Phosphine-bridged dinuclear gold(I) alkynyl complexes: Thioredoxin reductase inhibition and cytotoxicity

Article abstract of DOI:10.1016/j.ica.2012.12.013

The study of the biological properties of four dinuclear gold(I) alkynyl complexes with general formulae [(μ₂-diphos)(AuCCC ₅H₄N)₂] (diphos = dcypm, dcypb, dppm and dppb) is reported in this work. The biological evaluation included enzymatic inhibition and tumor cell proliferation studies. Inhibition of the enzyme thioredoxin reductase (TrxR) was confirmed for the gold derivatives containing dppm and dppb bridging ligands and indicated a preference for the shorter bridging ligand. Strong cytotoxic activities against two different cultured tumor cell lines (MCF-7 and HT-29) were noted for most of the compounds but were not correlated with an activity against TrxR.

Full text of DOI:10.1016/j.ica.2012.12.013

Inorganica Chimica Acta 398 (2013) 72–76
Contents lists available at SciVerse ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Phosphine-bridged dinuclear gold(I) alkynyl complexes: Thioredoxin
reductase inhibition and cytotoxicity
b,
Andreas Meyer a, Albert Gutiérrez b, Ingo Ott a, , Laura Rodríguez
⇑
⇑
a Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 38106 Braunschweig, Germany
b Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The study of the biological properties of four dinuclear gold(I) alkynyl complexes with general formulae
Received 25 September 2012
Received in revised form 6 December 2012
Accepted 7 December 2012
Available online 19 December 2012
[(l2-diphos)(AuC„CAC5H4N)2] (diphos = dcypm, dcypb, dppm and dppb) is reported in this work. The
biological evaluation included enzymatic inhibition and tumor cell proliferation studies. Inhibition of
the enzyme thioredoxin reductase (TrxR) was confirmed for the gold derivatives containing dppm and
dppb bridging ligands and indicated a preference for the shorter bridging ligand. Strong cytotoxic activ-
ities against two different cultured tumor cell lines (MCF-7 and HT-29) were noted for most of the com-
pounds but were not correlated with an activity against TrxR.
Keywords:
Gold alkynyl complexes
Thioredoxin reductase
Cytotoxicity
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
phosphines the uptake into lysosomes could be confirmed by fluo-
rescence microscopy [24]. Recently, we have reported on a series of
Gold complexes with thiolates and phosphine ligands (e.g.,
auranofin, aurothiomalate) have been used to treat symptoms of
rheumatoid arthritis for many years and nowadays there is an in-
creased interest in developing gold based anticancer drugs [1–4].
Types of ligands used for designing new gold metallodrugs include
among others bischelating phosphines [5,6], thiolates [7,8], N-het-
erocyclic carbenes [9–13], dithiocarbamates [14,15], thiosemicar-
bazones [16,17] or porphyrins [18,19].
Gold complexes with bischelating phosphines have been inten-
sively studied by Berners-Price et al. In several studies they could
clearly demonstrate that compounds such as complex I (see
Fig. 1) act as delocalized lipophilic cations against mitochondrial
biochemistry, inhibit the enzyme tumor-relevant enzyme thiore-
doxin reductase (TrxR) and accumulate inside mitochondria
[5,6,20,21].
(alkynyl)(triphenylphosphane)Au(I) complexes, which inhibited
TrxR, triggered antiproliferative effects in cancer cells, modified tu-
mour cell metabolism and led to anti-angiogenic effects in zebra-
fish embryos [26].
In this project we aimed to study the biological properties of
dinuclear gold(I) alkynyl complexes, in which the two gold alkynyl
fragments are connected by a bridging phosphine (compounds
1–4, Chart 1). Based on the above mentioned reports and recent
studies on dinuclear gold complexes [21,23,27,28] interesting bio-
logical activities could be expected. As crucial biological properties
of gold(I) bioactivity, the inhibition of TrxR and the triggering of
antiproliferative effects were studied.
2. Results and discussion
Recently first results on the anticancer and antimalarial proper-
ties of gold(I) alkynyl complexes have been reported (e.g., com-
pounds II–VI, Fig. 1) [22–26]. These studies overall show that this
class of gold(I) derivatives also exhibits a promising potential for
medicinal chemistry. For example, for one dinuclear bisalkynyl
compound first antitumor activities in xenografted nude mice
could be obtained [23] and for derivatives containing water soluble
2.1. Synthesis and characterization
Compounds 1–4 were synthesized following the method de-
scribed in the literature [29]. A dichloromethane suspension of
[Au(C„CAC5H4N)]n was stirred with the corresponding diphos-
phine in 2:1 ratio to give the dinuclear gold complexes (Chart 1).
Recrystallisation from a dichloromethane-petroleum ether mix-
ture gave white solids of 1–4 in good yields (ꢀ75%). Although
derivatives 3 and 4 were previously reported by us [29], the syn-
thesis of 1 and 2 has been carried out to analyze the potentially dif-
ferent biological behavior of the compounds taking into account
the different character of the diphosphines.
⇑
Corresponding authors. Tel.: +49 (0)531 391 2743; fax: +49 (0)531 391 8456
(I. Ott). Tel.: +34 934039130; fax: +34 934907725 (L. Rodríguez).
E-mail addresses: ingo.ott@tu-braunschweig.de (I. Ott), laura.rodriguez@qi.ub.es
(L. Rodríguez).
0020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2012.12.013

A. Meyer et al. / Inorganica Chimica Acta 398 (2013) 72–76
73
+
O
R2P
R2P
PR2
PR2
PPh3
Ph3P
Au
AuPPh3
Au
Cl-
O
Au
I
II
III
O
N
Au PPh3
Au PPh3
Au
P
O
N
O
N
O
IV
V
VI
Fig. 1. Examples of gold(I) complexes with bischelating phosphines or alkynyl ligands.
The reaction was followed by 31P NMR which clearly indicates
that the corresponding compound was successfully obtained after
1 h of stirring, since the 31P NMR signal is ca. 55 ppm downfield
shifted upon coordination to the metal atoms. Analytical and spec-
troscopic data agree with the proposed structures. 31P NMR indi-
ically structured bands in emission is indicative of the involvement
of ligand character in their origin. Interestingly, previous attempts
to carry out the emission spectra of 3 and 4 in dichloromethane
were not successful, since the compounds undergo rapid photode-
composition during the tracing of the emission spectrum, as ob-
served for other alkynyl–gold(I) complexes in this solvent
[29,33,34]. Excitation of the samples at the highest energy absorp-
tion bands (absorption of the ligands) displays lower intensity
emissions. Excitation spectra collected at ca. 440 nm reproduces
absorption spectra bands at 260–300 nm together with a new band
at 360–370 nm in all cases. Thus, our experimental results and the
comparison with previous assignment for 3 and 4 and related com-
cates the formation of
equivalent phosphorous atoms. 1H NMR experiments show the
and Hb protons of the pyridine units of the complexes and IR
a symmetrical complex with two
H
a
spectra show the typical vibration of the triple C„C bond at
approximately 2100 cmÀ1 and the presence of uncoordinated pyr-
idine (
m
(C@N) ꢀ1585 cmÀ1). ESI-MS spectra show the mono and
di-protonated molecular peaks of 1 and 2, being a clear evidence
of the formation of both compounds (Figs. S1 and S2-ESI). The com-
pounds are well soluble in DMSO, CH2Cl2, acetone and CH3CN,
however, solubility in water and ethanol is restricted.
plexes [30,34] led us to attribute the observed emission band to an
3
intraligand
[p–
p⁄(alkynyl)] origin.
Exploring in detail the emission bands shape we could expect
the possible presence of another broad emission band centered
at ca. 500 nm which should be buried under the intraligand emis-
sion and is also observed for similar related complexes. Accord-
ingly, the band at 360 nm increases on intensity when excitation
The optical properties of the compounds were studied in DMSO
(see Table 1). Absorption and emission of compounds 3 and 4 were
previously reported in dichloromethane. Interestingly, different
emission data could be observed herein.
The complexes exhibit intense high-energy and vibronically
structured absorption in the range 270–290 and in some cases
present a tail extending to ca. 370 nm (see Fig. S3). The former in-
tense bands display progressional spacings at ca. 1800 cmÀ1, typi-
spectra were recorded at 500 nm. This lower energy emission
broad band should be originated from the
(C„Cpy)] excited state, with contribution of Au centered states
as previously reported for 3 and 4 [29,30,35,36].
3
[r
(Au–P) ? p⁄
cal of
m
(C„C) stretching frequencies in the excited state, and is
assigned to intraligand (IL)
p
?
p⁄ (C„Cpy), as reported in other
2.2. Biological evaluation
published works on ethynylgold(I) complexes and for compounds
3 and 4 in dichloromethane [29–31]. Moreover, a broad band at
ꢀ340 nm is observed in almost all cases which has been recently
assigned to the formation of aggregates due to the establishment
For the biological evaluation the complexes were initially tested
as inhibitors of TrxR (here from rat liver), which is one of the
important targets of gold biological effects [37–40]. Glutathione
reductase (GR, from yeast) was used as a control to check for the
specificity of the enzymatic inhibition. In contrast to TrxR, GR does
not contain a selenocysteine in its active site but otherwise it is
structurally and functionally very similar to TrxR [41,42]. Evidence
suggests that the selenocysteine is the relevant binding site for
gold complexes [43,44]. Complexes 3 and 4 turned out to be effec-
of
p–p stacking interactions between ethynylpyridyl units to-
gether with aurophilic interactions [32].
The emission spectra of all the compounds upon excitation at
k = 360 nm in DMSO display a well-resolved emission band be-
tween 400 and 575 nm (Figs. 2 and S4). The observation of vibron-
(CH2)n
R = Cy; n = 1 (1); n = 4 (2)
tive inhibitors of TrxR with IC50 values below 10 lM and thereby
they are suitable starting compounds for further development of
dinuclear gold alkynyl anticancer agents (see Table 2). Their IC50
values, however, were higher than that of several mononuclear
gold(I) alkynyl phosphine complexes investigated in the same as-
say recently [26]. Complex 3 was more active than complex 4,
which might give a hint that shorter bridging ligands could be pre-
ferred. As expected GR was inhibited by 3 and 4 with more than
50-fold higher IC50 values, which confirmed the selectivity of the
gold complexes for TrxR. Complexes 1 and 2, all free diphosphine
ligands, as well as 4-ethynylpyridine were not active against TrxR
or GR.
R2P
Au
PR2
Au
R = Ph; n = 1 (3); n = 4 (4)
(CH2)n
R2P
PR2
R = Cy; n = 1: dcypm
R = Cy; n = 4: dcypb
R = Ph; n = 1: dppm
R = Ph; n = 4: dppb
N
N
Chart 1.

74
A. Meyer et al. / Inorganica Chimica Acta 398 (2013) 72–76
Table 1
4.0
Electronic absorption and emission data for compounds 1–4 in DMSO at room
temperature.
3.0
2.0
1.0
0.0
Compound
Absorption (nm)
Emission (nm)
(kexc = 360 nm)
(
e
 10À3, MÀ1 cmÀ1
)
1
2
3
4
274 (69.8), 288 (66.7)
276 (48.9), 286 (46.7)
280 (70.4), 291 (71.1)
270 (57.6), 285 (66.5)
415, 438, 461
415, 440, 461
415, 438, 461
415, 438, 459
4.0x105
0
1
2
4
6
72
*
[h]
Fig. 3. Cellular gold levels in HT-29 cells exposed to 5.0
l
M of 3.
the gold complexes were more active than the gold free diphos-
phines. It could be also observed in this case that the shorter con-
necting bridge of dcypm and 1 seems to be an advantage over the
longer connection in dcypb and 2. The metal free alkyne 4-ethyn-
ylpyridine did not trigger antiproliferative effects.
Complex 3 was selected as the most active compound for more
detailed studies on its uptake into HT-29 cells. For this purpose the
gold levels of HT-29 cells were measured using high resolution
continuum source atomic absorption spectroscopy and related to
the cellular protein content, which was determined by the Brad-
ford method. The experiments showed a fast increase in gold up-
take with values of 2–4 nmol gold per milligram cellular protein
after a few hours (see Fig. 3). After 72 h 0.80 nmol Au/mg protein
were found. This indicates on the one hand that gold is eliminated
from the cells over longer exposure but on the other hand that the
remaining cells still contain a considerable gold concentration. The
determined gold levels were higher than those observed with
mononuclear alkynyl gold(I) complexes, which had reached values
roughly in the range of 0.2–0.8 nmol/mg depending on the alkynyl
ligand (of note: 3 is a dinuclear compound containing 2 gold atoms
per molecule) [26].
0.0
400
450
500
550
600
650
Wavelength (nm)
Fig. 2. Emission spectrum of 1 in 1.5 Â 10À5 M DMSO solution at room temperature
(kexc = 360 nm). ⁄Raman band of the solvent.
Table 2
IC50 values (
and HT-29 cells.
lM) for inhibition of TrxR and GR and antiproliferative effects in MCF-7
TrxR
4-Ethynylpyridine >100
GR
GR/TrxR MCF-7
HT-29
>1000
>1000
>1000
>1000
>1000
>500
n.a.
n.a.
n.a
n.a
n.a
n.a.
n.a
>100
9.7 5.3
>40
0.8 0.5
0.7 0.1
1.1 0.3
23.8 4.9 15.3 1.6
1.4 0.2
2.8 0.6
>100
14.7 2.2
>100
2.1 1.1
1.2 0.1
0.6 0.2
dcypma
dcypba
dppb
dppm
1a
>100
>100
>100
>100
>50
Based on the above described spectroscopic properties, fluores-
cence microscopic experiments with HT-29 cells exposed for 6 h to
5.0 lM of 3 were performed. However, the fluorescence emission
2a
3
4
>50
>500
1.6 0.3 232 63 145
7.9 4.4 472 23 60
2.7 0.8
1.2 0.2
(upon excitation at 405 nm) of the cells was very low and did
not differ substantially from the background fluorescence of un-
treated control cells (data not shown).
n.a., not applicable.
a
Major solubility problems were experienced during the biological assays.
In progress experiments are being carried out in order to im-
prove solubility in water to obtain better biological activity.
A general observation from performing the biological assays
was the low solubility of the compounds in the biological media
and buffer solutions. This was more pronounced for the cyclohexyl
derivatives. Problematic solubility had already been reported re-
cently for other dinuclear gold species [27]. The missing activity
of 1 and 2 against the enzymes might therefore be related to insuf-
ficient dissolution in the assay buffer. Improving the solubility in
aqueous media could be a key issue for obtaining higher active
complexes.
3. Conclusions
Our study demonstrates that bridged dinuclear gold(I) alkynyl
complexes have a good potential for developing biologically active
gold(I) complexes. TrxR inhibition is moderate but might contrib-
ute to the biological spectrum of the complexes. Their application
in biological assays seems to be hampered to a certain extent by
solubility problems, which are most probably the consequence of
the large lipophilic residues at the phosphines. Concerning cyto-
toxic effects there was a considerable contribution of the metal
free phosphine ligands. For further development the study of ana-
logs with less lipophilic residues at the phosphines appears more
useful and is the subject of ongoing efforts.
The antiproliferative effects were assessed in two cultured tu-
mor cell lines (namely MCF-7 breast cancer and HT-29 colon carci-
noma cells) in comparison to the metal free ligands. Strong
antiproliferative effects in the range of 0.7–2.8 lM were obtained
for the active TrxR inhibitors 3 and 4 as well as for the respective
free diphosphines dppm and dppb, which were inactive against
TrxR and GR. Accordingly, TrxR inhibition of the gold derivatives
cannot be the only mechanism responsible for the tumor cell
growth inhibition for this set of complexes. Cytotoxic effects but
also inactivity of various free bischelating phosphines have already
been reported in vitro and in vivo [21,45]. Substantial cytotoxic
activities were also observed with 1 and 2 as well as dcypm, all
of which had shown no activity against TrxR and GR. In this case
4. Experimental
4.1. General procedures
All manipulations were performed under prepurified N2 using
standard Schlenk techniques. All solvents were distilled from

A. Meyer et al. / Inorganica Chimica Acta 398 (2013) 72–76
75
appropriate drying agents. Commercial reagents bis(dicyclohexyl-
phosphino)methane (dcypm, Sigma–Aldrich) and 1,4-bis(dicyclo-
hexylphosphino)butane (dcypb, Sigma–Aldrich) have been used
as received. Literature methods were used to prepare [AuCl(tht)]
[46], [Au(C„CAC5H4N)]n [47], NC5H4C„CH [48], bis(diphenyl-
To each well 225
consisted of 500
100 mM EDTA solution pH 7.5, 20
of 20 mM NADPH solution and 300
l
l
L of reaction mixture (1000
L potassium phosphate buffer pH 7.0, 80
l
L reaction mixture
l
l
L
L
l
L BSA solution 0.05%, 100
lL of distilled water) were
added and the reaction was started by addition of 25
l
L of an
phosphino)methane
phino)butane (dppb) [49], [(
[( 2-dppb)(AuC„CAC5H4N)2] [29].
(dppm)
[49],
1,4-bis(diphenylphos-
20 mM ethanolic dithio-bis-2-nitrobenzoic acid (DTNB) solution.
After proper mixing, the formation of 5-thio-2-nitrobenzoic acid
(5-TNB) was monitored with a microplate reader (Perkin Elmer
Victor X4) at 405 nm in 35 s intervals for 350 s. For each tested
compound the non interference with the assay components was
confirmed by a negative control experiment using an enzyme free
solution. The IC50 values were calculated as the concentration of
compound decreasing the enzymatic activity of the untreated con-
trol by 50% and are given as the means and error of 2–3 indepen-
dent experiments.
l2-dppm)(AuC°C-C5H4N)2] [29] and
l
4.2. Physical measurements
1H NMR (d (TMS) = 0.0 ppm), 31P{1H} NMR (d (85% H3PO4) =
0.0 ppm) spectra were obtained on a Varian Unity 400 and Brucker
DXR 250 spectrometers at 25 °C unless otherwise stated. Infrared
spectra were recorded on a FT-IR 520 Nicolet Spectrophotometer.
ES(+) mass spectra were recorded on a Fisons VG Quatro spectrom-
eter at the Servei d’Espectrometria de Masses (Universitat de
Barcelona). Elemental analyses of C, H, N and S were carried out
at the Centre Científics I Tecnològics (Universitat de Barcelona).
4.5. Cell culture and antiproliferative effects
MCF-7 breast adenocarcinoma and HT-29 colon carcinoma were
maintained in DMEM high glucose (PAA) supplemented with
50 mg/L gentamycin and 10% (V/V) fetal calf serum (FCS) at 37 °C
under 5% CO2 atmosphere and passed every seven days. Antiprolif-
erative effects were determined essentially as described in a recent
publication (see Ref. [25] of the main article).
4.3. Synthesis and characterization
4.3.1. Synthesis of [(l2-dcypm)(AuC„CAC5H4N)2] (1)
To a suspension of [Au(C„CAC5H4N)]n (120 mg, 0.40 mmol) in
CH2Cl2 (25 ml), solid dcypm (82 mg, 0.20 mmol) was added and
the mixture was stirred for 1 h and filtered through Celite. The
resulting solution was concentrated (10 ml), and n-hexane
(20 ml) was added to precipitate a white solid. The compound
was recrystallized in CH2Cl2/n-hexane (154 mg, 77%). 1H NMR dH
4.6. Cellular uptake
The cellular gold levels were determined using the same assay
as described recently (see Ref. [25] of the main article). In short:
HT-29 colon carcinoma cancer cells were grown until at least
80% confluence in 25 cm2 cell culture flasks. A stock solution of
5.0 mM of the gold complex 3 in DMF was freshly prepared and di-
luted with culture medium supplemented with 10% (V/V) FCS (fi-
(250.1 MHz; CDCl3): 8.37 (d, J = 5.7 Hz, 4 H, H -pyr), 7.33 (d,
a
J = 5.7 Hz, 4 H, Hb-pyr), 2.20–1.31 (m, 46 H, PCy2 + P-(CH2)-P).
31P{1H}NMR dP (101.3 MHz, CDCl3): 46.3 (s, dcypm). IR (KBr,
cmÀ1): 2097 (C„C), 1585 (C@N). ES-MS m/z: 1007.31 ([M+H+]+,
Calc.: 1007.31), 504.16 ([M+2H+]2+, Calc.: 504.16). Anal. Calc. for
C39H54Au2N2P2: C, 46.53; H, 5.41; N, 2.78. Found: C, 46.60; H,
nal concentrations: DMF: 0.1% v/v, 3: 5.0 lM). The cell culture
5.46; N, 2.82%.
medium of the flasks was replaced with 3.0 mL medium containing
the substances and incubated for the indicated periods at 37 °C/5%
CO2. Cell pellets were collected after trypsinisation (trypsin 0.05%)
and centrifugation (3000g, 5 min.), suspended in 1.0 mL water,
lysed by ultrasonication and investigated by high resolution atom-
ic absorption spectroscopy for their gold content and by the Brad-
ford method for their protein content. Results were expressed as
nmol gold/mg protein as mean and error of two independent
experiments.
4.3.2. Synthesis of [(l2-dcypb)(AuC„CAC5H4N)2] (2)
To a suspension of [Au(C„CAC5H4N)]n (120 mg, 0.40 mmol) in
CH2Cl2 (25 ml), solid dcypb (90 mg, 0.20 mmol) was added and the
mixture was stirred for 1 h and filtered through Celite. The result-
ing solution was concentrated (10 ml), and n-hexane (20 ml) was
added to precipitate a white solid. The compound was recrystal-
lized in CH2Cl2/n-hexane (157 mg, 75%). 1H NMR dH (250.1 MHz;
CDCl3): 8.46 (d, J = 5.7 Hz, 4H, H -pyr), 7.33 (d, J = 5.7 Hz, 4H, Hb-
a
pyr), 2.01–1.29 (m, 52 H, PCy2 + P-(CH2)4-P). 31P{1H}NMR dP
(101.3 MHz; CDCl3): 48.6 (s, dcypb). IR (KBr, cmÀ1): 2096 (C„C),
1588 (C@N). ES-MS m/z: 1049.36 ([M+H+]+, Calc.: 1049.36),
946.32 ([MÀC„CC6H4N], Calc.: 946.32); 525.19 ([M+2H+]2+, Calc.:
525.18). Anal. Calc. for C42H60Au2N2P2: C, 48.10; H, 5.77; N, 2.67.
Found: C, 48.15; H, 5.81; N, 2.70%.
Acknowledgements
Financial support for this research was provided by the Ministe-
rio de Ciencia e Innovación of Spain (Project CTQ2012-31335) and
the Deutsche Forschungsgemeinschaft (project FOR630, ‘‘Biological
Functions of Organometallic Compounds’’). The support and spon-
sorship provided by COST Action CM1105 is also acknowledged.
4.4. TrxR/GR inhibition assay
To determine the inhibition of TrxR and GR an established
microplate reader based assay was performed with minor modifi-
cations [11]. For this purpose commercially available rat liver TrxR
and baker yeast GR (both from Sigma–Aldrich) were used and di-
luted with distilled water to achieve concentrations of 3.0 U/mL
(TrxR) and 20.0 U/mL (GR). The compounds were freshly dissolved
Appendix A. Supplementary material
ESI-MS spectrum of [(l2-dcypm)(AuC„CAC5H4N)2], 1 (Fig. S1);
ESI-MS spectrum of [(
l
2-dcypb)(AuC„CAC5H4N)2], 2 (Fig. S2);
normalized absorption spectra of 1 Â 10À5 M DMSO solutions of
compounds 1–4 (Fig. S3); emission spectrum of 2–4 in 1.5 Â
as stock solutions in DMF. To each 25
lL aliquots of the enzyme
solution each 25 L of potassium phosphate buffer pH 7.0 contain-
l
10À5
M DMSO solution at room temperature (kexc = 360 nm).
ing the compounds in graded concentrations or vehicle (DMF)
without compounds (control probe) were added and the resulting
solutions (final concentration of DMF: max. 0.5% V/V) were incu-
bated with moderate shaking for 75 min at 37 °C in a 96 well plate.
⁄Raman band of the solvent (Fig. S4). This material is available free
of charge via the Internet at http://www.sciencedirect.com.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.ica.2012.12.013.

76
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