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Cyclometalated iridium(III) complex of 6-hydroxydipyrido[3 2-a 2 3-c]phenazine synthesis and acidЦbase and avid DNA binding properties.

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Full Paper
Received: 3 October 2010
Revised: 6 February 2011
Accepted: 10 February 2011
Published online in Wiley Online Library: 17 May 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1796
Cyclometalated iridium(III) complex
of 6-hydroxydipyrido[3,2-a:2 ,3-c]phenazine:
synthesis, and acid–base and avid DNA
binding properties
Yan-Min Chen, An-Guo Zhang and Ke-Zhi Wang∗
A new cyclometalated Ir(III) complex [Ir(ppy)2 (hdppz)]PF6 (Hppy = 2-phenylpyridine and hdppz = 6-hydroxydipyrido[3,2a:2 ,3 -c]phenazine) was synthesized and characterized. The pH effects on the UV–vis absorption spectra were studied and
ground-state acid ionization constant pKa values of the complex were derived. The calf thymus DNA (ct-DNA) binding properties
of the complex were investigated with UV-vis absorption spectrophotometric titrations, DNA competitive binding with ethidium
bromide, DNA melting experiments, viscosity measurements and density functional theory (DFT) calculations. The complex was
demonstrated to act as a ct-DNA intercalator with a large DNA binding constant value of (6.06 ± 0.32) × 106 M−1 in 50 mM NaCl.
c 2011 John Wiley & Sons, Ltd.
The avid DNA binding affinity observed was rationalized by the DFT calculations. Copyright Keywords: iridium; pH; DNA; spectroscopy
Introduction
Appl. Organometal. Chem. 2011, 25, 521–529
∗
Correspondence to: Ke-Zhi Wang, College of Chemistry, Beijing Normal
University, Beijing 100875, China. E-mail: kzwang@bnu.edu.cn
College of Chemistry, Beijing Normal University, Beijing 100875, China
c 2011 John Wiley & Sons, Ltd.
Copyright 521
Various metallointercalators of DNA have been the focus of
numerous studies over the past two decades.[1 – 3] The transition
metal polypyridyl complexes such as [Ru(bpy)2 (dppz)]2+ (bpy =
2,2 -bipyridine, dppz = dipyrido[3,2-a:2 ,3 -c]phenazine)[4] and
their analogs have provided structurally suitable tools for exploiting intercalative DNA interactions. Although Ru(II) and Rh(III)
metallointercalators have been widely studied, only a few reports
of related compounds with a central Ir(III) ion have previously
appeared.[5 – 7] These include [Ir(ppy)2 (dppzR)]3+ (dppzR = 7-ethyl
acetate-dipyrido[3,2-a:2 ,3 -c]phenazine), which has been employed to follow electron transfer in DNA,[5] DNA intercalators of
{(η5 -C5 Me5 )Ir[(NMe2 )2 CS](N-N)} (CF3 SO3 )2 (N-N = dppz and dppn,
where dppn = benzo[i]dipyrido[3,2-a:2 ,3 -c]phenazine),[6] and
luminescent dipyridoquinoxaline and dipyridophenazine complexes of the type [Ir(ppy)2 (N-N)](PF6 ) (N-N = dpq, dppz and dppn,
where dpq = 2-N-butylamidodipyrido[3,2-f :2 ,3 -h]quinoxaline).[7]
All the studies revealed that molecular modification of DNA
binders would lead to subtle or substantial changes in the
binding modes, location and affinities, providing the opportunity
to explore various valuable conformation- or site-specific DNA
probes and anticancer drugs. It is also well known that the
photophysical and electrochemical properties of Ir(III) complexes
depend on the electronic structures of their ligands and can be
finely tuned by modifying the chemical structures of the ligands.
The pH-responsive transition-metal complexes containing
N-heterocyclic ligands are one family of fundamental molecular
devices with adjustable ground- and excited-state properties.[8,9]
Many life processes, such as enzymes, operate within a very
narrow pH window, but more work is required to broaden
pH windows, and to improve the sensitivity of pH responses.
For example, the complex [Ru(η6 -p-cymene)Cl2 (pta)] (pta =
1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) was reported to
exhibit interesting pH-dependent DNA damage and selectivity
towards cancer cells.[10] In recent years, several reviews have also
appeared on synthetic fluorescent chemosensors which have
found widespread applications in cell biology for the intracellular
measurement of several species, from the zinc(II) cation[11] and
citrate anion[12] to singlet oxygen[13] and nitric oxide.[14]
In the past few years, the exciting luminescent properties
of Ir(III) complexes have been of particular interest because
of their extremely promising applications in organic lightemitting diodes.[15 – 19] Recently, the photophysical properties
of mononuclear[20 – 22] and polynuclear iridium(III) polypyridine
complexes[23 – 25] have also attracted much attention owing to
their interesting potential applications as sensory materials for
oxygen,[26] protons[27] and chloride ions,[28] as well as for labeling
biological substrates such as nucleic acids and proteins.[29]
By extension of our work from Ru(II)[30 – 38] to Ir(III) polypyridyl
complexes on acid-base and/or DNA binding properties, we
have found that an Ir(III) complex containing a dppz derivative
as a main ligand has a much more avid DNA affinity than the
Ru(II) analogous complexes (see Scheme 1). Moreover, theoretical
computations for the related complexes applying the density
functional theory (DFT) method were also performed in order to
obtain insight into their DNA binding properties.
Y.-M. Chen, A.-G. Zhang and K.-Z. Wang
Scheme 1. Molecular structures of [Ir(ppy)2 (hdppz)]+ , [Ru(bpy)2 (hdppz)]2+ and [Ru(phen)2 (hdppz)]2+ .
Experimental Section
Physical Measurements
Elemental analyses were performed on a Vario EL elemental
analyzer. Matrix-assisted laser desorption inoization mass spectra
(MALDI-TOF MS) were run on an API Q-star pulsar (Applied
Biosystems) mass spectrometer. UV–vis spectra were obtained
on a GBC Cintra 10e UV–vis spectrometer. 1 H NMR spectra were
collected on a Bruker DRX-400 NMR spectrometer with CDCl3
as solvent. Emission spectra were obtained on a Shimadzu RF5301PC spectrofluorimeter at room temperature. For pH titrations,
a pHS-3B pH-meter was used to read the pH values directly.
The acidities were adjusted with HCl or NaOH in aqueous
solutions containing a Britton–Robinson (BR) buffer and 0.1 M
NaCl to keep a constant ionic strength. DNA melting studies were
carried out in 1.5 mM Na2 HPO4 , 0.5 mM NaH2 PO4 and 0.25 mM
EDTA by continuous heating from 50 to 90 ◦ C at a rate of
1 ◦ C min−1 . Data were present as (A/A0 ) vs temperature, where
A0 and A are the initial and observed absorbance at 260 nm,
respectively. The concentration of calf thymus DNA (ct-DNA) was
determined spectrophotometrically by assuming ε260 = 6600
M−1 cm−1 .[39] All the experiments involving the interaction of the
complex with ct-DNA were carried out in deionized water buffered
with tris(hydroxymethyl)aminomethane (Tris, 5 mM) and sodium
chloride (50 mM), and adjusted to pH 7.1 with hydrochloric acid.
A solution of DNA gave a ratio of UV absorbance at 260 and
280 nm of ca. 1.9 : 1, indicating that the DNA was sufficiently free
of protein. In constructing the UV–vis spectrophotometric DNA
titration curves, the DNA absorption was subtracted. In order to
evaluate quantitatively the DNA-binding strength, the intrinsic
DNA-binding constant Kb was derived by nonlinear regression
analysis using equations (1) and (2):[40]
(εa − εf )/(εb − εf ) = [b − (b −
2
2Kb2 Ct [DNA]/n)1/2 ]/(2Kb Ct )
(1)
b = 1 + Kb Ct + Kb [DNA]/2n
(2)
522
where [DNA] is the concentration of DNA per base pairs, εa
is the apparent absorption coefficient, which was obtained by
calculating Aabs /[Ir], and εf and εb are the extinction coefficients
for the free iridium complex and the iridium complex in the fully
bound form, respectively. Ct is total Ir(III) complex concentration,
and n is the binding site size.
Viscosity measurements were carried out on an Ubbelohde
viscometer, immersed in a thermostated water bath maintained at
a temperature of 32.64±0.03 ◦ C. The DNA samples, approximately
200 base pairs in average length, were prepared by sonication
in order to minimize complexities arising from DNA flexibility.[41]
Data are presented as (η/η0 )1/3 vs the concentrations of iridium(III)
wileyonlinelibrary.com/journal/aoc
complex, where η is the viscosity of DNA in the presence of the
complex and η0 that of DNA alone. Viscosity values were calculated
from the observed flow time of DNA-containing solutions (t)
corrected for that of buffer alone (t0 ), η = t − t0 .[42]
Theoretical Calculation
The structural schematic diagrams of [Ir(ppy)2 (hdppz)]2+ , [Ru
(bpy)2 (hdppz)]2+ and [Ru(phen)2 (hdppz)]+ are shown in
Scheme 1; there is no symmetry in these three complexes. All
calculations were performed with the Gaussian 03 quantum chemistry program-package,[43] at the DFT/B3LYP level using the 6-31G∗
basis set on the carbon, nitrogen, oxygen and hydrogen atoms
and a LanL2DZ pseudo potential[44] on the iridium or ruthenium
atom. Full geometry optimization computations for the ground
states of these complexes with singlet state[45] were carried out. In
order to vividly depict the detail of the frontier molecular orbital
interactions, the stereographs of some related frontier molecular
orbitals of the complexes are shown in Fig. 1.
Materials
6-Hydroxydipyrido[3,2-a:2 ,3 -c]phenazine (hdppz),[30] 1,10-phenanthroline-5,6-dione[46] and [Ir(ppy)2 Cl]2 (ppy = 2-phenylpyridine)[47] were synthesized according to the literature methods.
The other chemicals were obtained from commercial sources
and used without further purification. [Ir(ppy)2 (hdppz)]PF6 was
synthesized according to the route shown in Scheme 2, and the
synthetic details are given below.
Preparation of [Ir(ppy)2 ](hdppz)]PF6
A suspension of [Ir(ppy)2 Cl]2 (108.8 mg, 0.1 mmol) and hdppz
(37.4 mg, 0.125 mmol) in a solvent mixture of CH2 Cl2 –CH3 OH
(v/v, 26/13 ml) was refluxed for 7 h under nitrogen. The solution
was filtrated upon cooling to room temperature, and saturated
aqueous NH4 PF6 solution was then added to the filtrate.
The crude product obtained by removing the solvent under
reduced pressure was purified by chromatography over silica
gel, eluting with a mixed solvent of CH2 Cl2 –CH3 COCH3 (v/v
= 20 : 1), and CH2 Cl2 –CH3 COOCH2 CH3 (v/v = 8 : 1), to deliver
[Ir(ppy)2 (hdppz)]PF6 as a yellow solid (67.3 mg, 46%). Anal. calcd
for C40 H26 F6 IrN6 OP·4C3 H6 O: C, 53.10; H, 4.28; N, 7.15%. Found: C,
53.02; H, 4.67; N, 7.28%. 1 H NMR (ppm, 400 MHz, CDCl3 ): δ = 9.87
(d, J = 7.7 Hz, 1H, H25 ), δ = 9.83 (d, J = 7.7 Hz, 1H, H36 ), δ = 8.36
(d, J = 4.8 Hz, 1H, H23 ), δ = 8.32 (d, J = 4.9 Hz, 1H H38 ), δ = 7.96
(m, 6H, H1 , H4 , H12 , H15 , H24 and H37 ), δ = 7.73 (t, J = 7.6 Hz, 4H,
H3 , H9 , H14 and H20 ), δ = 7.61 (d, J = 5.3 Hz, 1H, H30 ), δ = 7.56
(d, J = 5.4 Hz, 1H, H29 ), δ = 7.36 (d, J = 6.4 Hz, 1H, H31 ), δ = 7.11
(t, J = 6.8 Hz, 2H, H8 and H19 ), δ = 6.99(m, 4H, H2 , H7 , H13 and
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 521–529
Cyclometalated iridium(III) complex of 6-hydroxydipyrido[3,2-a:2 ,3 -c]phenazine
Figure 1. Frontier molecular orbitals of [Ir(ppy)2 (hdppz)]+ , [Ir(ppy)2 (dppz)]+ and [Ru(bpy)2 (hdppz)]2+ .
Scheme 2. The synthetic route to [Ir(ppy)2 (hdppz)]PF6 . The numbers 1–40 correspond to the assignments of 1 H NMR and 13 C NMR.
Appl. Organometal. Chem. 2011, 25, 521–529
Results and Discussion
Synthesis, Characterization and Common Spectral
Characteristics
Compared with Rh(III) or Ru(II) metal complexes, the third row
metal complexes, and most particularly Ir(III), are characterized
by the inertness of their coordination sphere, as evidenced
by the somewhat harsh experimental conditions required to
substitute the chloride ligands from the starting iridium salts.[48]
The composition of [Ir(ppy)2 (hdppz)]PF6 was confirmed by the
following facts: the experimental data of elemental analysis
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
523
H18 ), δ = 6.42 (d, J = 6.1 Hz, 2H, H10 and H21 ). 13 C NMR (ppm,
400 MHz, d6 -DMSO): δ = 166.76 (C5 and C16 ), 162.29 (C32 ), 153.65
(C27 ), 151.65 (C34 ), 151.30 (C28 ), 149.58 (C1 , C12 , C23 and C38 ), 149.49
(C33 ), 149.13 (C30 ), 143.98 (C3 , C6 , C14 and C17 ), 142.64 (C25 ), 139.98
(C36 ), 138.75 (C8 and C19 ), 137.92 (C35 ), 135.75 (C26 ), 135.02 (C40 ),
133.59 (C10 ), 133.52 (C21 ), 131.13 (C7 and C18 ), 131.08 (C39 ), 130.64
(C9 ), 130.25 (C20 ), 128.35 (C11 ), 128.19 (C22 ), 125.04 (C4 and C15 ),
123.76 (C37 ), 122.45 (C24 ), 119.93 (C2 and C13 ), 119.05 (C29 ), 112.93
(C31 ). Anal. calcd for MALDI-TOFMS: m/z 799.2 ([M − PF6 − ]+ );
found: m/z 799.6 ([M − PF6 − ]+ ).
Y.-M. Chen, A.-G. Zhang and K.-Z. Wang
coincided with the theoretical ones; the integrated intensities
of the proton resonance signals in the 1 H NMR spectrum
corresponded to 25 protons, being in agreement with the
anticipated value for [Ir(ppy)2 (hdppz)]PF6 (except for one active
hydroxyl hydrogen); and the MALDI-TOF mass spectrum of
[Ir(ppy)2 (hdppz)]PF6 showed a peak at m/z 799.6 ([M − PF6 − ]+ ),
consistent with a theoretical value of m/z 799.2 ([M − PF6 − ]+ ).
The complex [Ir(ppy)2 (hdppz)]PF6 in neutral water displays two
high-energy bands at ∼257 (ε = 31700 M−1 cm−1 ) and 303 nm
(28400 M−1 cm−1 ), which can be assigned to ligand-centered
(LC) transitions, and one lower-energy absorption band at 385 nm
(ε = 28700 M−1 cm−1 ) assigned to metal-to-ligand charge-transfer
(MLCT) transitions (Ir → ppy or hdppz), which is comparable to
[Ir(ppy)2 (dppz )]+ (dppz = (dipyrido[3,2-a:2 ,3 -c]phenazine-11yl)-hex-5-ynoic acid) that has dppz-centered IL π –π ∗ and MLCT
bands occurring at ∼295 and 393 nm.[49] Indeed, the absorption
of complexes made with Ir(III) generally corresponds to the
superposition of a different transition involving either the ligands
or both the metal and the ligand.[50]
Figure 2. Changes of UV–vis spectra of [Ir(ppy)2 (hdppz)]+ (9.45 µM) upon
raising the pH from 0.10 to 3.65.
Spectrophotometric pH Titrations
Electronic absorption spectra
UV–vis spectrophotometric pH titrations were carried out
over the pH range 0.10–9.73 and the spectral changes for
[Ir(ppy)2 (hdppz)]PF6 with pH were reversible. As pH increased
from 0.10 to 3.65 (see Fig. 2), the intensities of the bands at 253,
303 and 377 nm increased gradually, caused by the deprotonation of monoprotonated dipyrido[2,2-d:2 ,3 -f ]quinoxaline (dpq)
moiety on the complex. This indicates that the dpq moiety on
the complex behaves like a monobasic base over the pH range
from 0.10 to 3.65, since it was reported that the basicity of the
free nitrogen atom on the monoprotonated dpq became too
weak to accept proton owing to the strong electron-withdrawing
characteristics of the monoprotonated nitrogen on the dpq.
The second deprotonation step, which took place upon
increasing pH from 3.65 to 9.73, was due to the dissociation
of the proton on the hydroxy moiety, resulting in the following
spectral changes (Fig. 3): the absorption intensities for the π –π ∗
bands at 253 and 303 nm decreased with bathochromic shifts of 7
and 15 nm, respectively; the intensities of MLCT band at 385 nm
were evidently reduced.
It is clear from the discussion above that [Ir(ppy)2 (hdppz)]PF6
underwent two ground-state deprotonation processes upon
raising the pH from 0.10 to 9.73, as shown in Scheme 3. The
changes in absorbance at 303 nm as a function of pH are shown in
the insets of Figs 2 and 3. By sigmoidal fitting of data of Figs 2 and 3,
the negative logarithms of ground-state acid ionization constant
values, pKa1 = 2.01 ± 0.06 and pKa2 = 6.96 ± 0.22, were obtained.
The pKa2 is comparable with the pKa = 7.20–7.40 reported
Figure 3. Changes of UV–vis spectra of [Ir(ppy)2 (hdppz)]+ (9.45 µM) upon
raising pH from 3.65 to 9.73.
for [Ru(bpy)2 (hdppz)]2+ , [30] and more acidic than pKa = 8.6
reported for [Ru(bpy)2 (hpbpy)]2+ [hpbpy = 4-(4-hydroxyphenyl)2, 2 -bipyridine],[51] mainly owing to the fact that hdppz is more
conjugated than hpbpy. However, the pKa2 value of 6.96 is more
basic than hydroxy-deprotonated pKa of 6.0 (the first hydroxy) for
[Ru(bpy)2 dpq(OH)2 ]2+ {dpq(OH)2 = 2,3-dihydroxydipyrido[3,2f :2 ,3 -h]quinoxaline}, and 6.4 for [Ru(bpy)2 (dpqOHCOOH)]2+
(dpqOHCOOH = 3-hydroxydipyrido[3,2-f :2 ,3 -h]quinoxaline-2carboxylic acid),[52] owing to intra-molecular H-bonding effects.
Emission spectra
[Ir(ppy)2 (hdppz)]PF6 is nonluminescent in neutral water at room
temperature, remainin in emission ‘off’ state as the pH varied from
524
Scheme 3. The acid–base equilibria of [Ir(ppy)2 (hdppz)]+ .
wileyonlinelibrary.com/journal/aoc
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 521–529
Cyclometalated iridium(III) complex of 6-hydroxydipyrido[3,2-a:2 ,3 -c]phenazine
binding site size n of 0.82 was relatively low for exclusively
intercalative binding and this suggests that additional surface
stacking of hdppz may involve the DNA interaction at low [DNA]
concentrations.[6]
Ethidium bromide competition assay
Figure 4. (a) UV–vis spectra of [Ir(ppy)2 (hdppz)]+ (3.20 µM) in the absence
and the presence of rising DNA concentrations from 0 to 12.98 µM
in buffered 50 mM NaCl. (b) Changes in absorbances at 300 nm upon
increasing DNA concentrations from 0 to 12.98 µM.
0.10 to 9.73, in contrast to the pH-induced emission-switching
behavior we reported before for [Ru(bpy)2 (hdppz)]2+ ;[30] therefore
we failed to derive its excited-state acidity ionization constant
values.
DNA Binding Studies
UV–vis absorption spectra
Appl. Organometal. Chem. 2011, 25, 521–529
Thermal denaturation
Other strong evidence for intercalation of [Ir(ppy)2 (hdppz)]+
into the double helix of the DNA was obtained from the
DNA melting studies. Intercalation of small molecules into the
double helix is known to increase the helix melting temperature
(Tm ), the temperature at which the double helix denatures into
single-stranded DNA. The extinction coefficient of DNA bases
at 260 nm in the double-helical form is much less than in the
single-strand form; therefore, melting of the helix leads to an
increase in the absorption at this wavelength. Thus, the helixto-coil transition temperature can be determined by monitoring
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
525
Changes in absorption spectra of [Ir(ppy)2 (hdppz)]PF6 in the
absence and the presence of ct-DNA are illustrated in Fig. 4. Upon
successive addition of the DNA over concentrations of 0–12.98 µM,
the absorption peaks at 257, 300 and 385 nm underwent sharp
decreases in the intensities with hypochromisms as defined by
H% = 100(Afree − Abound )/Afree , being 85.5, 83.8 and 84.6%,
respectively. The large hypochromisms observed for the three
bands were much larger than 39% at 306 nm, 26% at 372 nm,
10% at 443 nm for [Ru(bpy)2 (hdppz)]2+[30] and 13.1% in the
MLCT transitions for [Ru(phen)2 (hdppz)]2+[53] at [Ru] = 4 µM
(see Table 1). These facts indicate that the complex strongly binds
to the DNA with hdppz moiety inserting into the adjacent base
pair of the DNA, probably via an intercalative mode, since bpy/ppy
was previously demonstrated to be at best only minimally efficient
at inducing intercalative binding with DNA.
In a plot of (εa − εf )/(εb − εf ) vs [DNA], the DNA-binding
constant Kb value was derived to be (6.06 ± 0.32) × 106 M−1
(n = 0.82 ± 0.04), which is larger than the Kb values previously
reported for DNA intercalators of [Ru(bpy)2 (dppz)]2+ (4.95 × 106
M−1 ),[54] {(η5 -C5 Me5 )Ir[(NMe2 )2 CS](dppz)}2+ (2.9 × 106 M−1 ),[6]
[Ru(bpy)2 (hdppz)]2+ (1.3 × 106 M−1 ),[30] [Ru(phen)2 (hdppz)]2+
(4.4 × 105 M−1 )[30] and [Ir(ppy)2 (dppz)]+ (2.4 × 104 M−1 ).[7] The
The fluorescence of ethidium bromide (EB) itself in aqueous
solution is very weak, but is greatly enhanced when it intercalates
between adjacent DNA base pairs of double-stranded DNA. If a
second DNA intercalator is added to the EB–DNA system, it will
compete with EB for the DNA binding site, and the fluorescence
of the EB–DNA system will be quenched, at least partially.[55] The
quenching extents of fluorescence of EB bound to DNA could be
used to determine the relative DNA binding affinities of the second
molecules. For [Ir(ppy)2 (hdppz)]+ , no emission was observed either
alone or in the presence of ct-DNA in buffer (5 mM Tris–50 mM NaCl,
pH = 7.1). The control experiments showed that there was almost
no change in the fluorescence intensities of free EB (in the absence
of DNA) on increasing concentrations of [Ir(ppy)2 (hdppz)]+ . The
changes in the emission spectra of the EB–DNA system in the
absence and presence of [Ir(ppy)2 (hdppz)]+ are shown in Fig. 5(a).
The addition of the complex to the DNA-bound EB solution
caused appreciable reduction in emission intensities, indicating
that the complex competitively bound to the DNA with EB. This
is because the free EB molecules were much less fluorescent
than the bound EB molecules,[56] and [Ir(ppy)2 (hdppz)]+ and DNAbound [Ir(ppy)2 (hdppz)]+ are also negligibly weakly emissive as
excited at λex = 537 nm. The quenching resulted in a linear
Stern–Volmer plot according to the equation I0 /I = 1 + Kr, where
I0 and I represent the fluorescence intensities of DNA-bound EB
in the absence and presence of complex, respectively; K is a
linear Stern–Volmer quenching constant dependent on the ratio
of the bound concentration of EB to the concentration of DNA;
and r is the ratio of the total concentration of the complex to
that of DNA ([Ir]/[DNA]). Figure 5(a) shows a slope of KD = 2.60
for [EB] = 20 µM and [DNA] = 100 µM. The KD value was
larger than the 1.64 for previously reported for [Ru(bpy)2 (aip)]2+
{aip = 2-(9-anthryl)-1H-imidazo[4,5-f ][1,10]phenanthroline},[32]
comparable to 2.72 for [Ru(dmp)2 (obpip)]2+ [dmp = 2,9-dimethyl1,10-phenanthroline; obpip = 2-(2-bromophenyl)imidazo[4,5f ]-1,10-phenanthroline],[57] but smaller than the K value of
19.3 for [Ru(bpy)(ppp)2 ]2+ (ppp = pyrido[2 ,3 :5,6]pyrazino[2,3f ][1,10]phenanthroline).[37] From the data in Fig. 5(b), we also know
that the addition of [Ir(ppy)2 (hdppz)]+ to the EB–DNA system
resulted in appreciable reduction in emission intensity by 92%
relative to that observed in the absence of the complex, supporting
the intercalative binding of the complex to the DNA. The groove
DNA binders were reported to be also capable of causing the
reduction in EB emission intensities, but only moderately.
Y.-M. Chen, A.-G. Zhang and K.-Z. Wang
Table 1. Comparisons of percentage of hypochromicities H%, bathochromic shift λ and the DNA binding constant Kb for some Ru(II) or Ir(III)
complexes binding to ct-DNA
Compounda
-[Ru(bpy)2 dppz]2+
-[Ru(bpy)2 dppz]2+
[Ir(ppy)2 (dppz)]+
[(η5 -C5 Me5 )Ir(NMe2 )2 CS(dppz)]2+
[Ru(bpy)2 (hdppz)]2+
[Ru(phen)2 (hdppz)]2+
[Ir(ppy)2 (hdppz)]+
H, % (λmax , nm)
41.2(370)
38(370)
–
44(383)
39(306), 26(372)b
13.1(450)
85.5(257), 83.8(300), 84.6(385)
λ, nm (λmax , nm)
Kb × 106 (M−1 )
Reference
6(370)
6(370)
–
–
0(372)
–
3(300)
4.95
4.95
0.024
2.9
1.3b
0.44
6.06
[54]
[54]
[7]
[6]
[30]
[53]
This work
a bpy, 2,2 -bipydidine; dppz, dipyrido[3,2-a:2 ,3 -c]phenazine; phen, 1,10-phenanthroline; ppy, 2-phenylpyridine; hdppz, 6-hydroxydipyrido[3,2-a:2,3 c]phenazine; dppn, benzo[i]dipyrido[3,2-a:2 ,3 -c]phenazine.
b The concentration of Ru(II) complex is 4 µM.
Figure 5. (a) Emission spectra of EB bound to DNA in the presence of
[Ir(ppy)2 (hdppz)]+ (0–90.1 µM). The arrows show the intensity changes
upon increasing concentrations of the complex. Inset: florescence
quenching curve of DNA-bound EB by the complex. (b) Plot of percentage
of free EB vs [Ir]/[EB]. [EB] = 20 µM, [DNA] = 100 µM, λex = 537 nm.
526
the absorbance of the DNA bases at 260 nm as a function of
temperature. As shown in Fig. 6, the Tm of ct-DNA was found
to be 67.1 ◦ C in the absence of [Ir(ppy)2 (hdppz)]+ , and was
successively increased upon increasing the concentrations of
the complex. The melting point difference of the DNA in the
presence and the absence of [Ir(ppy)2 (hdppz)]+ , Tm , was found
to be 1.3, 3.9 and 8.8 ◦ C for concentration ratios of [Ir]/[DNA]
= 1 : 60, 1 : 25 and 1 : 10, respectively. As shown in Table 2, the
Tm value of 8.8 ◦ C found for [(ppy)2 Ir(hdppz)]+ at [Ir]/[DNA] =
1 : 10 compares favorably with previously reported Tm values
wileyonlinelibrary.com/journal/aoc
Figure 6. (a) Thermal denaturnation curves of ct-DNA (61 µM) at different
[Ir(ppy)2 (hdppz)]+ concentrations of [DNA]/[Ir] = 10 : 1 (•), 25 : 1 (), 60 : 1
() and DNA alone (). (b) The plot of DNA helix melting temperature vs
[Ir]/[DNA].
of 5.8 ◦ C for [(η5 -Cp∗ )Ir(AcmetOMe)(dppz)]2+ ,[58] 7 ◦ C for [(η5 C5 Me5 )Ir(dppz)Cl]+ ,[6] 5 ◦ C for -[Ru(phen)2 (dppz)]2+ ([DNA]/[Ru]
= 1)[59] and 4 ◦ C for [(η5 -C5 Me5 )Ir(dpq){(NMe2 )2 CS}]+ .[6] However
it is smaller than 20 ◦ C for [Ru(bpy)2 (hdppz)]2+ .[30]
The DNA binding constants of the complex at Tm were
determined by McGee’s equation (3):[61]
1/Tm 0 − 1/Tm = (R/Hm ) ln(1 + KL)1/n
(3)
where Tm 0 is the temperature of ct-DNA alone, Tm is the
melting temperature in the presence of the complex, Hm
(6.9 kcal mol−1 )[62] is the enthalpy change of DNA melting, R
is the gas constant, L is the free Ir(III) complex concentration
(approximated by the total complex concentration at Tm ), and n
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 521–529
Cyclometalated iridium(III) complex of 6-hydroxydipyrido[3,2-a:2 ,3 -c]phenazine
Table 2. Comparison of Tm values of ct-DNA upon binding to some
representative drugs
DNA bindera
[DNA]/[Ru]
Tm , ◦ C
10
1
1
10
10
10
10
10
<2
5
5
5.8
7
4
20
8.8
[Ru(bpy)3 ]2+
-[Ru(phen)2 (dppz)]2+
AMAC
[(η5 -Cp∗)Ir(AcmetOMe)(dppz)]2+
[(η5 -C5 Me5 )Ir(dppz)Cl]+
[(η5 -C5 Me5 )Ir(dpq){(NMe2 )2 CS}]+
[Ru(bpy)2 (hdppz)]2+
[Ir(ppy)2 (hdppz)]+
a
Reference
[67]
[59]
[60]
[58]
[6]
[6]
[30]
This work
bpy, 2,2 -bipydidine; phen, 1,10-phenanthroline; dppz, dipyrido[3,2a:2 ,3 -c]phenazine; AMAC, (9-anthrylmethyl)ammonium chloride;
dpq, dipyrido[2,2-d:2 ,3 -f ]quinoxaline; hdppz, 6-hydroxydipyrido[3,2a:2 ,3 -c]phenazine; ppy, 2-phenylpyridine.
is the binding site size. By substituting the required parameters
into equation (3), the DNA binding constant K value at 75.9 ◦ C was
derived to be 8.68 × 103 M−1 by taking n = 0.82 (obtained by
UV–vis spectroscopy).
The changes of standard enthalpy H0 , standard free energy
GT 0 and standard entropy S0 were determined according to
van’t Hoff’s equation (4),[63] and equations (5) and (6), respectively.
ln(K1 /K2 ) = (H0 /R)[(T1 − T2 )/T1 T2 ]
GT = −RT ln K
0
GT = H − TS
0
0
(4)
(5)
0
(6)
where K1 and K2 are the DNA binding constants of the
complex at temperatures T1 and T2 , respectively. By use of a
K1 value of 6.06 × 106 M−1 at T1 = 298 K and a K2 value of
8.68 × 103 M−1 at T2 = 349 K, a H0 value was thus derived
to be −111.02 kJ mol−1 . By substituting K1 = 6.06 × 106 M−1
(T1 = 298 K) and H0 = −111.02 kJ mol−1 into equations (5) and
(6), G298K 0 = −38.69 kJ mol−1 and S0 = −242.72 J mol−1 K−1
were derived. The largely negative binding free energy change
implies that the sum of the free energies of free complex and DNA
is much higher than that of the adduct, and the binding of the
Ir(III) complex to ct-DNA is energically highly favorable at room
temperature, and the binding reaction was driven enthalpically.
While the large negative entropy change indicates that the
complexes were very restricted in freedom upon binding to DNA, it
is unfavorable for the DNA binding,[64] and intercalation produces
an extension, unwinding and stiffening of the DNA helix. These
changes are a consequence of the untwisting of the base pairs
and helical backbone needed to accommodate the intercalator.
Viscosity measurements
Appl. Organometal. Chem. 2011, 25, 521–529
exclusively in the DNA groove (e.g. netropsin and distmycine)
under the same conditions typically cause less pronounced
(positive or negative) or no change in DNA solution viscosity.[66]
Here, the viscosities of ct-DNA bound to the complex increased
with the increment of [Ir(ppy)2 (hdppz)]+ as shown in Fig. 7,
similarly to the trend observed for many well-known DNA
intercalator like EB under identical experimental conditions.
Theoretical explanation on the electronic effects on DNA binding
properties
The trend in DNA-binding affinities of the complexes can be
theoretically explained. The calculated selected geometric data,
some frontier molecular orbital energies and molecular orbital
diagrams of complexes of [Ir(ppy)2 (hdppz)]+ , [Ru(bpy)2 (hdppz)]2+
and [Ru(phen)2 (hdppz)]2+[53] are given in Tables 3 and 4 and Fig. 1,
respectively.
As is well established, there are π –π stacking interactions as
intercalative interaction between the DNA and the complexes
occurs; the base pairs of the DNA are electron-donors[68,69]
and the intercalated complex is an electron-acceptor, because
the LUMO–LUMO +2 energies (−7.32–4.52 eV) of the three
complexes are much lower than the previously reported HOMO,
HOMO-1 and HOMO-2 energies (−1.27, −1.33 and −1.69 eV)
of the DNA base pairs.[69,70] Based on the frontier molecular
orbital theory,[71,72] the DNA-binding affinity of the complex should
rely on three factors:[53] (i) the planarity area of the intercalative
ligand, because the larger planarity area is advantageous to the
interaction between DNA and the complex; (ii) the LUMO (the
lowest unoccupied molecular orbital) energy of the complex,
since lower LUMO energy of the complex is advantageous to
accepting the electrons offered from base pairs of DNA; and
(iii) the populations of LUMO and/or some virtual orbitals near
LUMO on the intercalative ligand, because more such populations
are also advantageous to the overlap between HOMO of DNA and
LUMO of the complex and thus to the interaction between DNA
and the complex.
From Table 3, we can also see that the planarity order of intercalative ligands in three complexes of [Ru(phen)2 (hdppz)]2+ ,
[Ru(bpy)2 (hdppz)]2+ and [Ir(ppy)2 (hdppz)]+ are comparable to
each other, making equal contributions of this factor to
the DNA binding affinities. From Table 4, we can clearly see
that the order of the energies (εi ) of the lowest unoccupied molecular orbital (LUMO) is εLUMO ([Ru(bpy)2 (hdppz)]2+ )
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
527
Hydrodynamic measurements that are sensitive to length change
(i.e. viscosity and sedimentation) are regarded as the least
ambiguous and the most critical tests of binding in solution
in the absence of crystallographic structural data.[62,65] To further
clarify DNA binding properties of [Ir(ppy)2 (hdppz)]+ , viscosity
measurements were carried out. Under appropriate conditions,
intercalation of drugs like EB causes a significant increase in
viscosity of DNA solution owing to an increase in the separation
of base pairs at intercalation sites and, hence, an increase in
overall DNA contour length. By contrast, drug molecules that bind
Figure 7. Effects of increasing amounts of [Ir(ppy)2 (hdppz)]+ on the
relative viscosities of ct-DNA (91.36 µM) in buffered 50 mM NaCl at
32.64 ± 0.03 ◦ C.
Y.-M. Chen, A.-G. Zhang and K.-Z. Wang
Table 3. Calculated selected bond lengths (nm), bond angles and dihedral angles (deg) of [Ru(phen)2 (hdppz)]2+ , [Ru(bpy)2 (hdppz)]2+ and
[Ir(ppy)2 (hdppz)]+
M–Nm a
M–C(N)co
C–C(N)m b
C–C(N)co
N–M–Nm
C(N)–M–Nco
0.2122
0.2124
0.1392
0.1395
78.4
78.6
[Ru(bpy)2 (hdppz)]2+
0.2125
0.2116
0.1394
0.1388
78.3
77.7
[Ir(ppy)2 (hdppz)]+
0.2223
0.2053
0.1393
0.1398
75.2
80.1
Compound
[Ru(phen)2
(hdppz)]2+
Dihedral angle
179.95c
179.90e
179.70g
−179.91c
180.00e
179.94g
−179.85c
−179.99e
179.92g
−0.01d
179.88f
179.74h
0.08d
179.99f
179.93h
0.11d
−179.94f
179.93h
a
M–Nm , the mean bond length between the center metal (M) and coordinated N-atoms of the main ligand hdppz; M–C(N)co , the mean bond length
between M and coordinated C(N)-atoms of the co-ligand of bpy or phen.
b
C–C(N)m , the mean C–C bond length of the main ligand skeleton; C–C(N)co , the mean C–C bond length of the co-ligand skeleton.
c Dihedral angles of C(31)–C(32)–O(41)–H(42) and d dihedral angles of C(33)–C(32)–O(41)–H(42) as defined in Scheme 1, the dihedral angles
between hydroxyl group and benzene ring.
e Dihedral angles of C(32)–C(33)–C(28)–N(44) and f dihedral angles of C(29)–C(28)–C(33)–N(43) as defined in Scheme 1, the dihedral angles between
benzene and pyrazine rings.
g Dihedral angles of C(26)–C(27)–C(34)–N(43) and h dihedral angles of C(35)–C(34)–C(27)–N(44) as defined in Scheme 1, the dihedral angles between
pyrazine and phenanthroline rings.
Table 4. Some frontier molecular orbital energies (εi /a.u.) of the complexes (1 a.u. = 27.21 eV)
Compound
[Ru(phen)2 (hdppz)]2+
[Ru(bpy)2 (hdppz)]2+
[Ir(ppy)2 (hdppz)]+
H-2
H-1
HOMOa
LUMOb
L+1
L+2
εL – H c
Reference
−0.4009
−0.4045
−0.3125
−0.3981
−0.4013
−0.2985
−0.3642
−0.3709
−0.2901
−0.2635
−0.2691
−0.1868
−0.2607
−0.2666
−0.1784
−0.2606
−0.2635
−0.1661
0.1007
0.1018
0.1033
This work
This work
[5]
a
HOMO (or H), the highest occupied molecular orbital.
LUMO (or L), the lowest unoccupied molecular orbital.
c ε
L – H , the energy difference between LUMO and HOMO.
b
< εLUMO ([Ru(phen)2 (hdppz)]2+ ) < εLUMO ([Ir(ppy)2 (hdppz)]+ ).
This factor is not advantageous to the DNA-binding affinity of [(ppy)2 Ir(hdppz)]+ . However, the LUMO component of
[Ir(ppy)2 (hdppz)]+ is predominantly distributed on the intercalative ligand whereas those of [Ru(bpy)2 (hdppz)]2+ and
[Ru(phen)2 (hdppz)]2+ are dominantly distributed on the coligands. The factor is very advantageous to the DNA-binding
affinity of [Ir(ppy)2 (hdppz)]+ . This led us to draw a conclusion
that the predominant distribution of the LUMO on the intercalative ligand Hdppz of [Ir(ppy)2 (hdppz)]+ makes a dominant
contribution to the large DNA binding constant (6.06 × 106 M−1 )
observed relative to the much lower DNA binding constants of
(0.44–1.3) ×106 M−1 previously reported for [Ru(bpy)2 (hdppz)]2+
and [Ru(phen)2 (hdppz)]2+ , [30,53] since the latter two complexes
have predominant distribution of their LUMO on their coligand
bpy rather than the intercalative ligand hdppz, and are unfavorable
for DNA binding.
Conclusions
528
In summary, our results demonstrate that the cyclometalated
complex [Ir(ppy)2 (hdppz)]PF6 binds to the DNA with a binding
constant of (6.06 ± 0.32) ×106 M−1 , and possesses acid ionization
constant values of pKa1 = 2.01±0.06, pKa2 = 6.96±0.22 driven for
the protonation/deprotonation of monoprotonated dpq moiety
and hydroxyl group, respectively. UV–vis spectroscopy showed
wileyonlinelibrary.com/journal/aoc
that the binding of the Ir(III) complex to ct-DNA caused the
hypochromisms of 85.5, 83.8 and 84.6% at 257, 300, and 385 nm,
respectively, favoring competitive binding to the DNA with EB.
The electrostatic binding free energy was much smaller than
the nonelectrostatic one. DNA melting temperature was raised by
8.8 ◦ C in the presence of the complex at [Ir]/[DNA] = 1 : 10; and DNA
viscosities evidently increased as the complex was successively
added. These results led to a self-consistent set of conclusions
concerning the mode and efficiency of binding of the complex to
ct-DNA: the complex avidly bound to ct-DNA in an intercalative
mode in buffered 50 mM NaCl. The predominant distribution of
the LUMO on the intercalative ligand Hddpz of [Ir(ppy)2 (hdppz)]+
is expected to make a contribution to the avid DNA binding of
[Ir(ppy)2 (hdppz)]+ observed.
Acknowledgments
The authors thank the National Natural Science Foundation
(20971016, 90922004 and 20771016), The Fundamental Research
Funds for the Central Universities (2009SC-1) and the Measurements Fund of Beijing Normal University for financial support.
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529
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