. 48, No. 19, 2009
Jain et al.
prepared in 1% v/v aqueous DMSO:H2O. Stock solu-
tions (2 mL) were made to have ∼1% DMSO, pUC18
DNA (15.3 μM (BP)) and 0.76 μM metal complex (MC)
(to achieve 20:1 BP to MC) in 10 mM NaH2PO4 buffer
(pH 7). Prior to photolysis, half of the stock solution was
deoxygenated by bubbling with argon for 20 min. The
samples were irradiated with light from a 1000 W xenon
arc lamp equipped with a water IR filter and a 450 nm
cutoff filter. Small aliquots of the solutions (10 μL con-
taining 0.1 μg of DNA) were mixed with 2 μL glycerol-
based gel loading buffer and loaded into the wells of a gel
made with 0.8% w/w agarose, 0.55% w/w boric acid, and
1.08% w/w tris base. Electrophoresis was performed
using an Owl Separation Systems, Inc. (Portsmouth,
NH) Model B1A electrophoresis stage at 104 V
(∼35 mA) for 1.5 h. Gels were stained with 0.5 μg/mL
ethidium bromide for 45 min followed by 45 min of
destaining in ddH2O. Gels were visualized on a Fisher
Biotech UV transilluminator. Photographs were taken
using an Olympus E-320 digital camera equipped with a
Peca Products Inc. ethidium bromide filter.
Figure 3. Building block method used to prepare mixed metal supra-
molecular complexes (tBu3tpy = 4,40,400-tri-tert-butyl-2,20:60,200-terpyri-
dine), and dpp = 2,3-bis(2-pyridyl)pyrazine). Adapted from ref 43.
Synthesis
[(tpy)RuCl(dpp)PtCl2](PF6). [(tpy)RuCl(dpp)PtCl2](PF6)
was prepared using a slight modification of the published
method.38 The[(tpy)RuCl(dpp)](PF6)42 (300 mg, 0.40 mmol)
and the [PtCl2(DMSO)2]45 (250 mg, 0.60 mmol) were heated
at reflux in 10 mL of 95% ethanol. During the 1 h reaction
time, the solution changed from red to purple. Once the
reaction mixture had cooled to room temperature, the purple
product precipitated and was separated by vacuum filtration
on a fine-porosity fritted funnel. The product was washed
with two 10 mL portions of ethanol and 10 mL of chloro-
form. The product obtained was purified using hot ethanol
recrystallization. The solid was redissolved in ca. 15 mL of
CH3CN and filtered. The product was then flash precipitated
by addition of 60 mL of stirring diethyl ether. Yield: 90%
(360 mg, 0.36 mmol). Electrospray ionization mass spectro-
metry of [(tpy)RuCl(dpp)PtCl2](PF6) was consistent with
its formulation. (m/z; relative abundance): [(tpy)RuCl-
(dpp)PtCl2]+ (870, 100); [(tpy)RuCl(dpp)PtCl]+ (834, 10)
(δ195Pt = -2199).
ionization mass spectrometry of [(tBu3tpy)RuCl(dpp)-
PtCl2](PF6) was consistent with its formulation complex.
(m/z; relative abundance): [(tBu3tpy)RuCl(dpp)PtCl2]+
(1 038, 100); [(tBu3tpy)RuCl(dpp)PtCl]+ (1 002, 10)
(δ195Pt = -2 220).
Results and Discussion
Metal complexes of the type TL-LA-BL-BAS (TL =
terminal ligand, LA =light absorber, BL =bridging ligand,
and BAS = bioactive site) were prepared, and their basic
chemical properties as well as ground- and excited-state
interactions with DNA were studied. The membrane perme-
ability of these metal complexes was varied by addition of
different substituents on the terminal tpy ligand. The building
block approach was used to synthesize the bimetallic com-
plexes in good yield (Figure 3). The building block method
allows for construction of this molecular architecture by first
binding the terminal ligand, tpy, to the ruthenium metal
center followed by attachment of the bridging ligand, dpp.
The PtII coordination is achieved in the final step. These
complexes contain a tunable light-absorbing unit and a cis-
PtIICl2 moiety. Herein, the variation in the light absorbing
unit was achieved by changing the substituents on the
tridentate terminal ligand. The light-absorbing unit contains
chloride in its sixth coordination site. These metal complexes
have been characterized by ESI MS spectral analysis, and the
fragmentation pattern observed was consistent with the
[(MePhtpy)RuCl(dpp)PtCl2](PF6). [(MePhtpy)RuCl-
(dpp)PtCl2](PF6) was prepared by a modification of the
method used for [(tpy)RuCl(dpp)PtCl2](PF6)38 using
[(MePhtpy)RuCl(dpp)](PF6) (330 mg, 0.40 mmol). The
resulting purple product was purified by hot ethanol
recrystallization. Yield: 84% (400 mg, 0.34 mmol). Elec-
trospray ionization mass spectrometry of [(MePhtpy)-
RuCl(dpp)PtCl2](PF6) was consistent with its formula-
tion complex. (m/z; relative abundance): [(MePhtpy)-
RuCl(dpp)PtCl2]+ (960, 40); [(MePhtpy)RuCl(dpp)-
PtCl]+ (924, 18); [(MePhtpy)RuCl(dpp)]+ (694, 100)
(δ195Pt = -2 201).
1
formulation of these complexes. H NMR is complicated
due to the presence of two isomers about the Ru center. 195Pt
NMR data show a single but broadened resonance for each
complex consistent with the proposed structures.
[(tBu3tpy)RuCl(dpp)PtCl2](PF6). [(tBu3tpy)RuCl(dpp)-
PtCl2](PF6) was prepared by a modification of the meth-
od used for [(tpy)RuCl(dpp)PtCl2](PF6)38 using [(tBu3-
tpy)RuCl(dpp)](PF6) (360 mg, 0.40 mmol). The resulting
purple product was purified by hot ethanol recrystalliza-
tion. Yield: 72% (340 mg, 0.29 mmol). Electrospray
Electrochemistry. Electrochemistry is used to under-
stand the energetics associated with the redox process
and the frontier orbitals in the Ru(II)-Pt(II) mixed
metal complexes. Ruthenium polypyridyl complexes ty-
pically display reversible Ru-based oxidations and a
series of reversible ligand-based reductions. The hetero-
nuclear bimetallic complexes and the previously reported
(45) Sahai, R.; Rillema, D. P. J. Chem. Commun. 1986, 1133–1134.

Article
Inorganic Chemistry, Vol. 48, No. 19, 2009 9081
Table 1. Cyclic Voltammetric Data for [(TL)RuCl(dpp)PtCl2](PF6) and Mono-
metallic Synthonsa
metal complex
E1/2ox(V)b
E1/2red(V)b
-0.50 dpp0/-
[(tpy)RuCl(dpp)PtCl2](PF6)c
þ1.10 RuII/III -1.15 dpp-/2-
-1.43 tpy0/-
-0.55 dpp0/-
[(MePhtpy)RuCl(dpp)PtCl2](PF6) þ1.10 RuII/III -1.20 dpp-/2-
-1.44 MePhtpy0/-
-0.59 dpp0/-
[(tBu3tpy)RuCl(dpp)PtCl2](PF6)
[(tpy)RuCl(dpp)](PF6)d
þ1.01 RuII/III -1.15 dpp-/2-
-1.59 tBu3tpy0/-
þ1.02 RuII/III -1.15 dpp0/-
-1.41 tpy0/-
Figure 4. Cyclic voltammograms of [(tpy)RuCl(dpp)PtCl2](PF6) (A),
[(MePhtpy)RuCl(dpp)PtCl2](PF6) (B), and [(tBu3tpy)RuCl(dpp)PtCl2]-
(PF6) (C) in 0.1 M Bu4NPF6 in CH3CN and reported vs Ag/AgCl (TL =
terminal ligand (tpy = 2,20:60,200-terpyridine, MePhtpy = 40-(4-Methyl-
phenyl)-2,20:60,200-terpyridine, tBu3tpy = 4,40,400-tri-tert-butyl-2,20:60,200-
terpyridine), dpp = 2,3-bis(2-pyridyl)pyrazine).
[(MePhtpy)RuCl(dpp)](PF6)e
[(tBu3tpy)RuCl(dpp)](PF6)
þ1.01 RuII/III -1.16 dpp0/-
-1.40 MePhtpy0/-
þ0.98 RuII/III -1.22 dpp0/-
-1.59 tBu3tpy0/-
Scheme 1. Electrochemical Mechanism for [(TL)RuCl(dpp)PtCl2]-
(PF6) with Synthesized Oxidation State in Bolda
a TL = terminal ligand (tpy = 2,20:60,200-terpyridine, MePhtpy =
t
40-(4-methylphenyl)-2,20:60,200-terpyridine, Bu3tpy = 4,40,400-tri-tert-
butyl-2,20:60,200-terpyridine) and dpp
= 2,3-bis(2-pyridyl)pyrazine.
b Potential reported in CH3CN with 0.1 M Bu4NPF6 and reported vs
Ag/AgCl (0.21 V vs NHE) reference electrode. c Redox potentials
recorded under our conditions are consistent with the previous report.38
d Redox potentials recorded under our conditions are consistent with the
previous report.42 e Redox potentials recorded under our conditions are
consistent with the previous report.29
monometallic precursors have been studied by cyclic
voltammetry, and the data are summarized in Table 1.
Cyclic voltammograms for the title [(TL)RuCl(dpp)-
PtCl2](PF6) systems in 0.1 M Bu4NPF6 in CH3CN are
shown in Figure 4.
The heterobimetallic complexes display electrochemis-
try consistent with their formulation. These complexes
display reversible RuII/III oxidation, establishing the Ru
metal center as a site for the localization of the HOMO.
The RuII/III oxidation in the [(tpy)RuCl(dpp)PtCl2]-
(PF6)38 and [(MePhtpy)RuCl(dpp)PtCl2](PF6) com-
plexes occurred at 1.10 V vs Ag/AgCl, which is shifted
to a more positive potential relative to the monometallic
synthons. The RuII/III oxidation couple occurs at a less
positive potential in [(tBu3tpy)RuCl(dpp)PtCl2](PF6)
complex compared to the other two heterobimetallic
complexes. This lowering of the oxidation potential re-
a TL = terminal ligand (tpy = 2,20:60,200-terpyridine, MePhtpy =
t
40-(4-methylphenyl)-2,20:60,200-terpyridine, Bu3tpy = 4,40,400-tri-tert-
butyl-2,20:60,200-terpyridine) and dpp = 2,3-bis(2-pyridyl)pyrazine).
consistent with the significant stabilization of the dpp
(π*) LUMO upon complexation to the PtII center.48 The
second reduction in the bimetallic complexes is dpp-/2- in
nature, indicative of a bridging dpp. Stabilization of the
dpp (π*) acceptor orbital, as a result of the coordination
to the cis-PtIICl2 moiety, shifts this dpp-/2- couple posi-
tive to the TL0/- couple. The third reduction in these metal
complexes is TL0/- in nature. The reduction of tpy and
MePhtpy in these heterobimetallic complexes occurred
t
sults from the electron-donating character of the Bu3
group, making the Ru center more electron rich and,
therefore, easy to oxidize. A similar effect was reported by
Hadda and LeBoez with a 75 mV decrease in the potential
t
t
t
at -1.40 and -1.46 V. The reduction of the Bu3tpy
when Bu3tpy and Bu3bpy were substituted for tpy and
bpy, respectively, in [Ru(tBu3tpy)Cl(bpy)]þ and [Ru-
(tBu3bpy)Cl(tpy)]þ.46,47 Each [(TL)RuCl(dpp)PtCl2]-
(PF6) complex displays a reversible dpp0/--based first
reduction, establishing the BL as a site of localization
of LUMO for these heterobimetallic complexes. This
dpp0/- couple is ca. 0.60 V more positive in the bime-
tallic complexes compared to the monometallic synthons
occurs at a more negative potential, -1.59 V, due to the
electron-donating character of Bu3 group. Scheme 1
t
summarizes the electrochemical mechanism for these
heterobimetallic complexes.
Electronic Absorption Spectroscopy. The electronic ab-
sorption spectra of heterobimetallic complexes of the
form [(TL)RuCl(dpp)PtCl2](PF6) in acetonitrile are
shown in Figure 5. All the heterobimetallic complexes
are efficient light absorbers with the spectrum dominated
by TL-LA-BL subunit. Ruthenium polyazine com-
plexes display a ligand-based πfπ* transition in the
UV region and a MLCT transition in the visible region,
(46) Hadda, T. B.; Bozec, H. L. Polyhedron 1988, 7, 575–578.
(47) Hadda, T. B.; Bozec, H. L. Inorg. Chim. Acta 1993, 204, 103–107.
(48) Swavey, S.; Williams, R. L.; Fang, Z.; Milkevitch, M.; Brewer, K. J.
Proc. SPIE-Int. Soc. Opt. Eng. 2001, 4512, 75–83.

9082 Inorganic Chemistry, Vol. 48, No. 19, 2009
Jain et al.
terminating in each acceptor ligand. The spectra of all the
complexes displayed intense TL-based πfπ* transitions in
the UV region with the two major peaks at 272 and 316 nm
attributed to the tpy ligand. The dpp-based πfπ* transition
occurred at a lower energy as a shoulder at ca. 354 nm. These
complexes display an intense MLCT band in the visible
region of the spectrum. The RufTL charge transfer band
occurs at a higher energy than the Rufdpp charge transfer
band and is centered at ca. 460 nm for all three complexes.
The Rufdpp CT band was centered at 540 nm and is red
shifted ca. 20 nm in the bimetallic complexes relative to the
corresponding [(TL)RuCl(dpp)](PF6) monometallic syn-
thons. This red shift is due to the stabilization of the dpp
π* orbitals by coordination to the electropositive Pt(II)
metal center and is consistent with the electrochemical
results. The electronic absorption spectral properties of
[(TL)RuCl(dpp)PtCl2](PF6) complexes and their mono-
metallic synthons are summarized in Table 2.
DNA-Binding Studies. The DNA-binding ability of the
heterobimetallic complexes, [(TL)RuCl(dpp)PtCl2](PF6),
was explored using agarose gel electrophoresis. These
metal complexes contain a cis-PtIICl2 moiety, which is
known to covalently bind to DNA and is the basis of a
class of anticancer agents. Figure 6 shows the gel electro-
phoresis study of these complexes compared to the stan-
dard, cisplatin, using linear pUC18 DNA. In this study,
each metal complex was combined with linearized pUC18
DNA at a range of base pair (BP) to metal complex (MC)
ratios. These mixtures were incubated for 1 h at 37 °C and
analyzed by agarose gel electrophoresis as shown in
Figure 6. Lane λ (one), is the molecular weight standard
(24, 9.4, 6.6, 4.4, 2.2, and 2.0 kb), lane C (two) is the
pUC18 DNA control without any metal complex present,
lane 5:1 (three) is the pUC18 DNA incubated with 5:1 BP:
MC, lane 10:1 (four) is the pUC18 DNA incubated with
10:1 BP:MC, and lane 20:1 (five) is the pUC18 DNA
Figure 5. Electronic absorption spectroscopy of [(tpy)RuCl(dpp)-
PtCl2](PF6) ( ), [(MePhtpy)RuCl(dpp)PtCl2](PF6) ()) and [(tBu3tpy)-
3 3 3
RuCl(dpp)PtCl2](PF6) (;) in CH3CN at room temperature (tpy =
2,20:60,200-terpyridine, MePhtpy = 40-(4-methylphenyl)-2,20:60,200-terpyr-
idine, tBu3tpy = 4,40,400-tri-tert-butyl-2,20:60,200-terpyridine), and dpp =
2,3-bis(2-pyridyl)pyrazine).
Table 2. Electronic Absorption Spectroscopy for [(TL)RuCl(dpp)PtCl2](PF6) and Related Monometallic Synthons in CH3CN at Room Temperaturea
complex
λmaxabs (nm)
ε ꢀ 10-4 (M-1cm-1
)
assignment
[(tpy)RuCl(dpp)PtCl2](PF6)b
236
317
354(sh)
462(sh)
544
2.87
3.22
1.40
0.490
1.53
πfπ* tpy
πfπ* tpy
πfπ* dpp
Ruftpy CT
Rufdpp CT
[(MePhtpy)RuCl(dpp)PtCl2](PF6)
[(tBu3tpy)RuCl(dpp)PtCl2](PF6)
[(tpy)RuCl(dpp)](PF6)c
227
318
354(sh)
464(sh)
548
4.67
4.82
1.90
0.670
2.09
πfπ* MePhtpy
πfπ* MePhtpy
πfπ* dpp
RufMePhtpy CT
Rufdpp CT
230
314
354(sh)
462(sh)
545
3.92
3.53
1.42
0.490
1.54
πfπ* tBu3tpy
πfπ* tBu3tpy
πfπ* dpp
RuftBu3tpy CT
Rufdpp CT
237
315
364(sh)
516
3.40
4.60
0.680
1.43
πfπ* tpy
πfπ* tpy
πfπ* dpp
Rufdpp CT
Ruftpy CT
[(MePhtpy)RuCl(dpp)](PF6)
[(tBu3tpy)RuCl(dpp)](PF6)
228
312
356(sh)
522
3.32
4.32
0.610
1.72
πfπ* MePhtpy
πfπ* MePhtpy
πfπ* dpp
Rufdpp CT
RufMePhtpy CT
240
314
360(sh)
521
4.20
5.02
0.801
1.53
πfπ* tBu3tpy
πfπ* tBu3tpy
πfπ* dpp
Rufdpp CT
RuftBu3tpy CT
a TL = terminal ligand (tpy = 2,20:60,200-terpyridine, MePhtpy = 40-(4-methylphenyl)-2,20:60,200-terpyridine, tBu3tpy = 4,40,400-tri-tert-butyl-2,20:60,200-
terpyridine) and dpp = 2,3-bis(2-pyridyl)pyrazine. b Extinction coefficients recorded under our conditions are consistent with the previous report.38
c Extinction coefficients recorded under our conditions are consistent with the previous report.42

Article
Inorganic Chemistry, Vol. 48, No. 19, 2009 9083
Figure 6. DNA-binding study for [(TL)RuCl(dpp)PtCl2](PF6) by agarose gel electrophoresis using linearized pUC18 DNA (dpp = 2,3-bis(2-
pyridyl)pyrazine, TL = terminal ligand (tpy = 2,20:60,200- terpyridine, MePhtpy = 40-(4-methylphenyl)-2,20:60,200-terpyridine, and tBu3tpy = 4,40,400-tri-
tert-butyl-2,20:60,200-terpyridine). λ is the molecular weight standard (24, 9.4, 6.6, 4.4, 2.3, and 2.0 kbp), C is the DNA control, 5:1 is the 5:1 base pairs (BP):
metal complex (MC) ratio, 10:1 is the 10:1 BP:MC ratio, and 20:1 is the 20:1 BP:MC ratio.
Figure 7. DNA-binding and photocleavage study for [(TL)RuCl(dpp)PtCl2](PF6) by agarose gel electrophoresis using circular pUC18 DNA (dpp = 2,3-
bis(2-pyridyl)pyrazine, TL = terminal ligand (tpy = 2,20:60,200-terpyridine, MePhtpy = 40-(4-methylphenyl)-2,20:60,200-terpyridine, tBu3tpy = 4,40,400-tri-
tert-butyl-2,20:60,200-terpyridine). λ is the molecular weight standard (24, 9.4, 6.6, 4.4, 2.3, and 2.0 kbp), C is the DNA control, RT is the 20:1 BP:MC
incubated at room temperature for 2 h, 37 is the 20:1 BP:MC incubated at 37 °C for 2 h, O2 is the 20:1 base pair (BP): metal complex (MC) photolyzed with
450-1000 nmlightfor 2 h under atmospheric conditions, and Aristhe 20:1BP:MC photolyzedwith450-1000 nmlightfor 2 h in the absence ofoxygen. The
[(tpy)RuCl(dpp)PtCl2]þ on the right is incubated and photolyzed for 4 h with other conditions remaining the same.
incubated with 20:1 BP:MC. Cisplatin is known to form
coordinate covalent bonds with DNA, and this can be
visualized in the gel as a decrease in DNA migration
through the gel, with the increase of MC concentration
moving from lane 20:1 to 10:1 to 5:1. The [(tpy)RuCl-
(dpp)PtCl2](PF6)40 and [(MePhtpy)RuCl(dpp)PtCl2]-
(PF6) complexes exhibited coordinate covalent binding
to DNA with a significant retardation of pUC18 DNA
migration through the gel and a greater effect at lower
BP:MC ratios. The reduction of the DNA migration through
the gel was found to be greater for these two complexes as
compared to that of cisplatin. The Rf values compared to the
2.0 kb λ control were calculated at a 5:1 BP:MC ratio
and found to be 0.68 (cisplatin), 0.62 ([(tpy)RuCl(dpp)-
PtCl2](PF6)), 0.64 ([(MePhtpy)RuCl(dpp)PtCl2](PF6)), and
0.74 ([(tBu3tpy)RuCl(dpp)PtCl2](PF6)) relative to 0.80 for
the DNA control. These types of metal complexes and
cisplatin have been shown to bind with the guanine (G-7)
base of DNA.34 The [(tBu3tpy)RuCl(dpp)PtCl2](PF6) com-
plex displayed somewhat less effect on DNA migration
through the agarose gel. The introduction of the tBu3 groups
on the terpyridine ligand makes the molecule sterically
hindered relative to the unsubstituted tpy-containing com-
plex and provides a lipophilic site remote from the cis-PtIICl2
site. It may be sterically difficult for cis-PtIICl2 subunits of
this metal complex to reach the G-7 of DNA. Baguely
and co-workers have also shown that the presence of
bulky groups lowers the DNA binding and cytotoxicity of
amsacrine.49 The monometallic synthons have been pre-
viously assayed for DNA interactions for TL = tpy and
MePhtpy and are not found to thermally bind DNA, such as
to impact electrophoretic mobility as is typical of most Ru
polyazine complexes.29 Ionic and intercalative binding of
cationic Ru polyazine complexes is typically not stable under
electrophoresis, and in fact, the monometallic systems are
typically observed migrating in the opposite direction of the
DNA due to their positive charge.
DNA Photocleavage Studies. The ability of the hetero-
bimetallic complexes to photocleave DNA was studied by
agarose gel electrophoresis using circular plasmid pUC18
DNA (Figure 7). In this study metal complexes were
combined with pUC18 DNA at a 20:1 BP:MC ratio.
The mixtures were irradiated with visible light (λirr
g
450-1000 nm) for 2 h, and the ability to photocleave
DNA was analyzed by gel electrophoresis. In each panel,
λ is the molecular weight standard, C is the DNA control
showing that pUC18 exists mostly in the supercoiled state
together with a small amount of nicked circular DNA,
RT is the DNA incubated with the metal complex in the
dark at room temperature, 37 is the DNA incubated with
the metal complex in the dark at 37 °C, O2 is the DNA and
metal complex irradiated with 450-1000 nm light for 2 h
under atmospheric conditions, and Ar is the DNA and
metal complex irradiated with 450-1000 nm light for 2 h
under argon. The complexes [(tpy)RuCl(dpp)PtCl2]þ and
[(tBu3tpy)RuCl(dpp)PtCl2]þ were also assayed at 4 h of
incubation and photolysis. No changes were observed for
the [(tBu3tpy)RuCl(dpp)PtCl2]þ, so it is not shown.
The gel electrophoresis studies using circular plasmid
pUC18 DNA show that the three metal complexes bind to
DNA at room temperature or upon 37 °C incubation (RT
and 37 lanes in the first two gels in Figure 7) and
photocleave DNA upon visible light irradiation (lanes
O2 in Figure 7). The observed DNA binding in lanes RT
and 37 are consistent with the DNA-binding studies using
linear pUC18 DNA (Figure 6). The [(tBu3tpy)RuCl(dpp)-
PtCl2](PF6) metal complex displayed reduced covalent
(49) Denny, W. A.; Twigden, S. J.; Baguley, B. C. Anti-Cancer Drug Des.
1986, 1, 125–132.

9084 Inorganic Chemistry, Vol. 48, No. 19, 2009
Jain et al.
binding to DNA upon thermal and room temperature
incubation as compared to that of the tpy analog. Similar
effects were observed in the DNA-binding studies using
linear pUC18 DNA. Photolysis under oxygenated con-
ditions yielded DNA photocleavage in the presence of
[(tpy)RuCl(dpp)PtCl2](PF6) and [(MePhtpy)RuCl(dpp)-
PtCl2](PF6), with most efficient conversion of the super-
coiled form into the open circular form in the presence of
[(MePhtpy)RuCl(dpp)PtCl2](PF6). The [(MePhtpy)Ru-
Cl(dpp)PtCl2](PF6) is a remarkably efficient DNA photo-
cleavage agent, leading to complete conversion of the SC
pUC18 to the OC form in 2 h photolysis at a low 20:1 BP:
MC ratio. Minimal to no photocleavage was observed
in the presence of the [(tBu3tpy)RuCl(dpp)PtCl2](PF6)
metal complex even when photolyzed for 4 h. The
[(tpy)RuCl(dpp)PtCl2](PF6) complex binds to DNA to
a larger extent when incubated for 4 h and cleaves DNA
more when photolyzed for 4 h, Figure 7 far right gel. This is
consistent with thermal binding by the Pt center being
enhanced at longer times, and the cleavage of DNA through
photosensitization of O2 by the Ru LA unit is more efficient.
Minor changes are seen when the [(MePhtpy)RuCl-
(dpp)PtCl2](PF6) is photolyzed under Ar potentially indi-
cative of minor photobinding of this complex.
that the [(MePhtpy)RuCl(dpp)PtCl2](PF6) complex has a
significantly larger degree of DNA photocleavage in this
bimetallic framework.
The ability to modulate DNA reactivity by enhancing
photocleavage with a MePhtpy ligand while impairing
photocleavage with a Bu3tpy ligand within a bimetallic
t
framework is unprecedented. The ability of the Pt
coordination to provide for efficient DNA photocleavage
to RuIItpy-containing chromophores provides for the
application of this class of generally unexplored light
absorbers for DNA photochemistry.
Conclusions
A series of multifunctional mixed metal supramolecular
complexes of the type [(TL)Ru(dpp)PtCl2](PF6) with varying
terminal ligands have been successfully synthesized using a
building block method, and they are shown to display multi-
functional interactions with DNA. These metal complexes
display reversible RuII/III-based oxidation and dpp0/-- and
dpp-/2--based reductions prior to the TL0/--based reduction
with only small variations in potential through the series
of complexes. The tpy-based reduction in the [(tBu3tpy)RuCl-
(dpp)PtCl2](PF6) complex occurred at a more negative
potential relative to those in the other two complexes due
t
to the electron-donating nature of the Bu3 group. These
The trend in the DNA photocleavage ability of these
complexes with TL variation shows the MePhtpy com-
plex to be an efficient DNA cleavage agent with the tpy
complexes display Rufdpp charge transfer bands in the
visible region of the spectrum with tails at lower energy
with all three complexes displaying similar and efficient
light absorbing properties. The coupling of the cisplatin unit
to a ruthenium-based chromophore provides not only the
cis-PtIICl2 coordinate covalent DNA-binding ability but
also the spectroscopic probe and photoactivity of these
supramolecules. The [(tpy)RuCl(dpp)PtCl2](PF6) and
[(MePhtpy)RuCl(dpp)PtCl2](PF6) complexes avidly bind to
DNA and cleave DNA by molecular oxygen sensitization
through the 3MLCT state of the Ru polyazine unit, represent-
ing one of only a handful of multifunctional DNA-binding
and photocleaving agents. The [(tBu3tpy)RuCl(dpp)PtCl2]-
(PF6) complex displays minimal coordinate covalent
binding to DNA compared to the other two complexes.
t
system significantly less functional and the Bu3tpy sys-
tem largely inactive. The log P values were determined to
assay lipophilicity of the complexes by the shake flask
method using water and octanol. The log P values were
found to be -2.00, -0.39, and 4.00 for [(tpy)RuCl(dpp)-
PtCl2]Cl, [(MePhtpy)RuCl(dpp)PtCl2]Cl, and [(tBu3tpy)-
RuCl(dpp)PtCl2]Cl, respectively, showing the highest
t
degree of octanol partitioning for the Bu3tpy complex.
The lipophilc nature of the Bu3tpy ligand and/or the steric
hindrance in the molecule may prevent Pt complexation
to the DNA, which would inhibit DNA photocleavage.
Baguely and co-workers have demonstrated that by
increasing the bulk of the group on the acridine moiety
of amsacrine from methyl to ethyl and isopropyl, the
intercalative binding to DNA was retained, but the
apparent unwinding angle was lowered to about 30%
by the isopropyl.49 In the presence of the t-butyl group,
they observed abrupt change to a nonintercalative bind-
ing from the intercalative binding mode.49 The bimetallic
complexes do not display a detectable emission from
t
The presence of the Bu3 group on the terpyridine moiety
lowers Pt coordination to the DNA. The presence of the
methylphenyl group on the tpy ligand improves the inter-
action of the molecule with DNA, providing more facile
DNA binding and photocleavage. With careful selection of
the substitutents on the ligands, the DNA interaction
properties of the molecules can be improved, and efficient
multifunctional molecules can be designed. Work is cur-
rently in progress to explore these and related systems in
detail to derive structure activity relationships.
3
their MLCT excited states likely due to the low energy
of these states. The previously reported emission from
the monometallic synthons [(tpy)RuCl(dpp)](PF6) and
[(MePhtpy)RuCl(dpp)](PF6) shows little difference
in their excited-state properties, τ = 17 and 16 ns,
respectively, with similar emission quantum yields.29
This suggests the rate of O2 quenching in the bimetallic
complexes is likely similar making somewhat surprising
Acknowledgment. The authors thank the National
Science Foundation (CHE-0408445) for their generous
support of this research and Ms. Samantha Hopkins for
her assistance with this work.