Novel gold(I)- and gold(III)-N-heterocyclic carbene complexes: Synthesis and evaluation of their anticancer properties

Article abstract of DOI:10.1021/om500118x

A novel Au(III)-N-heterocyclic carbene organometallic complex supported by two N-heterocyclic carbene (NHC) ligands was synthesized from Au(SMe ₂)Cl and 1-methyl-2-pyridin-2-yl-2H-imidazo[1,5-a]pyridin-4-ylium hexafluorophosphate via a Ag intermediate. X-ray crystallography revealed the first example of a square planar geometry adopted by a Au(III) species stabilized by two NHCs and two chloride ligands. The aforementioned Au(I)- and Au(III)-NHC complexes were found to be more potent than cisplatin against the HCT 116, HepG2, A549, and MCF7 cell lines.

Full text of DOI:10.1021/om500118x

Article
pubs.acs.org/Organometallics
Novel Gold(I)− and Gold(III)−N-Heterocyclic Carbene Complexes:
Synthesis and Evaluation of Their Anticancer Properties
Bidyut Kumar Rana,† Abhishek Nandy,‡ Valerio Bertolasi,§ Christopher W. Bielawski,∥
Krishna Das Saha,*,‡ and Joydev Dinda*,†,⊥
†School of Applied Science, Applied Synthetic Chemical Research Laboratory, Haldia Institute of Technology, Haldia, Purba
Medinipur 721657, West Bengal, India
‡Cancer and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata 700032, West Bengal,
India
§Dipartimento di Chimica and Centro di Strutturistica Diffrattometrica, Universita’ di Ferrara, Via L. Borsari, 46, Ferrara, Italy
∥Department of Chemistry, University of Texas at Austin, 1 University Station, A1590, Austin, Texas 78712, United States
⊥Department of Chemistry, ITM University-Gwalior, Gwalior 474001, MP, India
S
* Supporting Information
ABSTRACT: A novel Au(III)−N-heterocyclic carbene organo-
metallic complex supported by two N-heterocyclic carbene (NHC)
ligands was synthesized from Au(SMe2)Cl and 1-methyl-2-pyridin-2-
yl-2H-imidazo[1,5-a]pyridin-4-ylium hexafluorophosphate via a Ag
intermediate. X-ray crystallography revealed the first example of a
square planar geometry adopted by a Au(III) species stabilized by two
NHCs and two chloride ligands. The aforementioned Au(I)− and
Au(III)−NHC complexes were found to be more potent than cisplatin against the HCT 116, HepG2, A549, and MCF7 cell
lines.
rganogold chemistry is finding increasing utility in a
obstacles have been explored, many of which use other
transition metal complexes.9
1
Orange of catalytic and biomedical applications. Many of
the complexes used in these applications contain gold ions in
either the +1 or +3 oxidation state and are stabilized with
phosphine-based or N-heterocyclic carbene (NHC)-based
ligands.1a−c The Au complexes supported by NHCs, in
particular, have been widely studied for their abilities to
facilitate C−C, C−O, and C−N bond-forming reactions2 as
well as for their potential to function as anticancer, antiarthritis,
and antibacterial agents.3 While the majority of literature
reports describing the chemistry of Au−NHC complexes
involve gold ions in the +1 oxidation state, recent attention
has been directed toward Au(III)−NHC complexes.4 Such
complexes are generally synthesized via treatment of the
corresponding Au(I) complex with Cl2, Br2, or I2.4b,c For
comparison, more direct syntheses that utilize a Au(III)
precursor (e.g., KAuCl4) typically require specially designed
NHC ligands,5 although we recently circumvented this
limitation by developing a disproportionation scheme that
obviates the need for Cl2 or Br2.4d,e
Although the use of gold salts in medicinal chemistry has
been known for centuries, recent studies have capitalized on
their strong antiproliferative3,4,6,9 and bacteriostatic properties,
particularly for the treatment of tuberculosis.9a Unfortunately,
the in vitro biochemistry of gold remains largely unknown,
mainly because of the paucity of adequate models and an
inadequate understanding of its mechanism of reactivity.3,4b,6
As such, the synthesis and study of Au−NHC complexes in
therapeutic applications are warranted. Herein, we present the
synthesis, characterization, and anticancer properties of Au(I)
and Au(III) complexes supported by a novel NHC.
The synthesis of the requisite NHC precursor 1-methyl-2-
pyridin-2-yl-2H-imidazo[1,5-a]pyridin-4-ylium hexafluorophos-
phate (1) was accomplished using a previously reported
procedure.10 The transfer of imidazolium-derived NHC-based
ligands to group d10 metal complexes is often achieved via a
Ag(I) carbene transfer method;11 indeed, as summarized in
Scheme 1, Au(I)−NHC complex 2 was obtained via a similar
Recent biomedical studies involving various Cu(I)−, Ag(I)−,
Au(I)−, Pd(II)−, and Pt(II)−NHC complexes revealed their
potential for use as anticancer agents.3,4,6 Many of these studies
were prompted by the discovery of the antitumor properties of
cisplatin,7 PtCl2(NH3)2, by Rosenberg in 1963, which
established the field of metallo-organic therapeutics. As a result
of some of cisplatin’s setbacks, including resistance and other
side effects,8 promising new strategies for overcoming these
1
approach. The disappearance of the C2-H signal from the H
nuclear magnetic resonance (NMR) spectrum recorded at
10.32 ppm and the shift of the 13CNMR signal of C2 from
136.6 to 172.4 ppm indicated that 2 was successfully formed.4
Received: February 12, 2014
Published: May 5, 2014
© 2014 American Chemical Society
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Scheme 1. Synthesis of Au(I)− and Au(III)−NHC
Complexes
Figure 1. ORTEP view of 2 (30% probability). The PF6 counteranion
and the H atoms have been omitted for the sake of clarity. Key bond
lengths (angstroms) and angles (degrees): Au(1)−C(1) = 2.008(5),
Au(1)−C(14) = 2.018(5), N(1)−C(1) = 1.373(8), N(2)−C(1) =
1.359(7), C(14)−N(4) = 1.354(7), C(14)−N(5) = 1.351(7), C(1)−
Au(1)−C(14) = 176.7(2), N(1)−C(1)−N(2) = 104.1(5), and N(4)−
C(14)−C(5) = 103.5(5). Note that two asymmetric units were
present.
With Au(I)−NHC complex 2 in hand, gold(III)complex 3
was synthesized by treating the former with Au(SMe2)Cl.
Stirring a clear colorless acetonitrile solution of gold(I)−NHC
complex 2 and Au(SMe2)Cl at room temperature for 6 h
resulted in a change in the color to yellow, which was
accompanied by the formation of a precipitant. After separation
and purification, the desired Au(III)−NHC complex 3 was
obtained as a yellow solid in 33% yield. Notably, this synthetic
process capitalizes on a disproportionation reaction, wherein
the Au(I) supported by the NHCs underwent oxidation and
was accompanied by reduction of the Au(SMe2)Cl to Au(0),
which was subsequently isolated and reused.4d,e Regardless, the
1H NMR spectrum recorded for complex 3 was found to be
similar to the spectrum recorded for complex 2. In particular,
the resonance assigned to the NCN group in the 13C NMR
spectrum of 2 was found to be shifted downfield by 22.9 ppm
(173.38 ppm) compared to the signal for the same carbon in 1
(150.47 ppm). For comparison, the carbene nucleus was
recorded at 159.55 ppm in 3, because of an increase in the
Lewis acidity of the gold center.4a All of the new complexes
were also characterized by mass spectrometry to confirm that
their solution structures were similar to those observed in the
solid state. In the case of 2, a signal was recorded at m/z 615.3
and assigned to the binuclear species [Au(1-H)2]+; likewise, a
signal was observed at m/z 406.3 and assigned to [Au(1-H)]+
(Figure S1 of the Supporting Information). Mass analysis of 3
afforded a signal at m/z 847.2, which was assigned to {[Au(1-
H)2Cl2](PF6)-(H2O)}-2H] followed by signals at m/z 615.3
and 486.3 that were assigned to [Au(1-H)2]+ and [Au(1-H)]+,
respectively (Figure S2 of the Supporting Information). The
largest m/z signal observed for 3 stems from the removal of
hydrogen via a water contaminant, a result that was supported
by elemental analysis and X-ray crystallography.
indicated that the structure was nearly linear. Moreover, bond
distances consistent with aurophilic interactions were measured
[Au(1)−Au(2) = 3.3794(3) Å] and supported by a weak
luminescence observed at 410 nm. In the square planar Au(III)
complex (3), the Au(III)−Ccarbene lengths, Au(1)−C(1) and
Au(1)−C(14), were measured to be 1.996(6) and 2.014(5) Å,
respectively, and comparable to similar distances observed in
Au(I)−NHC complex 2. For complex 3, the Ccarbene−Au(III)
distances were in accord with known NHC−gold(III) chloride
complexes.4 The Cl−Au distances of 2.2984(16)−2.3150(16)
Å were shorter than reported values for known NHC−AuCl3
complexes.4d,e It is important to note that the NHCs described
herein can stabilize both Au(I) and Au(III) centers; in general,
linear biscarbene Au(I)−NHC complexes release one ligand
when they are oxidized to Au(III),4d,e but in 3, both ligands
remain intact after the oxidation of the precursor 2 (Figure 2).
In addition to the characterization of the aforementioned
complexes 2 and 3, their cytotoxicities were tested against
known human cancer cell lines, including HCT 116, HepG2,
A549, and MCF7, and compared to that displayed by
cisplatin,4b Close inspection of the results (Table 1 and Figure
S3 of the Supporting Information) revealed that 2 was more
potent than 3 and that both complexes were more efficient than
cisplatin. Complex 2 is more potent toward MCF7 cancer cells
than Au(I)−NHC complexes recently reported by Tacke.3f The
lower potency of 3 in comparison to that of 2 may due to the
reduction of Au(III) complexes via cellular compounds
containing thiols.9b However, the ligand showed negligible
cytotoxicity toward the cancer cells (Table S1 of the Supporting
Information), and the complexes themselves showed negligible
cytotoxicity toward human peripheral blood mononuclear cells
(PBMCs) (Table S2 of the Supporting Information).
To gain additional insight into the coordination chemistry
and the structural parameters of complexes 2 and 3, single
crystals were grown by slow evaporation of concentrated
acetonitrile solutions of the respective complexes into Et2O and
characterized by X-ray diffraction analysis. The molecular
structure of 2 is depicted in Figure 1. Typical Au−Ccarbene bond
lengths of 2.008(5) Å [Au(1)−C(7)] and 2.018(5) Å [Au(1)−
C(14)] were measured and determined to be shorter than the
sum of the van der Waals length (Au−C = 2.108 Å) but
consistent with other monocarbene and biscarbene systems.3f,6c
The Au(1)−C(7) separation is slightly longer than the Au−
Ccarbene separation [1.988(3) Å] recently reported by Tacke3f
Cancer cell death is often achieved through apoptosis.12 The
induction of apoptosis by 2 on HCT 116 cells was probed by
examining the different characteristic cellular changes in
apoptosis. Microscopic studies were used to distinguish
between control and treated cells undergoing apoptosis. In
particular, HCT 116 cells became rounded after treatment with
2 (at the IC50 concentration) for 24 h. Moreover, upon being
for the anticancer potent Au(I)−NHC complex. The Ccarbene
−
Au(1)−Ccarbene bond angle [C(1)−Au(1)−C(14) = 176.7(2)°]
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phosphatidylserine from the inner cellular membranes to the
outer membranes, which can bind with the protein annexin V.
Using a fluorescein isothiocyanate (FITC)-labeled annexin V,
exposure of phosphatidylserine to the outer membranes of cells
during apoptosis was measured by fluorescence-activated cell
sorting analysis.13 Upon treatment with complex 2 (IC50
concentration), the HCT 116 cells showed a 55.55% apoptotic
cell population compared to a 0.97% cell population in the
control after 24 h (Figure 4). Collectively, these findings
Figure 2. ORTEP view of 3 (30% probability). The H, PF6, and H2O
species have been omitted for the sake of clarity. Pertinent bond
lengths (angstroms) and angles (degrees): Au(1)−C(1) = 1.996(6),
Au(1)−C(14) = 2.014(5), Au(1)−Cl(1) = 2.2984(16), Au(1)−Cl(2)
= 2.3150(16), N(1)−C(1) = 1.360(7), N(2)−C(1) = 1.363(8),
C(14)−N(4) = 1.338(7), C(14)−N(5) = 1.347(7), N(1)−C(1)−
N(2) = 105.3(5), N(4)−C(14)−C(5) = 106.2(4), C(1)−Au(1)−
C(14) = 89.9(2), C(1)−Au(1)−Cl(1) = 88.08(17), C(14)−Au(1)−
Cl(1) = 177.89(15), C(1)−Au(1)−Cl(2) = 177.91(17), C(14)−
Au(1)−Cl(2) = 90.22(16), and Cl(1)−Au(1)−Cl(2) = 91.86(7).
Figure 4. Flow cytometric analysis of the induction of apoptosis in
HCT 116 cells upon treatment with 2 (IC50 concentration) for 24 h.
suggested to us that 2 induced the death of HCT 116 cells
because of apoptosis in a manner similar to previous reports
involving Au(I)−NHC complexes on other cancer cell lines4b
as well as a Ag(I)−NHC complex.14 However, to the best of
our knowledge, this is the first example of apoptotic induction
in HCT 116 cells using a Au(I)−NHC complex.
Au(I)−NHC complexes have been reported to generate
reactive oxygen species (ROS), which may be due to the
inhibition of the thioredoxin reductase (TrxR), which is a key
enzyme in a cell’s antioxidant defense system, and loss of
membrane potential (ΔΨm) following treatment of cancer
cells.15,16 Treatment of HCT 116 cells with complex 2 (at the
IC50 concentration) for 24 h led to the generation of ROS with
a FITC mean at 198 and 448, indicating a shift in the
generation of ROS from the control to complex 2 (IC50
concentration) as determined by the H2DCFDA assay (Figure
5 A). Treatment of HCT 116 cells with complex 2 (IC50
concentration) for 24 h led to the loss of the mitochondrial
a
Table 1. Summary of Measured IC50 Values (micromolar)
complex
A549
HCT 116
HepG2
MCF7
2
5.2 1.5
5.2 3.0
8.1 3.2
3.6 4.1
5.9 3.6
8.8 2.8
3.7 2.3
5.1 3.8
8.9 1.3
4.7 0.8
6.2 1.4
9.4 1.0
3
cisplatin
a
Legend: A549, human non-small lung carcinoma; HCT 116, human
colorectal carcinoma; HepG2, human hepatocellular carcinoma; MCF-
7, human breast adenocarcinoma. Cells were treated with different
concentrations of cisplatin or complexes 2 and 3 ranging from 0 to 10
μM for 24 h. The IC50 values were calculated from an MTT assay.
Values are means the standard deviation and represent one of three
representative experiments.
stained with the nuclear staining dye 4,6-diamidino-2-phenyl-
indole (DAPI), the cells showed bright, fragmented nuclei
under the fluorescence microscope (Figure 3). Both of the
aforementioned results are typical hallmarks of apoptosis.12
Another important feature of apoptosis is the externalization of
Figure 5. (A) Flow cytometric analysis of reactive oxygen species
generation in cells following treatment with complex 2 (IC50
concentration) after 24 h. (B) Flow cytometry analysis of the loss of
ΔΨm in the presence of complex 2 (IC50 concentration) after 24 h.
Figure 3. Fluorescent micrographs of the HCT 116 cells following
treatment with 2 (at the IC50 concentration) for 24 h and subsequent
staining with DAPI. The arrows denote DNA fragmentation.
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(m, 1H, Hc), 7.07 (t, J = 8.8 Hz, 1H, Hi), 6.95 (t, J = 8.7 Hz, 1H, Hi),
2.44 (s, 3H, CH3); 13C NMR (DMSO-d6, 300 MHz, 25 °C) δ 173.38,
150.58, 150.02, 140.22, 127.76, 127.16, 126.14, 123.06, 122.54, 121.93,
118.68, 116.48, 9.74; MS (FAB+) m/z 615.3 (M+ − PF6); UV−vis
(CH3CN) λmax [ε (×104 M−1 cm−1)] 230 (11.6), 244 (11.4), 345 br
(2.1), 375 br (1.8) nm. Anal. Calcd for Au2C52H44N12P2F12: C, 41.05;
H, 2.89; N, 11.05. Found: C, 40.84; H, 2.83; N, 10.87. Single-crystal
data: C52H44Au2N12P2F12, Mr = 1520.86, monoclinic, space group P21/
n, a = 14.18060(10) Å, b = 24.7767(2) Å, c = 15.1625(2) Å, β =
95.1790(5)°, U = 5305.57(9) Å3, Z = 4, Dc = 1.904 g cm−3, μ = 5.677
mm−1 (Mo Kα, λ = 0.71073 Å), T = 295 K, R [I > 2σ(I)] = 0.0462, Rw
(F2, all data) = 0.1220, and goodness of fit of 1.026 for 9294 observed
data (12777 unique; Rint = 0.1308; 2θ < 56°) and 725 refined
parameters. Denzo SMN, SHELXL-97, and SIR97 were used.18
Synthesis of 3. Complex 2 (106 mg, 0.14 mmol) was dissolved in
acetonitrile (10 mL) at room temperature. Au(SMe2)Cl (83 mg, 0.28
mmol) was then added to the solution, and the mixture was stirred for
an additional 5−6 h. The color of the solution changed from colorless
to yellow, which was accompanied by the formation of a precipitate.
The precipitate, which was found to be metallic gold, was reused to
synthesize Au(SMe2)Cl. After filtration, the residual acetonitrile was
evaporated under vacuum and at low temperature to yield a yellow
powder. The yellow complex was recrystallized from acetonitrile and
diethyl ether to give the desired compound in 33% yield (38 mg, 0.05
mmol): 1H NMR (DMSO-d6, 300 MHz, 25 °C) δ 8.48 (d, J = 6.4 Hz,
2H), 8.13 (d, J = 7.2 Hz, 2H), 7.84 (t, J = 12 Hz, 4H), 7.73 (d, J = 7.7
Hz, 2H), 7.26 (t, J = 9.2 Hz, 2H), 7.11 (m, 2H), 6.88 (d, J = 7.2 Hz,
2H), 2.48 (s, 3H); 13C NMR (DMSO-d6, 300 MHz, 25 °C) δ 159.7,
146.1, 141.3, 130.6, 126.0, 125.9, 125.73, 125.5, 125.0, 124.8, 119.4,
119.1, 118.8, 112.4, 110.4, 10.9; MS (FAB+) m/z 847.2; UV−vis
(CH2Cl2) λmax [ε (×104 M−1 cm−1)] 230 (12.1), 244 (11.8), 347 br
(2.5), 425 br (2.1) nm. Anal. Calcd for AuC26H22N6P2F12Cl·H2O: C,
36.75; H, 2.83; N, 9.89. Found: C, 36.58; H, 2.80; N, 9.87. Single-
crystal data: C26H24AuCl2OF6N6P′, Mr = 849.35, triclinic, space group
membrane potential (ΔΨm), with 21.0 and 42.4% of the cells
showing loss of ΔΨm following treatment with complex 2
(IC50 concentration) as compared to the control cells after 24 h
as determined by the JC-1 assay (Figure 5B). Collectively, these
data indicate that 2 can mediate apoptosis in HCT 116 cells by
the generation of ROS and loss of ΔΨm.
Apoptosis of cancer cells following treatment with Au(I)−
NHC complexes was further explored by monitoring the
expression of caspase 9 and caspase 3 to determine if a
mitochondrial death pathway was involved.17 Treatment of
HCT 116 cells with complex 2 (at the IC50 concentration) for
24 h led to an increase in the caspase 9 (initiation phase) and
caspase 3 (execution phase) activities. As such, it appears that
complex 2-mediated cell death proceeds via a mitochondrial
death pathway (Figure 6).
Figure 6. Increase in caspase 3 and caspase 9 activity following
treatment of HCT 116 cells with complex 2 (0, 2.5, 5, 7.5, and 10 μM)
for 24 h, as determined by a colorimetric caspase assay kit. Values are
P1, a = 9.4952(12) Å, b = 10.7425(14) Å, c = 14.3591(19) Å, α =
̅
means
the standard deviation and represent one of three
85.821(3)°, β = 89.612(3)°, γ = 87.081(3)°, U = 1458.9(3) Å3, Z = 2,
Dc = 1.934 g cm−3, μ = 5.352 mm−1 (Mo Kα, λ = 0.71073 Å), T =
293(2) K, R [I > 2σ(I)] = 0.0343, Rw (F2, all data) = 0.0858, and
representative experiments. *P < 0.05, and **P < 0.01.
goodness of fit of 1.051 for 4513 observed data (5115 unique; Rint
=
In conclusion, the synthesis, characterization, and cytotox-
icities of novel Au(I)− and Au(III)−NHC complexes are
described. The Au(III)−NHC complex was synthesized
directly from an appropriate Au(I) precursor by capitalizing
on a disproportionation process. Gold(I) complex 2 was found
to be more potent as an anticancer agent than 3 or cisplatin in
four cell lines. Furthermore, treatment of HCT 116 cells with 2
at the IC50 concentration for 24 h yielded results that were
hallmarks of apoptosis, including nuclear condensation,
externalization of annexin V, production of ROS, and a loss
of ΔΨm. Finally, treatment of HCT 116 cells with complex 2
led to increased caspase 3 and caspase 9 activities, reflecting the
fact that a pathway involving mitochondrial death is involved in
the aforementioned processes.
0.0415; 2θ < 50°) and 381 refined parameters. Standard Bruker AXS
control and integration software and SHELXTL were used.18
ASSOCIATED CONTENT
* Supporting Information
■
S
Summary of biological studies, mass spectra, and crystallo-
graphic data for complexes 2 and 3 in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: dassahakrishna@gmail.com.
■
*E-mail: joydevdinda@gmail.com or dindajoy@yahoo.com.
Author Contributions
EXPERIMENTAL SECTION
J.D. is grateful to Hon’ble Chancellor and Vice Chancellor of
the ITM University-Gwalior for constant encouragement and
DST, India, for financial support under the “Young Scientist
Scheme” (SR/FT/CS-046/2009).
■
Synthesis of 2. The proligand 1 (250 mg, 0.70 mmol) and silver
oxide (85 mg, 0.37 mmol) were added to dry acetonitrile (10 mL), and
the mixture was stirred at room temperature for 4 h. The mixture was
filtered through a plug of Celite to remove the unreacted Ag2O. The
filtrate was concentrated to dryness and the residue dried under
reduced pressure. An acetonitrile solution of Au(SMe2)Cl (103 mg,
0.35 mmol) was added dropwise to the pre-prepared solution of the
silver complex in acetonitrile (15 mL), and an immediate white
precipitate was observed. The filtrate was evaporated to dryness and
the solid dried over silica after removal of AgCl by filtration. The
compound was recrystallized from a CH3CN/Et2O mixture to afford
Author Contributions
B.K.R. and A.N. contributed equally to this work.
Notes
The authors declare no competing financial interest.
REFERENCES
■
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