Antiproliferative activity of gold(I) alkyne complexes containing water-soluble phosphane ligands

Article abstract of DOI:10.1021/om100300a

A series of mono-, di-, and trinuclear organometallic alkynyl phosphane gold(I) complexes containing the stable and water-soluble PTA and DAPTA ligands have been synthesized and characterized. The solid-state structure of one of these compounds was also established by X-ray crystallography. Luminiscence was observed for most of these Au(I) alkynyl derivatives in the solid state. The cytotoxicity of the complexes was evaluated on A2780 ovarian cancer cells and on their cisplatin-resistant cell line A2780cisR; the compounds showed an activity in the low μM range, being markedly more active than cisplatin in the A2780cisR cell line. The intracellular distribution of some representative compounds was determined using epifluorescence microscopy. The presented results are discussed in relation to the putative mechanism of action of this family of gold-based cytotoxic agents.

Full text of DOI:10.1021/om100300a

2596 Organometallics 2010, 29, 2596–2603
DOI: 10.1021/om100300a
Antiproliferative Activity of Gold(I) Alkyne Complexes Containing
Water-Soluble Phosphane Ligands
Elena Vergara,† Elena Cerrada,† Angela Casini,‡ Olivier Zava,‡ Mariano Laguna,*,† and
Paul. J. Dyson*,‡
†
´
ꢀ
ꢀ
Departamento de Quımica Inorganica, Instituto de Ciencia de Materiales de Aragon, Universidad de
ꢀ
‡
Zaragoza-CSIC, 50009 Zaragoza, Spain, and Institut des Sciences et Ingenierie Chimiques,
Ecole Polytechnique Fedeꢀrale de Lausanne (EPFL), 1015 Lausanne, Switzerland
Received April 14, 2010
A series of mono-, di-, and trinuclear organometallic alkynyl phosphane gold(I) complexes containing
the stable and water-soluble PTA and DAPTA ligands have been synthesized and characterized. The solid-
state structure of one of these compounds was also established by X-ray crystallography. Luminiscence
was observed for most of these Au(I) alkynyl derivatives in the solid state. The cytotoxicity of the
complexes was evaluated on A2780 ovarian cancer cells and on their cisplatin-resistant cell line A2780cisR;
the compounds showed an activity in the low μM range, being markedly more active than cisplatin in the
A2780cisR cell line. The intracellular distribution of some representative compounds was determined
using epifluorescence microscopy. The presented results are discussed in relation to the putative
mechanism of action of this family of gold-based cytotoxic agents.
Introduction
phosphane ligands, have been described as potential antitumor
agents that selectively target the mitochondria of cancer cells.5
Alkynyl Au(I) derivatives with phosphane ligands have been
extensively studied,6 with a focus on their luminescent properties,7
nonlinear optical properties,8 and supramolecular chemistry.9 In
contrast, biological studies of metal acetylide compounds are
extremely scarce. Platinum arylacetylides, with the formula [Pt-
(terpy)(CtC-Ar)]þ (terpy=terpyridine ligand, CtC-Ar=gly-
cosylated acetylides and arylacetylide ligands),10 were shown to
be more cytotoxic than the related complex [Pt(terpy)Cl]þ and
about 100 times more cytotoxic than cisplatin. Gold(I) diethynyl-
fluorene derivatives have been studied for their antitumor activity
against human carcinoma cells both in vitro and in vivo.11 These
compounds display a higher cytotoxicity than cisplatin, and no
evidence of necrosis was found from autopsies of mice vital
organs.
Cisplatin (cis-diaminodichloroplatinum(II)) is one of the
most widely employed anticancer drugs used to treat, but not
restricted to, testicular, ovarian, head and neck, and bladder
cancers.1 However, its use is severely hindered by side effects and
the frequent occurrence of resistance to the treatment. These
drawbacks are among the reasons for the research efforts to
identify other metal complexes for cancer treatment. In this
context, gold complexes have been extensively studied due to the
clinically established antiarthritic properties of Au(I) thiolates,
such as sodium aurothiomalate (Myocrisin), aurothioglucose
(Solganol), and [(1-thio-β-D-glucopyranose-2,3,4,6-tetraaceta-
to-S)(triethylphosphane)gold] (auranofin) (Chart 1).2 Cytotoxi-
city profiles rivalling those of cisplatin have been observed for
auranofin and related thiolate gold phosphane and gold phos-
phane derivatives.3 Additionally, it has been shown that gold(I)
complexes inhibit mitochondrial functions and stimulate the
release of cytochrome c, which induces apoptosis.4 Very re-
cently, organometallic gold(I) derivatives with N-heterocyclic
carbene ligands, which exhibit comparable binding properties to
(6) (a) Grohmann, A.; Schmidbaur, H. Comprehensive Organometal-
lic Chemistry II; Wardell, J., Eds.; Pergamon: Oxford, 1995. (b) Schmidbaur,
H.; Grohmann, A.; Olmos, M. E., Gold Progress in Chemistry, Biochem-
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Chem. 2004, 689, 4451. (b) Lu, W.; Xiang, H. F.; Zhu, N.; Che, C. M.
Organometallics 2001, 21, 2343. (c) Che, C. M.; Chao, H. Y.; Miskowski,
V. M.; Li, Y.; Cheung, K. K. J. Am. Chem. Soc. 2001, 123, 4985. (d) Yam,
V. W. W.; Choi, S. W. K. J. Chem. Soc., Dalton Trans. 1996, 4227.
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Eur. J. 2002, 723. (d) Mohr, F.; Jennings, M. C.; Puddephatt, R. J. Eur. J.
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*Corresponding authors. (M.L.) Fax: (þ34) 976-761187. E-mail:
mlaguna@unizar.es. (P.J.D.) Fax: (þ41) 21-6939885. E-mail: paul.dyson@
epfl.ch.
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r
pubs.acs.org/Organometallics
Published on Web 05/11/2010
2010 American Chemical Society

Article
Organometallics, Vol. 29, No. 11, 2010 2597
Chart 1
Scheme 1. Synthesis of Mononuclear Alkynyl Gold(I) Derivatives and a Trinuclear Derivative
In the past few years, metallic derivatives with the water-
Within this frame, we have developed new organometallic
alkynyl phosphane gold(I) complexes with the PTA and
DAPTA co-ligands. Herein, we describe the synthesis and
characterization of mononuclear and dinuclear alkynyl Au-
(I) derivatives and the cytotoxic properties of some of them
against the human ovarian carcinoma cell lines sensitive
(A2780) and resistant (A2780cisR) to cisplatin.
soluble phosphane PTA (1,3,5-triaza-7-phosphaadamantane)
have been shown to possess anticancer properties,12 the arene-
ruthenium(II) complexes, named RAPTA, being studied in vitro
and in vivo.13,14 In most of these cases, the PTA ligand provides a
degree of water solubility that could facilitate drug administra-
tion and transport in the body. In previous papers,15 we have
described gold(I) derivatives with PTA and the diacetylated
derivative DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo-
[3.3.1]nonane), exploring the anticancer activity of the corre-
sponding thiolate complexes against human cancer cells.15a,c
Some of them exhibited excellent in vitro anticancer activity
against human ovarian carcinoma cells, with the ability to
overcome the resistance to cisplatin, possibly by inhibiting the
seleno-enzyme thioredoxinereductase (TrxR).15a
Results and Discussion
The mononuclear phosphane Au(I) acetylides 1-7 were
prepared by treatment of [AuCl(PR03)] (PR03 corresponding to
the water-soluble phosphanes PTA and DAPTA) with terminal
acetylenes in the presence of a base (KOH in methanol) (Scheme
1). The 31P{1H} NMR spectra of 1-7 display singlet resonances
at ca. -50 ppm in the case of the PTA ligand and around -20
ppm for the DAPTA derivatives, in accordance with P-donor
ligand coordination. Their 1H NMR spectra show, apart from
the corresponding signals of the alkyne fragment, a singlet
resonance and an AB system due to the NCH2P and NCH2N
groups in the PTA complexes. The presence of a singlet instead
of a doublet for the NCH2P group has been observed in other
metallic derivatives.16 The displacement of this singlet is depen-
dent on the alkyne substituents, being downfield shifted in the
(12) Ang, W. H.; Dyson, P. J. Eur. J. Inorg. Chem. 2006, 3993.
(13) (a) Scolaro, C.; Geldbach, T. J.; Rochat, S.; Dorcier, A.;
Gossens, C.; Bergamo, A.; Cocchietto, M.; Tavernelli, I.; Sava, G.;
Rothlisberger, U.; Dyson, P. J. Organometallics 2006, 25, 756. (b)
Scolaro, C.; Bergamo, A.; Brescacin, L.; Delfino, R.; Cocchietto, M.;
Laurenczy, G.; Geldbach, T. J.; Sava, G.; Dyson, P. J. J. Med. Chem.
2005, 48, 4161.
(14) (a) Ang, W. H.; Parker, L. J.; Luca, A. D.; Juillerat-Jeanneret, L.;
Morton, C. J.; Bello, M. L.; Parker, M. W.; Dyson, P. J. Ang. Chem., Int.
Ed. 2009, 48, 3854. (b) Bergamo, A.; Masi, A.; Dyson, P. J.; Sava, G. Int. J.
Oncol. 2008, 33, 1281. (c) Chatterjee, S.; Kundu, S.; Bhattacharyya, A.;
Hartinger, C. G.; Dyson, P. J. J. Biol. Inorg. Chem. 2008, 13, 1149.
(15) (a) Vergara, E.; Casini, A.; Sorrentino, F.; Zava, O.; Cerrada, E.;
Rigobello, M. P.; Bindoli, A.; Laguna, M.; Dyson, P. J. ChemMedChem
2010, 5, 96. (b) Miranda, S.; Vergara, E.; Mohr, F.; de Vos, D.; Cerrada, E.;
Mendia, A.; Laguna, M. Inorg. Chem. 2008, 47, 5641. (c) Vergara, E.;
Miranda, S.; Mohr, F.; Cerrada, E.; Tiekink, E. R. T.; Romero, P.; Mendia, A.;
Laguna, M. Eur. J. Inorg. Chem. 2007, 2926. (d) Mohr, F.; Cerrada, E.;
Laguna, M. Organometallics 2006, 25, 644.
(16) (a) Mohr, F.; Sanz, S.; Tieknik, E. R. T.; Laguna, M. Organo-
metallics 2006, 25, 3084. (b) Ang, W. H.; Daldini, E.; Scolaro, C.; Scopelliti,
R.; Juillerat-Jeannerat, L. Inorg. Chem. 2006, 45, 9006. (c) Fleischer, A.;
Roller, A.; Arion, V. B.; Keppler, B.; Mohr, F. Can. J. Chem. 2008, 87, 146.
(d) Dolfen, D.; Schottler, K.; Vaiahdi, S.-M.; Jakupec, M. A.; Keppler, B. K.;
Tieknik, E. R. T.; Mohr, F. J. Inorg. Biochem. 2008, 102, 2067. (e) Wanke,
R.; Smolenski, P.; Silva, M. F. C. G. d.; Martins, L. M. D. R. S.; Pombeiro, A.
J. L. Inorg. Chem. 2008, 47, 10158.

2598 Organometallics, Vol. 29, No. 11, 2010
Vergara et al.
˚
distances in the alkyne unit (C1-C2 = 1.212(8) A and C7-
˚
C8=1.202(8) A) are similar to those found in the unique alkyne
Au derivative with PTA described in the literature.16a Similar
Au-C and Au-P bond lengths have been observed in related
alkynyl phosphane gold(I) derivatives, for example in [Au(Ct
C-Ph)(PMe3)],18 [Au(CtCC(Et)(Me)(OH)(PMe3)],19 and
[(PPh3)Au(CtC)(C6H2S2)(CtC)Au(PPh3)].20 Disorder was
observed in the thiophene moiety in both molecules in the
form of a 2-fold rotation of the group about its longitudinal
axis. The principal effect of the disorder is to generate
cogeneric S,C sites for both termini.
The packing of the molecules (Figure 1b) is dominated
˚
by short Au S (3.569 A) and S N (3.322 A) interac-
˚
3 3 3
3 3 3
tions between isolated and associated molecules and addi-
˚
tional S S interactions of 3.413 A between the isolated
molecules.
3 3 3
Deprotonation of the alkyne with a propargyl alcohol sub-
stituent by KOH probably gives an equilibrium between the
alkoxide (-OCRR0CtCH) and the acetylide (HOCRR0CtC-)
anions, the latter being displaced by the former because of its
lower pKa.21 However the affinity of Au(I), a soft acid, toward C
displaces the equilibrium to give the corresponding acetylides
8-11. The PTA derivatives 8a-11a have been described
previously.16a Compounds 8b-11b, with the DAPTA ligand,
display a singlet in the 31P{1H} NMR as in the previous deriva-
1
tives (1-7) and a similar pattern in the H NMR with the
characteristic signals of the DAPTA ligand. Their IR spectra
display, apart from the band due to the CtC stretch at ca. 2100
cm-1, a very broad band at ca. 3400 cm-1 due to the O-H
stretch.
Figure 1. (a) Molecular structure of [Au(CtC-3-SC4H3)(PTA)]
˚
(4a). Selected bond lengths [A] and angles [deg], #1 -x, -yþ1,
These alkyne derivatives (8-11) are all soluble in water,
with higher solubility for the DAPTA complexes, with the
most soluble derivative being [Au(CtCC(CH2CH3)(CH3)-
(OH))(DAPTA)] (11b), with a value of s25° =15 mg/mL.
Complexes 1-7 are essentially insoluble in water, except 5a
(s25° = 1.3 mg/mL) and 5b (s25° = 2.5 mg/mL), but soluble in
DMSO and partially soluble in alcohol/water mixtures. The
presence of the OH groups in the propargyl alcohol deriva-
tives clearly enhances the water solubility. Thus, reaction of
the propargyl amines R1R2NCH2CtCH in basic media with
[AuCl(PR03)] (PR03 = PTA and DAPTA) gave the corre-
sponding alkynyl derivatives (12, 13) with similar solubilities
to those of the other propargyl alcohol compounds. Notably,
water solubility is markedly reduced when more than one
Au-PR03 unit is added to the propargyl amine, as in the tri-
nuclear complexes N[Au(CtCCH2)(PR03)]3 (PR03 = PTA,
14a, and DAPTA, 14b).
Dinuclear alkynyl Au(I) compounds were prepared start-
ing from the bis-alkynes depicted in Scheme 2. Complexes
15-17 exhibit similar spectroscopic properties to the mono-
nuclear derivatives, with one signal in 31P{1H} NMR at ca.
-50 ppm for the PTA complexes and in the range -20 to -25
ppm for the DAPTA systems, and also display very low
solubility in water.
-zþ2: Au(1)-C(1) 1.997(6), Au(1)-P(1) 2.2580(17), Au(2)-C(7)
2.004(6), Au(2)-P(2) 2.2650(17), Au(2)-Au(2)#13,1389(9) C(1)-
C(2) 1.212(8), C(7)-C(8) 1.202(8), C(1)-Au(1)-P(1) 175.55(19),
C(7)-Au(2)-P(2) 167.13(19), C(7)-Au(2)-Au(2)#1 82.42(18),
P(2)-Au(2)-Au(2)#1 110.27(5). H atoms are omitted for clarity.
(b) View of the packing in the unit cell of complex 4a.
cases of the aryl radicals. Only in the case of [Au(CtCPh)-
(PTA)] (1a) can the resonances of the alkyne units be observed in
the 13C NMR spectrum: two singlets centered at 63.8 ppm for
AuCtC and at 82.7 ppm for AuCtC. Lower solubilities of the
other alkynyl derivatives in CDCl3 prevented the detection of
these resonances. Nevertheless, the IR spectra of 1-7 exhibit a
characteristic absorption band for the CtC unit at ca. 2100
cm-1, which is hardly influenced by the substituent on the
acetylene unit.
Coordination of the alkyne unit to the gold(I) center was
confirmed by X-ray diffraction analysis of [Au(CtC-3-SC4-
H3)(PTA)] (4a). The structure (Figure 1) consists of two
independent molecules in the unit cell, one of them asso-
ciated with a third unit related by symmetry in a nearly
parallel rearrangement (torsion angle of 173.23°) with a
head-to-tail disposition and with a Au Au distance of
3 3 3
˚
3.1389(9) A. This short interaction is in the range observed
for aurophilic bonds between two gold(I) centers.17 Both
independent molecules display a typical linear geometry
around the metal, although, in the case of the associated
molecule, the presence of Au-Au interactions gives a smaller
P-Au-C angle (P1-Au1-C1=175.55(19)° and P2-Au2-
Luminiscence was observed for most of these alkynyl
derivatives in the solid state at room temperature (Table 1
(18) Schuster, O.; Liau, R. Y.; Schier, A.; Schmidbaur, H. Inorg.
Chim. Acta 2005, 358, 1429.
(19) Ferguson, G.; J. F. G., Kennedy, J. D.; Kelleher, A.-M.; Spalding,
T. R.; , Dalton Trans. 2006, (2133).
(20) Li, P.; Ahrens, B.; Feeder, N.; Raithby, P. R.; Teat, S. J.; Khan,
M. S. Dalton Trans. 2005, 874.
˚
C7 = 167.13(19)°). The Au-C (Au1-C1 = 1.997(6) A and
˚
˚
Au2-C7=2.004(6) A) and Au-P (Au1-P1=2.2580(17) A
˚
and Au2-P2 = 2.2650(17) A) bond lenghts and the C-C
(21) Smith, M. B. Advanced Organic Chemistry, 5th ed.; Wiley & Sons:
New York, 2001.
(17) Schmidbaur, H. Chem Soc. Rev. 1995, 24, 391.

Article
Organometallics, Vol. 29, No. 11, 2010 2599
Scheme 2. Synthesis of Dinuclear Alkynyl Gold(I) Derivatives
Table 1. Excitation and Emission Data in the Solid State at Room
Temperature
complex
λ
exc/nm
λ
emis/nm
complex
λ
exc/nm
λ
emis/nm
Figure 2. Excitation and emission spectra of 1b (dark blue), 2a
(green), 7b (blue), 16b (yellow), and 17b (pink).
1a
1b
2a
2b
4a
4a
2a
2b
6a
6b
7a
7b
8a
8b
387
411
420
426
365
370
412
398
356
369
370
382
380
364, 411
499
534
510
541
467
488
525
513
473
498
486
490
491
481
9a
9b
372
372
382
370
380
374
384
370
422
486
423
428
410
416
496
498
502
487
504
488
486
495
645
657
540
555
542
553
This effect might be attributed to a πfπ*(CtC) or σ(Au-
P)fπ*(CtC) transition, as reported for similar Au(I) alky-
nyl phosphane derivatives.22c,k In 4a the origin of the emis-
sion may also be tentatively attributed to aurophilic
10a
10b
11a
11b
14a
14b
15a
15b
16a
16b
17a
17b
interactions, since its X-ray analysis displays short Au Au
˚
interactions of 3.1389(9) A.
3 3 3
Biological Evaluation. The cytotoxic properties of some of
the alkynyl derivatives were analyzed in vitro against the cispla-
tin sensitive (A2780) and cisplatin-resistant (A2780cisR) human
ovarian cancer cells. The mononuclear complexes [Au(Ct
CPh)(DAPTA)] (1b), [Au(CtC-3-SC4H3)(PR3)] (4a,b), and
[Au(CtCCH2OH)(PR3)] (8a,b) and the trinuclear derivative
with the propargyl amine N[Au(CtCCH2)(PR3)]3 (14a,b) (PR3=
PTA and DAPTA) were evaluated in comparison to cisplatin
and auranofin. All the complexes display moderate to high
cytotoxicities, with IC50 values ranging from 0.8 to 14 μM.
Notably, 1b is more potent than cisplatin in both cell lines,
with IC50 values more than 20-fold lower for the resistant cell
line. These values are similar to those observed for auranofin.23
These data suggest that 1b can overcome the resistance to
cisplatin and support the hypothesis of a different mechanism
of action of the gold(I) complexes with respect to cisplatin.2b,4b,24
It has been shown that phosphane Au(I) thiolates, such as
auranofin, are more cytotoxic than gold thiolates and their
chloride analogues,25 indicating the importance of the pre-
sence of both thiolate and phosphane ligands for the ob-
served pharmacological effects. With the complexes des-
cribed herein the thiolate unit has been replaced by an alkyne
ligand while maintaining the Au-phosphane fragment.
Although the exact mechanism of Au(I) phosphane-induced
cytotoxicity is unclear, several lines of evidence point to the
involvement of mitochondria.4b The high affinity of Au(I)
for S- and Se-donor ligands suggests that proteins, including
enzymes and transport proteins, might be possible targets.
Studies of gold(I) complexes such as auranofin and myo-
chrysine indicate that ligand displacement reactions between
and Figure 2). The excitation maxima are in the range 356-
428 nm in the majority of the complexes, except for the
dinuclear species [Au2{(CtC)2-1,4-C6H4)}(DAPTA)2] (15b),
which displays an excitation at 486 nm and a shorter range for
the propargyl compunds 8-11 (360-380 nm). The emission
maxima are between 486 and 555 nm, although a red-shifted
emission is observed for complexes [Au2{(CtC)2-1,4-C6-
H4)}(PTA)2] (15a) (645 nm) and [Au2{(CtC)2-1,4-C6H4)}-
(DAPTA)2] (15b) (657 nm).
Alkynyl gold(I) phosphane derivatives frequently display
lumiscence at room temperature, which is associated with
intraligand electronic transitions, gold-centered transitions,
Au-P to alkyne transitions, or even Au-Au bond to alkyne
transitions, with the Au-PR3 unit able to enhance the emis-
sion from the triplet states of CtCR luminomophores.22
Emission values (see Table 1) are dependent on the nature of
the phosphane ligand and on the substituents of the alkyne
ligand in most cases. The presence of phenyl groups, with
more extensive electron delocalization, on the alkyne ligand
produces a red-shift in the emission values, being more pro-
nounced in the case of the dinuclear derivatives (15-17).
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Bindoli, A.; Rigobello, M. P.; Scutari, G.; Gabbiani, C.; Casini, A.; Messori,
L. Coord. Chem. Rev. 2009, 253, 1692.
(25) Mirabelli, C. K.; Johnson, R. K.; Hill, D. T.; Faucette, L. F.;
Girard, G. R.; Kuo, G. Y.; Sung, C.; Crooke, S. T. J. Med. Chem. 1986,
29, 218.

2600 Organometallics, Vol. 29, No. 11, 2010
Vergara et al.
Table 2. IC50 Values of 1, 4, 8, and 14 against Ovarian Carcinoma
Cell Lines Sensitive (A2780/S) or Resistant (A2780/R) to
Cisplatin Compared with Cisplatin and Auranofin
IC50 (μM)
A2780
A2780cisR
[Au(CtCPh)(DAPTA)] (1b)
[Au(CtC-3-SC4H3)(PTA)] (4a)
[Au(CtC-3-SC4H3)(DAPTA)] (4b)
[Au(CtCCH2OH)(PTA)] (8a)
[Au(CtCCH2OH)(DAPTA)] (8b)
N[Au(CtCCH2)(PTA)]3 (14a)
N[Au(CtCCH2)(DAPTA)]3 (14b)
cisplatin
1.2 ( 0.4
1.0 ( 0.3
0.8 ( 0.1
10.1 ( 0.3
38 ( 2.1
3.3 ( 0.2
1.1 ( 0.2
4.3 ( 0.5
1.25 ( 0.5
2.8 ( 0.4
4.5 ( 2.1
6.7 ( 1.8
11.2 ( 1.1
11.0 ( 1.9
10.7 ( 1.1
14.7 ( 1.3
18.2 ( 1
Figure 3. Cellular distribution of 14a in A2780 cancer cells after
6 h incubation at 37 °C (left, transmitted light; right, 14a fluore-
scence).
DAPTA appears to be particularly advantageous, over the
triethylphosphane ligand present in auranofin, since the
latter ligand is unstable and toxic. The compounds studied
were shown to enter cells, and since they do not damage
DNA, they probably exert their in vitro antiproliferative
effect via interactions with critical proteins/enzymes in keep-
ing with other gold complexes.
auranofin
1.5 ( 0.5
cysteine residues and the thiol bound to the gold center take
place on binding.26 For the compounds reported herein, the
thiolate unit has been replaced by an alkyne ligand, while
maintaining the Au-phosphane fragment. The alkyne ligand
bonded to the gold center probably undergoes the same sub-
stitution reaction with cysteines. In addition, the phosphane
PTA would play a similar role to PEt3 in auranofin, since the
nucleophilicity of PTA is comparable to other trialkyl-
phosphanes.27 In keeping with the possibility of protein
targets of these compounds, no significant interactions were
observed with plasmid pBR322 DNA after incubation at
37 °C with 4b, 8a, and 8b and compared to cisplatin28 (see
Supporting Information). The lack of reactivity with DNA is
comparable to that observed for auranofin.29
Some of the cytotoxic compounds show luminescence, and
this property was used to determine their intracellular dis-
tribution using epifluorescence microscopy. Related studies
of N-hetereocyclic carbene Au(I) complexes30 and the anti-
arthritic drug myocrisin31 provided evidence of intracelular
gold localization in the lysosomes rather than in the mito-
condria. Complexes 4a, 14a, and 14b were incubated with
the A2780 cells for 6 h at 37 °C, and the images recorded
(Figure 3) reveal luminescence throughout the entire cell,
indicating that the alkynyl derivatives enter the cells. How-
ever, the relatively low level of the fluorescence observed
prevented the subcellular compartments where the com-
plexes accumulate from being identified. Nevertheless, the
images show that the complexes are efficiently and rapidly
taken up by the cancer cells.
Experimental Section
General Procedures. NMR spectra were recorded on 400
MHz Varian Inova or Bruker Avance spectrometers. Chemical
shifts are quoted relative to external TMS (1H) or 85% H3PO4
(31P); coupling constants are reported in Hz. FAB mass spectra
were measured on a Micromass Autospec spectrometer in
positive ion mode using NBA as matrix. IR spectra were
recorded as KBr or polyethylene disks on a Nicolet Impact
410 or JASCO FTIR (far-IR) spectrometer. Steady-state photo-
luminescence spectra were recorded on a Jobin-Yvon-Horiba
fluorolog FL-3-11 spectrometer using band pathways of 3 nm
for both excitation and emission. Elemental analyses were
obtained using a LECO CHNS-932 microanalyzer. Epifluore-
cence microscope images were recorded using de Epifluores-
cence Zeiss Axiovert 200M microscope with filters: Nikon UV-
2E/C DAPI (absortion 325-375 nm, emission 435-485 nm).
PTA,32 DAPTA,33 and [AuCl(PR03)]15c,34 were prepared ac-
cording to literature methods.
Preparation of [Au(CtCR)(PR03)] Complexes. To a solution
of KOH (0.022 g, 0.385 mmol) in MeOH (ca. 10 mL) containing
the alkyne (0.308 mmol) was added [AuCl(PR03)] (PR03 = PTA,
DAPTA) (0.257 mmol). The mixture was stirred for ca. 20 h, and
the precipitate was isolated by filtration, washed with methanol
and diethyl ether, and dried in air. Using this method the
following complexes were prepared:
To conclude, the gold(I) alkynyl complexes described
herein, containing the stable and water-soluble PTA and
DAPTA ligands, behave in vitro in a similar way to clinically
used phosphane Au(I) thiolates. Replacement of the thiolate
by the alkynyl ligand appears to lead to a similar biological
function at the molecular level, although further experiments
are required to confirm this hypothesis. The use of PTA and
[Au(CtCPh)(PTA)] (1a): 73% yield, yellow solid. 1H NMR
(400 MHz, CDCl3, 25 °C): δ 4.28 (s, 6H, NCH2P), 4.48, 4.53
(JAB=13.3 Hz, 6H, NCH2N), 7.20-7.31 (m, 3H, m- and p-Ph),
7.43-7.50 (m, 2H, o-Ph) ppm. 31P{1H} NMR (162 MHz, CDCl3,
25 °C): δ -51.5 ppm. 13C{1H} NMR (CDCl3, 400 MHz): δ 52.4 (d,
3C, J=21.6 Hz, NCH2P), 63.8 (s, 1C, AuCtC), 73.3 (d, J=7.8 Hz,
3C, NCH2N), 82.7 (s, 1C, AuCtC), 127.30 (s, 2C, p-Ph (CPh2-
OH)), 128.51 (s, 4C, o-Ph (CPh2OH)), 132.4 (s, 4C, m-Ph (CPh2-
OH)) ppm. IR(KBr):2112cm-1 ν(CtC). FAB-MS: m/z456 [M]þ.
Anal. Calcd (%) for C14H17AuN3P (455.25): C 36.94, H 3.76, N
9.23. Found: C 36.35, H 3.23, N 9.11
(26) (a) Shaw, C. F.; Schaeffer, N. A.; Elder, R. C.; Eidness, M. K.;
Trooster, J. M.; Calis, G. H. M. J. Am. Chem. Soc. 1984, 106, 3511. (b)
Cottrill, S. M.; Sharma, H. L.; Dyson, D. B.; Parish, R. V.; McCauliffe, C. A.
J. Chem. Soc., Perkin Trans. 1989, 11, 150. (c) Coffer, M. T.; Sahw, C. F.;
Watkins, M. K. E. J. W.; Elder, R. C. Inorg. Chem. 1986, 25, 333. (d) Shoeib,
T.; Atkinson, D. W.; Sharp, B. L. Inorg. Chim. Acta 2010, 363, 184.
(27) Abu-Omar, M. M.; Espenson, J. H. J. Am. Chem. Soc. 1995, 117,
272.
(28) Reedijk, J. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 3611.
(29) Mirabelli, C. K.; Sung, C.; Whitman, M. H.; Hill, D. T.; Mong,
S.; Crooke, S. T. Biochem. Pharmacol. 1986, 35, 1427.
(30) 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.
[Au(CtCPh)(DAPTA)] (1b): 79% yield, yellow solid. 1H
NMR (400 MHz, CDCl3, 25 °C): δ 2.09 (s, 6H, DAPTA-Me),
3.70 (d, J=16.2 Hz, 1H, NCH2P), 4.05 (s, 2H, NCH2P), 4.10 (d,
J=14.3 Hz, 1H, NCH2N), 4.32 (d, J=15.6 Hz, 1H, NCH2P), 4.73
(d, J=14.3 Hz, 1H, NCH2N), 4.80 (dd, J=15.9, 10.1 Hz, 1H,
(32) Daigle, D. J. Inorg. Synth. 1998, 32, 40.
(33) Darensbourg, D. J.; Ortiz, C. G.; Kamplain, J. W. Organome-
tallics 2004, 23, 1747.
(34) Sanz, S.; Jones, L. A.; Mohr, F.; Laguna, M. Organometallics
(31) Aaseth, J.; Haugen, M.; Forre, Ø. Analyst 1998, 123, 3.
2007, 26, 952.

Article
Organometallics, Vol. 29, No. 11, 2010 2601
NCH2P), 4.97 (d, J=14.1 Hz, 1H, NCH2N), 5.60 (dd, J=15.7/7.9
Hz, 1H, NCH2P), 5.78 (d, J=14.4 Hz, 1H, NCH2N), 7.17-7.28 (m,
3H, m- and p-Ph), 7.32-7.41 (m, 2H, o-Ph) ppm. 31P{1H} NMR
(162 MHz, CDCl3, 25 °C): δ -24.9 ppm. IR (KBr): 2106 cm-1
ν(CtC). FAB-MS: m/z 528 [M]þ. Anal. Calcd (%) for C17H21Au-
N3O2P (527.31): C 38.72, H 4.01, N 7.97. Found: C 38.95, H 3.65, N
7.39.
[Au(CtC-2-NC5H4)(PTA)] (2a): 78% yield, pale yellow solid.
1H NMR (400 MHz, CDCl3, 25 °C): δ 4.44 (m, 12H, PTA),
7.09 (dd, J=4.8/1.0 Hz, 1H, NC5H4 (H5)), 7.38 (dd, J=7.8/1.0
Hz, NC5H4 (H3)), 7.55 (dt, J=7.6/1.5 Hz, 1H, NC5H4 (H4)),
8.50 (d, J=4.8 Hz, 1H, NC5H4 (H6)) ppm. 31P{1H} NMR (162
MHz, CDCl3, 25 °C): δ -51.8 ppm. IR (KBr): 2105 cm-1
ν(CtC). FAB-MS: m/z 457 [M]þ. Anal. Calcd (%) for C13-
H16AuN4P (456.23): C 34.22, H 3.53, N 12.28. Found: C 34.55,
H 3.75, N 12.50.
[Au(CtC-2-NC5H4)(DAPTA)] (2b): 63% yield, pale yellow
solid. 1H NMR (400 MHz, dmso-d6, 25 °C): δ 1.96 (s, 6H,
DAPTA-Me), 3.72 (d, J=16.0 Hz, 1H, NCH2P), 3.97 (s, 2H,
NCH2P), 4.09 (d, J=15.1 Hz, 1H, NCH2N), 4.27 (d, J=15.8 Hz,
1H, NCH2P), 4.64 (d, J=14.1 Hz, 1H, NCH2N), 4.80 (m, 1H,
NCH2P), 4.91 (d, J=13.9 Hz, 1H, NCH2N), 5.38 (dd, J=15.2/
7.4 Hz, 1H, NCH2P). 5.54 (d, J = 14.2 Hz, 1H, NCH2N), 7.05
(m, 1H, py-H5), 7.48 (dd, J = 7.9/1.0 Hz, 1H, py-H3), 7.63 (dt,
J=5.3/1.3 Hz, 1H, py-H4), 8.21 (d, J=5.0 Hz, 1H, py-H6) ppm.
31P{1H} NMR (162 MHz, dmso-d6, 25 °C): δ -19.3 ppm. IR
(KBr): 2114 cm-1 ν(CtC). FAB-MS: m/z 529 [M]þ. Anal.
Calcd (%) for C16H20AuN4O2P (528.3): C 36.38, H 3.82, N
10.61. Found: C 36.18, H 3.67, N 10.22.
[Au(CtC-2-C10H6OMe-6)(PTA)] (3a): 79% yield, yellow
solid. 1H NMR (400 MHz, CDCl3, 25 °C): δ 3.48 (s, 3H, OMe),
4.36 (s, 6H, NCH2P), 4.45, 4.51 (JAB=13.1 Hz, 6H, NCH2N),
7.06 (d, J=2.3 Hz, 1H, C10H6 (H5), 7.10 (dd, J=8.8/2.5 Hz, 1H,
C11H9O (H7)), 7.49 (dd, J=8.3/1.5 Hz, 1H, C10H6 (H3)), 7,63 (t,
J=9.1 Hz, 2H, C10H6 (H4)(H8), 7.89 (d, J = 2.3 Hz, 1H, C11H9O
(H1)) ppm. 31P{1H} NMR (162 MHz, CDCl3, 25 °C): δ -51.09
ppm. IR (KBr): 2096 cm-1 ν(CtC). FAB-MS: m/z 535 [M]þ.
Anal. Calcd (%) for C19H21AuN3OP (535.3): C 42.63, H 3.95, N
7.85. Found: C 42.30, H 3.67, N 7.49.
16.0/7.4 Hz, 1H, NCH2P), 5.67 (d, J=14.0 Hz, 1H, NCH2N),
7.03 (d, J=4.8 Hz, 1H, SC4H3, H5), 7.34 (s, 1H, SC4H3, H2),
7.36-7.38 (m, 1H, SC4H3, H4) ppm. 31P{1H} NMR (162 MHz,
dmso-d6, 25 °C): δ -19.2 ppm. IR (Nujol): 2095 cm-1 ν(CtC).
FAB-MS: m/z 534 [M]þ. Anal. Calcd (%) for C15H19AuN3O2PS
(533.3): C 33.78, H 3.59, N 7.88. Found: C 33.11, H 2.95, N 7.72.
[Au(CtC-5-C3H2MeN2-1)(PTA)] (5a): 82% yield, white so-
lid. 1H NMR (400 MHz, dmso-d6, 25 °C): δ 3.53 (s, 3H, NCH3),
4.29 (s, 6H, NCH2P), 4.44, 4.51 (JAB=13.1 Hz, 3H, NCH2N),
6.89 (s, 1H, N2C4H5 (H4)), 7.53 (s, 1H, N2C4H5 (H2)) ppm.
31P{1H} NMR (162 MHz, dmso-d6, 25 °C): δ -49.3 ppm. IR
(Nujol): 2110 cm-1 ν(CtC). FAB-MS: m/z 460 [M]þ. Anal.
Calcd (%) for C12H17AuN5P (459.24): C 31.38, H 3.73, N 15.25.
Found: C 31.50, H 3.95, N 15.60.
[Au(CtC-5-C3H2MeN2-1)(DAPTA)] (5b): 80% yield, white
solid. 1H NMR (400 MHz, CDCl3, 25 °C): δ 1.97 (s, 6H,
DAPTA-Me), 3.63 (s, 3H, NCH3), 4.17 (d, J =16.1 Hz, 1H,
NCH2P), 4.21 (s, 2H, NCH2P), 4.52 (d, J = 14.4 Hz, 1H,
NCH2N), 4.61 (d, J=15.6 Hz, 1H, NCH2P), 4.90 (s, 1H, NC-
H2N), 4.95 (s, 1H, NCH2P), 5.01 (d, J=14.0 Hz, 1H, NCH2N),
5.43 (s, 1H, NCH2P), 5.53 (d, J=14.0 Hz, 1H, NCH2N), 6.99 (s,
1H, N2C4H5 (H2)), 7.49 (s, 1H, N2C4H5 (H4)) ppm. 31P{1H}
NMR (162 MHz, CDCl3, 25 °C): δ -25.3 ppm. IR (Nujol): 2110
cm-1 ν(CtC). FAB-MS: m/z 532 [M]þ. Anal. Calcd (%) for
C15H21AuN5O2P (531.11): C 33.91, H 3.98, N 13.18. Found: C
33.94, H 3.30, N 13.26.
[Au{CtC(C4H9)}(PTA)] (6a): 73% yield, white solid. 1H
NMR (400 MHz, CDCl3, 25 °C): δ 0.88 (t, J = 7.1 Hz, 3H,
CH3), 1.42-1.49 (m, 4H, CH2), 2.29 (t, J = 7.1 Hz, 2H,
CH2CtC), 4.22 (s, 6H, NCH2P), 4.50, 4.57 (JAB = 12.9 Hz,
6H, NCH2N) ppm. 31P{1H} NMR (162 MHz, CDCl3, 25 °C): δ
-49.6 ppm. IR (Nujol): 2103 cm-1 ν(CtC). FAB-MS: m/z 436
[M]þ. Anal. Calcd (%) for C12H21AuN3P (435.26): C 33.11, H
4.86, N 9.65. Found: C 33.50, H 4.75, N 9.30.
[Au{CtC(C4H9)}(DAPTA)] (6b): 62% yield, white solid. 1H
NMR (400 MHz, CDCl3, 25 °C): δ 0.92 (t, J=7.1 Hz, 3H, CH3),
1.46-1.49 (m, 4H, CH2), 2.21 (s, 6H, DAPTA-Me), 2.35 (t, J=
6.7 Hz, 2H, CH2CtC), 3.51 (d, J=16.1 Hz, 1H, NCH2P), 3.82
(s, 2H, NCH2P), 4.02 (d, J=14.4 Hz, 1H, NCH2N), 4.17 (d,
J=15.6 Hz, 1H, NCH2P), 4.30 (d, J=14.0 Hz, 1H, NCH2N),
4.51 (d, J =15.6 Hz 1H, NCH2P), 4.82 (d, J = 14.0 Hz, 1H,
NCH2N), 5.66 (dd, J=16.0/7.4 Hz, 1H, NCH2P), 5.82 (d, J=
14.0 Hz, 1H, NCH2N) ppm. 31P{1H} NMR (162 MHz, CDCl3,
25 °C): δ -21.5 ppm. IR (Nujol): 2096 cm-1 ν(CtC). FAB-MS:
m/z 508 [M]þ. Anal. Calcd (%) for C15H25AuN3O2P (507.32):
35.51, H 4.97, N 8.28. Found: C 35.46, H 4.40, N 8.10.
[Au(CtC-2-C10H6OMe-6)(DAPTA)] (3b): 82% yield, white
solid. 1H NMR (400 MHz, CDCl3, 25 °C): δ 2.02 (s, 6H, DAPTA-
Me), 3.48 (s, 3H, OMe), 3.82 (d, J=16.1 Hz, 1H, NCH2P), 3.99 (s,
2H, NCH2P), 4.03 (d, J=14.4 Hz, 1H, NCH2N), 4.17 (d, J = 15.6
Hz, 1H, NCH2P), 4.31 (d, J=14.0Hz, 1H, NCH2N), 4.51 (dd, J=
15.6/9.7 Hz, 1H, NCH2P), 4.83 (d, J = 14.0 Hz, 1H, NCH2N), 5.66
(dd, J = 16.0/7.4 Hz, 1H, NCH2P), 5.67 (d, J = 14.0 Hz, 1H,
NCH2N), 7.11 (dd, J=8.8/2.0 Hz, 1H, C10H6 (H5), 7.18 (s, 1H,
C11H9O (H7)), 7.64 (d, J=8.3 Hz, 1H, C10H6 (H3)) ppm. 31P{1H}
NMR (162 MHz, CDCl3, 25 °C): δ -22.8 ppm. IR (Nujol): 2095
cm-1 ν(CtC). FAB-MS: m/z 608 [M]þ. Anal. Calcd (%) for C22-
H25AuN3O3P (607.39): C 43.50, H 4.15, N 6.92. Found: C 43.29, H
3.95, N 7.01.
[Au(CtCtBu)(PTA)] (7a): 77% yield, yellow solid. 1H NMR
(400 MHz, CDCl3, 25 °C): δ 1.24 (s, 9 H, CH3), 4.15 (s, 6H,
NCH2P), 4.47, 4.55 (JAB=13.1 Hz, 6H, NCH2N) ppm. 31P{1H}
NMR (162 MHz, CDCl3, 25 °C): δ -48.8 ppm. 13C{1H} RMN
(CDCl3, 400 MHz): δ 29.07 (s, 1C, CCH3), 32.44 (s, 3C, CH3),
51.8 (d, 3C, J = 20.6 Hz, NCH2P), 72.6 (d, J = 7.6 Hz, 3C,
NCH2N) ppm. IR (Nujol): 2104 cm-1 ν(CtC). FAB-MS: m/z
436 [M]þ. Anal. Calcd (%) for C12H21AuN3P (435.26): C 33.11,
H 4.86, N 9.65. Found: C 33.50, H 4.75, N 9.30.
1
[Au(CtC-3-SC4H3)(PTA)] (4a): 79% yield, white solid. H
NMR (400 MHz, CDCl3, 25 °C): δ 4.28 (s, 6H, NCH2P), 4.43,
4.50 (JAB=12.9 Hz, 6H, NCH2N), 6.96 (dd, J=5.1/1.3 Hz, 1H,
SC4H3, H5), 7.38 (dd, J=2.8/1.1 Hz, 1H, SC4H3, H2), 7.45 (dd,
J=5.1/3.0 Hz, 1H, SC4H3, H4) ppm. 31P{1H} NMR (162 MHz,
CDCl3, 25 °C): δ -49.06 ppm. 13C{1H} NMR (CDCl3, 400
MHz): δ 52.2 (d, 3C, J=20.3 Hz, NCH2P), 72.4 (d, J=7.6 Hz,
3C, NCH2N), 99.83 (s, 1C, SC4H3 (C3)), 125.78 (s, 2C, SC4H3
((C2, C5)), 128.38 (s, 1C, SC4H3 (C4)) ppm. IR (KBr): 2113 cm-1
ν(CtC). FAB-MS: m/z 462 [M]þ. Anal. Calcd (%) for
C12H15AuN3PS (461.27): C 31.25, H 3.28, N 9.11. Found: C
31.67, H 3.65, N 9.01.
[Au(CtC-3-SC4H3)(DAPTA)] (4b): 63% yield, white solid.
1H NMR (400 MHz, dmso-d6, 25 °C): δ 2.02 (s, 6H, DAPTA-
Me), 3.80 (d, J=16.1 Hz, 1H, NCH2P), 3.97 (s, 2H, NCH2P),
4.03 (d, J=14.4 Hz, 1H, NCH2N), 4.17 (d, J=15.6 Hz, 1H,
NCH2P), 4.30 (d, J=14.0 Hz, 1H, NCH2N), 4.52 (d, J=15.6 Hz,
1H, NCH2P), 4.82 (d, J=14.0 Hz, 1H, NCH2N), 5.46 (dd, J=
[Au(CtCtBu)(DAPTA)] (7b): 82% yield, yellow solid. 1H
NMR (400 MHz, CDCl3, 25 °C): δ 1.30 (s, 9H, CH3), 2.11 (s,
6H, DAPTA-Me), 3.47 (d, J=16.1 Hz, 1H, NCH2P), 3.77 (s,
2H, NCH2P), 4.06 (d, J=14.3 Hz, 1H, NCH2N), 4.10 (s, 1H,
NCH2P), 4.53 (s, 1H, NCH2N), 4.63 (d, J = 15.9 Hz, 1H,
NCH2P), 4.94 (d, J = 14.3 Hz, 1H, NCH2N), 5.55 (dd, J =
15.6/7.7 Hz, 1H, NCH2P), 5.78 (d, J=14.3 Hz, 1H, NCH2N)
ppm. 31P{1H} NMR (162 MHz, CDCl3, 25 °C): δ -21.3 ppm.
IR (Nujol): 2104 cm-1 ν(CtC). FAB-MS: m/z 508 [M]þ, 933 [M
þ (AuDAPTA)]þ, 655 [Au(DAPTA)2]þ. Anal. Calcd (%) for
C15H25AuN3O2P (507.32): C 35.51, H 4.97, N 8.28. Found: C
35.26, H 5.18, N 7.96.
[Au(CtCCH2OH)(DAPTA)] (8b): 72% yield, white solid. 1H
NMR (400 MHz, D2O, 25 °C): δ 2.08 (s, 6H, DAPTA-Me), 3.83
(d, J=15.5 Hz, 1H, NCH2P), 3.92 (s, 2H, CH2), 4.19 (s, 2H,

2602 Organometallics, Vol. 29, No. 11, 2010
Vergara et al.
NCH2P), 4.25 (d, J=14.1 Hz, 1H, NCH2N), 4.33 (d, J=15.6 Hz,
1H, NCH2P), 4.73 (d, J=14.1 Hz, 1H, NCH2N), 4.83 (dd, J=
15.9/10.1 Hz, 1H, NCH2P), 5.08 (d, J=14.1 Hz, 1H, NCH2N),
5.44 (dd, J=15.7/7.9 Hz, 1H, NCH2P), 5.59 (d, J = 14.3 Hz, 1H,
NCH2N) ppm. 31P{1H} NMR (162 MHz, D2O, 25 °C): δ -17.6
ppm. IR (Nujol): 2089 cm-1 ν(CtC). FAB-MS: m/z 482 [M]þ,
678 [M þ Au]þ, 426 [Au(DAPTA)]þ, 907 [M þ Au(DAPTA)]þ.
Anal. Calcd (%) for C12H19AuN3O3P (481.24): C 29.95, H 3.98,
N 8.73. Found: C 30.2, H 4.13, N 8.82.
[Au(CtCC(CH3)2OH)(DAPTA)] (9b): 70% yield, white so-
lid. 1H NMR (400 MHz, D2O, 25 °C): δ 1.52 (s, 6H, CH3), 2.15
(s, 6 H, DAPTA-Me), 3.84 (d, J=15.3 Hz, 1H, NCH2P), 4.10 (s,
2H, NCH2P), 4.32 (d, J=14.1 Hz, 1H, NCH2N), 4.40 (d, J =
15.6 Hz, 1H, NCH2P), 4.83 (d, J=14.1 Hz, 1H, NCH2N), 4.95
(dd, J=15.9/10.1 Hz, 1H, NCH2P), 5.10 (d, J=14.2 Hz, 1H,
NCH2N), 5.43 (dd, J=15.6/7.9 Hz, 1H, NCH2P), 5.67 (d, J=
14.2 Hz, 1H, NCH2N) ppm. 31P{1H} NMR (162 MHz, D2O,
25 °C): δ -17.0 ppm. IR (Nujol): 2090 cm-1 ν(CtC). FAB-MS:
m/z 510 [M]þ, 836 [M þ Au(DAPTA)]þ. Anal. Calcd (%) for
C14H23AuN3O3P (509.29): C 33.02, H 4.55, N 8.25. Found: C
34.01, H 4.68, N 8.58.
[Au(CtCC(Ph)2OH)(DAPTA)] (10b): 62% yield, white solid.
1H NMR (400 MHz, CDCl3, 25 °C): δ 1.91 (s, 6H, DAPTA-
Me), 3.65 (d, J=15.4 Hz, 1H, NCH2P), 3.80 (s, 2H, NCH2P),
4.05 (d, J=14.1 Hz, 1H, NCH2N), 4.45 (d, J=15.6 Hz, 1H,
NCH2P), 4.65 (s, 1H, NCH2N), 4.80 (s, 1H, NCH2P), 5.4 (d, J =
14.2 Hz, 1H, NCH2N), 5.53 (s, 1H, NCH2P), 5.63 (s, 1H,
NCH2N), 7.17-7.47 (m, 6H, m- and p-Ph), 7.61-7.73 (m, 2H,
o-Ph), 7.73-7.92 (m, 2H, o-, m-, and p-PPh) ppm. 31P{1H}
NMR (162 MHz, CDCl3, 25 °C): δ -23.4 ppm. IR (Nujol): 2115
cm-1 ν(CtC). FAB-MS: m/z 634 [M]þ, 545 [M - OH]þ, 655
[Au(DAPTA)2]þ, 426 [Au(DAPTA)]þ. Anal. Calcd (%) for
C24H27AuN3O3P (633.43): C 45.51, H 4.30, N 6.63. Found: C
45.08, H 4.01, N 6.82.
6H, NCH2N) ppm. 31P{1H} NMR (162 MHz, CDCl3, 25 °C): δ
-49.5 ppm. IR (KBr): 3207 ν(N-H), 2132 cm-1 ν(CtC). FAB-
MS: m/z 437 [M]þ, 791 [M þ AuPTA]þ. Anal. Calcd (%) for
C11H20AuN4P (436.24): C 30.29, H 4.62, N 12.84. Found: C 30.59,
H 4.25, N 12.30.
[Au((CtCC(CH2)(N(CH3)2)(DAPTA)] (13b): 62% yield,
1
white solid. H NMR (400 MHz, MeOD, 25 °C): δ 2.12 (s, 6H,
DAPTA-Me), 2.30 (s, 6H, N(CH3)2), 3.85 (d, J=15.4 Hz, 1H,
NCH2P), 4.05 (s, 2H, NCH2P), 4.32 (d, J = 14.1 Hz, 1H, NCH2N),
4.40 (d, J = 15.6 Hz, 1H, NCH2P), 4.83 (d, J = 14.1 Hz, 1H,
NCH2N), 4.95 (dd, J=15.9/10.1 Hz, 1H, NCH2P), 5.10 (d, J=14.2
Hz, 1H, NCH2N), 5.43 (dd, J=15.6/7.9 Hz, 1H, NCH2P), 5.67 (d,
J=14.2 Hz, 1H, NCH2N) ppm. 31P{1H} NMR (162 MHz, MeOD,
25 °C): δ -46.0 ppm. IR (Nujol): 3424 ν(N-H), 2100 cm-1
ν(CtC). FAB-MS: m/z 510 [M]þ, 936 [M þ AuDAPTA]þ, 426
[AuDAPTA]þ, 655 [Au(DAPTA)2]þ. Anal. Calcd (%) for C14H24-
AuN4O2P (508.31): C 32.91, H 4.76, N 11.02. Found: C 32.90, H
4.67, N 10.58.
N[Au(CtCCH2)(PTA)]3 (14a): 69% yield, white solid. 1H
NMR (400 MHz, CDCl3, 25 °C): δ 3.48 (s, 6H, CH2), 4.36 (s,
18H, CH2P), 4.40, 4.50 (JAB =13.1 Hz, 18H, NCH2N) ppm.
31P{1H} NMR (162 MHz, CDCl3, 25 °C): δ -50.2 ppm. IR
(ATR): 2095 ν(CtC) cm-1. FAB-MS: m/z 1190 [M]þ, 354
[AuPTA]þ, 511 [Au(PTA)2]þ. Anal. Calcd (%) for C27H42Au3-
N10P3 (1190.51): C 27.24, H 3.56, N 11.77. Found: C 27.59, H
3.35, N 12.00.
N[Au(CtCCH2)(DAPTA)]3 (14b): 72% yield, white solid.
1H NMR (400 MHz, CDCl3, 25 °C): δ 2.15 (s, 18H, DAPTA-
Me), 3.52 (s, 6H, CH2), 3.85 (d, J=15.4 Hz, 3H, NCH2P), 4.10
(s, 6H, NCH2P), 4.32 (d, J=14.1 Hz, 3H, NCH2N), 4.40 (d, J =
15.6 Hz, 3H, NCH2P), 4.83 (d, J=14.1 Hz, 3H, NCH2N), 4.95
(dd, J=15.9/10.1 Hz, 3H, NCH2P), 5.10 (d, J=14.2 Hz, 3H,
NCH2N), 5.43 (dd, J=15.6/7.9 Hz, 3H, NCH2P), 5.67 (d, J=
14.2 Hz, 3H, NCH2N) ppm. 31P{1H} NMR (162 MHz, CDCl3,
25 °C): δ -47.0 ppm. IR (ATR): 2117 ν(CtC) cm-1. FAB-MS:
m/z 1422 [M]þ, 426 [AuDAPTA]þ, 655 [Au(DAPTA)2]þ. Anal.
Calcd (%) for C37H56Au3N10O6P3 (1406.70): C 29.13, H 3.73, N
10.79. Found: C 29.24, H 3.77, N 9.58.
Preparation of [Au2(CtCRCtC)(PR03)2] Complexes. To a
solution of KOH (0.022 g, 0.385 mmol) in MeOH (ca. 10 mL)
containing the alkyne (0.308 mmol) was added [AuCl(PR03)]
(PR03=PTA, DAPTA) (0.257 mmol). After stirring the mixture
for ca. 20 h the precipitate was isolated by filtration, washed
with methanol and diethyl ether, and dried in air.
[Au2{(CtC)2-1,4-C6H4)}(PTA)2] (15a): 79% yield, yellow
solid. 1H NMR (400 MHz, CDCl3, 25 °C): δ 4.14 (s, 12H,
NCH2P), 4.49, 4.58 (JAB=13.1 Hz, 12H, NCH2N), 7.17-7.40
(m, 4H, Ph) ppm. 31P{1H} NMR (162 MHz, CDCl3, 25 °C): δ
-51.9 ppm. IR (Nujol): 2094 cm-1 ν(CtC). FAB-MS: m/z 833
[M]þ. Anal. Calcd (%) for C22H28Au2N6P2 (832.38): C 31.74, H
3.39, N 10.10. Found: C 31.29, H 3.79, N 10.18.
[Au(CtCC(CH2CH3)(CH3)(OH))(DAPTA)] (11b): 85% yield,
white solid. 1H NMR (400 MHz, D2O, 25 °C): δ 1.05 (t, J=7.2 Hz,
3H, CH3CH2), 1.47 (s, 3H, CH3), 1.56-1.71 (m, 2H, CH3-CH2),
2.12 (s, 6H, DAPTA-Me), 3.85 (d, J=15.3 Hz, 1H, NCH2P), 4.05
(s, 2H, NCH2P), 4.27 (d, J=14.2 Hz, 1H, NCH2N), 4.39 (d, J =
15.6 Hz, 1H, NCH2P), 4.78 (s, 1H, NCH2N), 4.90 (s, 1H, NCH2P),
5.15 (d, J=14.2 Hz, 1H, NCH2N), 5.45 (s, 1H, NCH2P), 5.65 (s,
1H, NCH2N) ppm. 31P{1H} NMR (162 MHz, D2O, 25 °C):
δ -23.2 ppm. IR (Nujol): 2019 cm-1 ν(CtC). FAB-MS: m/z
524 [M]þ, 507 [M - OH]þ. Anal. Calcd (%) for C15H25AuN3-
O3P (523.32): C 34.43, H 4.82, N 8.03. Found: C 34.92, H 5.02, N
8.53.
1
[Au(CtCCH2NH2)(PTA)] (12a): 79% yield, white solid. H
NMR (400 MHz, CDCl3, 25 °C): δ 2.22 (s, 2H, NH2), 3.48 (s, 2H,
CH2), 4.36 (s, 6H, CH2P), 4.40 (JAB=13.1 Hz, 3H, NCH2N), 4.50
(J = 13.1 Hz, 6H, NCH2N) ppm. 31P{1H} NMR (162 MHz, CD-
Cl3, 25 °C): δ -12.5 ppm. IR (ATR): 3284 ν(N-H), 2164 ν(CtC)
cm-1. FAB-MS: m/z 409 [M]þ, 763 [M þ AuPTA]þ. Anal. Calcd
(%) for C9H16AuN4P (408.19): C 26.48, H 3.95, N 13.73. Found: C
26.80, H 3.75, N 14.20.
[Au(CtCCH2NH2)(DAPTA)] (12b): 82% yield, white solid.
1H NMR (400 MHz, CDCl3, 25 °C): δ 2.08 (s, 6 H, DAPTA-Me),
3.42 (s, 2H, CH2), 3.83 (d, J=15.5 Hz, 1H, NCH2P), 3.92 (s, 2H,
CH2), 4.19(s, 2H, NCH2P), 4.25 (d, J=14.1 Hz, 1H, NCH2N), 4.33
(d, J=15.6 Hz, 1H, NCH2P), 4.73 (d, J=14.1 Hz, 1H, NCH2N),
4.83 (dd, J=15.9/10.1 Hz, 1H, NCH2P), 5.08 (d, J=14.1 Hz, 1H,
NCH2N), 5.44 (dd, J=15.7/7.9 Hz, 1H, NCH2P), 5.59 (d, J=14.3
Hz, 1H, NCH2N) ppm. 31P{1H} NMR (162 MHz, CDCl3, 25 °C):
δ-10.2 ppm. IR (Nujol): 3359 ν(N-H), 2163 cm-1 ν(CtC). FAB-
MS: m/z 482 [M]þ, 678 [M - Au]þ, 907 [M - AuDAPTA]þ, 426
[AuDAPTA]þ, 655 [Au(DAPTA)2]þ. Anal. Calcd (%) for
C12H20AuN4O2P (480.25): C 30.01, H 4.20, N 11.67. Found: C
30.22, H 4.13, N 11.82.
[Au2{(CtC)2-1,4-C6H4)}(DAPTA)2] (15b): 68% yield, yel-
low solid. 1H NMR (400 MHz, CDCl3, 25 °C): δ 2.11 (s, 12H,
DAPTA-Me), 3.15 (d, J=15.4 Hz, 2H, NCH2P), 3.49 (s, 2H,
NCH2P), 4.08 (d, J=13.7 Hz, 2H, NCH2N), 4.12 (d, J=15.6 Hz,
2H, NCH2P), 4.73 (d, J=14.3 Hz, 2H, NCH2N), 4.80 (dd, J=
15.9/10.1 Hz, 2H, NCH2P), 4.97 (d, J = 14.1 Hz, 2H, NCH2N),
5.60 (dd, J=15.7/7.9 Hz, 2H, NCH2P), 5.78 (d, J=14.4 Hz, 2H,
NCH2N), 7.18-7.29 (m, 3H, m- and p-Ph), 7.31-7.40 (m, 4H,
Ph) ppm. 31P{1H} NMR (162 MHz, CDCl3, 25 °C): δ -21.9
ppm. IR (KBr): 2098 cm-1 ν(CtC). FAB-MS: m/z 977 [M]þ.
Anal. Calcd (%) for C28H36Au2N6O4P2 (976.50): C 34.44, H
3.72, N 8.61. Found: C 34.09, H 3.69, N 8.18.
[Au2{(CtC)2-1,3-C6H4}(PTA)2] (16a): 69% yield, yellow
1
solid. H NMR (400 MHz, dmso-d6, 25 °C): δ 4.36 (s, 12H,
NCH2P), 4.46, 4.59 (JAB= 13.1 Hz, 12H, NCH2N), 7.13-7.36
(m, 4H, m- and p-Ph) ppm. 31P{1H} NMR (162 MHz, dmso-d6,
25 °C): δ -49.3 ppm. IR (Nujol): 2109 cm-1 ν(CtC). FAB-MS:
m/z 833 [M]þ. Anal. Calcd (%) for C22H28Au2N6P2 (832.38): C
31.74, H 3.39, N 10.10. Found: C 31.18, H 3.89, N 10.59.
[Au((CtCC(CH2)(N(CH3)2)(PTA)] (13a): 75% yield, white
solid. 1H NMR (400 MHz, CDCl3, 25 °C): δ 2.28 (s, 6H, N(CH3)2),
3.38 (s, 2H, CH2), 4.19 (s, 6H, NCH2P), 4.49, 4.51 (JAB=13.1 Hz,

Article
Organometallics, Vol. 29, No. 11, 2010 2603
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3
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[Au2{(CtC)2-1,3-C6H4)}(DAPTA)2] (16b): 69% yield, yellow
solid. H NMR (400 MHz, dmso-d6, 25 °C): δ 2.01 (s, 12H,
2645(2) A ; Z, 4; density (calculated), 2.316 Mg/m ; absorption
coefficient, 11.386 mm-1; theta range for data collection, 1.79° to
28.33°; reflections collected, 17 697; independent reflections, 6320
[R(int) = 0.0491]; R1(F2> 2σ(F2)), 0.0354; wR2(all data), 0.0678;
S(all data), 0.939.
1
DAPTA-Me), 3.10 (d, J=15.4 Hz, 2H, NCH2P), 3.46 (s, 2H,
NCH2P), 4.11 (d, J=13.7 Hz, 2H, NCH2N), 4.15 (d, J=15.6 Hz,
2H, NCH2P), 4.72 (d, J = 14.3 Hz, 2H, NCH2N), 4.83 (dd, J=
15.9/10.1 Hz, 2H, NCH2P), 4.95 (d, J=14.1 Hz, 2H, NCH2N),
5.61 (dd, J=15.7/7.9 Hz, 2H, NCH2P), 5.78 (d, J=14.4 Hz, 2H,
NCH2N), 7.03-7.16 (m, 4H, Ph) ppm. 31P{1H} NMR (162
MHz, dmso-d6, 25 °C): δ -19.2 ppm. 13C{1H} RMN (dmso-d6,
400 MHz): δ 51.9 (d, 3C, J=20.7 Hz, NCH2P), 72.8 (d, J=7.3
Hz, 3C, NCH2N), 126.20 (s, 2C, C6H4 (C1, C3)), 129.10 (s, 1C,
C6H4 (C5)), 131.60 (s, 2C, C6H4 (C4, C6)), 136.47 (s, 1C, C6H4
(C2)) ppm. IR (Nujol): 2098 cm-1 ν(CtC). FAB-MS: m/z 977
[M]þ. Anal. Calcd (%) for C28H36Au2N6O4P2 (976.50): C 34.44,
H 3.72, N 8.61. Found: C 34.64, H 3.70, N 7.98.
Cells and Cell Treatment. Human A2780 and A2780cisR cells
were obtained from the European Centre of Cell Cultures
(ECACC, Salisbury, UK). All cell culture reagents were ob-
tained from Gibco-BRL (Basel, Switzerland). Cells were grown
in RPMI 1640 medium containing 10% fetal calf serum (FCS)
and antibiotics. Stock solutions of the complexes (16 mM in
DMSO) were diluted in complete medium to the required
concentration. DMSO at comparable concentrations did not
show any effects on cell cytotoxicity.
Determination of Cytotoxicity. Cells were grown in 96-well
cell culture plates (Corning, NY) at a density of ca. 25 ꢀ 103 cells
per well. The culture medium was replaced with fresh medium
containing complexes 1b, 4a/b, 8a/b, and 14a/b at various
concentrations with an exposure time of 72 h. Thereafter, the
medium was replaced by fresh medium, and cell survival was
measured using the MTT test as previously described. Briefly,
3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyltetrazolium bromide
(MTT, Merck) was added at 250 μg/mL, and incubation was
continued for 2 h. Then the cell culture supernatants were
removed, the cell layer was dissolved in DMSO, and absorbance
at 540 nm was measured in a 96-well multiwell plate reader
(iEMS Reader MF, Labsystems, Bioconcept, Switzerland) and
compared to the values of control cells incubated in the absence
of complexes. Experiments were conducted in quadruplicate
wells and repeated at least twice.
Fluorescence Microscopy Studies. Cells were grown for 24 h
on chambered cover glass slides (Lab-Tek, NUNC) in complete
medium at a density of ca. 1 ꢀ 104 and then exposed to the
appropriate compounds at 50% of the IC50 concentrations at
37 °C in the dark. Excess complex was removed with PBS, and
the cells were fixed with 4% formaldehyde in PBS for 30 min in
the dark and rinsed twice with PBS before observation. Cells
were mounted in PBS before being observed by fluorescence
microscopy using a Zeiss Axiovert 200M microscope equipped
with a 40ꢀ air immersion objective. Filters used for excitation
and detection of DAPI were 345 and 448 nm, respectively.
Fluorescence signal intensities were evaluated using Meta-
Morph software.
[(PTA)AuCtC-CtCAu(PTA)] (17a): 82% yield, white so-
lid. 1H NMR (400 MHz, dmso-d6, 25 °C): δ 4.35 (s, 12H,
NCH2P), 4.48, 4.60 (JAB = 13.1 Hz, 12H, NCH2N). 31P{1H}
NMR (162 MHz, dmso-d6, 25 °C): δ -47.3 ppm. IR (Nujol):
2081 cm-1 ν(CtC). FAB-MS: m/z 757 [M]þ. Anal. Calcd (%)
for C16H24Au2N6P2 (756.28): C 25.41, H 3.20, N 11.11. Found:
C 25.50, H 3.76, N 11.30.
[(PTA)AuCtC-CtCAu(DAPTA)] (17b): 87% yield, yellow
1
solid. H NMR (400 MHz, dmso-d6, 25 °C): δ 2.12 (s, 12H,
DAPTA-Me), 3.68 (d, J = 15.3 Hz, 2H, NCH2P), 3.97 (s, 2H,
NCH2P), 4.10 (d, J = 13.7 Hz, 2H, NCH2N), 4.22 (d, J = 15.6
Hz, 2H, NCH2P), 4.62 (d, J = 14.3 Hz, 2H, NCH2N), 4.80 (dd,
J = 15.9/10.1 Hz, 2H, NCH2P), 4.90 (d, J = 14.1 Hz, 2H,
NCH2N), 5.31 (dd, J = 15.7/7.9 Hz, 2H, NCH2P), 5.50 (d, J =
14.4 Hz, 2H, NCH2N) ppm. 31P{1H} NMR (162 MHz, dmso-d6,
25 °C): δ -19.2 ppm. IR (Nujol): 2099 cm-1 ν(CtC). FAB-MS:
m/z 901 [M]þ. Anal. Calcd (%) for C22H32Au2N6O4P2 (900.41):
C 29.35, H 3.58, N 9.33. Found: C 28.89, H 3.70, N 9.98.
Crystallographic Studies. Crystals of 4a suitable for X-ray
diffraction were obtained by slow diffusion of diethyl ether into
an ethanolic solution of the compound. The crystal was mounted
on a glass fiber with inert oil and centered in a Bruker-Smart CCD
diffractometer with graphite-monochromated Mo KR (λ = 0.7107
˚
A) radiation for data collection. The diffraction frames were
integrated using the SAINT35 package and corrected for absorption
with SADABS.36 The structure was solved by direct methods using
SHELXS.37 Full-matrix least-squares refinement was carried out
2
using SHELXL38 minimizing w(Fo * - Fc2)2. Hydrogen atoms
were included using a riding model. Disorder was observed in the
thiophene units of both independent molecules. Restraints were
applied to both components of both groups, in an attempt to model
the resulting average electron density without losing chemically
reasonable geometrical parameters. The complete crystallographic
data have been deposited with the Cambridge Crystallographic
Data Centre [CCDC 773431]. Principle crystal and refinement data:
empirical formula, C24H30Au2N6P2S2; formula weight, 922.53;
crystal system and space group, monoclinic, P2(1)/n; a = 6.215-
Acknowledgment. We thank the Ministerio de Ciencia e
ꢀ
Innovacion (CTQ2008-06716-CO3-01) and the Fonds
National Suisse de la Recherche Scientifique for financial
support and Dr. Lucienne Juillerat (IUP, Lausanne,
Switzerland), who kindly provided the A2780 and
A2780cisR cell lines. A.C gratefully acknowledges the
Swiss National Science Foundation (AMBIZIONE pro-
ject no. PZ00P2_121933) and the Swiss Confederation
(Action COST D39, Accord de Recherche, SER project
no. C09.0027) for financial support. A.D. and P.J.D.
gratefully acknowledge COST D39 action for funding
and fruitful discussion.
˚
˚
˚
(5) A, b=18.705(5) A, c=22.755(5) A, β=90.069(5)°; volume,
(35) Papadogianakis, C.; Sheldon, R. A. New J. Chem. 1996, 20, 175.
(36) Sheldrick, G. M. SADABS, Empirical Absorption Program;
€
€
University of Gottingen: Gottingen, Germany, 1996.
€
€
(37) Sheldrick, G. M. SHELXS; University of Gottingen: Gottingen,
Germany, 1997.
Supporting Information Available: This material is available
free of charge via the Internet at http://pubs.acs.org.
€
€
(38) Sheldrick, G. M. SHELXTL; University of Gottingen: Gottingen,
Germany, 1997.