Synthesis, structural characterization, solution behavior, and in vitro antiproliferative properties of a series of gold complexes with 2-(2′-pyridyl)benzimidazole as ligand: Comparisons of gold(III) versus gold(I) and mononuclear versus binuclear derivatives

Article abstract of DOI:10.1021/ic202639t

A variety of gold(III) and gold(I) derivatives of 2-(2′-pyridyl) benzimidazole (pbiH) were synthesized and fully characterized and their antiproliferative properties evaluated in a representative ovarian cancer cell line. The complexes include the mononuclear species [(pbi)AuX₂] (X = Cl, 1; OAc, 2), [(pbiH)AuCl] (3), [(pbiH)Au(PPh₃)][PF₆] (4-PF₆), and [(pbi)Au(L)] (L = PPh₃, 5; TPA, 6), and the binuclear gold(I)/gold(I) and gold(I)/gold(III) derivatives [(PPh ₃)₂Au₂(μ₂-pbi)][PF₆] (10-PF₆), [ClAu(μ₃-pbi)AuCl₂] (7),and [(PPh₃)Au(μ₃-pbi)AuX₂][PF₆] (X = Cl, 8-PF₆; OAc, 9-PF₆). The molecular structures of 6, 7, and 10-PF₆ were determined by X-ray diffraction analysis. The chemical behavior of these compounds in solution was analyzed both by cyclic voltammetry in DMF and absorption UV-vis spectroscopy in an aqueous buffer. Overall, the stability of these gold compounds was found to be acceptable for the cellular studies. For all complexes, relevant antiproliferative activities in vitro were documented against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin, with IC₅₀ values falling in the low micromolar or even in the nanomolar range. The investigated gold compounds were found to overcome resistance to cisplatin to a large degree. Results are interpreted and discussed in the frame of current knowledge on cytotoxic and antitumor gold compounds.

Full text of DOI:10.1021/ic202639t

Article
pubs.acs.org/IC
Synthesis, Structural Characterization, Solution Behavior, and in
Vitro Antiproliferative Properties of a Series of Gold Complexes with
2-(2′-Pyridyl)benzimidazole as Ligand: Comparisons of Gold(III)
versus Gold(I) and Mononuclear versus Binuclear Derivatives
Maria Serratrice,† Maria A. Cinellu,*,† Laura Maiore,† Maria Pilo,† Antonio Zucca,† Chiara Gabbiani,‡
Annalisa Guerri,§ Ida Landini,∥ Stefania Nobili,∥ Enrico Mini,∥ and Luigi Messori*,§
†Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy.
‡Department of Chemistry and Industrial Chemistry, University of Pisa, Via Risorgimento 35, 56126 Pisa, Italy
§Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy
∥Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy
S
* Supporting Information
ABSTRACT: A variety of gold(III) and gold(I) derivatives of
2-(2′-pyridyl)benzimidazole (pbiH) were synthesized and fully
characterized and their antiproliferative properties evaluated
in a representative ovarian cancer cell line. The complexes
include the mononuclear species [(pbi)AuX2] (X = Cl, 1;
OAc, 2), [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)][PF6] (4-PF6),
and [(pbi)Au(L)] (L = PPh3, 5; TPA, 6), and the binuclear
gold(I)/gold(I) and gold(I)/gold(III) derivatives
[(PPh3)2Au2(μ2-pbi)][PF6] (10-PF6), [ClAu(μ3-pbi)AuCl2] (7),
and [(PPh3)Au(μ3-pbi)AuX2][PF6] (X = Cl, 8-PF6; OAc, 9-PF6). The molecular structures of 6, 7, and 10-PF6 were
determined by X-ray diffraction analysis. The chemical behavior of these compounds in solution was analyzed both by cyclic
voltammetry in DMF and absorption UV−vis spectroscopy in an aqueous buffer. Overall, the stability of these gold
compounds was found to be acceptable for the cellular studies. For all complexes, relevant antiproliferative activities in vitro
were documented against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin, with IC50 values
falling in the low micromolar or even in the nanomolar range. The investigated gold compounds were found to overcome
resistance to cisplatin to a large degree. Results are interpreted and discussed in the frame of current knowledge on cytotoxic
and antitumor gold compounds.
ligands, and some organogold(III) derivatives, that revealed
very attractive antiproliferative profiles in vitro.12 Very recently,
a series of gold(III) and gold(I) derivatives of the saccharinato
ligand, both homoleptic and heteroleptic, were prepared and
their reactions with model proteins and cytotoxic activity
against cancer cell lines studied in depth, allowing a comparison
to be made between derivatives of the same ligand with gold in
its two different oxidation states.13 Therefore, relying on the
promising results obtained for both gold(III) and gold(I) com-
plexes with nitrogen donor ligands, and considering it of
interest to compare the different biological profiles displayed by
gold in its two different oxidation states, yet linked to the same
organic carrier, we looked for a polytopic nitrogen ligand which
might give stable gold(III) and gold(I) complexes and, hopefully,
afford binuclear species. Spurred by our previous experience
with gold(III) derivatives of substituted 2,2′-bipyridines and of
phenanthrolines,7 this latter objective was specifically pursued.
INTRODUCTION
■
Gold compounds are drawing increasing attention within the
bioinorganic and medicinal chemistry communities for their
very encouraging antiproliferative and antitumor properties.1
Indeed, a number of interesting compounds were recently
described and characterized showing favorable pharmacological
profiles among which we like to highlight gold(III) porphyrins,2
gold(III) dithiocarbamates,3 and a variety of gold(I) complexes
with phosphine and/or N-heterocyclic carbene ligands.4,5
A
limited number of binuclear gold(III)6−8 as well as gold(I)9,10
complexes were also reported which display quite exciting bio-
logical properties.
It was established that the relevant antiproliferative actions of
these metallodrugs depend on the presence of either a gold(III)
or a gold(I) center although the respective cytotoxic mechanisms
seem to be rather distinct.11 On the whole, gold compounds con-
stitute a very promising family of potential anticancer agents and
deserve further and deeper investigations.
Remarkably, during the past decade, we have prepared and
evaluated several gold(III) complexes, mainly of nitrogen donor
Received: December 7, 2011
Published: February 17, 2012
© 2012 American Chemical Society
3161
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
Indeed, we observed that the binuclear derivatives featured
higher performances than the corresponding mononuclear
species, both in terms of stability in solution and of bio-
logical activity. Here, our main goal was to join within the
same chemical entity a gold(III) and a gold(I) center with
the idea that it might result in innovative medicinal chemi-
stry and hopefully in a synergism between the biological
actions of the two different gold centers.
gold(III) complexes are quite stable both in solid state and in
solution; complex 1 is very insoluble in most organic solvents
likely due to intermolecular stacking. In both complexes the
ligand is in its deprotonated form as shown by the IR and
1H NMR spectra. This is surprising, in particular for complex 2,
having been obtained in AcOH. Notably, under various reac-
tion conditions, reaction of pbiH with palladium(II) and
platinum(II) chlorides gives [(pbiH)MCl2].16g−k Attempts to
protonate complex 1 with protic acids HX (X = BF4, PF6) failed
to give the cationic complex [(pbiH)AuCl2][X] (1-X); never-
theless, “protonated” forms of 1 and 2 were easily obtained by
reaction of the complexes with [(L)Au]+ (L = PPh3, TPA =
1,3,5-triaza-7-phosphaadamantane), i.e., the isolobal ana-
logues20 of H+ (vide infra). The IR spectrum of 1, in the low
frequency region, is characterized by the presence of two strong
bands at 374 and 359 cm−1 due to Au−Cl stretching vibrations;
the different stretching frequencies are indicative of the differ-
ent trans-influence exhibited by the sp2 and sp3 N atoms.21 In
the IR of 2 the two acetato ligands give rise to very strong
bands at 1685(sh), 1672 (νasym(CO2)), and 1255 cm−1
(νsym(CO2)); two medium intensity bands at 322 and 280
cm−1 are attributed to Au−O vibrational modes.22
2-(2′-Pyridyl)benzimidazole, pbiH, a potentially tridentate
ligand featuring two sp2-hybridized and one sp3-hybridized
nitrogen atoms, seemed to us particularly appropriate for reach-
ing the above goals. Moreover, this ligand displays valuable
pharmacological activities in its own right, being, for example,
an anti-inflammatory agent14 and an inhibitor of Escherichia coli
methionine aminopeptidase.15 Metal complexes of 2-(2′-
pyridyl)benzimidazole and related ligands are the subject of
intensive research,16 not only owing to their rich coordination
chemistry but also due to a number of established and potential
application areas, including medicinal chemistry.16h,j,k Gold(III)
and gold(I) derivatives of this ligand were reported several
years ago by Dash: they were tentatively formulated, respec-
tively, as five- and three-coordinated complexes of the neutral
ligand on the basis of analytical and spectroscopic (IR and
A 1H NMR spectrum of 1 could be obtained only in DMSO-
d6: it shows six resonances, with integral ratio of 2:1:1:2:1:1,
most of which shifted downfield with respect to those of free
pbiH in the same solvent (see Experimental Section and Table S1),
the most affected by coordination being those of the H6 and H3′
protons (see Scheme 1 for the numbering scheme), with Δδ
Mossbauer) data.17 Later on, the gold(I) derivative [(PPh3)-
̈
Au(pbiH)][ClO4] was structurally characterized showing a
linear coordination at the gold atom.18
We report here the synthesis and structural and spectro-
scopic characterization of mononuclear gold(III) and gold(I)
complexes and binuclear gold(I)/gold(I) or gold(III)/gold(I)
complexes of 2-(2′-pyridyl)benzimidazole, pbiH, and of its
deprotonated form pbi. The solution chemistry of the various
complexes and their in vitro cytotoxic actions toward two
established tumor cell lines are investigated in detail.
Scheme 1. Numbering Scheme of pbiH and of Complexes 1
and 2
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Mononuclear
Complexes. The ligand 2-(2′-pyridyl)benzimidazole, pbiH,
was synthesized by condensation between pyridine-2-carboxylic
acid and 1,2-phenylenediamine in the presence of polyphos-
phoric acid at 180 °C, according to a literature method.19 The
gold(III) derivatives [(pbi)AuX2] (X = Cl, 1; OAc, 2) (see
Chart 1) have been obtained by reaction of pbiH with
(δcoord − δfree) of 0.52 and 0.86 ppm, respectively, as a
consequence of the neighborhood of the Cl− ligands. At
variance with 1, complex 2 is very soluble in most organic
solvents; its proton spectrum in CDCl3 shows two signals at δ
2.29 and 2.36 ppm for the methyl protons of the two acetato
ligands. In the aromatic region, the H6 resonance is found at
slightly higher fields (Δδ = −0.23 ppm) while that of H3′ is
shifted downfield with respect to the free ligand; in both com-
plexes the chemical shift of H4′ and H5′ is almost unchanged.
This is a common feature of most of the other complexes,
although the H4′, H5′ multiplet structure changes its appearance
dramatically as a consequence of the different environment
experienced by the ortho protons H3′ and H6′, depending on
coordination to gold of the adjacent nitrogen atoms.
Chart 1. Gold(III) (1 and 2) and Gold(I) (3, 4-PF6, 5, and 6)
Mononuclear Derivatives
Reaction of pbiH with (THT)AuCl and [(PPh3)Au][PF6]
afforded, respectively, [(pbiH)AuCl] (3) and [(pbiH)Au-
(PPh3)][PF6] (4-PF6), both containing the neutral ligand.
Deprotonation of the coordinated ligand of 4-PF6 with KOH in
MeOH gave [(pbi)Au(PPh3)] (5), while [(pbi)Au(TPA)] (7)
was obtained one-pot from reaction of pbiH with (TPA)AuCl
in the presence of KOH. Any attempt to deprotonate the ligand
of the chloride complex 3 failed to give the expected anionic
derivative [(pbi)AuCl]−: large decomposition was instead
observed.
Na[AuCl4]·2H2O in H2O−MeCN at room temperature and
with Au(OAc)3 in AcOH at reflux, respectively. The two
3162
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
The IR and 1H NMR spectra of 3 and 4-PF6 give evidence of
N−H groups (see Experimental Section). In complex 3 the
ν(Au−Cl) is observed at 347 cm−1. In both cases the N−H
resonance is strongly deshielded with respect to the free ligand,
which suggests that the complexes are more acidic than the
ligand. In the proton spectrum of 3 (CDCl3) two sets of signals
are found with a 3:1 integral ratio; the signals of the minor
species, with the exception of the N−H resonance which is
found at a lower frequency, are superimposable with those of
pbiH in the same solvent. The signals of 3 are well resolved
multiplets shifted downfield with respect to those of the un-
coordinated ligand, with the H3 proton being the most
deshielded with a Δδ of 1.29 ppm. Treatment of 3·1/3pbiH
with diethyl ether failed to give the free complex, which
suggests that pbiH is either clathrated and/or hydrogen-bonded
to [(pbiH)AuCl] units.23 At variance with 3, only one set of
signals is found for complex 4-PF6: the spectrum is char-
acterized by broad poorly resolved signals. The main feature of
the spectrum of 4-PF6, as that of the other PPh3 derivatives
here described, is the upfield shift of H6 (Δδ = −0.34 ppm),
while the resonance of the H6′ proton could not be attributed
with certainty. The 31P{1H} NMR spectrum of 4-PF6 exhibits
two signals: a multiplet centered at −143.9 ppm is assigned to
Note that 4-PF6, 10-PF6, and [pbiH2][PF6] are connected
with each other owing to the isolobal analogy between H+ and
(PPh3)Au+.20
1
The H NMR spectrum of 5 in CDCl3 shows one well
resolved set of signals; as in the case of 4-PF6, the H3 proton
at δ 8.57 is the most deshielded and downfield shifted of
0.12 ppm with respect to the free ligand, while the resonance of
the H6 proton is shifted upfield of 0.44 ppm which suggests
some involvement of the pyridinic nitrogen in the PPh3Au-
pbi bonding. The H4′, H5′, H3′, H6′ protons give rise to a
well separated AA′BB′ spin system with Δδ (δBB′ − δAA′) of
0.65 ppm. An analogous pattern for these protons was found
also in the proton spectrum (in acetone-d6) of complex 6
(Δδ = 0.56 ppm). In this case the H6 proton is the most
deshielded, although slightly upfield shifted (Δδ = −0.06 ppm)
with respect to the free ligand. The N−CH2−N protons of
the TPA ligand give rise to an AB spin system centered at
δ 4.67 ppm (JAB = 12.8 Hz) and the N−CH2−P a singlet
resonance at δ 4.58 ppm. In the 31P{1H} NMR spectra of 5 and
6 only one resonance is found for the coordinated P atom of
the phosphane ligand, respectively, at δ 33.8 and −65.1 ppm.
Single crystals of 6 were obtained by slow diffusion of diethyl
ether into an acetone solution. The X-ray structure analysis of
compound 6 allowed us to establish that the isolobal (TPA)Au
unit replaces the H atom of the N−H group in the imidazole
ring.
−
the PF6 ion, and a singlet resonance at 31.4 is consistent for
linear gold(I) PPh3 derivatives having a phosphorus trans to a
1
nitrogen atom. The broad signals in the H NMR spectrum
suggest a fluxionality process involving positional exchange of
the (PPh3)Au+ group between the two iminic nitrogen coordina-
tion sites. The site-exchange mode is represented in Scheme 2.
Synthesis and Characterization of Binuclear Complexes.
Binuclear derivatives 7, 8-PF6, 9-PF6, and 10-PF6 (Chart 2)
Chart 2. Gold(III)/Gold(I) (7, 8-PF6, and 9-PF6) and
Gold(I)/Gold(I) (10-PF6) Binuclear Derivatives
Scheme 2
A similar behavior was previously observed for 4-ClO4 as
well as for other (PPh3)Au+ derivatives of bidentate nitrogen
ligands.18 Ligand redistribution to give the homoleptic cations
[(PPh3)2Au]+ and [(pbiH)2Au]+ was ruled out by the absence
in the 31P NMR spectrum of any signal ascribable to the
[(PPh3)2Au]+ species, typically at ca. 45 ppm.24
Attempts to grow crystals of 4-PF6, by slow diffusion of
diethyl ether into a concentrated chloroform solution of the
complex, afforded crystals of the dinuclear complex [(PPh3)2-
Au2(μ-pbi)][PF6] (10-PF6) (vide infra) and a white powder
identified as [pbiH2][PF6]. These products very likely originate
from an equilibrium reaction according to eq 1:
have been obtained by reaction of the metalloligands 1, 2, and 5
with (THT)AuCl, 7, or [(PPh3)Au][PF6], 8-PF6, 9-PF6, and
10-PF6; the latter complex was also obtained in a crystalline form
from a CHCl3−Et2O solution of 4-PF6 as a result of a redis-
tribution of the H+ and (PPh3)Au+ cations according to
eq 1. The IR spectrum of 7 is almost unchanged with respect
to that of its parent compound 1 both in the high and low
frequencies region. The 1H NMR spectra of 7 and 1 in the same
solvent (DMSO-d6) show differences either in the chemi-
cal shift and in the appearance of the signals; e.g., the resonance
of the H6 proton, the most deshielded in both compounds, in
7 is less downfield shifted with respect to the free ligand, with Δδ
of 0.18 ppm (0.52 ppm in 1). The H4′, H5′, H3′, H6′ protons give
rise to a well resolved AA′BB′ spin system, while in 1 the same
protons display an ABCD pattern. In the IR spectra of
3163
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
Figure 1. ORTEP drawings (5% probability ellipsoids) of complex 6 (a), 7 (b), and 10 (c).
compounds 8-PF6 and 9-PF6 new vibrational bands relative to
the PPh3 ligand and to the PF6− anion are found, in addition to
those exhibited by their parent compounds 1 and 2. Compound
8-PF6 is much more soluble than 1 and 6, and 1H NMR spectra
have been recorded in various solvents; with the obvious
exception of the signals of the PPh3 protons, the spectrum in
DMSO-d6 is almost superimposable with that of 1. At variance,
the proton spectrum of 9-PF6 shows for the pbi protons different
chemical shifts from that of the parent compound 2; moreover,
the H4′, H5′, H3′, H6′ protons give rise to an AA′BB′ spin system,
while in 2 the same protons display an ABCD pattern. In the 31P
NMR spectrum of 8-PF6 and 9-PF6, one resonance is observed
for the PPh3 ligand, respectively, at δ 32.8 and 30.8 ppm; the
resonance of the PF6− ion is observed at −143.5 and −144.3
ppm, respectively.
cted in Table 1. All these complexes feature an imidazolate unit
acting in all possible coordination modes, i.e., as a monodentate
Table 1. Bond Lengths (Å) and Angles (deg) for
Compounds 6, 7, and 10-PF6
6
7
10-PF6
Au(1)P(1)
2.205(4)
2.06(1)
2.70(1)
2.222(2)
2.092(5)
2.691(9)
Au(1)N(1)
1.97(3)
2.05(1)
2.26(1)
2.24(1)
2.236(5)
2.086(4)
Au(1)N(3)
Au(1)Cl(1)
Au(1)Cl(2)
Au(2)Cl(3)
Au(2)N(2)
2.065(5)
2.237(2)
173.7(2)
113.2(2)
68.8(2)
Au(2)P(2)
P(1)Au(1)N(1)
P(1)Au(1)N(3)
N(1)Au(1)N(3)
N(1)Au(1)Cl(1)
N(1)Au(1)Cl(2)
N(3)Au(1)Cl(1)
N(3)Au(1)Cl(2)
Cl(1)Au(1)Cl(2)
N(2)Au(2)Cl(3)
N(2)Au(2)P(2)
177.6(3)
107.8(2)
69.9(4)
With the exception of a new band relative to the PF6− anion,
no significant differences are found in the IR spectrum of
78.6(8)
96.8(9)
175.4(9)
174.6(4)
96.8(4)
87.8(4)
178.5(2)
1
10-PF6 with respect to that of 5. Comparison of the H NMR
spectrum of 10-PF6 (in CDCl3) with those of the mononuclear
derivatives 4-PF6 and 5 in the same solvent showed significant
differences of chemical shifts of most of the pbi protons; e.g.,
the H3 proton, the most deshielded in all complexes, in 10-PF6
is further downfield shifted ca. 0.2 ppm with respect to that of
4-PF6 and 5, likely due to coordination of the neighboring
nitrogen atom. This suggests that also in solution in 4-PF6 and
5 the pyridinic N atom is oriented toward the PPh3Au group
bound to one of the imidazolic N atom, as found in the solid
175.0(2)
ligand in complex 6, as a μ2-bridging form in 10-PF6, and as a
μ3-bridging form in 7. The latter form, also featured by com-
plexes 8-PF6 and 9-PF6, is a rare phenomenon in the litera-
ture.26 The asymmetric units 6 and 7 contain only the metal
complex while for 10-PF6 one hexafluorophosphate anion is
also present. The gold(I) ion is arranged in all complexes in the
usual linear coordination geometry, and the gold(III) atom has
the common square planar geometry. Bond lengths and angles
(Table 1) are in agreement with those found in the CSD
(v 5.32 + update27) for fragments similar to the complexes
under study.
18
state for 4-ClO4 and for the (TPA)Au group in complex 6
(vide infra). This is in line with what is observed for some
gold(I) complexes with other N/N ligands.25 The 31P NMR of
10-PF6 shows only one singlet resonance at 32.6 ppm for the
two PPh3 ligands, which indicates equivalence of the two
nitrogen atoms of the imidazolato anion; it is noteworthy that
this value is exactly half way between 31.4 ppm of 4-PF6 (PPh3
trans to the iminic N) and 33.8 ppm of 5 (PPh3 trans to the
amidic N).
Crystal Structures of Complexes 6, 7, and 10-PF6.
Complexes 6, 7, and 10-PF6 were characterized by X-ray
diffraction; perspective views of the complexes are shown in
Figure 1a−c, respectively and selected bond parameters colle-
In complexes 6 and 10-PF6 the relative rigidity of the 2-(2′-
pyridyl)benzimidazolate ligand automatically brings atom N(3)
to a distance from the gold atom, ca. 2.7 Å, which is well below
3164
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
the sum of the van der Waals radii of Au and N (2.2 + 1.5 =
3.7 Å)28 but much longer than the usual AuIII−Npy single bonds
[for instance, it is 2.05(1) Å in 7]. A longer distance of 2.930 Å
was found in 4-ClO4 between the same atoms.18 Similar Au−N
interactions have been previously observed in a number of
cases.25,29 They have generally been considered fairly weakly
bonding; however, it has been pointed out that they take place
only when sterically enforced by the presence of relatively rigid
multidentate ligands. Moreover, the dihedral angles formed by
the plane containing the pyridyl residue and that containing the
benzimidazolate moiety are different in 6 and 10-PF6 compared
to the following latter value: 12.7(5)°, 18.2(4)°, and 2.81°,
respectively. These differences could be ascribed to the differ-
ent steric hindrance present in the three complexes: in 6 the
less hindered TPA ligand allows the tilting of the ring, and in
10-PF6 the μ2-bridging arrangement constrains the conforma-
tion as it is. Moreover, in the crystal lattice of this complex, an
intramolecular C−H···π interaction can be detected which
contributed to the conformation of the molecule: the hydrogen
atom H(12) of the pyridyl ring points to the centroid of one of
the phenyl rings being this distance Ct···H(12) 3.09 Å and the
angle Ct···H(12)−C(12) 157°. In addition, the lines defined by
the atoms P(1)−Au(1)−N(1) and P(2)−Au(2)−N(2) draw an
angle of 50.2(2)°. Concerning compound 7, the planes
including the pyridyl moiety and that containing the benzi-
midazolate residue form an angle of only 2.3(3)°. This different
behavior could be attributed to the μ3-bridging role played by
the pbi ligand in this complex. Moreover, the mean planes
defined by this moiety and the atoms coordinating the gold
metal ion [Cl(1), Cl(2), N(1), and N(3)] are almost coplanar.
It can be pointed out that complex 6 piles up in the crystal
lattice in a head-to-tail fashion. The distance between the mean
planes containing the pbi residue is 3.6 Å; ca. C−H···π inter-
actions can be found between the hydrogen atoms of the
adamantane ring and the phenyl ring. Moreover, some
hydrogen bond interactions are detected in the crystal lattice
which contribute to the packing of the compound in the crystal.
In the crystal lattice, complex 7 also stacks in head to tail
mode. Different M−Cl···H interactions were detected in the
crystal lattice involving Cl(1) and Cl(3) and hydrogen atoms
belonging to molecules of different asymmetric units. In addi-
tion the chlorine atom Cl(3) weakly interacts with Au(1)
reported by −x; −y + 1; −z + 2 (3.282(4) Å).
Also, complex 10 stacks along the x direction in the crystal
lattice: the distance between the mean planes containing the
pbi moieties is 3.5 Å ca. Many C−H···π interactions can be
detected, involving both the aromatic rings of the PPh3 moie-
ties and the benzimidazolate ring and the hydrogen atoms
belonging to these same rings.
Solution Studies. Compounds 1−10-PF6 are poorly
soluble in water but very soluble in DMSO and MeCN; the
gold(I) derivatives and the dinuclear derivatives containing the
Au(PPh3) unit are also soluble in chlorinated solvents. The
solution chemistry of the complexes was analyzed by absorp-
tion UV−vis spectrophotometry. Spectra have been recorded in
some cases in various solvents (see Experimental Section and
Table S2). The gold(III) derivatives 1 and 2 and the mixed-
valence complexes 7, 8-PF6, and 9-PF6 exhibit, in MeCN,
intense transitions in the range 345−358 nm which are
assigned as LMCT bands characteristic of the gold(III)
chromophore.30 Additional bands at ca. 290 nm are attributed
to a metal-perturbed intraligand (IL) π−π* transition within
the pbi ligand. The gold(I) derivatives 3−6 and the mixed-
valence complexes 7 and 10-PF6 show in MeCN a common
absorption band at 306−308 nm (at 313 nm in DMSO),
assigned to π−π* transitions located in the heteroaromatic
rings.31 Complexes 4-PF6, 5, 8-PF6, 9-PF6, and 10-PF6, all
containing the ancillary ligand PPh3, display additional bands at
268 and 275 nm; complex 6, with TPA as ancillary ligand, and
the mixed-valence derivative 7, with all chlorides as ancillary
ligands, show in addition a band at 321 nm. In DMSO the latter
band is observed for almost all complexes at 325 nm.
For the stability tests as well as for the biological studies,
concentrated DMSO solutions of each gold complex (1 × 10−2)
were diluted in the reference phosphate buffer (PB), at pH 7.4,
to final concentrations of 10−5 to 10−4 M, and the samples were
monitored over 24 h at 25 °C.
The resulting spectral profiles are shown in Figure S1 in the
Supporting Information. In this medium the absorption maxi-
ma of the characteristic chromophores observed in CH3CN are
either blue- or red-shifted (see Table S2). In most cases the
observed transitions remain substantially unmodified over 24 h
observation, implying a substantial stability of the respective
chromophore under the present solution conditions. Never-
theless, a slight progressive decrease in intensity, of the char-
acteristic bands, is noticed with time, although without signi-
ficant shape modifications. Later, these effects could be ascribed
to the occurrence of some precipitation phenomena. Only in
the case of complex 5 are significant spectral changes observed
which suggest its conversion into 4+.32 All complexes exhibit
high stability toward reduction: negligible amounts of colloidal
gold, revealed by a broad absorption band around 550 nm, are
observed in a few cases.
Finally, the stability of the various compounds toward bio-
logically relevant reducing agents was evaluated. Sodium
ascorbate (Asc) was selected as the reference reducing agent.
Asc was added to freshly prepared solutions of the various com-
pounds in a 10:1 molar ratio, and UV−vis spectra were
recorded. The resulting spectral profiles are shown in Figure S2.
We found that most of the complexes are fairly stable to
reduction, with complexes 6 and 1 being, respectively, the most
and the least stable compounds.
Electrochemical Properties. The electrochemical behavior
of compounds 1−10-PF6 was investigated in DMF−TBAPF6
0.1 M solvent system through cyclic voltammetry. The volta-
mmetric curves of the chloro complexes 1, 3, and 7 are shown
in Figure 2, and Table 2 summarizes the voltammetric data of
all the study compounds. The ligand (pbiH) appears not to be
electroactive in this solvent system.
The gold(I) derivatives (3−6) show one or no reduction
process. In particular, the voltammetric response of 3 (Figure 2A)
evidences a cathodic process attributable to the gold(I)→
gold(0) reduction, as confirmed by the appearance of a gold
film on the working electrode surface when the potential is
scanned over the peak value (−1.09 V). The deposition of a
gold film is not evident in the case of 4-PF6, maybe due to the
very cathodic value of the reduction process (−1.93 V), near to
the solvent system reduction. The voltammetric responses of 5
and 6 do not show cathodic or anodic processes, probably due
to a stabilizing effect of PPh3 and TPA ligand on the neutral
complexes.
The gold(III) complexes (1 and 2) undergo two irreversible
reduction processes, the first one at −0.41 and −0.70 V and the
second one at −0.75 and −0.87 V, respectively. By comparison
with the gold(I) derivatives, we ascribed the more cathodic pro-
cess to the gold(I)→gold(0) reduction, and as a consequence
3165
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
Table 2. Voltammetric Data (E in V) in DMF/TBAPF6
0.1 M Solvent System
compd
Epc,1
Epc,2
Epa
b
a
[(pbi)AuCl2], 1
−0.41
−0.70
−0.75
−0.87
−1.09
−1.93
[(pbi)Au(OAc)2], 2
0.5
c
[(pbiH)AuCl], 3
0.51
d
e
[(pbiH)Au(PPh3)]PF6, 4-PF6
[(pbi)Au(PPh3)], 5
[(pbi)Au(TPA)], 6
[ClAu(pbi)AuCl2], 7
−0.56
−0.47
−0.74
−1.17
−0.83
−1.15
[(PPh3)Au(pbi)AuCl2]PF6, 8-PF6
[(PPh3)Au(pbi)Au(OAc)2]PF6, 9-PF6
[(PPh3)Au(pbi)Au(PPh3)]PF6, 10-PF6
a
b
Associated backward peak at +0.64 V. Broad, with an associated
c
backward peak at −0.35 V. Associated backward peak at −0.18 V.
d
e
Associated backward peak at −0.58 V. Associated backward peaks at
+0.09 V and about 0.5 V (broad). When reversing again the scan after
the backward peaks, another cathodic peak is evident at −0.15 V.
gold(I)→gold(0) reduction, respectively. As observed for
complex 3, also in the case of 7 the reduction to gold(0) is
confirmed by the presence of a thin gold layer on the electrode
surface reaching potential values more cathodic than the second
reduction process (Figure 2C). The dinuclear gold(I)−gold(I)
derivative (10-PF6) appears not electroactive under the experi-
mental conditions.
Voltammetric results, on the whole, suggest that these com-
pounds are quite stable toward gold(I)→gold(0) reduction.
The electrochemical data are in agreement with the absorption
spectra, suggesting that TPA and PPh3 ligands stabilize the
gold(I) derivatives (4-PF6, 5, 6, 10-PF6).
Antiproliferative Properties of Study Compounds.
The antiproliferative effects of the study compounds have been
determined according to established protocols, after 72 h of
exposure in three independent experiments.
Most of the gold compounds were found to show remarkable
antiproliferative effects when tested in vitro against the cisplatin-
sensitive A2780 ovarian cancer cell line and its cisplatin-resistant
counterpart. The resulting IC50 values are shown in Table 3 in
comparison to those of cisplatin and of the free pbiH ligand.
Table 3. IC50 Values Determined after 72 h of Exposure to
a
pbiH and Gold Complexes 1−10-PF6 (μM)
compd
A2780/S
A2780/R
RI
Figure 2. Cyclic voltammograms of 3 (A), 1 (B), and 7 (C) in DMF/
TBAPF6 0.1 M at Pt; potential scan rate = 100 mV s ; indicates
starting point.
b
c
pbiH
45.30 1.40 60.00 3.40 1.3
−1
●
d
[(pbi)AuCl2], 1
6.60 4.01
1.90 0.20
6.70 + 1.40
1.50 0.10
0.60 0.05
5.31 0.66 0.8
e
[(pbi)Au(OAc)2], 2
4.40 1.10 2.3
[(pbiH)AuCl], 3
8.30 + 1.40
1.2
[(pbiH)Au(PPh3)]PF6, 4-PF6
[(pbiH)Au(PPh3)], 5
[(pbi)Au(TPA)], 6
2.00 0.10 1.3
0.90 0.02 1.5
the less cathodic one to the gold(III)→gold(I) process. This
pattern is in line with that featured by analogous gold(III)
complexes which in nonaqueous solvents undergo a two-step
reduction, where the first is a gold(III)→gold(I) and the
second a gold(I)→gold(0) process.7b As previously observed
for analogous gold(III) complexes, substitution of the chloride
ligands with the O-donor ligands acetato results in a more
stable complex.33
13.30 2.61 28.83 1.04 2.2
f
[ClAu(pbi)AuCl2], 7
2.90 0.60
0.60 0.09
9.70 1.60 3.3
1.25 0.06 1.9
1.50 0.10 2.6
3.57 0.80 6.0
[(PPh3)Au(pbi)AuCl2]PF6, 8-PF6
[(PPh3)Au(pbi)Au(OAc)2]PF6, 9-PF6 0.60 0.05
[(PPh3)Au(pbi)Au(PPh3)]PF6, 10-PF6 0.60 0.01
CDDP
2.10 0.40 18.60 3.70 9.1
a
Mean
ES of three independent experiments performed with
triplicate cultures at each concentration tested; % of DMSO inhibition
at IC50 concentrations listed in the following footnotes. 15%. 10%.
Similarly to the gold(III) complexes, also in the case of the
mixed-valence gold(III)−gold(I) species (7−9-PF6), we ascribe
the two cathodic processes to the gold(III)→gold(I) and
b
c
d
e
f
10%. 2%. 2%.
3166
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
The latter was found to be poorly cytotoxic with IC50 values
of 45.30 and 60.00 μM against the two cell lines, respectively.
Notably, 4 compounds out of 10, namely, 5, 8-PF6, 9-PF6, and
10-PF6, show high cytotoxic activity against the cisplatin sensi-
tive cell line, with IC50 values falling in the nanomolar range,
and are also good in the cisplatin sensitive cell line (IC50 in the
range 0.9−3.57 μM). Overall, all investigated compounds, with
the exception of complex 6, are more active than cisplatin in the
A2780/R cell line with resistance index (RI) value ranging from
0.8 to 6.0. In particular, complex 1 was more active in the
resistant cell line than in the sensitive one (RI = 0.8). These
findings may suggest that these gold compounds might partially
overcome some of the mechanisms of resistance to cisplatin. At
variance, in the heteroleptic complex 6 the presence of the TPA
ligand causes a substantial decrease of biological activity in
comparison to the other compounds of this series.
Structure−function relationships, although still preliminary,
may be proposed for this series of gold compounds chara-
cterized by the presence of the pbiH or pbi ligand. Notably,
within the series of the mononuclear species, the chloro
complexes [(pbi)AuCl2], 1, and [(pbiH)AuCl], 3, despite the
different oxidation state, display similar antiproliferative effects,
with IC50 values of 6.60 and 6.70 μM in A2780/S cells, and 5.31
and 8.30 μM in A2780/R cells, respectively. This suggests that
gold(III) in complex 1 may undergo reduction to gold(I) in the
biological fluids and then act through the same molecular
mechanism of gold(I) complex 3. Notably, when changing from
the dichloro complex 1 to the bis(acetato) complex 2, an in-
crease in the cytotoxic potency (from 6.60 to 1.90 μM in
A2780/S cells) was observed. An even more substantial
increase of the antiproliferative activity against both cell lines
was found when changing from the gold(I) chloro complex 3 to
the triphenylphosphine derivatives 4-PF6 and 5. Notably, the
neutral complex 5, i.e., the deprotonated counterpart of 4-PF6,
is more than 2-fold more active than its protonated analogue.
As far as binuclear complexes are concerned, they manifest in
general quite remarkable antiproliferative properties. Compared
to the parent mononuclear compounds 1 and 3, only a modest
improvement of the cytotoxic activity against the sensitive
cell line was found for the mixed valence complex [ClAu(μ-
pbi)AuCl2], 7. The mixed valence complexes 8-PF6 and 9-PF6
appear to be the most effective of the series, although differ-
ences with the gold(I)/gold(I) derivative 10-PF6 are not very
large. In fact, all these complexes have in common a pbiAuPPh3
moiety (corresponding to compound 5) which displays per se a
very high antiproliferative potential. Thus, the high antiprolifer-
ative properties typically observed for most of the binuclear
complexes might be ascribed to the remarkable biological
actions of the pbiAuPPh3 moiety.
The biological properties of the studied compounds are
promising both in terms of significant stability under physio-
logical-like conditions and of antiproliferative potency effects.
Remarkably, all tested compounds turned out to cause relevant
growth inhibition of two representative ovarian cancer cell lines
with IC50 values falling in the low micromolar and even nano-
molar range. In addition, most compounds turned out to
overcome resistance to cisplatin to a great extent. Though we
reported that the pbiH ligand manifests as such some minor
antiproliferative effects it is evident that the remarkable cyto-
toxicity observed for the tested compounds is to be ascribed
primarily to the presence of the gold center. Comparative
analysis of the biological behavior of the various compounds
allowed us to draw some initial structure−activity relationships.
Notably, similar cytotoxic properties were observed in parent
complexes only differing in the oxidation state of the gold
center, possibly implying that gold(III) to gold(I) reduction
occurs in the cellular milieu. Also, we could establish that the
pbiAuPPh3 moiety displays the highest antiproliferative effects
and that there is no particular advantage in terms of cytotoxicity
in joining two gold centers within the same binuclear species.
Further studies will be carried out in the near future to expand
the knowledge of the biological effects of these compounds,
and to identify the mechanism of interaction with proteins and
the nature of their actual biological targets.
EXPERIMENTAL SECTION
■
General. All starting materials were used as received from
commercial sources: Na[AuCl4]·2H2O and [Au(OAc)3] were
purchased from METALOR and AlfaAesar, respectively; 2-(2-
pyridyl)benzimidazole,19 [(Ph3P)AuCl],34 and [(THT)AuCl]35 were
prepared according to literature methods. Buffer solutions were freshly
prepared before use. Elemental analysis was performed with a Perkin-
Elmer elemental analyzer 240B by Mr. A. Canu (Dipartimento di
̀
Chimica, Universita di Sassari). Conductivity measurements were
performed with a Philips PW 9505 conductivity meter. Infrared spectra
were recorded with a Jasco FTIR 480 Plus spectrophotometer using
Nujol mulls. UV−vis spectra were recorded on a Varian Cary 50 or on
1
a Hitachi U-2010 UV−vis spectrophotometer. H and 31P{1H} NMR
spectra were recorded at room temperature (20 °C) with a Varian
VXR 300 spectrometer operating at 300.0 and 121.4 MHz,
respectively. Chemical shifts are given in ppm relatively to internal
TMS (1H), and external H3PO4 (31P). Cyclic voltammetric tests were
performed using a CHI650 computerized instrument, in a single-
compartment three-electrode cell, at room temperature, under Ar
atmosphere, at a potential scan rate of 100 mV s−1. A 3 mm diameter
Pt disk electrode (CH Instruments) was used as working electrode, an
aqueous Ag/AgCl (Amel) with suitable salt bridge was the reference
electrode, and a graphite rod was the auxiliary electrode. All the
experiments were carried out in DMF (Sigma-Aldrich, anhydrous,
99.8%) using 0.1 M tetrabutylammonium hexafluorophosphate
(TBAPF6, Sigma-Aldrich, for electrochemical analysis, ≥99.0%) as
supporting electrolyte. The tests have been performed at room
temperature, and the reported potential values are referred to bis-
cyclopentadienyliron(III) iron(II) couple (Fc+/0, E1/2,r = +0.50 V
versus Ag/AgCl in DMF solvent).
CONCLUSIONS
■
In conclusion, we have designed and obtained here a series of
novel gold complexes, either mononuclear or binuclear, based
on the pbiH ligand, and explored some aspects of their bio-
logical behavior. The pbiH ligand, mainly in its deprotonated
form pbi, turned out to be a very appropriate and a very
versatile one and allowed us to obtain the designed com-
pounds, either mononuclear or binuclear. It is notable that
pbi may serve as a bridge connecting two gold centers, even
in different oxidation states; owing to this favorable property
it might be at the basis of even more complex molecular
architectures.
Syntheses. Spectroscopic Data of 2-(2-Pyridyl)benzimidazole
(pbiH). Selected IR bands (νmax/cm−1): 3060 ν(N−H), 1593,
1568, 1400, 1314, 1280, 744, 703. UV−vis (CH3CN): λmax (ε)
1
222sh, 240, 308 (74 405) nm (mol−1 dm3 cm−1). H NMR
(CDCl3): δ 7.30 (m, 2H, J = 9.3, 6.7, 5.4, 1.2, 0.8 Hz; H4′, H5′),
7.38 (ddd, 1H, J = 7.5, 4.8, 1.2 Hz; H5), 7.49 (m, 1H, J =
9.3, 5.6, 1.9 Hz; H3′), 7.86 (m, 1H, J = 9.1, 1.6, 1.3 Hz; H6′),
7.88 (td, 1H, J = 8.4, 1.7 Hz; H4), 8.44 (dt, 1H, J = 7.9, 1.1
Hz; H3), 8.64 (dd, 1H, J = 4.8, 1.7 Hz; H6), 10.77 (broad s,
1H; NH).
3167
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
concentrated to a small volume; addition of diethyl ether afforded the
precipitation of 4-PF6 as a white solid. Yield 221.5 mg, 55%; mp
160 °C. Anal. Calcd for C30H24AuF6N3P2: C 45.07; H 3.03, N 5.26%.
Found: C 45.26; H 2.97; N 5.12%. ΛM (acetone, 5 × 10−4 mol.L−1):
115 Ω−1 cm2 mol−1. Selected IR bands (νmax/cm−1): 3323 ν(N−H),
−
1587, 1439, 1105 (PPh3), 841 (PF6 ), 748, 694, 557, 548, 505. UV−
[Au(pbi)Cl2] (1). To a stirred solution of pbiH (195.2 mg, 1.0
mmol) in CH3CN (2 mL) was added an aqueous solution (50 mL) of
NaAuCl4·2H2O (397.9 mg, 1.0 mmol); the resulting suspension was
stirred in the dark for 24 h at room temperature. The brown solid
which formed was filtered off; washed with water, EtOH, and Et2O;
and dried under vacuum. Recrystallization from CH3NO3/Et2O gave 1
as a brown solid. Yield 423.8 mg, 92%; mp 220 °C. Anal. Calcd for
C12H8AuCl2N3: C 31.19; H 1.75, N 9.09%. Found: C 31.27; H 1.61; N
8.91%. Selected IR bands (νmax/cm−1): 1612, 1564, 1531, 740, 553,
432 ν(Au−N), 374 and 359 ν(Au−Cl). UV−vis (CH3CN): λmax (ε) 292
vis (CH3CN): λmax (ε): 268 (9566), 275 (10 340), 308 (19 147) nm
(mol−1 dm3 cm−1). 1H NMR (CDCl3): δ 7.44 (m, 2H; J = 8.7, 6.0, 2.6
Hz; H4′, H5′), 7.50 (broad m, 1H; H5), 7.58−7.70 (m, 15H; H PPh3),
7.86 (broad m, 1H; H6′), 7.94 (broad m, 1H; H3′), 7.98 (broad t, 1H,
J = 7.0 Hz; H4), δ 8.27 (broad d, 1H, J = 5.0 Hz; H6), 8.53 (broad d,
1H, J = 7.0 Hz; H3), 13.11 (s, 1H, NH). 31P NMR (CDCl3): δ 31.4 (s,
−
PPh3), δ −143.9 (sept, JP−F = 711.8 Hz; PF6 ).
[(pbi)Au(PPh3)] (5). A methanol solution of KOH (14.0 mg, 0.24
mmol) was added to a solution of 4-PF6 (191.0 mg, 0.24 mmol) in the
same solvent (25 mL); the resulting mixture was stirred in the dark for
1 h at room temperature. Then the solvent was removed under
vacuum, the residue taken up with CH2Cl2 and filtered through Celite,
and the solution concentrated to a small volume; addition of diethyl
ether afforded 5 as a white solid. Yield 100.3 mg, 64%; mp 110 °C.
Anal. Calcd for C30H23AuN3P: C 55.14; H 3.55, N 6.43%. Found: C
54.87; H 3.48; N 6.28%. Selected IR bands (νmax/cm−1): 1606, 1587,
1566, 1101 (PPh3), 739, 694, 546, 509. UV−vis (CH3CN): λmax (ε):
236 (26941), 268 (17 682), 275 (18 372), 296 (19 640), 306 (19 993)
1
(7087), 358 (11 424) nm (mol−1 dm3 cm−1). H NMR (DMSO-d6):
δ 7.27 (m, 2H, J = 9.3, 6.3, 4.8, 2.0 Hz; H4′, H5′), 7.75 (m, 1H, J = 9.3,
6.2, 3.0 Hz; H6′), 7.8 (td, 1H, J = 7.7, 1.8 Hz; H5), 8.35 (d, 1H, J =
7.9 Hz; H3), 8.38 (m, 1H, J = 9.3, 4.8, 3.0 Hz; H3′), 8.46 (t, 1H, J =
7.8 Hz; H4), 9.24 (d, 1H, J = 6.0 Hz; H6).
[Au(pbi)(OAc)2] (2). A solution of pbiH (97.6 mg, 0.5 mmol) and
[Au(OAc)3] (187.6 mg, 0.5 mmol) in acetic acid (30 mL) was refluxed
for 3 h. After cooling, the yellow solution was filtered through Celite
and the solvent removed under reduced pressure. The crude product
was recrystallized from CH2Cl2/Et2O to give 2 as a yellow solid. Yield
155.3 mg, 61%; mp 170 °C. Anal. Calcd for C16H14AuN3O4: C 37.73;
H 2.77, N 8.25%. Found: C 37.52; H 2.69; N 8.05%. Selected IR bands
(νmax/cm−1): 1685sh and 1672 νa(COO), 1614, 1562, 1525, 1255
νs(COO), 746, 553, 438 ν(Au−N), 322, and 280 ν(Au−O). UV−vis
(CH3CN): λmax (ε): 290 (12 411), 350 (17 603) nm (mol−1 dm3
cm−1). 1H NMR (CDCl3): δ 2.29 (s, 3H; Me), 2.36 (s, 3H; Me), 7.30
(m, 2H, J = 9.3, 4.8, 3.3 Hz; H4′, H5′), 7.57 (m + m, 2H, H6′ + H5),
7.76 (m, 1H, J = 9.3, 4.8, 3.3 Hz; H3′), 8.24 (td, 1H, J = 7.8, 1.3 Hz;
1
nm (mol−1 dm3 cm−1). H NMR (CDCl3): δ 7.19 (m, BB′ part of an
AA′BB′, 2H, J = 9.3, 6.0, 3.2 Hz, H4′, H5′), 7.21 (ddd, 1H, J = 7.7, 4.8,
1.3 Hz, H5), 7.49−7.59 (m + m, 9H; Hm, Hp PPh3), δ 7.71 (m, 6H; Ho
PPh3), 7.77 (td, 1H, J = 8.0, 1.7 Hz, H4), 7.84 (m, AA′ part of an
AA′BB′, 2H, J = 9.1, 5.9, 3.2 Hz; H3′, H6′), 8.20 (dd, 1H, J = 4.8,
0.9 Hz, H6), δ 8.57 (d, 1H, J = 8.1 Hz, H3). 31P NMR (CDCl3): δ 33.8
(s, PPh3).
[(pbi)Au(TPA)] (6). An aqueous solution of KOH (26.5 mg, 0.5
mmol) (20 mL) was added to a solution of pbiH (97.61 mg, 0.5
mmol) in CH3CN (3 mL); the resulting solution was added to an
aqueous suspension of [(TPA)AuCl] (195.0 mg, 0.5 mmol) (20 mL).
The resulting suspension was stirred in the dark for 24 h at room
temperature. Afterward, the white solid was collected by filtration
under vacuum and washed with H2O, EtOH, Et2O. Recrystallization
from acetone/Et2O gave the analytical sample. Yield 135.1 mg, 49%;
mp 235 °C. Anal. Calcd for C18H20AuN6P: C 39.43; H 3.68;
N 15.33%. Found: C 39.28; H 3.48; N 15.19%. Selected IR bands
(νmax/cm−1): 1590, 1281, 1241, 1094, 1011, 970, 949, 738, 585. UV−
vis (CH3CN): λmax (ε): 308 (14 878), 321 (16 800) nm (mol−1 dm3
cm−1). 1H NMR (acetone-d6): δ 4.58 (s, 6H; N−CH2−P), 4.67 (AB q,
6H, J = 12.8 Hz; N−CH2−N), 7.03 (m, BB′ part of an AA′BB′, 2H, J =
9.3, 6.0, 3.2 Hz; H4′, H5′), 7.40 (ddd, 1H, J = 7.5, 4.8, 1.2 Hz; H5), 7.59
(m, AA′ part of an AA′BB′, 2H, J = 9.1, 5.9, 3.2 Hz; H3′, H6′), 7.88 (td,
1H, J = 7.9, 1.8 Hz; H4), 8.43 (dt, 1H, J = 7.9, 1.2 Hz; H3), 8.61 (ddd,
1H, J = 4.8, 1.8, 0.9 Hz; H6). 31P NMR (acetone-d6): δ −65.1 (s,
TPA). X-ray quality crystals of 6 were obtained by slow diffusion of
diethyl ether into an acetone solution.
1
H4), 8.36 (d, 1H, J = 8.1 Hz; H3), 8.41 (d, 1H, J = 6.0 Hz; H6). H
NMR (acetone-d6): δ 2.14 (s, 3H; Me), 2.23 (s, 3H; Me), 7.28 (m,
2H, J = 8.0, 7.1, 1.3 Hz; H4′, H5′), 7.56 (m, 1H, J = 7.2, 1.8, 1.3 Hz;
H6′), 7.70 (m, 1H, J = 7.2, 1.3 Hz; H3′), 7.86 (ddd, 1H, J = 7.7, 6.0, 1.6
Hz; H5), 8.39 (dd, 1H, J = 7.8, 1.2 Hz; H3), 8.54 (td, 1H, J = 7.8, 1.3
Hz; H4), 8.67 (d, 1H, J = 6.0 Hz; H6).
[(pbiH)AuCl]·1/3pbiH (3·1/3pbiH). A solution of pbiH (195.2 mg,
1 mmol) in CH2Cl2 (10 mL) was added to a solution of (THT)AuCl
(321.1 mg, 1 mmol) in the same solvent (10 mL); the resulting
colorless solution was stirred in the dark for 24 h at room temperature.
After removal of the solvent under reduced pressure, the residue was
taken up with CHCl3 and filtered through Celite and the solution
concentrated to a small volume; addition of diethyl ether afforded a
white precipitate which was fitered off, washed with diethyl ether, and
dried under vacuum to give the analytical sample. The elemental
1
analyses and H NMR spectra indicated the presence of a clathrated
pbiH molecule with a 3/pbiH molar ratio of 3/1. Yield 229.8 mg, 70%;
mp 220 °C. Anal. Calcd for C16H12AuClN4: C 39.00; H 2.45, N
11.37%. Found: C 38.87; H 2.37; N 11.15%. ΛM (acetone, 5 × 10−4
mol.L−1): 8 Ω−1 cm2 mol−1. Selected IR bands (νmax/cm−1): 3174
(broad) ν(N−H), 1589, 736, 553, 497, 428 ν(Au−N), 399, 347
ν(Au−Cl). UV−vis (CH3CN): λmax (ε): 240, 295sh, 307 (24 604),
[ClAu(μ-pbi)AuCl2] (7). A solution of [(THT)AuCl] (112.2 mg,
0.35 mmol) in CH3CN (10 mL) was added to a suspension of 1
(230.2 mg, 0.35 mmol) in CH3CN (50 mL); the resulting mixture was
stirred for 24 h at room temperature. Afterward, the unreacted insolu-
ble adduct was removed by filtration and the solution concentrated to
a small volume; addition of diethyl ether afforded 7 as an orange solid.
Yield 138.1 mg, 57%; mp 193−195 °C. Anal. Calcd for C12H8Au2-
Cl3N3: C 20.75; H 1.16, N 6.05%. Found: C 20.54; H 0.98; N 5.95%.
Selected IR bands (νmax/cm−1): 1612, 1566, 1531, 822, 777, 761, 740,
434 ν(Au−N), 376 and 359 ν(Au−Cl). UV−vis (CH3CN): λmax (ε):
1
319sh nm (mol−1 dm3 cm−1). H NMR (CDCl3): δ 7.32 (m, 2H, J =
9.0, 6.3, 2.7 Hz; H4′, H5′ pbiH), 7.38 (dd, 1H, J = 7.5, 4.2; H5 pbiH),
7.48 (m, 2H, J = 9.3, 6.3, 3.0 Hz; H4′, H5′ 3), 7.56 (dd, 1H, J = 7.8, 4.8
Hz; H5 3), 7.61 (m, 1H, J = 9.3, 6.3, 3.0 Hz; H3′ 3), 7.85 (m, 1H; H6′
pbiH), 7.87 (t, 1H, J = 7.5 Hz; H4 pbiH), 8.00 (td, 1H, J = 8.4, 1.8 Hz;
H4 3), 8.08 (m, 1H, J = 9.3, 6.3, 3.0 Hz; H6′ 3), 8.43 (d, 1H, J = 8.1 Hz;
H3 pbiH), 8.65 (d, 1H, J = 5.7 Hz; H6 pbiH), 8.73 (d, 1H, J = 4.5 Hz;
H6 3), 9.72 (d, 1H, J = 7.8 Hz, H3 3), 10.50 (broad s, 1H, NH pbiH),
11.12 (broad s, 1H, NH 3).
1
307 (22 050), 321 (17 145), 350sh nm (mol−1 dm3 cm−1). H NMR
(DMSO-d6): δ 7.53 (m, BB′ part of an AA′BB′, 2H, J = 9.3, 6.2, 3.2 Hz;
H4′, H5′), 7.74 (ddd, 1H, J = 7.7, 4.8, 1.2 Hz; H5), 7.81 (m, AA′ part,
2H, J = 9.3, 6.2, 3.2 Hz; H3′, H6′), 8.20 (td, 1H, J = 7.8, 1.5 Hz, H4),
8.40 (d, 1H, J = 7.8 Hz, H3), 8.90 (d, 1H, J = 4.8 Hz; H6). Crystals
were obtained by slow diffusion of diethyl ether into a CH3CN
solution. The quality for X-ray measurement was not very good, and
despite various attempts, we were not able to improve them.
[(pbiH)Au(Ph3P)][PF6] (4-PF6). A solution of [(Ph3P)AuCl] (247.4
mg, 0.5 mmol) and AgPF6 (127.0 mg, 0.5 mmol) in dichloromethane
(40 mL) was stirred in the dark until AgCl precipitation was
completed. Then, the filtered solution was added to a solution of pbiH
(97.6 mg, 0.5 mmol) in the same solvent (15 mL) and stirred in the
dark for 3 h at room temperature. After this period, the solution was
3168
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
[(PPh3)Au(μ-pbi)AuCl2][PF6] (8-PF6). A solution of [(Ph3P)AuCl]
(247.4 mg, 0.5 mmol) and AgPF6 (127.0 mg, 0.5 mmol) in acetone
(30 mL) was stirred in the dark until AgCl precipitation was
completed. Then, the filtered solution was added to a suspension of
1 (230.0 mg, 0.5 mmol) in 20 mL of acetone and the resulting mixture
stirred for 2 h at room temperature; during this time the color of the
suspension turned to orange. Then, the orange solid was collected by
filtration and recrystallized from MeCN/Et2O to give the analytical
sample. Yield 341.2 mg, 64%; mp 225 °C. Anal. Calcd for
C30H23Au2Cl2F6N3P2: C 33.79; H 2.17, N 3.94%. Found: C 33.52;
H 2.04; N 3.88%. ΛM (acetone, 5 × 10−4 mol L−1): 120 Ω−1 cm2
mol−1. Selected IR bands (νmax/cm−1): 1721, 1698, 1608, 1103
in the above-mentioned program. All the structures were solved using
direct methods executed by Sir9737 and refined with the full-matrix
least squared on F2 by SHELX.38 In all the structure refinements there
are some high residual electron density peaks around the gold atom,
especially for compound 7. This can be ascribed to a redundancy of
the data not too high (ca. 2 for complex 7). Moreover, a crystal of 6
showed a very low degree of twinning. An attempt to include it in the
refinement of the structure did not lead to a significant improvement
both of the R factor and of the thermal parameters. Geometrical
calculations were carried out by PARST97,39 and molecular plots were
produced by the program ORTEP3 (ref 5).40
Crystal and structure refinement data are reported in Table 4.
CCDC files 859567 (compound 6), 859568 (compound 1), and
−
(PPh3), 841 (PF6 ), 750, 694, 558, 546, 380 ν(Au−Cl). UV−vis
(CH3CN): λmax (ε): 267 (5205), 275 (5589), 291 (6118), 353 (10
1
926) nm (mol−1 dm3 cm−1). H NMR (CDCl3): δ 7.32 (m, 2H, J =
9.1, 4.8, 4.3 Hz; H4′, H5′), 7.47−7.56 (m, 15H; H PPh3), 7.64 (dd, 1H,
J = 7.5, 6.0 Hz; H5), 7.80 (m, 1H, J = 6.1, 4.8 Hz, H6′), 8.25 (pseudo t,
1H, J = 7.8, 7.5 Hz, H4), δ 8.42 (d, 1H, J = 7.8 Hz; H3), 8.53 (m, 1H,
J = 9.3, 5.1, 4.2 Hz; H3′), 9.40 (d, 1H, J = 6.0 Hz; H6). 31P NMR
Table 4. Crystal and Structure Refinement Data for
Compounds 6, 7, and 10-PF6
6
7
10-PF6
−
empirical
formula
C18H20AuN6P
C12H8Au2Cl3N3 C48H38Au2F6N3P3
(acetone-d6): δ 32.7 (s, PPh3), −143.5 (sept, JP−F = 706.3 Hz; PF6 ).
[(PPh3)Au(μ-pbi)Au(OAc)2][PF6] (9-PF6). A solution of [(Ph3P)-
AuCl] (227.5 mg, 0.46 mmol) and AgPF6 (116.3 mg, 0.46 mmol) in
CH2Cl2 (30 mL) was stirred in the dark until AgCl precipitation was
completed. Then, the filtered solution was added to a solution of 2
(116.3 mg, 0.46 mmol) in the same solvent (20 mL). The resulting
yellow solution was stirred for 2 h at room temperature, and then
concentered to a small volume; addition of diethyl ether afforded a
yellow precipitate of 9-PF6 which was filtrated and dried in vacuo.
Yield 268.9 mg, 52%; mp 160 °C. Anal. Calcd for
C34H29Au2F6N3O4P2: C 36.67; H 2.63; N 3.77%. Found: C 36.46;
H 2.53; N 3.65%. ΛM (acetone, 5 × 10−4 mol L−1): 112 Ω−1 cm2
mol−1. Selected IR bands (νmax/cm−1): 1716sh and 1676 νa(COO),
fw
548.34
293
694.50
293
1257.66
293
T (K)
wavelength (Å)
0.710 69
0.710 69
0.710 69
cryst syst,
space group
monoclinic,
P21/n
monoclinic,
P21/c
triclinic, P1
̅
unit cell
dimensions
(Å, deg)
a = 7.0844(3)
a = 9.923(1)
a = 12.9029(4)
α=73.756(3)
b = 13.2996(5)
β = 77.057(2)
c = 17.0278(4)
γ = 64.136(3)
2506.73(14)
2, 1.666
b = 12.0678(5) b = 17.850(2)
β = 94.982(4)
c = 21.1691(8)
β = 98.92(1)
c = 8.531(1)
−
1614, 1265 νs(COO), 1103 (PPh3), 841 (PF6 ), 750, 694, 546, 499,
V (Å3)
1802.97(13)
1492.8(3)
4, 3.090
20.160
401. λmax (ε): 267 (13 788), 275 (13 932) 345 (14 833) nm (mol−1
1
Z, Dc (mg/cm3) 4, 2.020
dm3 cm−1). H NMR (CDCl3): δ 2.29 (s, 3H; CH3), 2.34 (s, 3H;
μ (mm−1
)
8.263
1056
5.998
CH3), 7.39 (m, BB′ part of an AA′BB′, 2H, J = 9.3, 6.0, 3.0 Hz; H4′,
H5′) 7.59−7.66 (m, 15H; H PPh3), 7.81 (m, AA′ part, 2H, J = 9.3, 6.0,
3.0 Hz; H3′,H6′), 7.85 (pseudo t, 1H, J = 7.2, 6.9 Hz; H5), 8.47 (t, 1H,
J = 8.1 Hz; H4), 8.49 (d, 1H, J = 5.4 Hz; H6), 8.73 (d, 1H, J = 7.5 Hz,
H3). 31P NMR (CD2Cl2): δ 30.8 (s, PPh3), −144.3 (sept, JP−F = 711.1
F(000)
1240
1208
cryst size (mm3) 0.4 × 0.3 × 0.3 0.3 × 0.2 × 0.07 0.4 × 0.1 × 0.1
θ range (deg)
4.22−29.11
4.19−27.48
5238/2828
4.35−29.32
37 484/11 979
reflns collected/ 7511/4074
unique
−
Hz; PF6 ).
[(Ph3P)Au(μ-pbi)Au(PPh3)][PF6] (10-PF6). A solution of [(Ph3P)-
AuCl] (247.4 mg, 0.5 mmol) and AgPF6 (126.3 mg, 0.5 mmol) in
acetone (30 mL) was stirred in the dark until AgCl precipitation was
completed. Then, the filtered solution was added to a H2O−CH3CN
solution of pbiH (97.6 mg, 0.5 mmol) and KOH (26.5 mg, 0.5 mmol).
A white solid was instantaneously formed, and the resulting suspension
was stirred in the dark for 12 h at room temperature. Afterward, the
solvent was removed under vacuum, the residue taken up with CH2Cl2
and filtered through Celite, and the solution concentrated to a small
volume; addition of diethyl ether afforded 10-PF6 as a white solid.
Yield 213.7 mg, 34%; mp 240 °C. Anal. Calcd for C48H38Au2F6N3P3: C
45.84; H 3.05, N 3.34%. Found: C 46.02; H 3.14; N 3.31%. ΛM
(acetone, 5 × 10−4 mol L−1): 116 Ω−1 cm2 mol−1. Selected IR bands
data/restraints/
params
4074/2/223
2828/0/79
11979/0/475
GOF on F2
1.086
0.872
0.935
final R indices
[I > 2σ(I)]
R1 = 0.0616,
wR2 = 0.1781
R1 = 0.1101,
wR2 = 0.1974
R1 = 0.0392,
wR2 = 0.1072
R indices
(all data)
R1 = 0.0999,
wR2 = 0.1858
R1 = 0.2453,
wR2 = 0.2287
R1 = 0.0890,
wR2 = 0.1131
859569 (compound 10-PF6) contain the supplementary crystallo-
graphic data for this paper.
Cell Growth Inhibition Studies. For cytotoxicity studies the
cisplatin-sensitive human ovarian carcinoma cell line (A2780/S) and
its cisplatin-resistant cell subline (A2780/R) were used. Cell lines were
maintained in RPMI1640 medium supplemented with fetal bovine
serum (FBS) and antibiotics at 37 °C in a 5% CO2 atmosphere and
subcultured twice weekly.
The cytotoxic effects of studied gold compounds were evaluated
against both these cell lines according to the procedure described by
Skehan et al.41 All gold compounds were diluted in DMSO as stock
solutions (10 mM).
Exponentially growing cells were seeded in 96-well microplates at a
density of 5 × 103 cell/well. After cell inoculation, the microtiter plates
were incubated under standard culture conditions (37 °C, 5% CO2, 95%
air, and 100% relative humidity) for 24 h prior to the addition of study
compounds. After 24 h, the medium was removed and replaced with
fresh medium containing drug concentrations ranging from
0.003 to 100 μM for a continuous 72 h exposure for all compounds.
For comparison purposes, the cytotoxic effects of cisplatin (CDDP),
measured under the same experimental conditions, were also determined.
−
(νmax/cm−1): 1605, 1587, 1565, 1104 (PPh3), 841 (PF6 ), 749, 693,
558, 556, 511. λmax (ε): 237, 267 (13 788), 275 (13 932), 308 (18 982)
nm (mol−1 dm3 cm−1). 1H NMR (CD2Cl2): δ 7.43 (m, BB′ part of an
AA′BB′ system, 2H, J = 9.3, 6.0, 3.2 Hz; H4′, H5′), 7.51 (ddd, 1H, J =
7.5, 4.8, 1.1; Hz, H5), δ 7.57−7.70 (m, 30H, H PPh3), 7.78 (td, 1H, J =
7.8, 1.8 Hz; H4), 8.01 (m, AA′ part, 2H, J = 9.3, 6.0, 3.2 Hz; H3′, H6′),
8.41 (d, 1H, J = 4.8 Hz; H6), δ 8.93 (d, 1H, J = 7.7 Hz; H3). 31P NMR
−
(CD2Cl2): δ 32.6 (s, PPh3), −143.4 (sept, JP−F = 710.2 Hz; PF6 ).
X-ray quality crystals of 10-PF6 were obtained by slow diffusion of
diethyl ether.
X-ray Crystallography. Reflection intensity data for 6, 7, and 10-
PF6 were collected at 293 K on an Oxford diffraction Xcalibur
Sapphire3 with Enhance (Mo) X-ray Source (λ = 0.7107) using the ω
technique. The program used for this purpose was CrysAlis CCD.36
Data were reduced with the program CrysAlis RED.34 Absorption
correction was applied through the program ABSPACK implemented
3169
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
Then the cells were fixed with 100 μL of ice-cold 10% trichloroacetic
acid (TCA) for 60 min at 4 °C, rinsed 6 times with water, and air-
dried. Fixed cells were stained with 50 μL of sulforhodamine B (SRB)
solution (0.4% SRB/0.1% acetic acid), rinsed with 0.1% acetic acid,
and air-dried. At the end of the staining period, SRB was dissolved in
150 μL of 10 mM Tris−HCl solution (pH 10.5) for 10 min in a
gyratory shaker. Optical density was read in a microplate reader
interfaced with the software Microplate Manager/PV version 4.0
(Bio-Rad Laboratories, Milan, Italy) at 540 nm.
The IC50 drug concentration resulting in a 50% reduction in the net
protein content (as measured by SRB staining) in drug-treated cells as
compared to untreated control cells was determined after 72 h of drug
exposure. The IC50 data represent the mean of at least three
independent experiments.
Bagowski, C. P. J. Med. Chem. 2009, 52, 763−770. (b) Vergara, E.;
Casini, A.; Sorrentino, F.; Zava, O.; Cerrada, E.; Rigobello, M. P.;
Bindoli, A.; Laguna, M.; Dyson, P. J. ChemMedChem 2010, 5, 96−102.
(c) Urig, S.; Fritz-Wolf, K.; Reau, R.; Herold-Mende, C.; Toth, K.;
Davioud-Charvet, E.; Becker, K. Angew. Chem., Int. Ed. 2006, 45,
1881−1886. (d) Scheffler, H.; You, Y.; Ott, I. Polyhedron 2010, 29,
66−69. (e) Bagowski, C. B.; You, Y.; Scheffler, H.; Vlecken, D. H.;
Schmitz, D. J.; Ott, I. Dalton Trans. 2009, 10799−10805.
(5) (a) Weaver, J.; Gaillard, S.; Toye, C.; Macpherson, S.; Nolan,
S. P.; Riches, A. Chem.Eur. J. 2011, 17, 6620−6624. (b) Rubbiani, R.;
Kitanovic, I.; Alborzinia, H.; Can, S.; Kitanovic, A.; Onambele, L. A.;
Stefanopoulou, M.; Geldmacher, Y.; Sheldrick, W. S.; Wolber, G.;
Prokop, A.; Wolfl, S.; Ott, I. J. Med. Chem. 2010, 53, 8608−8618.
̈
(c) Hickey, J. L.; Ruhayel, R. A.; Barnard, P. J.; Baker, M. V.; Berners-
Price, S. J.; Filipovska, A. J. Am. Chem. Soc. 2008, 130, 12570−12571.
(d) Barnard, P. J.; Berners-Price, S. J. Coord. Chem. Rev. 2007, 251,
1889−1902. (e) Baker, M. V.; Barnard, P. J.; Berners-Price, S. J.;
Brayshaw, S. K.; Hickey, J. L.; Skelton, B. W.; White, A. H. Dalton
Trans. 2006, 3708−3715. (f) Baker, M. V.; Barnard, P. J.; Berners-
Price, S. J.; Brayshaw, S. K.; Hickey, J. L.; Skelton, B. W.; White, A. H.
J. Organomet. Chem. 2005, 690, 5625−5635. (g) Barnard, P. J.; Baker,
M. V.; Berners-Price, S. J.; Skelton, B. W.; White, A. H. J. Chem. Soc.,
Dalton Trans. 2004, 1038−1047. (h) Ray, S.; Mohan, R.; Singh, J. K.;
Samantaray, M. K.; Shaikh, M. M.; Panda, D.; Ghosh, P. J. Am. Chem.
Soc. 2007, 129, 15043−15053.
To evaluate presence or lack of cross-resistance to study
compounds of cisplatin-resistant cells, A2780/R as compared to the
parental A2780/S cells, the resistance index (RI) was calculated as the
ratio of the IC50 values in the resistant cell line and the IC50 values in
the sensitive one.
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic data in CIF format. NMR data and absorption
characteristics of the complexes in various solvents; UV−vis
spectral profiles of the complexes. This material is available free
of charge via the Internet at http://pubs.acs.org.
(6) Li, C. K.-L.; Sun, R. W.-Y.; Kui, S. C.-F.; Zhu, N.; Che, C.-M.
Chem.Eur. J. 2006, 12, 5253−5266.
(7) (a) Cinellu, M. A.; Maiore, L.; Manassero, M.; Casini, A.; Arca,
M.; Fiebig, H.-H.; Kelter, G.; Michelucci, E.; Pieraccini, G.; Gabbiani,
C.; Messori, L. ACS Med. Chem. Lett. 2010, 1, 336−339. (b) Gabbiani,
C.; Casini, A.; Messori, L.; Guerri, A.; Cinellu, M. A.; Minghetti, G.;
Corsini, M.; Rosani, C.; Zanello, P.; Arca, M. Inorg. Chem. 2008, 47,
2368−2379. (c) Casini, A.; Cinellu, M. A.; Minghetti, G.; Gabbiani, C.;
Coronnello, M.; Mini, E.; Messori, L. J. Med. Chem. 2006, 49, 5524−
5531.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cinellu@uniss.it (M.A.C.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
M.A.C. gratefully acknowledges the Fondazione Banco di
■
(8) Fan, D.; Yang, C.-T.; Ranford, J. D.; Vittal, J. J. Dalton Trans.
2003, 4749−4753.
Sardegna and the Universita
̀
degli Studi di Sassari for financial
(9) Barreiro, E.; Casas, J. S.; Couce, M. D.; San
́
chez, A.; San
́
chez-
support and the Regione Autonoma della Sardegna (RAS) for
the grant “Premialita Regionale 2009”. L.M. and C.G. express
Gonzal
́
ez, A.; Sordo, J.; Varela, J. M.; Vaz
́
quez Lopez, E. M. J. Inorg.
́
̀
Biochem. 2010, 104, 551−559.
their gratitude to Nanotreat project (Regione Toscana) and to
Beneficentia Stiftung (Vaduz, Liechtenstein) for generous
grants.
(10) (a) Barnard, P. J.; Wedlock, L. E.; Baker, M. V.; Berners-Price,
S. J.; Joyce, D. A.; Skelton, B. W.; Steer, J. H. Angew. Chem., Int. Ed.
2006, 45, 5966−5970. (b) Barnard, P. J.; Baker, M. V.; Berners-Price,
S. J.; Day, D. A. J. Inorg. Biochem. 2004, 98, 1642−1647.
(11) (a) Nobili, S.; Mini, E.; Landini, I.; Gabbiani, C.; Casini, A.;
Messori, L. Med. Res. Rev. 2010, 30, 550−580. (b) Ott, I. Coord. Chem.
Rev. 2009, 253, 1670−1681. (c) Bindoli, A.; Rigobello, M. P.; Scutari,
G.; Gabbiani, C.; Casini, A.; Messori, L. Coord. Chem. Rev. 2009, 253,
1692−1707. (d) Milacic, V.; Ping Dou, Q. Coord. Chem. Rev. 2009,
253, 1649−1660.
(12) (a) Messori, L.; Abbate, F.; Marcon, G.; Orioli, P.; Fontani, M.;
Mini, E.; Mazzei, T.; Carotti, S.; O’Connell, T.; Zanello, P. J. Med.
Chem. 2000, 43, 3541−3548. (b) Abbate, F.; Orioli, P.; Bruni, B.;
Marcon, G.; Messori, L. Inorg. Chim. Acta 2000, 311, 1−5. (c) Marcon,
G.; Carotti, S.; Coronnello, M.; Messori, L.; Mini, E.; Orioli, P.;
Mazzei, T.; Cinellu, M. A.; Minghetti, G. J. Med. Chem. 2002, 45,
1672−1677. (d) Coronnello, M.; Mini, E.; Caciagli, B.; Cinellu, M. A.;
Bindoli, A.; Gabbiani, C.; Messori, L. J. Med. Chem. 2005, 48, 6761−
6765. (e) Messori, L.; Marcon, G.; Cinellu, M. A.; Coronnello, M.;
Mini, E.; Gabbiani, C.; Orioli, P. Bioorg. Med. Chem. 2004, 12, 6039−
6043.
REFERENCES
■
(1) Berners-Price, S. J.; Filipovska, A. Metallomics 2011, 3, 863−873.
(2) (a) Sun, R. W.-Y.; Li, C. K.-L.; Ma, D.-L.; Yan, J. J.; Lok, C.-N.;
Leung, C.-H.; Zhu, N.; Che, C.-M. Chem.Eur. J. 2010, 16, 3097−
3113. (b) Sun, R. W.-Y.; Che, C.-M. Coord. Chem. Rev. 2009, 253,
1682−1691. (c) Lum, C. T.; Yang, Z. F.; Li, H. Y.; Sun, R. W.-Y.; Fan,
S. T.; Poon, R. T. P.; Lin, M. C. M.; Che, C.-M.; Kung, H. F. Int. J.
Cancer 2006, 118, 1527−1538. (d) Wang, Y.; He, Q.-H.; Sun, R. W.-Y.;
Che, C.-M.; Chiu, J.-F. Cancer Res. 2005, 65, 11553−11564.
(e) Wang, Y.; He, Q.-Y.; Che, C.-M.; Chiu, J.-F. Proteomics 2006, 6,
131−142. (f) Sun, R. W.-Y.; Yu, W.-Y.; Sun, H.; Che, C.-M.
ChemBioChem 2004, 5, 1293−1298. (g) Che, C.-M.; Sun, R. W.-Y.;
Yu, W.-Y.; Ko, C.-B.; Zhu, N.; Sun, H. Chem. Commun. 2003, 1718−
1719.
(3) (a) Ronconi, L.; Giovagnini, L.; Marzano, C.; Bettio, F.; Graziani,
R.; Pilloni, G.; Fregona, D. Inorg. Chem. 2005, 44, 1867−1881.
(b) Giovagnini, L.; Ronconi, L.; Aldinucci, D.; Lorenzon, D.; Sitran, S.;
Fregona, D. J. Med. Chem. 2005, 48, 1588−1595. (c) Mlacic, V.; Chen,
D.; Ronconi, L.; Landis-Piwowar, K. R.; Fregona, D.; Dou, Q. P.
Cancer Res. 2006, 66, 10478−10486. (d) Saggioro, D.; Rigobello,
M. P.; Paloschi, L.; Folda, A.; Moggach, S. A.; Parsons, S.; Ronconi,
L.; Fregona, D.; Bindoli, A. Chem. Biol. 2007, 14, 1128−1139.
(4) (a) Ott, I.; Quian, X.; Xu, Y.; Vlecken, D. H. W.; Marques,
I. J.; Kubutat, D.; Will, J.; Sheldrick, W. S.; Jesse, P.; Prokop, A.;
(13) Maiore, L.; Cinellu, M. A.; Michelucci, E.; Monetti, G.; Nobili,
S.; Landini, I.; Mini, E.; Guerri, A.; Gabbiani, C.; Messori, L. J. Inorg.
Biochem. 2011, 105, 230−237.
(14) Tsukamoto, G.; Yoshino, K.; Kohono, T.; Ohtaka, H.; Kagaya,
H.; Ito, K. J. Med. Chem. 1980, 23, 734−738.
(15) Schiffmann, R.; Neugebauer, A.; Klein, C. D. J. Med. Chem.
2006, 49, 511−522.
3170
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171

Inorganic Chemistry
Article
(16) Some recent examples: (a) Mock, C.; Puscasu, I.; Rauterkus,
M. J.; Tallen, G.; Wolff, J. E. A.; Krebs, B. Inorg. Chim. Acta 2011, 319,
109−116. (b) Shen, M.; Huang, W.; Zhang, W.; Hao, X.; Sun, W.-H.;
Redshaw, C. Dalton Trans. 2010, 39, 9912−9922. (c) Huang, W.-K.;
Cheng, C.-W.; Chang, S.-M.; Lee, Y.-P.; Diau, E. W.-G. Chem. Commun.
2010, 46, 8992−8994. (d) Wu, J.; Li, H.-Y.; Kang, L.-C.; Li, D.-P.; Xu,
Q.-L.; Zhu, Y.-C.; Tao, Y.-M.; Zheng, Y.-X.; Zuo, J.-L.; You, X.-Z.
J. Organomet. Chem. 2010, 695, 2048−2056. (e) Altaf, M.; Stoeckli-
Evans, H. Transition Met. Chem. 2009, 34, 613−620. (f) Machura, B.;
Switlicka, A.; Wolff, M.; Kusz, J.; Kruszynski, R. Polyhedron 2009, 28,
1348−1354. (g) Haneda, S.; Gan, Z.; Eda, K.; Hayashi, M.
(37) SIR97: Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano,
G. L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.;
Spagna, R. J. Appl. Crystallogr. 1999, 32, 115−119.
(38) SHELX: Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122.
(39) Nardelli, M. J. Appl. Crystallogr. 1995, 28, 659.
(40) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(41) Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.;
Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl.
Cancer Inst. 1990, 82, 1107−1112.
Organometallics 2007, 26, 6551−6555. (h) Casas, J. S.; Castineiras,
̃
A.; García-Martínez, E.; Parajo,
Gonzalez, A.; Sordo, J. Z. Anorg. Allg. Chem. 2005, 631, 2258−2264.
(i) Shavaleev, N. M.; Bell, Z. R.; Easun, T. L.; Rutkaite, R.; Swanson, L.;
Ward, M. D. Dalton Trans. 2004, 3678−3688. (j) Gumus, F.; Pamuk, I.;
́ ́ ́ ́
Y.; Perez-Paralle, M. L.; Sancez-
́
̈
̈
̈
̈
̈
Ozden, T.; Yldiz, S.; Diril, N.; Oksuzoglu, E.; Gur, S.; Ozkul, A. J. Inorg.
̈
̈
Biochem. 2003, 94, 255−262. (k) Mock, C.; Puscasu, I.; Rauterkus,
M. J.; Tallen, G.; Wolff, J. E. A.; Krebs, B. Inorg. Chim. Acta 2001, 319,
109−116.
(17) Dash, K. C. Indian J. Chem. 1986, 25A, 552−556.
(18) Munakata, M.; Yan, S.-G.; Maekava, M.; Akiyama, M.; Kitagava,
S. J. Chem. Soc., Dalton Trans. 1997, 4257−4262.
(19) (a) Addison, A. W.; Rao, T. N.; Waslgren, C. G. J. Heterocycl.
Chem. 1983, 20, 1481−1484. (b) Alcalde, E.; Dinares
́ ́
, I.; Perez-Garzia,
L.; Roca, T. Synthesis 1992, 395−398.
(20) (a) Mingos, D. M. P. J. Chem. Soc., Dalton Trans. 1976, 1163−
1169. (b) Evans, D. G.; Mingos, D. M. P. J. Organomet. Chem. 1982,
232, 171−191. (c) Lauher, J. W.; Wald, K. J. Am. Chem. Soc. 1981, 103,
7648−7650. (c) Liang, X.; Wu, X.; Dong, T.; Qin, Z.; Tan, K.; Lu, X.;
Tang, Z. Angew. Chem., Int. Ed. 2011, 50, 2166−2170.
(21) For example, only one band at 377 cm−1 is observed for [(bipy)
AuCl2]+: Cinellu, M. A.; Minghetti, G.; Pinna, M. V.; Stoccoro, S.;
Zucca, A.; Manassero, M. J. Chem. Soc., Dalton Trans. 2000, 1261−
1265.
(22) Bessonov, A. A.; Basova, T. V.; Kiselev, V. G.; Sheludyakova,
L. A.; Morozova, N. B.; Igumenov, I. K. Vib. Spectrosc. 2009, 51, 283−
288.
(23) Bonatti, F.; Felici, M.; Pietroni, B. R.; Burini, A. Gazz. Chim. Ital.
1982, 112, 5−8.
(24) See, for example: Cinellu, M. A.; Stoccoro, S.; Minghetti, G.;
Bandini, A. L.; Demartin, F. Inorg. Chim. Acta 1990, 168, 33−41.
(25) See for example: Thwaite, S. E.; Schier, A.; Schmidbaur, H.
Inorg. Chim. Acta 2004, 357, 1549−1557.
(26) Tzeng, B.-C.; Chen, B.-S.; Chen, C.-K.; Chang, Y.-P.; Tzeng,
W.-C.; Lin, T. Y.; Lee, G.-H.; Chou, P. T.; Fu, Y.-J.; Chang, A. H.-H.
Inorg. Chem. 2011, 50, 5379−5388.
(27) Allen, F. H. Acta Crystallogr. Sect. B 2002, B58, 380−388.
(28) Pauling, L. The Nature of the Chemical Bond, 3rd ed.; Cornell
University Press: Ithaca, NY, 1960.
(29) Cinellu, M. A.; Zucca, A.; Stoccoro, S.; Minghetti, G.;
Manassero, M.; Sansoni, M. J. Chem. Soc., Dalton Trans. 1996,
4217−4225 and references therein.
(30) Ivanov, M. A.; Puzyk, M. V.; Tkacheva, T. A.; Balashev, K. P.
Russ. J. Gen. Chem. 2006, 76, 165−169.
(31) Fernan
M.; Montiel, M.; Olmos, M. E.; Per
Bull. 2007, 40, 172−183.
́
dez, E. J.; Laguna, A.; Lop
́
ez-de-Luzuriaga, J. M.; Monge,
́
ez, J.; Rodríguez-Castillo, M. Gold
(32) Nevertheless, complex 5 was restored after the solvent was
evaporated to dryness (1H NMR criterium).
(33) Sanna, G.; Pilo, M. I.; Minghetti, G.; Cinellu, M. A.; Spano, N.;
Seeber, R. Inorg. Chim. Acta 2000, 310, 34−40.
(34) McAuliffe, C. A.; Parish, R. V.; Randall, P. D. J. Chem. Soc.,
Dalton Trans. 1979, 1730−1735.
(35) Uson, R.; Laguna, A.; Laguna, M. Inorg. Synth. 1989, 26, 85.
(36) CrysAlisPro, Version 1.171.33.41 (release 06−05−2009 CrysA-
lis171 .NET); Oxford Diffraction Ltd., (compiled May 6,
2009,17:20:42).
3171
dx.doi.org/10.1021/ic202639t | Inorg. Chem. 2012, 51, 3161−3171