Cationic gold(i) heteroleptic complexes bearing a pyrazole-derived N-heterocyclic carbene: Syntheses, characterizations, and cytotoxic activities

Article abstract of DOI:10.1039/c3dt51071a

A series of cationic gold(i) heteroleptic complexes bearing the pyrazole-derived N-heterocyclic carbene (NHC) FPyr (1,2,3,4,6,7,8,9- octahydropyridazino[1,2-a]indazolin-11-ylidene), and either a 1,3-disubstituted benzimidazole-derived NHC of the type RR′-bimy (3: R = R′ = CHPh₂; 4: R = CHPh₂, R′ = ⁱPr; 5: R = R′ = CH₂Ph; 6: R = R′ = ⁱBu; 7: R = R′ = n-Pr; 8: R = R′ = Et; 9: R = R′ = 2-propenyl) or a non-NHC co-ligand L (10: L = PPh₃; 11: L = P(OPh)₃; 12: L = DMAP) (DMAP = 4-dimethylaminopyridine) have been synthesized from [AuCl(FPyr)] (1). Complexes 3-12 have been characterized using multinuclei NMR spectroscopies, ESI mass spectrometry, and elemental analysis. X-ray diffraction analyses have been performed on complexes 5, 6, and 9-11. To the best of our knowledge, 11 represents the first gold-NHC complex to bear the P(OPh)₃ ligand. The cytotoxic activities of complexes 3-12 have been studied in vitro with the NCI-H1666 non-small cell lung cancer cell line.

Full text of DOI:10.1039/c3dt51071a

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Cationic gold(I) heteroleptic complexes bearing a
pyrazole-derived N-heterocyclic carbene: syntheses,
characterizations, and cytotoxic activities†
Cite this: Dalton Trans., 2013, 42, 12421
Haresh Sivaram,a Jackie Tanb and Han Vinh Huynh*a
A series of cationic gold(I) heteroleptic complexes bearing the pyrazole-derived N-heterocyclic carbene
(NHC) FPyr (1,2,3,4,6,7,8,9-octahydropyridazino[1,2-a]indazolin-11-ylidene), and either a 1,3-disubstituted
i
benzimidazole-derived NHC of the type RR’-bimy (3: R = R’ = CHPh2; 4: R = CHPh2, R’ = Pr; 5: R = R’ =
CH2Ph; 6: R = R’ = iBu; 7: R = R’ = n-Pr; 8: R = R’ = Et; 9: R = R’ = 2-propenyl) or a non-NHC co-ligand L (10:
L = PPh3; 11: L = P(OPh)3; 12: L = DMAP) (DMAP = 4-dimethylaminopyridine) have been synthesized from
[AuCl(FPyr)] (1). Complexes 3–12 have been characterized using multinuclei NMR spectroscopies, ESI
mass spectrometry, and elemental analysis. X-ray diffraction analyses have been performed on complexes
5, 6, and 9–11. To the best of our knowledge, 11 represents the first gold–NHC complex to bear the
P(OPh)3 ligand. The cytotoxic activities of complexes 3–12 have been studied in vitro with the NCI-H1666
non-small cell lung cancer cell line.
Received 24th April 2013,
Accepted 15th June 2013
DOI: 10.1039/c3dt51071a
www.rsc.org/dalton
cationic bis(carbene) complexes are far more active as cytotoxic
agents when compared with the neutral monocarbene com-
Introduction
Interest in the cytotoxic activities of gold complexes has grown plexes. The gold(I) hetero-bis(carbene) complex 2 (Fig. 1), in
tremendously over the years.1,2 In particular, gold complexes particular, shows superior performance with an IC50 value of
bearing N-heterocyclic carbenes (NHCs) have been gaining 0.241 μM. Based on these findings, it was proposed that a
much attention,3 given the ease with which NHC precursors heteroleptic system in which a strongly donating ligand is situated
can be tuned, both electronically and sterically, by varying the trans to a relatively weaker donating ligand was necessary for
N-substituents.4 This in turn allows for synthetic control of the the labilization of the latter. This would create a vacant coordi-
hydro- and lipophilic properties of the resultant complexes; nation site that may be essential for the cytotoxic activity of
properties that have been shown to be important factors in the the complex. For example, donor atoms on target proteins,
development of gold-based anti-cancer agents.2,3 However, such as thioredoxin reductase,2,5,7 could bind to the complex
only gold mono- and homo-bis(carbene) complexes bearing fragment when a free coordination site is made available.
imidazolin-2-ylidenes have been extensively studied,2,3 whereas
complexes bearing other types of NHCs, as well as heteroleptic extended the investigation to consider a range of other cationic
complexes, have been scarcely considered.5
gold(I) heteroleptic complexes bearing the strongly donating
Spurred by the findings of our initial study, we have
Therefore, as our maiden contribution to this field of pyrazole-derived FPyr (1,2,3,4,6,7,8,9-octahydropyridazino[1,2-a]-
research, we had recently published the cytotoxic activities of a indazolin-11-ylidene) ligand, and either a 1,3-disubstituted
range of gold(I) and gold(III) mono-, homo-bis- and hetero-bis- benzimidazole-derived NHC, or a non-NHC co-ligand. Ben-
(carbene) complexes bearing benzimidazole- and/or pyrazole- zimidazolin-2-ylidenes bearing a variety of N-substituents have
derived NHC ligands on the NCI-H1666 non-small cell lung
cancer cell line.6 The preliminary study revealed that the
aDepartment of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543, Republic of Singapore. E-mail: chmhhv@nus.edu.sg;
Fax: +65 6779 1691; Tel: +65 6516 2670
bDepartment of Biological Sciences, National University of Singapore,
14 Science Drive 4, Singapore 117543, Republic of Singapore
†Electronic supplementary information (ESI) available: Dose–response curves
for 3–12. CCDC 935297–935301. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3dt51071a
Fig. 1 Gold(I) hetero-bis(carbene) complex [Au(FPyr)(iPr2-bimy)]PF6 (2).
Dalton Trans., 2013, 42, 12421–12428 | 12421
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been considered, in an effort to study the effect on the cytotoxi- reference.6 The chemical shift(s) of the carbene carbon atom(s)
city of the resultant complexes. For the purpose of compari- in complexes 3–12 are presented in Table 1.
son with our previous work, the cytotoxic activities of the
Considering the chemical shift of the FPyr carbene carbon,
complexes were studied in vitro with the NCI-H1666 non-small it is overt that as compared to the gold(I) chlorido monocar-
cell lung cancer cell line. We herein report on the syntheses, bene complex 1 (cf. 167.8 ppm),6 the FPyr carbene carbon in
characterizations, and cytotoxic activities of the aforemen- complexes 3–11, resonate at a much more downfield region,
tioned complexes.
ranging from 178.8–182.4 ppm. This is due to the replacement
of the chlorido co-ligand in 1 with a stronger donating ligand
situated trans to the FPyr ligand in the mentioned complexes,
leading to the observed downfield shift of the signal.6,8 On the
other hand, complex 12, with its DMAP co-ligand, shows a
more upfield FPyr carbene carbon resonance as compared to
1, which is the result of DMAP being a weaker donating ligand
as compared to the chlorido ligand.
The changes in the chemical shift of the FPyr carbene
carbon also reveal other interesting, albeit unexpected, find-
ings. For example, when focusing on the relevant data for
hetero-bis(carbene) complexes 3–9, it is noteworthy that no
real correlation can be drawn between the chemical shift of
the FPyr carbene carbon and the N-substituents of the RR′-
bimy ligands, where the latter would inadvertently influence
the overall donating ability of said RR′-bimy ligands. This is
Results and discussion
Syntheses and characterizations
The gold(I) chlorido-monocarbene complex [AuCl(FPyr)] (1)
was synthesized according to the previously reported pro-
cedure.6 Reaction of 1 with the appropriate 1,3-disubstituted
benzimidazolium salts in the presence of K2CO3 afforded the
gold(I) hetero-bis(carbene) complexes 3–9 in very good yields
ranging from 72 to 82% (Scheme 1). The heteroleptic com-
plexes 10–12, which bear non-NHC co-ligands, were syn-
thesized via straightforward ligand exchange reactions.
Complex 1 was reacted with the appropriate pro-ligand in the
presence of a large excess of KPF6 in acetone, and the products
were obtained in very good yields of 77 to 94% (Scheme 1). All
ten complexes were obtained as white powders, and are
soluble in most polar organic solvents. It should be noted that
11 represents the first gold–NHC complex to bear a phosphite
co-ligand.
Table 1 Chemical shift(s) of the carbene carbon atom(s) in complexes of the
type [Au(FPyr)(L)]PF6 (3–12)a
Complex
L
FPyr
RR′-bimy
Complexes 3–12 were characterized using MS (ESI) and
multinuclei NMR spectroscopies. The MS (ESI) spectra of the
complexes were particularly useful in confirming the for-
mation of the compounds, given that the base peak observed
3
4
5
6
7
8
9
10
11
12
(CHPh2)2-bimy
(iPr2)(CHPh2)-bimy
(CH2Ph)2-bimy
iBu2-bimy
n-Pr2-bimy
Et2-bimy
(2-Propenyl)2-bimy
PPh3
P(OPh)3
178.8
179.2
179.9
180.2
180.0
180.7
179.9
182.4
179.6b
161.0
197.8
195.1
195.7
194.8
194.8
194.1
196.0
—
in all cases corresponds to the [M − PF6]+ fragment. H NMR
1
spectroscopy corroborated the successful formation of the
complexes, whereby signals from both ligands are observed in
the respective spectra. For complexes 3–9, the 13C NMR spectra
correspondingly featured two downfield signals as a result of
the presence of two carbene carbon atoms in the molecules.
These two signals were assigned to their respective carbene
—
—
DMAP
a All 13C NMR spectra were measured in CDCl3, except for complexes 7,
9 and 12, which were measured in CD3CN due to poor solubility in
carbon atoms by using the previously reported complex 2 as a chloroform. b Doublet, 2J(C,P) = 178 Hz.
Scheme 1 Syntheses of cationic gold(I) hetero-bis(carbene) complexes of the type [Au(FPyr)(RR’-bimy)]PF6 (3–9), and heteroleptic complexes of the type [Au(FPyr)-
(L)]PF6 (10–12).
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unlike the 13C NMR spectroscopic methodology for determin- are arranged in a syn arrangement, which is a result of achiev-
ing ligand donor strengths that has been reported by our ing optimum packing in the unit cell. Two of the carbon
group, wherein even small changes to the N-substituents of atoms (C29 and C30) in the alicyclic ring of the FPyr ligand in
various NHCs are shown to affect the donating ability of the 5 were also disordered into two positions, with an occupancy
i
ligands, and can be detected by the Pr2-bimy probe in com- ratio of 50 : 50. The molecular structure of complex 11 is par-
plexes of the type [PdBr2(iPr2-bimy)(NHC)].4a Therefore, the ticularly interesting, in that two of the phenyl rings of the
data presented in this work seems to suggest that the Au(I) P(OPh)3 ligand are pointed towards the gold metal center. The
system is less sensitive than the Pd(II) system when it comes to remaining one is pointed away as a result of the close proxi-
−
detecting small changes in donor strength. Furthermore, while mity of a PF6 anion. The potential steric shielding of the
the Pd(II) system is able to confirm the stronger donating metal center accorded by the phenyl rings is unique to this
ability of NHCs as compared to phosphines, the Au(I) system ligand, and could prove beneficial for the overall stability of
studied in this work suggests the reverse, with the FPyr the complex. Furthermore, it is worth noting that none of the
carbene carbon in [Au(FPyr)(PPh3)]PF6 (10) resonating at complexes showed evidence for intermolecular aurophilic
182.4 ppm, which is significantly more downfield as compared interactions in the solid state.9
to the hetero-bis(carbene) complexes 3–9. This may be due to
some unique interactions that the phosphorus donor in PPh3
Cytotoxicity study
has with the electron-rich gold(I) metal center, and warrants
further investigation.
The cytotoxic activities of complexes 3–12 were investigated
through a cell proliferation assay conducted on the NCI-H1666
non-small cell lung cancer cell line, and IC50 values were
obtained from best-fit dose response curves (see ESI†). The
performance of each complex in comparison to the previously
reported complex 2, as well as cisplatin, is tabulated in
Table 2.
Considering the hetero-bis(carbene) complexes 3–9, it is
noted that they do not perform as well as the previously
reported complex 2, although 3 does come close with an IC50
value of 0.346 μM. Also, there seems to be no con-
sistent relationship between the nature and length of the
Single crystals suitable for X-ray diffraction analysis were
obtained for complexes 5, 6, and 9–11 via vapour diffusion of
diethyl ether into solutions of the compounds in either CHCl3
or CH2Cl2. The determined molecular structures were as
expected, with all complexes adopting a linear geometry about
the gold(I) metal center (Fig. 2). Complex 5 crystallised as the
chloroform solvate, while all other complexes crystallised
unsolvated. It is interesting to note that unlike 5, where both
the benzyl N-substituents are arranged in an anti arrangement
across the benzimidazole plane, the N-substituents in 6 and 9
Fig. 2 Molecular structures of complexes 5·CHCl3, 6, and 9–11 showing 50% probability ellipsoids; hydrogen atoms, PF6− anions, and solvent molecules (if any) are
omitted for clarity. Selected bond lengths [Å] and angles [°]: 5·CHCl3: Au1–C1 2.017(5), Au1–C22 2.015(5); C1–Au1–C22 177.7(2); 6: Au1–C1 2.027(5), Au1–C16
2.013(5); C1–Au1–C16 174.85(19); 9: Au1–C1 2.020(3), Au1–C14 2.018(3); C1–Au1–C14 176.81(12); 10: Au1–C1 2.035(6), Au1–P1 2.2843(17); C1–Au1–P1 175.43(17);
11: Au1–C1 2.030(6), Au1–P1 2.2426(18); C1–Au1–P1 177.17(18).
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synthesized using 1 and the necessary pro-ligand in the pres-
ence of an excess of KPF6. The cytotoxic activities of all ten
complexes were studied with the NCI-H1666 non-small cell
lung cancer cell line, and their performances were compared
with the previously reported activity of the gold(I) hetero-bis
(carbene) complex [Au(FPyr)(iPr2-bimy)]PF6 (2), and cisplatin.
While the complexes reported in this work are not as cytotoxic
as 2, some do show comparable performance, and most com-
plexes perform better than cisplatin. Our lab is currently in the
midst of further investigations of some of the complexes,
focussing primarily on their physiochemical and pharmaco-
kinetic properties, as well as their in vitro toxicities to healthy
cell lines. We look forward to reporting our findings from
these studies in the near future.
Table 2 Cytotoxicity of complexes of the type [Au(FPyr)(L)]PF6 (2–12) and
cisplatin expressed as IC50 values
Complex
L
IC50 (μM)
26
3
4
5
6
7
8
9
iPr2-bimy
0.241 0.01
0.346 0.03
2.01 0.20
0.720 0.18
0.964 0.06
1.91 0.40
0.747 0.08
5.10 0.10
2.15 0.22
3.04 0.27
>10
(CHPh2)2-bimy
(iPr)(CHPh2)-bimy
(CH2Ph)2-bimy
iBu2-bimy
n-Pr2-bimy
Et2-bimy
(2-Propenyl)2-bimy
PPh3
P(OPh)3
10
11
12
DMAP
—
Cisplatin6
2.51 0.11
N-substituents on the benzimidazole-derived NHC and the
activity of the complexes. However, it is worth noting that com-
plexes 2 and 3, which both bear symmetrically substituted benz-
imidazole-derived NHCs, with both N-substituents being 2°
carbon atoms, show superior performance as compared to
complexes that bear benzimidazole-derived NHCs with either
asymmetric N-substituents (i.e. complex 4), or 1° carbon atom
N-substituents (i.e. complexes 5–9). This does suggest some
form of structure–activity relationship, although further
studies would be necessary to better understand the relative
performance. Among the hetero-bis(carbene) complexes, 9 is
an exception, and this may be attributed to the presence of
reactive allyl moieties that make the complex more susceptible
to addition and redox reactions, possibly degrading and/or
deactivating the complex.
While the presence of a labile ligand seems necessary for
the superior activity of these gold(I) complexes, it is apparently
also important that the ligand trans to the FPyr ligand is not
too weakly bound to the metal center. Evidence for this is
found when considering complexes 10–12. As we progress
from the stronger donating PPh3 to the much weaker donating
DMAP, there is an increase in the IC50 values. Since the mode
of action of other cationic gold–NHC complexes has been
reported to involve permeation into the mitochondria,1,2,7 it is
possible that in the case of complex 12, for example, the
DMAP ligand detaches from the complex cation prematurely
and prior to entering the mitochondria. This may potentially
deactivate the compound even before it reaches its target site.
Therefore, a fine balancing of these various properties seems
necessary for the development of an optimum complex.
Experimental
General considerations
All operations were performed without taking precautions to
exclude air and moisture, and all solvents and chemicals were
used as received. 1H, 13C, 19F and 31P NMR spectra were
recorded on a Bruker ACF 300 spectrometer or a Bruker AMX
500 spectrometer. The chemical shifts (δ) were internally refer-
enced to the residual solvent signals relative to tetramethylsi-
lane (1H and 13C), or externally to CF3CO2H (19F) and 85%
H3PO4 (31P). ESI mass spectra were measured using a Finnigan
LCQ spectrometer. Elemental analyses were performed on an
Elementar Vario Micro Cube elemental analyser at the Depart-
ment of Chemistry, National University of Singapore. Complex 1
was synthesized as previously reported.6 The azolium salts 1,3-
dibenzhydrylbenzimidazolium bromide,10 1,3-dibenzylbenzimi-
dazolium bromide,10 1,3-diisobutylbenzimidazolium bromide,10
1,3-dipropylbenzimidazolium bromide,11 1,3-diethylbenzimida-
zolium bromide,12 and 1,3-di(2-propenyl)benzimidazolium
bromide13 were synthesized according to literature procedures,
albeit with slight modifications. 1-Benzhydryl-3-isopropylbenz-
imidazolium bromide was synthesized from 1-benzhydrylbenz-
imidazole, and the procedures for the syntheses of both are
reported in this section. All azolium salts were converted to
their hexafluorophosphate analogues via salt metathesis
reaction with KPF6 in acetone, stirred overnight at ambient
temperature.
1-Benzhydrylbenzimidazole. Benzimidazole
(1.18
g,
10 mmol) was suspended in CH3CN (20 mL). NaOH (1.60 mL,
10 mmol, 6.25 M) was added to the suspension, and the reac-
tion mixture was stirred for 30 min before a solution of benz-
hydryl bromide (2.47 g, 10 mmol) dissolved in CH3CN (10 mL)
was added. The reaction mixture was heated under reflux over-
Conclusion
We have reported on the syntheses and characterizations of a night, following which it was filtered through Celite. The fil-
series of cationic gold(I) heteroleptic complexes bearing the trate was dried over anhydrous Na2SO4, filtered, and all
pyrazole-derived FPyr ligand, and either a benzimidazole- volatiles were removed under vacuum affording a beige oil.
derived NHC of the type RR′-bimy (3–9), or a non-NHC co- The crude product was purified by flash column chromato-
ligand L (10–12). Complexes 3–9 were synthesized using [AuCl- graphy (silica gel, ether) (1.45 g, 5.1 mmol, 51%). 1H NMR
(FPyr)] (1) and the appropriate disubstituted benzimidazolium (300 MHz, CDCl3): δ 7.84 (d, 1 H, Ar–H), 7.63 (s, 1 H, NCHN),
salt in the presence of K2CO3. 10–12, on the other hand, were 7.38–7.14 (m, 13 H, Ar–H), 6.76 (s, 1 H, NCHPh2). 13C{1H}
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NMR (75.5 MHz, CDCl3): δ 144.0 (Ar–C), 142.5 (NCHN), 138.0, 129.6, 129.3, 129.0, 126.4, 125.13, 125.07, 114.6, 113.5 (Ar–C),
134.0, 129.0, 128.5, 128.2, 123.0, 122.4, 120.3, 110.7 (Ar–C), 68.8 (NCHPh2), 54.0 (NCH(CH3)2), 51.7, 46.6 (NCH2), 23.31
63.6 (NCHPh2).
1-Benzhydryl-3-isopropylbenzimidazolium bromide. 1-Benz- NMR (202.4 MHz, CDCl3): δ −143.8 (m, PF6). 19F{1H} NMR
hydrylbenzimidazole (1.42 g, 5.0 mmol) was suspended in (282.4 MHz, CDCl3): 2.34 (d, PF6). Anal. Calc. for
(CH2), 23.29 (CH3), 23.0, 22.5, 21.9, 21.2, 21.0 (CH2). 31P{1H}
δ
CH3CN (2 mL). Isopropyl bromide (0.5 mL, 5.3 mmol) was C34H38N4AuPF6·0.3CH2Cl2·0.6Et2O: C, 48.20; H, 4.92; N, 6.13.
added to the suspension, and the reaction mixture was Found: C, 48.29; H, 4.71; N, 6.01%. MS (ESI): m/z = 699
refluxed for 24 h. After cooling to ambient temperature, all [M − PF6]+.
volatiles were removed under vacuum. The crude product was
[Au(FPyr)((CH2Ph)2-bimy)]PF6 (5). Yield: 80%. 1H NMR
washed several times with ethyl acetate and dried under (500 MHz, CDCl3): δ 7.44–7.31 (m, 14 H, Ar–H), 5.77 (s, 4 H,
3
vacuum to yield a white solid (1.58 g, 3.9 mmol, 78%). 1H NCH2Ph), 4.22 (t, 2 H, J(H,H) = 5.70 Hz, NCH2), 4.03 (t, 2 H,
NMR (300 MHz, CDCl3): δ 11.32 (s, 1 H, NCHN), 7.99 (s, 1 H, 3J(H,H) = 5.70 Hz, NCH2), 2.57 (t, 2 H, 3J(H,H) = 6.30 Hz, CH2),
3
NCHPh2), 7.80–7.17 (m, 14 H, Ar–H), 5.18–5.04 (m, 1 H, NCH 2.50 (t, 2 H, J(H,H) = 6.30 Hz, CH2), 2.09 (m, 4 H, CH2), 1.83
(CH3)2), 1.83 (d, 6 H, CH3). 13C{1H} NMR (75.5 MHz, CDCl3): δ (m, 2 H, CH2), 1.72 (m, 2 H, CH2). 13C{1H} NMR (125.8 MHz,
147.9 (NCHN), 141.9, 135.6, 131.3, 131.0, 129.2, 129.1, 128.6, CDCl3): δ 195.7 (Ccarbene ((CH2Ph)2-bimy)), 179.9 (Ccarbene
126.82, 126.76, 115.8, 113.7 (Ar–C), 66.5 (NCHPh2), 52.2 (NCH (FPyr)), 144.4, 135.8, 134.2, 129.8, 129.2, 127.9, 126.7, 125.6,
(CH3)2), 22.2 (CH3). MS (ESI): m/z = 327 [M − Br]+.
112.8 (Ar–C), 52.9 (NCH2Ph), 51.7, 46.6 (NCH2), 23.3, 22.9,
22.5, 21.9, 21.3, 21.1 (CH2). 31P{1H} NMR (202.4 MHz, CDCl3):
δ −143.7 (m, PF6). 19F{1H} NMR (282.4 MHz, CDCl3): δ 2.59 (d,
PF6). Anal. Calc. for C32H34N4AuPF6: C, 47.07; H, 4.20; N, 6.86.
General procedure for the synthesis of gold(I) hetero-bis-
(carbene) complexes 3–9
Complex 1 (1 equiv.) and the appropriate azolium hexafluoro- Found: C, 47.15; H, 4.25; N, 6.87%. MS (ESI): m/z = 671
phosphate salt (1 equiv.) were dissolved in acetone. K2CO3 (1.3 [M − PF6]+.
equiv.) was added to the solution, and the resulting mixture
[Au(FPyr)(iBu2-bimy)]PF6 (6). Yield: 74%. 1H NMR
was stirred for 24 h at ambient temperature. The solvent of the (500 MHz, CDCl3): δ 7.52 (dd, 2 H, Ar–H), 7.44 (dd, 2 H, Ar–H),
reaction mixture was then removed under vacuum. The residue 4.40 (br t, 2 H, NCH2), 4.31 (d, 4 H, 3J(H,H) = 7.55 Hz, NCH2CH-
3
was suspended in CH2Cl2 and filtered over Celite. The solvent (CH3)2), 4.10 (br t, 2 H, NCH2), 2.62 (t, 2 H, J(H,H) = 6.30 Hz,
of the filtrate was removed under vacuum, and the resulting CH2), 2.59 (t, 2 H, 3J(H,H) = 6.30 Hz, CH2), 2.44 (m, 2 H,
residue was washed thrice with ethyl acetate or diethyl ether. NCH2CH(CH3)2), 2.19 (br t, 4 H, CH2), 1.87 (m, 2 H, CH2), 1.79
3
The crude product was purified by crystallization via vapour (m, 2 H, CH2), 1.03 (d, 12 H, J(H,H) = 6.30 Hz, CH3). 13C{1H}
diffusion of diethyl ether into a solution of the compound in NMR (125.8 MHz, CDCl3): δ 194.8 (Ccarbene (iBu2-bimy)), 180.2
CHCl3 or CH2Cl2. All complexes were obtained as colourless (Ccarbene (FPyr)), 144.5, 134.3, 126.6, 125.3, 112.5 (Ar–C), 56.4
crystals.
(NCH2CH(CH3)2), 51.8, 46.6 (NCH2), 30.2 (NCH2CH(CH3)2),
[Au(FPyr)((CHPh2)2-bimy)]PF6 (3). Yield: 82%. 1H NMR 23.4, 23.0, 22.5, 22.0, 21.3, 21.1 (CH2), 21.0 (CH3). 31P{1H}
(500 MHz, CDCl3): δ 7.66 (s, 2 H, NCH), 7.40–7.38 (m, 12 H, NMR (202.4 MHz, CDCl3): δ −143.7 (m, PF6). 19F{1H} NMR
Ar–H), 7.28–7.27 (m, 8 H, Ar–H), 7.17 (dd, 2 H, Ar–H), 7.05 (dd, (282.4 MHz, CDCl3):
δ 2.49 (d, PF6). Anal. Calc. for
3
2 H, Ar–H), 4.02 (t, 2 H, J(H,H) = 5.70 Hz, NCH2), 3.88 (t, 2 H, C26H38N4AuPF6: C, 41.72; H, 5.12; N, 7.48. Found: C, 41.52; H,
3J(H,H) = 5.70 Hz, NCH2), 2.56 (t, 2 H, 3J(H,H) = 6.30 Hz, CH2), 5.10; N, 7.31%. MS (ESI): m/z = 603 [M − PF6]+.
3
2.34 (t, 2 H, J(H,H) = 5.70 Hz, CH2), 2.12 (m, 2 H, CH2), 2.01
[Au(FPyr)(n-Pr2-bimy)]PF6 (7). Yield: 79%. 1H NMR
(m, 2 H, CH2), 1.82 (m, 2 H, CH2), 1.70 (m, 2 H, CH2). 13C{1H} (500 MHz, CD3CN): δ 7.67 (dd, 2 H, Ar–H), 7.47 (dd, 2 H, Ar–
NMR (125.8 MHz, CDCl3): δ 197.8 (Ccarbene ((CHPh2)2-bimy)), H), 4.49 (t, 4 H, J(H,H) = 6.90 Hz, NCH2CH2CH3), 4.41 (br t,
3
178.8 (Ccarbene (FPyr)), 144.4, 137.9, 134.5, 129.7, 129.5, 129.0, 2 H, NCH2), 4.04 (br t, 2 H, NCH2), 2.60 (m, 4 H, CH2), 2.10 (br t,
126.3, 125.3, 114.6 (Ar–C), 68.8 (NCH), 51.5, 46.5 (NCH2), 23.3, 4 H, CH2), 1.99 (m, 4 H, CH2), 1.84 (m, 2 H, CH2), 1.76 (m,
3
22.9, 22.5, 21.9, 21.2, 21.0 (CH2). 31P{1H} NMR (202.4 MHz, 2 H, CH2), 0.98 (t, 6 H, J(H,H) = 7.60 Hz, CH3). 13C{1H} NMR
CDCl3): δ −143.8 (m, PF6). 19F{1H} NMR (282.4 MHz, CDCl3): δ (125.8 MHz, CD3CN): δ 194.8 (Ccarbene (n-Pr2-bimy)), 180.0 (Ccarbene
2.30 (d, PF6). Anal. Calc. for C44H42N4AuPF6: C, 54.55; H, 4.37; (FPyr)), 144.5, 134.2, 126.3, 125.1, 112.7 (Ar–C), 51.8 (NCH2),
N, 5.78. Found: C, 54.54; H, 4.26; N, 5.61%. MS (ESI): m/z = 50.6 (NCH2CH2CH3), 46.6 (NCH2), 24.2 (NCH2CH2CH3), 23.4,
823 [M − PF6]+.
22.8, 22.5, 21.7, 21.1, 20.8 (CH2), 11.5 (CH3). 31P{1H} NMR
[Au(FPyr)((iPr)(CHPh2)-bimy)]PF6 (4). Yield: 76%. 1H NMR (202.4 MHz, CD3CN):
(500 MHz, CDCl3): δ 7.73 (d, 1 H, Ar–H), 7.68 (s, 1 H, NCHPh2), (282.4 MHz, CD3CN):
δ
−143.2 (m, PF6). 19F{1H} NMR
δ
3.43 (d, PF6). Anal. Calc. for
7.42–7.28 (m, 11 H, Ar–H), 7.22 (t, 1 H, Ar–H), 7.03 (d, 1 H, Ar– C24H34N4AuPF6: C, 40.01; H, 4.76; N, 7.78. Found: C, 40.04;
H), 5.40 (m, 1 H, 3J(H,H) = 6.30 Hz, NCH(CH3)2), 4.20 (br t, H, 4.40; N, 7.73%. MS (ESI): m/z = 575 [M − PF6]+.
1
2 H, NCH2), 4.09 (br t, 2 H, NCH2), 2.62 (br t, 2 H, CH2), 2.52
[Au(FPyr)(Et2-bimy)]PF6 (8). Yield: 72%. H NMR (500 MHz,
(br t, 2 H, CH2), 2.16 (br m, 4 H, CH2), 1.88 (d, 6 H, 3J(H,H) = 6.30 CDCl3): δ 7.53 (dd, 2 H, Ar–H), 7.46 (dd, 2 H, Ar–H), 4.57 (m, 4
Hz, CH3), 1.77 (br m, 2 H, CH2), 1.31 (br m, 2 H, CH2). 13C{1H} H, 3J(H,H) = 7.55 Hz, NCH2CH3), 4.47 (t, 2 H, 3J(H,H) = 5.65
NMR (125.8 MHz, CDCl3): δ 195.1 (Ccarbene ((iPr)(CHPh2)- Hz, NCH2), 4.09 (t, 2 H, J(H,H) = 6.30 Hz, NCH2), 2.62 (t, 4 H,
3
bimy)), 179.2 (Ccarbene (FPyr)), 144.4, 138.0, 134.2, 133.4, 129.7, 3J(H,H) = 6.30 Hz, CH2), 2.21 (m, 4 H, CH2), 1.89 (m, 2 H,
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3
2
CH2), 1.80 (m, 2 H, CH2), 1.60 (t, 6 H, J(H,H) = 7.60 Hz, CH3). (d, J(C,P) = 178 Hz, Ccarbene), 150.1, 144.6, 131.3, 127.5, 126.6,
13C{1H} NMR (125.8 MHz, CDCl3): δ 194.1 (Ccarbene (Et2-bimy)), 121.9 (d, Ar–C), 51.5, 46.6 (NCH2), 23.1, 22.4, 22.3, 21.4,
180.7 (Ccarbene (FPyr)), 144.3, 133.7, 126.7, 125.3, 112.1 (Ar–C), 21.2, 20.7 (CH2). 31P{1H} NMR (202.4 MHz, CDCl3): δ 139.3
52.0, 46.7 (NCH2), 44.4 (NCH2CH3), 23.4, 23.0, 22.6, 22.0, 21.4, (P(OPh)3), −143.8 (m, PF6). 19F{1H} NMR (282.4 MHz, CDCl3): δ
21.2 (CH2), 16.6 (CH3). 31P{1H} NMR (202.4 MHz, CDCl3): δ 2.35 (d, PF6). Anal. Calc. for C29H31N2O3AuP2F6: C, 42.04; H,
−143.8 (m, PF6). 19F{1H} NMR (282.4 MHz, CDCl3): δ 2.27 (d, 3.77; N, 3.38. Found: C, 42.30; H, 3.77; N, 3.62%. MS (ESI): m/z =
PF6). Anal. Calc. for C22H30N4AuPF6: C, 38.16; H, 4.37; N, 8.09. 683 [M − PF6]+.
Found: C, 38.38; H, 4.04; N, 8.09%. MS (ESI): m/z = 547
[Au(FPyr)(DMAP)]PF6 (12). Yield: 81%. 1H NMR (500 MHz,
CD3CN): δ 7.99 (d, 2 H, Ar–H), 6.68 (d, 2 H, Ar–H), 4.37 (br t,
[M − PF6]+.
[Au(FPyr)((2-propenyl)2-bimy)]PF6 (9). Yield: 75%. 1H NMR 2 H, NCH2), 4.00 (br t, 2 H, NCH2), 3.05 (s, 6 H, NCH3), 2.54
(500 MHz, CD3CN): δ 7.63 (dd, 2 H, Ar–H), 7.47 (dd, 2 H, Ar– (m, 4 H, CH2), 2.06 (m, 4 H, CH2), 1.82 (br m, 2 H, CH2), 1.73
H), 6.14 (m, 2 H, NCH2CHvCH2), 5.28 (dm, 2 H, 3J(H,H) = (br m, 2 H, CH2). 13C{1H} NMR (125.8 MHz, CD3CN): δ 161.0
10.10 Hz, NCH2CHvCHHtrans), 5.16–5.19 (m,
6
H, (Ccarbene), 156.1, 150.4, 144.7, 125.9, 108.3 (Ar–C), 52.1, 46.7
3
NCH2CHvCH2 and NCH2CHvCHHcis), 4.39 (t, 2 H, J(H,H) = (NCH2), 39.5 (NCH3), 23.3, 23.0, 22.5, 21.7, 21.1, 20.9 (CH2).
5.70 Hz, NCH2), 4.04 (t, 2 H, 3J(H,H) = 5.70 Hz, NCH2), 2.59 31P{1H} NMR (202.4 MHz, CD3CN): δ −143.1 (m, PF6). 19F{1H}
(m, 4 H, CH2), 2.09 (br t, 4 H, CH2), 1.84 (m, 2 H, CH2), 1.76 NMR (282.4 MHz, CD3CN): δ 3.46 (d, PF6). Anal. Calc. for
(m, 2 H, CH2). 13C{1H} NMR (125.8 MHz, CD3CN): δ 196.0 (Ccarbene C18H26N4AuPF6: C, 33.76; H, 4.09; N, 8.75. Found: C, 33.85; H,
((2-propenyl)2-bimy)), 179.9 (Ccarbene (FPyr)), 144.7, 134.4, 4.10; N, 8.51%. MS (ESI): m/z = 405 [M − PF6 − DMAP +
133.7, 126.5, 125.6, 118.6, 113.1 (Ar–C and vinylic–C), 52.0 CH3OH]+, 495 [M − PF6]+.
(NCH2), 51.5 (NCH2CHvCH2), 46.8 (NCH2), 23.6, 23.0, 22.7,
X-ray diffraction studies
21.9, 21.3, 21.0 (CH2). 31P{1H} NMR (202.4 MHz, CD3CN): δ
−144.0 (m, PF6). 19F{1H} NMR (282.4 MHz, CD3CN): δ 3.46 (d, X-ray data for 5·CHCl3, 6, and 9–11 were collected with a
PF6). Anal. Calc. for C24H30N4AuPF6: C, 40.23; H, 4.22; N, 7.82. Bruker AXS SMART APEX diffractometer, using Mo Kα radi-
Found: C, 40.14; H, 4.36; N, 7.64%. MS (ESI): m/z = 571 ation at 100(2) K with the SMART suite of programs.14 Data
[M − PF6]+.
were processed and corrected for Lorentz and polarization
effects with SAINT,15 and for absorption effect with SADABS.16
Structural solution and refinement were carried out with the
SHELXTL suite of programs.17 The structures were solved by
General procedure for the synthesis of gold(I) heteroleptic
complexes 10–12
Complex 1 (1 equiv.) and the appropriate pro-ligand (1.2 direct methods to locate the heavy atoms, followed by differ-
equiv.) were dissolved in acetone. KPF6 (3 equiv.) dissolved in ence maps for the light, non-hydrogen atoms. All hydrogen
acetone was added to the solution, and the resulting mixture atoms were placed in calculated positions. All non-hydrogen
was stirred for 1 h at ambient temperature. The solvent of the atoms were generally given anisotropic displacement para-
reaction mixture was then removed under vacuum. The residue meters in the final model. A summary of the most important
was suspended in CH2Cl2 and filtered over Celite. The solvent crystallographic data is provided in Table 3.
of the filtrate was removed under vacuum, and the resulting
Cytotoxicity studies
residue was washed thrice with diethyl ether. The crude
product was purified by crystallization via vapour diffusion of In vitro toxicities of 3–12 were determined by CellTiter 96
diethyl ether into a solution of the compound in CH2Cl2. All AQueous Non-Radioactive Cell Proliferation Assay (MTS).
complexes were obtained as colourless crystals.
NCI-H1666 cells were maintained in complete RPMI medium
[Au(FPyr)(PPh3)]PF6 (10). Yield: 94%. 1H NMR (500 MHz, with 10% FBS and 1% PenStrep. Standard DMSO solutions of
CDCl3): δ 7.54–7.41 (m, 15 H, Ar–H), 4.41 (br t, 2 H, NCH2), 3–12 were diluted with complete RPMI medium, with the final
4.12 (br t, 2 H, NCH2), 2.60 (m, 4 H, CH2), 2.18 (br m, 4 H, concentration of DMSO in each diluted solution being less
CH2), 1.86 (br m, 2 H, CH2), 1.77 (br m, 2 H, CH2). 13C{1H} than 0.5%. The cells were seeded in 96-well plates at a density
NMR (125.8 MHz, CDCl3): δ 182.4 (Ccarbene), 144.7 (Ar–C), of 2000 cells per well in 100 μL of complete RPMI medium
134.6, 132.5, 130.1, 130.0 (d, Ar–C), 126.4 (Ar–C), 52.0, 46.7 without antibiotics and cultured overnight at 37 °C in a
(NCH2), 23.2, 22.9, 22.5, 21.8, 21.2, 20.9 (CH2). 31P{1H} NMR humidified atmosphere containing 5% CO2. A 100 μL portion
(202.4 MHz, CDCl3): δ 41.3 (PPh3), −143.8 (m, PF6). 19F{1H} of media containing different concentrations of 3–12 was
NMR (282.4 MHz, CDCl3): δ 2.32 (d, PF6). Anal. Calc. for added in the wells to a final concentration from 0.0005 to
C29H31N2AuP2F6: C, 44.63; H, 4.00; N, 3.59. Found: C, 44.88; H, 50 μM. Compound-free solvent controls were also included.
3.89; N, 3.40%. MS (ESI): m/z = 635 [M − PF6]+.
After a 72-hour incubation period, 20 μL of CellTiter 96
[Au(FPyr)(P(OPh)3)]PF6 (11). Yield: 77%. 1H NMR (500 MHz, AQueous One Reagent containing the tetrazolium compound
CDCl3): δ 7.48–7.27 (m, 15 H, Ar–H), 4.02 (t, 2 H, 3J(H,H) = 5.70 MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-
3
Hz, NCH2), 3.79 (t, 2 H, J(H,H) = 6.30 Hz, NCH2), 2.52 (t, 2 H, 2-(4-sulfophenyl)-2H-tetrazolium, inner salt) was added to each
3
3J(H,H) = 6.30 Hz, CH2), 2.20 (t, 2 H, J(H,H) = 6.30 Hz, CH2), well. After incubation for about 3 h, the absorbance was
2.10 (m, 2 H, CH2), 2.00 (m, 2 H, CH2), 1.78 (m, 2 H, CH2), measured at 490 nm using a Tecan Infinite M200 plate reader.
1.65 (m, 2 H, CH2). 13C{1H} NMR (125.8 MHz, CDCl3): δ 179.6 Nonlinear regression analysis was performed using GraphPad
12426 | Dalton Trans., 2013, 42, 12421–12428
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Table 3 Selected X-ray crystallographic data for complexes 5·CHCl3, 6, 9, 10 and 11
5·CHCl3
33H35N4AuCl3PF6
6
9
10
11
Formula
fw
C
C26H38N4AuPF6
748.54
C24H30N4AuPF6
716.46
C29H31N2AuP2F6
780.46
C29H31N2O3AuP2F6
828.46
935.94
Colour, habit
Crystal size (mm)
Temp (K)
Cryst syst
Space group
a (Å)
b (Å)
c (Å)
α (°)
β (°)
Colourless, block
0.13 × 0.11 × 0.04
100(2)
Triclinic
ˉ
P1
8.5921(10)
11.9088(14)
17.348(2)
87.324(2)
87.300(2)
80.596(2)
1747.9(4)
2
Colourless, block
0.27 × 0.11 × 0.05
100(2)
Triclinic
ˉ
P1
11.000(3)
12.126(3)
12.426(3)
109.051(5)
98.373(5)
108.802(5)
1423.7(6)
2
Colourless, block
0.36 × 0.26 × 0.10
100(2)
Triclinic
ˉ
P1
9.7407(7)
12.5859(9)
12.8314(9)
60.9630(10)
73.3970(10)
68.0160(10)
1264.80(16)
2
Colourless, block
0.28 × 0.08 × 0.06
100(2)
Orthorhombic
Pna21
20.319(4)
13.683(3)
10.2795(19)
90
90
90
2857.9(9)
4
1.814
Colourless, block
0.17 × 0.11 × 0.08
100(2)
Orthorhombic
P212121
10.5523(6)
14.9858(8)
19.0095(10)
90
90
90
3006.1(3)
4
1.831
γ (°)
V (Å3)
Z
Dc (g cm−3
)
1.778
1.746
1.881
Radiation used
Mo Kα
Mo Kα
Mo Kα
Mo Kα
Mo Kα
μ (mm−1
θ (°)
)
4.546
5.285
5.944
5.321
5.072
1.18–27.50
8012
0.8391, 0.5895
2.04–27.49
6505
0.7456, 0.5412
1.83–27.50
5813
0.5879, 0.2234
2.48–27.50
6506
0.7407, 0.3173
2.14–27.50
6905
0.6871, 0.4793
No. of unique data
Max, min
transmission
Final R indices
[I > 2σ(I)]
R1 = 0.0400,
wR2 = 0.0890
R1 = 0.0469,
wR2 = 0.1057
R1 = 0.0384,
wR2 = 0.0850
R1 = 0.0449,
wR2 = 0.0873
1.068
R1 = 0.0244,
wR2 = 0.0622
R1 = 0.0263,
wR2 = 0.0703
1.266
R1 = 0.0373,
wR2 = 0.0764
R1 = 0.0494,
wR2 = 0.0816
0.973
R1 = 0.0452,
wR2 = 0.0847
R1 = 0.0514,
wR2 = 0.0869
1.004
R indices (all data)
Goodness-of-fit on F2 1.132
Peak/hole (e Å−3
)
1.687/−2.077
2.285/−2.254
1.227/−0.647
2.555/−0.638
2.037/−1.176
Prism version 5.00 for Windows to calculate the IC50 value of
each compound.
I. Ott, Dalton Trans., 2013, 42, 3269; (c) A. Gautier and
F. Cisnetti, Metallomics, 2012, 4, 23.
4 (a) H. V. Huynh, Y. Han, R. Jothibasu and J. A. Yang, Organo-
metallics, 2009, 28, 5395; (b) D. Yuan and H. V. Huynh,
Organometallics, 2012, 31, 405.
Acknowledgements
5 (a) R. Rubbiani, I. Kitanovic, H. Alborzinia, S. Can,
A. Kitanovic, L. A. Onambele, M. Stefanopoulou,
Y. Geldmacher, W. S. Sheldrick, G. Wolber, A. Prokop,
S. Wölfl and I. Ott, J. Med. Chem., 2010, 53, 8608;
(b) R. Rubbiani, S. Can, I. Kitanovic, H. Alborzinia,
M. Stefanopoulou, M. Kokoschka, S. Mönchgesang,
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The authors thank the National University of Singapore (NUS)
for financial support (WBS R-143-000-410-112). Technical
support from staff at the CMMAC of the Department of Chem-
istry, NUS is appreciated. In particular, we thank Prof. Lip Lin
Koh, Ms Geok Kheng Tan and Ms Yimian Hong for determin-
ing the X-ray molecular structures. The authors also thank
Dr Wei Peng Yong of the Department of Haematology-Oncol-
ogy, National University Hospital for providing the facilities for
the cytotoxicity studies.
6 H. Sivaram, J. Tan and H. V. Huynh, Organometallics, 2012,
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