(Pyrazolylmethyl)pyridine platinum(II) and gold(III) complexes: Synthesis, structures and evaluation as anticancer agents

Article abstract of DOI:10.1016/j.ica.2009.02.046

Reactions of 2-(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L1), 2-(3,5-diphenylpyrazol-1-ylmethyl)pyridine (L2), 2-(3,5-di-tert-butylpyrazol-1-ylmethyl)pyridine (L3) and 2-(3-p-tolylpyrazol-1-ylmethyl)pyridine (L4) with K₂[PtCl₄] in a mixture of ethanol and water formed the dichloro platinum complexes [PtCl₂(L1)] (1), [PtCl₂(L2)] (2), [PtCl₂(L3)] (3) and [PtCl₂(L4)] (4). Complex 1, [PtCl₂(L1)], could also be prepared in a mixture of acetone and water. Performing the reactions of L2 and L3 in a mixture of acetone and water, however, led to C-H activation of acetone under mild conditions to form the neutral acetonyl complexes [Pt(CH₂COCH₃)Cl(L2)] (2a) and [Pt(CH₂COCH₃)Cl(L3)] (3a). The same ligands reacted with HAuCl₄ · 4H₂O in a mixture of ethanol and water to form the gold salts [AuCl₂(L1)][AuCl₄] (5) [AuCl₂(L2)][Cl] (6) [AuCl₂(L3)][Cl] (7) and [AuCl₂(L4)][AuCl₄] (8); however, with the pyrazolyl unit in the para position of the pyridinyl ring in 4-(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L5), 4-(3,5-diphenylpyrazol-1-ylmethyl)pyridine (L6) neutral gold complexes [AuCl₃(L5)] (9) and [AuCl₂(L6)] (10) were formed; signifying the role the position of the pyrazolyl group plays in product formation in the gold reactions. X-ray crystallographic structural determination of L6, 2, 3 3a, 8 and 10 were very important in confirming the structures of these compounds; particularly for 3a and 8 where the presence of the acetonyl group confirmed C-H activation and for 8 where the counter ion is AuCl₄ ^-. Cytotoxicity studies of L2, L4 and complexes 1-10 against HeLa cells showed the Au complexes were much less active than the Pt complexes.

Full text of DOI:10.1016/j.ica.2009.02.046

Inorganica Chimica Acta 362 (2009) 3314–3324
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
(Pyrazolylmethyl)pyridine platinum(II) and gold(III) complexes: Synthesis,
structures and evaluation as anticancer agents
Tebogo V. Segapelo a, Ilia A. Guzei b, Lara C. Spencer b, Werner E Van Zyl a,1, James Darkwa a,
*
a Department of Chemistry, University of Johannesburg, Auckland Park Kingsway Campus, P.O. Box 524, Johannesburg 2006, South Africa
b Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Reactions of 2-(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L1), 2-(3,5-diphenylpyrazol-1-ylmethyl)pyri-
dine (L2), 2-(3,5-di-tert-butylpyrazol-1-ylmethyl)pyridine (L3) and 2-(3-p-tolylpyrazol-1-ylmethyl)pyri-
dine (L4) with K2[PtCl4] in a mixture of ethanol and water formed the dichloro platinum complexes
[PtCl2(L1)] (1), [PtCl2(L2)] (2), [PtCl2(L3)] (3) and [PtCl2(L4)] (4). Complex 1, [PtCl2(L1)], could also be pre-
pared in a mixture of acetone and water. Performing the reactions of L2 and L3 in a mixture of acetone
and water, however, led to C–H activation of acetone under mild conditions to form the neutral acetonyl
complexes [Pt(CH2COCH3)Cl(L2)] (2a) and [Pt(CH2COCH3)Cl(L3)] (3a). The same ligands reacted with
Received 4 September 2008
Received in revised form 18 February 2009
Accepted 28 February 2009
Available online 9 March 2009
Keywords:
(Pyrazol-1-ylmethyl)pyridine ligands
Platinum complexes
Gold complexes
C–H activation
Antitumor activity
HAuCl4 ꢀ 4H2O in
a mixture of ethanol and water to form the gold salts [AuCl2(L1)][AuCl4] (5)
[AuCl2(L2)][Cl] (6) [AuCl2(L3)][Cl] (7) and [AuCl2(L4)][AuCl4] (8); however, with the pyrazolyl unit in
the para position of the pyridinyl ring in 4-(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L5), 4-(3,5-diph-
enylpyrazol-1-ylmethyl)pyridine (L6) neutral gold complexes [AuCl3(L5)] (9) and [AuCl2(L6)] (10) were
formed; signifying the role the position of the pyrazolyl group plays in product formation in the gold
reactions. X-ray crystallographic structural determination of L6, 2, 3 3a, 8 and 10 were very important
in confirming the structures of these compounds; particularly for 3a and 8 where the presence of the
acetonyl group confirmed C–H activation and for 8 where the counter ion is AuCl4ꢁ. Cytotoxicity studies
of L2, L4 and complexes 1–10 against HeLa cells showed the Au complexes were much less active than
the Pt complexes.
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
Me
Pt
Extensive study of metals in medicine is largely due to the ap-
proval of cisplatin as a cancer drug more than three decades ago
[1]. Although it is still one of the most widely used drugs in the
world, the impetus to find new drugs stems from drug resistance
[2–4] and severe side effects associated with the use of cisplatin
[5,6]. It has been suggested that the reaction of cisplatin with some
kidney enzymes’ sulfhydryl groups is responsible for the drug’s
most severe side effects [7,8]. Over the years considerable amount
of interest has focused on the use of pyridine platinum(II) com-
plexes as mimics of cisplatin [9–13]. These studies have shown
that the use of planar ligands, such as the substituted pyridines
(I–III) in platinum(II) complexes, can reduce the rate of deactiva-
tion by sulfhydryl groups without interfering with DNA binding,
considered to be the mode of action of cisplatin [11,12].
H2N
H2N
Cl
N
Pt
N
Cl
Cl
R = H (I), Me (II)
Cl
(III)
Several non-platinum metal complexes have also been studied as
potential anticancer agents [13]. The rationale for these studies is
that metal centers other than platinum might produce improved
anticancer activity in vitro and in vivo. Gold(III) is one such metal
ion which typically adopts a four-coordinate, square-planar geome-
try and is therefore expected to mimic the structural and electronic
properties of platinum(II). Recent studies have shown that several
gold(III) complexes are highly cytotoxic against different tumor
cells [14–16], including some which are active even against the cis-
platin-resistant cell lines [17–20]. Unfortunately, the use of gold(III)
* Corresponding author.
E-mail address: jdarkwa@uj.ac.za (J. Darkwa).
Present address: School of Chemistry, University of KwaZulu Natal, Westville
1
Campus, Private Bag X54001, Durban, South Africa.
0020-1693/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2009.02.046

T.V. Segapelo et al. / Inorganica Chimica Acta 362 (2009) 3314–3324
3315
complexes is often limited by their instability under physiological
conditions, attributed to their high reduction potential and fast
hydrolysis rate [17,21]. These problems can possibly be circum-
vented by forming gold(III) compounds with one or more multiden-
tate nitrogen-donor ligands to enhance the stability of gold(III)
complexes [21–23].
Recent reports that pyrazoles and substituted pyrazoles plati-
num complexes show cytotoxicity, while exhibiting lower toxicity
than cisplatin [24,25], suggest that pyrazolyl ligands could stabilize
gold(III) centers and overcome complex instability under physio-
logical conditions. We have used pyrazolyl–pyridine ligands to
prepare new platinum(II) and gold(III) complexes, as well as inves-
tigate their anticancer activity.
the two types of complexes could be separated by recrystallization
and revealed that the dichloro complexes were the major constit-
uents of the mixtures. In one such separation acetonitrile solvated
crystals of 2 could be isolated from the mixture as established from
its crystal structure (Supplementary material CCDC 697856). Inter-
estingly, all attempts to prepare what would have been 1a resulted
in isolation of the dichloroplatinum(II) complex 2, most likely be-
cause it precipitated before it could be converted to its ketonyl
analogue. Based on this observation it is reasonable to suggest that
the formation of the monoacetonyl complexes is preceded by the
formation of dichloro analogues. On prolonged heating (ca. 2 days)
yields of 2 and 3 improved but with the formation of a more
insoluble diacetonylplatinum(II) complex 2b in the case of 2.
Acetonylplatinum(II) complexes have been shown to undergo dis-
proportionation to form the diacetonylplatinum(II) complexes
[27]. It can therefore be inferred that the diacetonylplatinum com-
plex 2b is formed as a secondary disproportionation product as de-
picted in Scheme 3.
2. Results and discussion
2.1. Preparation of ligands
1H NMR spectrum of 3a showed AB doublets for CH2 protons in
the ligand backbone at 6.57 and 5.72 ppm as two diastereotopic
protons (axial and equatorial) that do not interconvert on the
NMR time-scale. A distinguishing feature of spectrum of 3a is a
doublet resonance at 3.03 ppm, flanked by 195Pt satellites, assigned
to the methylene protons of the Pt–CH2 bond. This chemical shift is
comparable to a bipyridyl Pt–acetonyl complex reported by Falv-
ello et al. [28]. Because of the poor solubility of 2a evidence for
the presence of the acetonyl functionality was provided by IR spec-
troscopy. A peak in the IR spectrum of 2a at 1602 cmꢁ1 was as-
Six (pyrazolylmethyl)pyridine ligands were used to prepare
platinum(II) and gold(III) complexes. These ligands were synthe-
sized using the literature procedure reported for L1 [26] (Scheme
1). These ligands had to be washed with copious amounts of water
in order to remove the phase transfer catalyst used in their prepa-
ration which would otherwise coordinate to the metal precursors
used in complexation of L1–L6. The two ligands prepared from
3,5-dimethypyrazole (L1 and L5) were obtained as yellow and
red oils, while those prepared from diphenylpyrazole (L2 and L6),
di-tert-butylpyrazole (L3) and p-tolylpyrazole (L4) were obtained
as off-white to light brown solids. Ligands with bulky substituents
on the pyrazolyl moiety (L2, L3 and L6) required reaction times of
at least 72 h to ensure reasonable yields and all of them were char-
acterized by 1H and 13C NMR spectroscopy, and elemental analy-
ses. The structure of L6 was confirmed by X-ray crystallography
(Fig. 1 and Table 1) and had no special features.
signed to the
m(C@O) stretching mode of the acetonyl ligand.
Peaks for related nitrogen-donor platinum–acetonyl complexes
are [Pt(CH2COCH3)Cl(bipy)] (1639 cmꢁ1
) [29], trans-[Pt(CH2-
COCH3)2(bipy)] (1648 cmꢁ1) [30] and [Pt(CH2COCH2CH3)2(bipy)]
(1642 cmꢁ1) [30].
The molecular structure of 3a (Fig. 2) confirmed presence of the
acetonyl ligand. The platinum atom is coordinated to the (pyrazol-
1-ylmethyl)pyridine ligand through the pyridyl nitrogen atom
N(1), the pyrazolyl nitrogen N(3), to a chlorine atom, Cl(1), and
to the acetonyl ligand through the methylene carbon C(18). The
Pt–N bond distances of Pt(1)–N(1) (2.149 (3) Å) and Pt(1)–N(3)
(2.021(3) Å) are typical, with the longer Pt–N distance being trans
to the acetonyl ligand. This is longer than the bond distance ob-
served for ketonyl bipyridine platinum complexes, with Pt–N bond
distances of 2.082(3) and 2.091(3) Å for a diketonyl complex [31]
and 2.082(11) Å for a monoketonyl complex [28]. The Pt(1)–
C(18) distance of 2.077 (3) Å and the Pt(1)–Cl(1) distance of
2.3059 (8) Å are typical of these kinds of bonds. The C@O distance
in the acetonyl ligand of 1.222 (4) Å is also typical of similar com-
pounds [32–34].
2.2. Preparation of (pyrazol-1-ylmethyl)pyridine platinum(II)
complexes in water–acetone mixture: formation of acetonyl
platinum(II) compounds
Ligands L1–L3 reacted with K2[PtCl4] in a mixture of water and
acetone at 60 °C (Scheme 2). Except in the case of L1 that afforded
1 as the sole product in quantitative yield, L2 and L3 produced
mixtures of the dichloroplatinum(II) complexes 2 and 3, and the
monoacetonylplatinum(II) complexes 2a and 3a. The mixtures of
R'
R
R'
N
N
Cl
N
N
H
2.3. Preparation of (pyrazol-1-ylmethyl)pyridine platinum(II)
complexes in water–ethanol mixture
N
N
TBAB, NaOH, Benzene
R
In view of the C–H activation observed with acetone, acetone
was replaced with ethanol in order to isolate complexes 1–4
(Scheme 4). The complexes precipitated from the reaction medium
and could easily be isolated by filtration. Complexes 1 and 4 were
sparingly soluble but both 2 and 3 were soluble in common organic
solvents, and could be characterized by 1H and 13C NMR spectros-
copy, and in the case of 2 and 3 by X-ray crystallography. The 1H
NMR spectra of all complexes showed AB doublets for CH2 protons
in the ligand backbone with coupling constants of between 14.7
and 15.6 Hz, typical for geminal coupling. These peaks confirm
the presence of two diastereotopic protons and are a distinguishing
feature between the complexes and their respective ligands.
Molecular structures for 2 and 3 are shown in Figs. 3 and 4,
respectively, and their crystallographic data is in Table 1. The
Position
R
Me
Ph
R’
Ligand
L1
2-
2-
2-
2-
4-
4-
Me
Ph
L2
tBu
p-Tol
Me
Ph
tBu
H
L3
L4
Me
Ph
L5
L6
Scheme 1. Preparation of ligands L1–L6.

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T.V. Segapelo et al. / Inorganica Chimica Acta 362 (2009) 3314–3324
Fig. 1. Ortep diagram of L6 drawn with 50% probability ellipsoids. Selected interatomic distances (Å) and angles (°) for L6. C(5)–C(6) 1.5135(17); C(14)–C(15) 1.4060(17);
N(2)–N(3) 1.3630(14); C(1)–N(1) 1.343(2); C(2)–N(1) 1.3373(19); C(7)–N(2) 1.3643(15); C(15)–N(3) 1.3418(15); C(6)–N(2) 1.4598(15); N(2)–C(6)–C(5) 114.94(10), C(2)–
N(1)–C(1) 115.70(12); N(3)–N(2)–C(7) 112.20(10); C(15)–N(3)–N(2) 104.84(10).
Table 1
Crystallographic data for L6, 2, 3a, 3, 8 and 10.
L6
2
3a
3
8
10
Empirical formula
Formula weight
T (K)
C21H17N3
311.38
173(2)
C21H17Cl2N3Pt
577.37
105(2)
C20H30ClN3OPt
559.01
105(2)
C17H25Cl2N3Pt
537.39
105(2)
C16H15Au2Cl6N3
855.94
100(2)
C21H17Au Cl3N3
614.69
100(2)
Wavelength (Å)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
0.71073
monoclinic
P21/n
12.1849(7)
10.4719(6)
13.7416(8)
90
0.71073
monoclinic
P21/n
12.1148(8)
14.6424(9)
12.2761(8)
90
0.71073
monoclinic
P21/c
10.2878(7)
22.1057(15)
10.4044(7)
90°
0.71073
monoclinic
P21/n
12.2277(9)
11.2407(8)
13.4521(10)
90
0.71073
monoclinic
P21/c
6.9788(4)
36.4603(18)
8.5149(4)
90
0.71073
monoclinic
P21/n
10.0555(5)
9.1926(4)
22.4962(11)
90
a
(°)
b (°)
110.875(3)
90
1638.32(16)
4
1.262
7.600
116.8030(10)
90
1943.7(2)
4
1.973
7.505
117.4910(10)
90
2099.0(2)
4
1.769
91.5010(10)
90
1848.3(2)
4
1.931
7.883
101.7540(10)
90
2121.18(19)
4
2.680
14.581
91.7560(10)
90
2078.49(17)
4
1.964
7.476
c
(°)
V (Å3)
Z
Density (calculated) (Mg/m3)
Absorption coefficient
6.826
(mmꢁ1
)
Crystal size (mm3)
Reflections collected
Absorption correction
0.50 ꢂ 0.46 ꢂ 0.30
15648
multi-scan with
SADABS
0.46 ꢂ 0.15 ꢂ 0.14
26591
multi-scan with
SADABS
0.27 ꢂ 0.11 ꢂ 0.06
28775
empirical with
SADABS
0.21 ꢂ 0.12 ꢂ 0.08
27248
empirical with
SADABS
0.43 ꢂ 0.32 ꢂ 0.25
27325
multi-scan with
SADABS
0.39 ꢂ 0.35 ꢂ 0.29
29247
multi-scan with
SADABS
Maximum and minimum
transmission
0.978 and 0.940
0.4197 and 0.1297
0.6849 and 0.2601
0.5712 and 0.2883
0.1215 and 0.0619
0.2204 and 0.1586
Goodness-of-fit (GOF) on F2
1.168
0.960
1.023
1.067
1.111
1.007
Final R indices [I > 2
r(I)]
R1 = 0.0449,
wR2 = 0.1118
R1 = 0.0619,
wR2 = 0.1190
R1 = 0.0153,
wR2 = 0.0394
R1 = 0.0173,
wR2 = 0.0405
R1 = 0.0243,
wR2 = 0.0490
R1 = 0.0400,
wR2 = 0.0537
R1 = 0.0307,
wR2 = 0.0636
R1 = 0.0575,
wR2 = 0.0752
R1 = 0.0253,
wR2 = 0.0616
R1 = 0.0291,
wR2 = 0.0629
R1 = 0.0181,
wR2 = 0.0440
R1 = 0.0189,
wR2 = 0.0443
R indices (all data)
geometry around both metals is distorted square-planar. While the
metric parameters of 2 and 3 fall in the usual ranges, it is interest-
ing to comment on the difference in the Pt(1)–N(3) bond lengths in
the two complexes. The Pt(1)–N(3) bond in 2 is 0.022 Å shorter,
and the difference is statistically significant. This fact is in accord
with the ligand steric requirement expressed by their solid angles
but in contrast to their minimum volumes [the volumes calculated
assuming all space about the ligand is accessible by a probe atom
or a solvent molecule]. Ligand L2 shields 42.7% (5.36 sr) of the
Pt1 coordination sphere while L3 shields 44.5% (5.59 sr) [35]. The

T.V. Segapelo et al. / Inorganica Chimica Acta 362 (2009) 3314–3324
3317
N
N
K2[PtCl4]
Cl
Pt
N
N
R
R
N
N
H2O : (CH3)2CO (1:4)
Cl
R
R
1- 3
+
N
Pt
N
R
O
N
Cl
R
Fig. 2. A molecular drawing of 3a drawn with 50% probability ellipsoids. All
hydrogen atoms were omitted for clarity. Selected interatomic distances (Å) and
angles (°) for 3a: Pt(1)–N(1) 2.149(3); Pt(1)–N(3) 2.021(3); Pt(1)–C(18) 2.077(3);
Pt(1)–Cl(1) 2.3059(8); O(1)–C(19) 1.222(4); N(3)–Pt(1)–C(18) 90.41(11); N(3)–
Pt(1)–N(1) 85.17(10); C(18)–Pt(1)–Cl(1) 87.65(9); N(1)–Pt(1)–Cl(1) 96.50(7),
C(18)–Pt(1)–N(1) 174.17(10); N(3)–Pt(1)–Cl(1) 175.73(7).
2a, 3a
R= Me (1), Ph (2), tBu (3)
Scheme 2.
N
N
Cl
Cl
2
H2O : (CH3)2CO (1:4)
Pt
N
Pt
N
N
N
Ph
Ph
N
N
Cl
K2[PtCl4]
Cl
Pt
N
N
R'
R'
N
N
O
H2O : EtOH (1:1)
Ph
Cl
Ph
2a
2
+
R
R
R
R’
Me
Ph
tBu
H
Complex
O
N
Me
Ph
1
2
3
4
Pt
N
Ph
N
tBu
p-tol
O
Ph
2b
Scheme 4.
Scheme 3. Disproportionation of 2a to a diacetonyl complex
metal–ligand distances may noticeably affect the solid angles.
The presence of an acetonyl ligand in 3a resulted in a substantially
more congested environment (see the buried volumes) about the
Pt center, however, the congestion does not manifest itself in an
elongation of Pt–N(pz) and Pt–Cl bond distances. Thus, the larger
Pt–N(py) distance in 3a as compared to that in 3 is a consequence
of the acetonyl trans-influence only, and not a result of unfavorable
steric interactions among the ligands.
volume of L2 (281.34(8) Å3) exceeds that of L3 (267.90(9) Å3) by
13.44 Å3, however, the bulkiness of the L2 is due to the larger num-
ber of atoms in the Ph rings that do not play a role in shielding of
the central metal. We also computed the ‘‘buried volumes” [36] of
a 3.0 Å sphere about the central metals in 2 and 3 that can be used
as a measure of steric crowding in coordination compounds. The
‘‘buried volume” for ligand L2 is smaller (62.43(3) Å3) than that
for L3 (63.78(3) Å3), a result consistent with our ligand solid angle
considerations [37].
2.4. Preparation of gold(III) complexes
It is instructive to compare and contrast the ligand solid angles
in 3 and 3a since both complexes contain ligand L3. The extent to
which the bidentate L3 shields the metal center in 3a is 42.7% (5.34
sr), the ligand volume is 267.63(8) Å3, and the ‘‘buried volume” of a
3.0 Å sphere about Pt1 in 3a is 68.06(4) Å3. The L3 volumes com-
puted for 3 and 3a are in excellent agreement indicating that small
conformational changes do not affect the ligand volume. The L3’s
solid angle in 3a is smaller than in 3 by 0.25 sr (or 1.8% less effec-
tive metal shielding) due to the longer Pt1–N(py) bond distance in
3a positioned trans to the acetonyl ligand. It is well-known that
Addition of one equivalent of ethanolic solution of H[AuCl4] ꢀ
4H2O to solutions of the (pyrazol-1-ylmethyl)pyridine ligands pro-
duced new gold complexes 5–10 (Schemes 5 and 6). Interestingly,
only the methylenic protons in 5 showed AB doublets in its 1H
NMR spectrum, reminiscent of the platinum complexes. It also
took several microanalyses of samples 5–8 from different experi-
ments to establish that there were two types of anions in the gold
salts. Complexes 5 and 8 were found to have [AuCl4]ꢁ as counter
ions, whereas 6 and 7 had Clꢁ as counter ions. This is not the first

3318
T.V. Segapelo et al. / Inorganica Chimica Acta 362 (2009) 3314–3324
X
N
N
H[AuCl4]
Cl
Au
N
N
R'
R'
N
N
H2O : EtOH (1:2)
Cl
R
R
R
R’
Me
Ph
tBu
H
X
[AuCl4]-
Cl-
Complex
Me
Ph
5
6
7
8
tBu
Cl-
p-Tol
[AuCl4]-
Scheme 5.
R'
R'
Fig. 3. A molecular drawing of
2 drawn with 50% probability ellipsoids. All
hydrogen atoms were omitted for clarity. Selected interatomic distances (Å) and
angles (°) for 2: Pt(1)–N(1) 2.0220(17); Pt(1)–N(3) 2.0193(16); Pt(1)–Cl(1)
2.2902(5); Pt(1)–Cl(2) 2.2970(5); N(1)–Pt(1)–N(3) 87.02(7), N(1)–Pt(1)–Cl(2)
177.15(5); N(1)–Pt(1)–Cl(1) 89.19(5); N(3)–Pt(1)–Cl(2) 93.20(5); N(3)–Pt(1)–Cl(1)
175.72(5), Cl(1)–Pt(1)–Cl(2) 90.501(18).
N
N
N
R
R
N
H[AuCl4]
H2O : EtOH (1:1)
N
Au
Cl
N
Cl
Cl
R
R’
Complex
Me
Ph
Me
Ph
9
10
Scheme 6.
which is then converted into the isolated cationic species; stabi-
lized by the pyrazolyl unit (Scheme 7). By modifying the connectiv-
ity within the bidentate ligand and preventing its binding to the
gold centre in a k2-fashion we could isolate trichlorogold(III) com-
plexes with ligands L5 and L6. The X-ray structure of 10 confirmed
the formation of the expected trichlorogold(III) complex and sup-
ports the proposed pathway to the formation of the gold(III) salts
5–8 (Scheme 7).
The X-ray structure of 8 confirmed that the cationic salt 8 has
[AuCl4]ꢁ as a counter-ion. The six-membered metallacycle is in a
boat conformation, whereas the coordination geometry about the
gold is a distorted square-planar. The two heterocyclic rings are
not coplanar with the coordination plane of the gold centre. The
Au(1)–N(1) bond distance is (2.036(4) Å) is found to be longer than
the Au(1)–N(3) bond [2.018(4) Å]. As expected, the Au(1)–Cl(1)
bond [2.2686(12) Å] which is trans to the pyrazolyl nitrogen
N(3), is slightly longer than the Au(1)–Cl(2) bond of
2.2598(12) Å, trans to the pyridine nitrogen N(1). This can be
attributed to a greater trans influence of the pyrazolyl nitrogen.
The Au–N and Au–Cl distances are similar to Au–N [2.028(6)°]
and Au–Cl [2.251(2)°] those found for [AuCl2(N^N)][AuCl4] where
N^N = N-isopropyl-N-2-ethylpyridine [39], and other related gold-
(III) compounds [22].
Fig. 4. A molecular drawing of 3 drawn with 50% probability ellipsoids. Selected
interatomic distances (Å) and angles (°) for 3: Pt(1)–N(1) 2.012(4); Pt(1)–N(3)
2.041(4); Pt(1)–Cl(1) 2.2895(11), Pt(1)–Cl(2) 2.3069(12), N(1)–Pt(1)–N(3)
85.53(14), N(1)–Pt(1)–Cl(2) 173.99(11), N(3)–Pt(1)–Cl(1) 175.38(10); N(1)–Pt(1)–
Cl(1) 90.18(10), N(3)–Pt(1)–Cl(2) 94.74(10), Cl(1)–Pt(1)–Cl(2) 89.70(4).
example where different counter ions are formed in a gold complex
involving bidentate nitrogen ligands. Shi et al. [38] have made sim-
ilar observations for 1,4,7-triazacyclonane gold(III) salts, but for
these gold salts the stoichiometry of the reaction influenced the
cation formed. In reactions where ligand to H[AuCl4] was 1:1 the
counter ion is Clꢁ and for 2:1 ratio the counter ion was [AuCl4]ꢁ.
However, using the exact stoichiometry in our reactions did not
show a detectable impact on the nature of the counter ions ob-
served for 5–8. It is not clear to us what dictates the nature of
the counter ion formed.
It is plausible that the formation of the gold salts 5–8 are pre-
ceded by the formation of a neutral trichlorogold(III) intermediate,

T.V. Segapelo et al. / Inorganica Chimica Acta 362 (2009) 3314–3324
3319
N
N
R
H[AuCl4]
-HCl
Au
Cl
N
N
Cl
R
Cl
N
N
R
+
R
HCl
HAuCl4
-
AuCl4
+
-
AuCl4
N
Cl
Au
N
R'
N
Cl
Fig. 5. An ORTEP diagram of 8 drawn with 50% probability ellipsoids. Selected
interatomic distances (Å) and angles (°) for 8. Au(1)–N(1) 2.036(4); Au(1)–N(3)
2.018(4); Au(1)–Cl(1) 2.2686(12); Au(1)–Cl(2) 2.2598(12); N(3)–Au(1)–Cl(1)
175.82(12); N(1)–Au(1)–Cl(2) 178.12(13); N(3)–Au(1)–N(1) 86.73(17).
R
Scheme 7.
Complex 10 is also square-planar, with the gold atom coordi-
nated to three chlorine atoms and the nitrogen of the pyridine li-
gand. It is well-known that the pyrazolyl ring nitrogens are more
weakly coordinating to metal centres and also less basic than the
pyridyl ring nitrogen [40], and it is thus no surprise that the
gold(III) atom is bound through the nitrogen of the pyridine. The
Au–N(1) distance of 2.029(2) Å is similar to those found in gold(III)
complexes containing a pyridine ligand which is not strained [41–
43]. The distance between Au–Cl(2) distance trans to the pyridine
nitrogen of 2.261(2) Å is slightly shorter than those of Au(1)–
Cl(1) (2.2811(8) Å and Au(1)–Cl(3) (2.2813(8) Å) bonds which are
opposite to one another, owing to the reciprocal trans influence
of Cl atoms [44]. The Au–N and Au–Cl bond lengths are in the ex-
pected regions for gold(III) complexes [41–43] (see Figs. 5 and 6).
2.5. Cytotoxicity studies
The cytotoxicity of ligands L2 and L4 and complexes 1–10 were
evaluated against HeLa (Human adenocarcinoma of the cervix)
cancer cell line using cisplatin as standard. For comparison pur-
poses, the cytotoxic activity of cisplatin was also evaluated under
the same experimental conditions. The results from these experi-
ments are summarized as bar charts (Figs. 7 and 8). The inhibition
of the growth of normal cells by the complexes tested was also
measured by employing human lymphocytes (PBMC) cells, using
the same procedure for the HeLa cells, except that treated PBMC
cells were incubated for 3 days and not 7 days for the HeLa cells.
This allowed for the determination of tumor specificity, which
was calculated using Eq. (1)
Fig. 6. An ORTEP diagram of 10 drawn with 50% probability ellipsoids. Selected
interatomic distances (Å) and angles (°) for 10. Au(1)–N(1) 2.029(2); Au(1)–Cl(1)
2.2811(8); Au(1)–Cl(2) 2.2681(8); Au(1)–Cl(3) 2.2813(8); N(1)–Au(1)–Cl(2)
178.60(7); Cl(1)–Au(1)–Cl(3) 176.79(3), Cl(2)–Au(1)–Cl(1) 91.24(3); Cl(2)–Au(1)–
Cl(3) 91.26(3); N(1)–Au(1)–Cl(3) 88.43(7); N(1)–Au(1)–Cl(1) 89.11(7).
For the platinum complexes (Fig. 7), complexes bearing alkyl
substituents on the pyrazolyl ring (1 and 3) were less active than
those with aryl substituents (2 and 4). Although in terms of IC50
Mean IC50 of the normal cellsðstimulated þ resting lymphocytesÞ
TS ¼
Mean IC50 of the cancer cells
values, activity of 2 (IC50 = 3.849 lM) and 4 (IC50 = 8.920 lM) were
ð1Þ
approximately eight and nineteen times lower than that of cis-
platin, they were much better than those exhibited by all other
compounds tested (Figs. 7 and 8). Despite their better cytotoxicity
both were found to show poor selectivity, killing both normal and
deceased cells indiscriminately. On the other hand, the gold(III)
In doing so, the lymphocytes were divided into two. The first was
normal cells that were stimulated using PHA-P so as to increase
their proliferation rate (stimulated lymphocytes) and the second
was un-stimulated normal cells (resting lymphocytes).

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50
45
40
35
30
25
20
15
10
5
Me
Ph
tBu
p-tol
0
1
2
3
4
Cisplatin
COMPOUNDS
Fig. 7. Cytotoxicity of (pyrazolylmethyl)pyridine platinum(II) complexes
60
50
40
30
20
10
0
Me
Ph
p-tol
5
L2
6
L4
8
9
10 Cisplatin
COMPOUNDS
Fig. 8. Cytotoxicities of (pyrazolylmethyl)pyridine ligands and their gold(III) complexes.
complexes 5–10 (the best IC50 of 18.050
l
M was for 6) exhibited
reduction is possible and could explain the low activity of com-
much lower cytotoxicity compared to cisplatin, but their cytotox-
icities were better than the free ligands. The very low cytotoxcity
of the gold complexes could be due to the low stability of gold(III)
which generally reduce to gold(I). We have recently shown that the
reduction of the gold(III) complex, [AuCl2(3,5-Me2bpza)]Cl
(bpza = bis(pyrazolyl) acetic acid), is very fast (k1 = 0.8 Mꢁ1 sꢁ1 at
293 K; followed by a much slower reaction of the ensuing gold(I)
plexes 5–10.
3. Conclusions
In preparing the platinum(II) complexes the choice of solvent is
crucial in determining the products formed. When a mixture of
water–acetone is used acetonylplatinum(II) complexes are formed,
whereas the use of water–ethanol mixture affords the desired plat-
inum(II) complexes, 1–4. The C–H bonds
acetone were activated in forming the acetonylplatinum(II)
complex with
L ) [45]. A similar
-cysteine (k2 = 300.8 Mꢁ1 sꢁ1
reduction process is when the gold(III) complexes 5–10 were
tested, since in the biological milleu used in the testing such
a to an oxygen atom in

T.V. Segapelo et al. / Inorganica Chimica Acta 362 (2009) 3314–3324
3321
3
3
complexes whereas unactivated C–H bonds in ethanol were nei-
ther attacked nor oxidized.
(d, JH,H = 6.90 Hz, 1H, py), 7.57 (q, JH,H = 5.40 Hz, 1H, py), 7.13, (t,
3JH,H = 5.40 Hz, 1H, py) 6.48 (d, JH,H = 8.10 Hz, 1H, py), 5.89 (s, 1H,
3
Two types of novel gold complexes were also prepared. The
bidentate cationic gold(III) complexes (5–8) bind through both
the pyridine and pyrazole nitrogen atoms, while the neutral mono-
dentate gold(III) complexes, 9 and 10, bind exclusively through the
pyridine nitrogen atom. The gold complexes showed low cytotox-
icity when tested against HeLa cells. Some of the platinum com-
plexes showed good anticancer activity, but unfortunately
exhibited low tumor specificity.
pz), 5.57 (s, 2H, CH2–), 1.32 (s, 9H, tBu), 1.25 (s, 9H, tBu). Anal. Calc.
for C17H25N3: C, 75.23; H, 9.28; N, 15.48. Found: C, 75.18; H, 9.66;
N, 15.52%.
4.2.3. Synthesis of 2-(3-para-tolylpyrazol-1-ylmethyl)pyridine (L4)
Compound L4 was prepared from picolyl chloride hydrochlo-
ride (0.30 g, 2.33 mmol) and 3-tolylpyrazole (0.370 g, 2.33 mmol).
The product was obtained as a light brown solid. Yield = 0.373 g,
3
63%. 1H NMR (CDCl3): d 8.58 (d, JH,H = 4.5 Hz, 2H, py), 7.73 (s,
3
1H, py), 7.70 (s, 1H, py), 7.64 (t, JH,H = 4.50 Hz, 1H, py), 7.53 (d,
3
3JH,H = 2.10 Hz, 1H, pz), 7.21 (d, JH,H = 7.80 Hz, 3H, p-tolpz), 7.04
4. Experimental
3
3
(d, JH,H = 7.8 Hz, 1H, p-tolpz), 6.59 (d, JH,H = 2.10 Hz, 1H, pz),
5.50 (s, 2H, CH2–), 2.37 (s, 3H, Me-p-tolpz). 13C{1H} NMR
(300 MHz, CDCl3): d 156.81 (C2-py), 152.03 (C3-pz), 149.19 (C6-
py), 137.33 (ptol-Cpara), 137.08 (C4-py), 131.26 (C1-ptol), 130.53
(C5-pz), 129.21 (ptol-Cmeta), 125.48 (ptol-Cortho), 122.63 (C3-Py),
121.58 (C5-py), 103.3 (C4-pz), 57.56 (–CH2), 21.22 (Me-ptol) ppm.
Anal. Calc. for C16H15N3: C, 77.08; H, 6.06; N, 16.85. Found: C,
76.38; H, 6.10; N, 16.83%.
4.1. Materials and instrumentation
All manipulations were performed under a dry, deoxygenated
nitrogen atmosphere using standard Schlenk techniques. NMR
spectra were recorded on a Gemini 2000 instrument. The chemical
shifts are reported in d (ppm) referenced to residual 1H and 13C sig-
nals of deuterated chloroform as internal standard. Hexane, ben-
zene, toluene, and diethyl ether were purified by distillation from
sodium benzophenone ketyl under a nitrogen atmosphere. All
other solvents were of reagent grade and were used without fur-
ther purification, unless oxygen-free solvent was needed, then
the solvent was purged with nitrogen for ca. 15 min. Picolylchlo-
ride hydrochloride and 4-(bromomethyl)pyridine hydrobromide
and cisplatin were obtained from Aldrich, while p-tolylpyrazole
was purchased from Acros. Phosphate Buffered Saline (PBS), Eagle’s
RPMI-1640 medium, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide (MTT) kit, phytohemagglutinin-protein form
(PHA-P) and the 96-well flat-bottomed culture plates were all pur-
chased from BD Biosciences Ltd. All chemicals were used as re-
ceived. Diphenylpyrazole [46] and di-tert-butylpyrazole [47]
were prepared following literature procedures.
4.2.4. Synthesis of 4-(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L5)
Compound L5 was prepared from 4-(bromomethyl)pyridine
hydrobromide (1.00 g, 3.95 mmol) and 3,5-dimethylpyrazole
(0.380 g, 3.95 mmol). The product was obtained as red oil.
3
Yield = 0.70 g, 95%. 1H NMR (CDCl3): d 8.53 (d, JH,H = 5.40 Hz, 2H,
3
H2,6-py), 6.93 (d, JH,H = 6.20 Hz, 2H, H3,5-py), 5.89 (s, 1H, H4-pz),
5.22 (s, 2H, –CH2–), 2.24 (s, 3H, Me-pz), 2.14 (s, 3H, Me-pz).
13C{1H} NMR (CDCl3): d 148.5 (C3-pz), 147.60 (C2,6-py), 138.65
(C4-py), 134.0 (C3,5-py), 105.4 (C4-pz), 49.5 (–CH2), 13.0 (Me-pz),
10.0 (Me-pz) ppm.
4.2.5. Synthesis of 4-(3,5-diphenylpyrazol-1-ylmethyl)pyridine (L6)
Compound L6 was prepared from 4-(bromomethyl)pyridine
hydrobromide (0.98 g, 3.88 mmol) and 3,5-diphenylpyrazole
(0.85 g, 3.88 mmol), the mixture was refluxed for 72 h. The product
was obtained as colorless crystals. Yield = 0.78 g, 65%. 1H NMR
4.2. Preparation of ligands
3
4
4.2.1. Synthesis of 2-(3,5-diphenylpyrazol-1-ylmethyl)pyridine (L2)
(300 MHz, CDCl3, 25 °C): d 8.55 (dd, JH,H = 2.80 Hz, JH,H = 1.60 Hz,
2H, H3,5-py), 7.88 (d, 2H, Ph, 3JH,H = 10.0 Hz), 7.36 (m, 8H, Ph), 7.06
(d, 2H, H2,6-py, JH,H = 5.80 Hz), 6.71 (s, 2H, H4-pz), 5.41 (s, 2H,
A
mixture of 2-picolylchloride hydrochloride (0.25 g, 1.53
3
mmol) and 3,5-diphenylpyrazole (0.34 g, 1.53 mmol) was dis-
solved in benzene (40 mL), to which 40% aqueous NaOH (12 mL)
and 10 drops of 40% aqueous tetrabutylammonium bromide
(TBAB) was added. The mixture was refluxed for 72 h after which
the organic phase was extracted and evaporated under reduced
pressure to afford yellow oil. The oil was redissolved in dichloro-
methane and washed with water to remove the phase transfer cat-
alyst and the organic extract evaporated to give an off-white solid.
–CH2–). 13C{1H} NMR (75 MHz, CDCl3, 25 °C): d 151.5 (C3-pz),
150.1 (C2,6-py), 146.6 (C5-pz), 145.7 (C4-py), 133.0 (Ph), 130.0
(Ph), 128.9 (Ph), 128.8 (Ph), 128.6 (Ph), 127.9 (Ph), 125.6 (Ph),
121.4 (C3,5-py), 103.9 (C4-pz), 52.1 (–CH2) ppm. Anal. Calc. for
C21H17N3: C, 81.00; H, 5.50; N, 13.49. Found: C, 80.75; H, 5.42; N,
13.47%.
Yield = 0.41 g, 84%. 1H NMR (300 MHz, CDCl3, 25): d 8.57 (d, 3JH,H
=
4.3. Preparation of (pyrazolylmethyl)pyridine platinum(II) complexes
4.40 Hz, 1H, H6-py), 7.90 (d, 3JH,H = 1.40 Hz, 1H, H3-py), 7.86 (s, 1H,
H5-py), 7.58 (td, 3JH,H = 7.60 Hz, 1H, H4-py), 7.39 (m, 10H, Ph), 6.70
(s, 1H, H4-pz), 5.54 (s, 2H, –CH2–). 13C{1H} NMR (75 MHz, CDCl3,
25): d 157.7 (C2-py), 151.4 (C3-pz), 149.3 (C6-py), 145.9 (C5-pz),
137.0 (Ph), 133.2 (C4-py), 130.2 (Ph), 128.7 (Ph), 128.6 (Ph),
127.8 (Ph), 125.7 (C3-py), 122.3 (C5-py), 103,7 (C4-pz), 55.0
(–CH2) ppm. Anal. Calc. for C21H17N3: C, 81.00; H, 5.50; N, 13.49.
Found: C, 81.10; H, 5.37; N, 13.05%.
4.3.1. Synthesis of dichloro[2-(3,5-dimethylpyrazol-1-
ylmethyl)pyridine]platinum(II) (1)
To a stirred solution of L1 (0.094 g, 0.50 mmol) in ethanol
(5 mL) was added dropwise an aqueous solution (5 mL) of K2[PtCl4]
(0.21 g, 0.50 mmol). The resulting solution was heated at 60 °C for
16 h, after which the precipitated yellow solid was collected by fil-
tration, washed with water and ether and dried. Yield = 0.19 g, 85%.
3
1H NMR (300 MHz, DMSO-d6, 25 °C): d 8.94 (d, JH,H = 6.90 Hz, 1H,
Ligands L3–L6 were prepared following the same procedure for
L2.
py), 8.13 (t, 3JH,H = 7.80 Hz, 1H, py), 7.94 (d, 3JH,H = 6.90 Hz, 1H, py),
3
7.56 (t, JH,H = 7.80 Hz, 1H, py), 6.13 (s, 1H, pz), 5.84 (d,
2
2JH,H = 15.6 Hz, 1H, –CH2), 5.65 (d, JH,H = 15.6 Hz, 1H, –CH2,), 2.43
4.2.2. Synthesis of 2-(3,5-di-tert-butylpyrazol-1-ylmethyl)-
pyridine (L3)
Compound L3 was prepared from picolyl chloride hydrochlo-
ride (0.50 g, 3.05 mmol) and 3,5-tert-butylpyrazole (0.55 g, 3.05
mmol), and the mixture was refluxed for 72 h. The product was ob-
tained as a white solid. Yield = 0.63 g, 76%. 1H NMR (CDCl3): d 8.52
(s, 3H, Me), 2.41 (s, 3H, Me). 13C{1H} NMR (75 MHz, DMSO-d6,
25 °C): d 153.5 (C2-py), 152.5 (C3-pz), 150.9 (C6-py), 142.5 (C4-
py), 140.5, 126.2 (C3-py), 125.7 (C5-py), 107.7 (C4-pz), 52.6
(–CH2), 13.9 (Me), 11.2 (Me) ppm. Anal. Calc. for C11H13Cl2N3Pt:
C, 29.15; H, 2.89; N, 9.27. Found: C, 28.90; H, 2.79; N, 9.02%.

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4.4. Compounds 2–4 were prepared following the same procedure
for 1
4.5. Preparation of (pyrazolylmethyl)pyridine gold(III) complexes
4.5.1. Synthesis of dichloro[2-(3,5-dimethylpyrazol-1-
4.4.1. Synthesis of dichloro 2-(3,5-diphenylpyrazol-1-
ylmethyl)pyridine]gold(III) tetrachloro-aurate (5)
ylmethyl)pyridine platinum(II) (2)
To a solution of L1 (0.20 g, 1.07 mmol) in ethanol (10 mL) was
added dropwise an aqueous solution (5 mL) of H[AuCl4] ꢀ 4H2O
(0.44 g, 1.07 mmol). The solution became turbid followed by pre-
cipitation of the expected product within 5 min. After 30 min the
yellow precipitate was filtered, washed with copious amounts of
water and diethyl ether, and then dried under vacuum.
Yield = 0.15 g, 35%. 1H NMR (300 MHz, CD3CN, 25 °C): d 9.04 (d,
Compound 2 was prepared using L2 (0.10 g, 0.33 mmol) and
K2[PtCl4] (0.14 g, 0.33 mmol). The product was product was ob-
tained as a cream white solid. Yield = 0.17 g, 86%. Crystals of 2 suit-
able for X-ray structure determinations were obtained from
acetonitrile solution by slow evaporation of solvent at room tem-
perature in the dark. 1H NMR (300 MHz, CD3CN, 25 °C): d 9.20 (d,
3JH,H = 5.10 Hz, 1H, py), 8.28 (d, JH,H = 7.80 Hz, 1H, py), 8.27 (d,
3JH,H = 6.0 Hz, 1H, py), 8.35 (t, JH,H = 7.8 Hz, 1H, py), 8.00 (d,
3
3
3
3
3JH,H = 7.80 Hz,1H, py), 8.00 (t, JH,H = 7.50 Hz, 1H, py), 7.54 (m,
3JH,H = 7.8 Hz, 1H, py), 7.86 (t, 1H, py, JH,H = 7.5 Hz), 6.34 (s, 1H,
2
2
2
10H, Ph), 6.77 (s, 1H, pz), 6.20 (d, JH,H = 15.3 Hz, 1H, –CH2), 5.34
pz), 5.82 (d, JH,H = 16.5 Hz, 1H, –CH2) 5.65 (d, JH,H = 16.5 Hz, 1H,
–CH2), 2.59 (s, 3H, Me), 2.48 (s, 3H, Me). 13C{1H} NMR (75 MHz,
CD3CN, 25 °C): d 153.2 (C2-py), 152.3 (C3-pz), 150.3 (C6-py),
147.8 (C5-pz), 146.5 (C4-py), 129.7 (C3-py), 129.4 (C5-py), 110.7
(C4-pz), 53.7 (–CH2), 14.7 (Me), 12.2 (Me) ppm. Anal. Calc. for
C11H13Au2Cl6N3: C, 16.64; H, 1.65; N, 5.29. Found: C, 16.91; H,
1.58; N, 5.11%.
2
(d, JH,H = 15.3 Hz, 1H, –CH2). 13C{1H} NMR (75 MHz, CD3CN,
25 °C): d 154.8 (C2-py), 141.3 (C3-py), 131.3 (C6-py), 130.4 (C4-
py), 130.2 (Ph), 129.8 (Ph), 128.9 (Ph), 127.3 (Ph), 126.7 (Ph),
108.9 (C4-pz), 55.7 (–CH2) ppm. Anal. Calc. for C21H17Cl2N3Pt: C,
43.69; H, 2.97; N, 7.28. Found: C, 42.06; H, 2.99; N, 6.68%.
Complexes 6–8 were prepared following the same procedure
used for 5.
4.4.2. Synthesis of dichloro 2-(3,5-di-tert-butylpyrazol-1-
ylmethyl)pyridineplatinum(II) (3)
Compound 3 was prepared from L3 (0.06 g, 0.22 mmol) and
K2PtCl4 (0.09 g, 0.22 mol). The product was product was obtained
as a light brown solid. Yield = 0.10 g, 86%. Recrystallization from
a mixture of dichloromethane and hexane in the dark at room tem-
perature gave colorless crystals of 3 suitable for X-ray structure
4.5.2. Synthesis of dichloro[2-(3,5-diphenylpyrazol-1-
ylmethyl)pyridine]gold(III) chloride (6)
Compound 6 was prepared from L2 (0.15 g, 0.48 mmol) and
H[AuCl4] ꢀ 4H2O (0.20 g, 0.48 mmol). The product precipitated as
a yellow solid but was obtained as orange solid after recrystalliza-
tion from dichloromethane and hexane. Yield = 0.13 g, 44%. 1H
determination. 1H NMR (300 MHz, CDCl3, 25 °C):
d 9.12 (d,
3
3JH,H = 6.00 Hz, 1H, py), 7.91 (t, JH,H = 6.30 Hz, 1H,py), 7.49 (d,
3
3JH,H = 7.50 Hz, 1H, py), 7.41 (t, JH,H = 6.30 Hz, 1H, py), 6.66 (d,
3
NMR (300 MHz, CDCl3, 25 °C): d 8.73 (d, JH,H = 5.10 Hz, 1H, py),
3
3
2JH,H = 14.7 Hz, 1H, –CH2), 6.00 (s, 1H, pz), 5.52 (d, JH,H = 14.7 Hz,
2
8.04 (t, JH,H = 7.8 Hz, 1H, py), 7.89 (d, JH,H = 5.10 Hz, 1H, py),
3
1H, –CH2), 1.69 (s, 9H, tBu), 1.45 (s, 9H, tBu). 13C{1H} NMR
(75 MHz, CDCl3, 25 °C): d 154.2 (C2-Py), 148.5 (C3-pz), 139.2 (C6-
py), 126.1 (C3-py), 124.1 (C5-py), 104.7 (C4-pz), 53.4 (–CH2), 31.5
(tBu), 30.1 (tBu) ppm. Anal. Calc. for C17H25Cl2N3Pt: C, 38.00; H,
4.69; N, 7.82. Found: C, 37.49; H, 4.64; N, 7.65%.
7.62 (t, JH,H = 7.80 Hz, 1H, py), 7.45 (m, 10H, Ph), 6.81 (s, 1H, pz),
6.06 (s, 2H, –CH2). 13C{1H} NMR (300 MHz, CDCl3, 25 °C): d 157.7
(C2-py), 151.4 (C3-pz), 149.3 (C6-py), 145.9 (C5-pz), 137.0 (Ph),
133.2 (C4-py), 130.2 (Ph), 128.7 (Ph), 128.6 (Ph), 127.8 (Ph),
125.7 (C3-py), 122.3 (C5-py), 103,7 (C4-pz), 55.0 (–CH2) ppm. Anal.
Calc. for C21H17AuCl3N3: C, 41.03; H, 2.79; N, 6.84. Found: C, 40.40;
H, 2.61; N, 6.42%.
4.4.3. Synthesis of 3a
To a refluxing stirred solution of L3 (0.10 g, 0.37 mmol) in ace-
tone (20 mL) was added dropwise with stirring, an aqueous solu-
tion (5 mL) of K2PtCl4 (0.15 g, 0.37 mmol). The resulting solution
was heated at 60 °C for 16 h. The precipitated green fluffy solid
was collected by filtration, washed with water and ether and dried.
Yield = 0.11 g, 54%. Recrystallization from a mixture of dichloro-
methane and hexane in the dark at room temperature gave color-
less crystals of 3a suitable for X-ray structure determination. 1H
4.5.3. Synthesis of dichloro[2-(3,5-di-tert-butylpyrazol-1-
ylmethyl)pyridine]gold(III) chloride (7)
Compound 7 was prepared from L3 (0.09 g, 0.32 mmol) and
H[AuCl4] ꢀ 4H2O (0.13 g, 0.32 mmol). The product was obtained as
a yellow powder after recrystallization from dichloromethane
and hexane. Yield = 0.11 g, 60%. 1H NMR (300 MHz, CD3CN,
3
3
25 °C): d 8.97 (d, JH,H = 5.70 Hz, 1H, py), 8.10 (t, JH,H = 7.80 Hz,
3
3
1H, py), 7.70 (t, JH,H = 6.90 Hz, 1H, py), 6.48 (d, JH,H = 7.80 Hz,
1H, py), 6.16 (s, 1H, pz), 5.96 (s, 2H, –CH2), 1.58 (s, 9H, tBu), 1.45
(s, 9H, tBu). 13C{1H} NMR (75 MHz, CD3CN, 25 °C): d 159.0 (C2-
Py), 154.3 (C3-pz),150.6 (C6-py), 144.8 (C5-pz), 128.4 (C3-py),
128.1 (C5-py), 102.6 (C4-pz), 56.5 (–CH2), 30.7 (tBu), 30.4 (tBu).
Anal. Calc. for C17H25AuCl3N3: C, 35.53; H, 4.38; N, 7.31. Found:
C, 35.13; H, 3.93; N, 6.91%.
3
NMR (300 MHz, CD3CN, 25 °C): d 8.88 (d, JH,H = 6.30 Hz, 1H, py,),
3
3
7.99 (t, JH,H = 6.00 Hz, 1H, py), 7.67 (d, JH,H = 8.1 Hz, 1H, py),
3
2
7.45 (t, JH,H = 6.00 Hz, 1H, py), 6.57 (d, JH,H = 15.3 Hz, 1H, –CH2),
2
6.19 (s, 1H, pz), 5.72 (d, JH,H = 15.3 Hz, 1H, –CH2), 3.03 (s, 1H,
–CH2-Pt), 2.98 (s, 1H, –CH2-Pt), 1.68 (s, 1H, Me), 1.55 (s, 9H, tBu),
1.41 (s, 9H, tBu). 13C{1H} NMR (75 MHz, CD3CN, 25 °C): d 180.5
(–C@O), 154.5 (C2-py), 141.3 (C3-py), 127.2 (C6-py), 126.1 (C4-
py), 105.9 (C4-pz), 56.8 (–CH2), 53.9 (Pt-CH2), 34.1 (tBu),
32.7(tBu), 31.8 (tBu), 30.2 (tBu), 20.6 (Me) ppm. Anal. Calc. for
C19H28ClN3OPt: C, 41.87; H, 5.18; N, 7.71. Found: C, 42.03; H,
5.37; N, 7.87%.
4.5.4. Synthesis of dichloro[2-(3-para-tolylpyrazol-1-
ylmethyl)pyridine]gold(III) tetrachloro-aurate (8)
Compound 8 was prepared from L4 (0.12 g, 0.48 mmol) and
H[AuCl4] ꢀ 4H2O (0.12 g, 0.48 mmol). The product was obtained as
a red solid. Yield = 0.17 g, 42%. Red crystals of 9 suitable for X-ray
structure determination were obtained by slow evaporation of ace-
tonitrile solution at room temperature. 1H NMR (CD3CN): d 7.80 (d,
1H, pz, 3 JH,H = 2.40 Hz), 7.78 (s, 1H, py), 7.73 (s, 1H, py), 7.27 (s, 2H,
4.4.4. Synthesis of dichloro 2-(3-p-tolylpyrazol-1-
ylmethyl)pyridineplatinum(II) (4)
Compound 4 was prepared from L4 (0.09 g, 0.35 mmol) and
HAuCl4 (0.14 g, 0.35 mmol). The product was product was obtained
3
Ph), 7.25 (s, 2H, Ph), 6.76 (d, 1H, pz, JH,H = 2.40 Hz), 5.74 (s, 2H,
–CH2), 2.36 (s, 3H, ptol). 13C{1H} NMR (75 MHz, CD3CN, 25): d
149.1 (2-py), 142.7 (C3-pz), 139.3 (6-py), 134.6 (ptol-para), 131.2
(4-py), 131.2 (C1-ptol), 130.4 (C5-pz), 129.2 (ptol-meta), 128.1
as
a pale brown solid. Yield = 0.14 g, 80%. Anal. Calc. for
C16H15N3PtCl2: C, 37.29; H, 2.93; N, 8.15. Found: C, 37.45; N,
2.91; H, 7.81%.

T.V. Segapelo et al. / Inorganica Chimica Acta 362 (2009) 3314–3324
3323
(ptol-ortho), 127.7 (3-py), 126.7 (5-Py), 104.8 (C4-pz), 52.5 (–CH2),
21.3 (Me-ptol) ppm. Anal. Calc. for C16H15Au2Cl6N3: C, 22.45, H,
1.77; N, 4.91. Found: C, 23.10; H, 1.75; N, 4.84%.
pared MTT (5 mg/mL) was added to each well and the cells incu-
bated for another 4 h. Cell survival was evaluated by measuring
absorbance at 570 nm, using a Whittaker Microplate Reader
2001. The IC50 values were calculated with the GRAPHPAD pro-
gramme. All experiments were performed in triplicates.
4.5.5. Synthesis of trichloro[4-(3,5-dimethylpyrazol-1-
ylmethyl)pyridine]gold(III) (9)
To a solution of L5 (0.03 g, 0.17 mmol) in ethanol (2 mL) was
added dropwise a solution of H[AuCl4] ꢀ 4H2O (0.07 g, 0.17 mmol)
also dissolved in ethanol (2 mL). A precipitate formed within
3 min. The yellow precipitate was filtered, washed with water fol-
lowed by ether, and then dried under vacuum. Yield = 0.06 g, 72%.
Acknowledgements
We gratefully acknowledge financial support for this work from
Project AuTek (Mintek and Harmony gold, South Africa) and the
University of Johannesburg. We also wish to thank the Pharmacol-
ogy department at the University of Pretoria for screening our
compounds for their anticancer activity.
3
1H NMR (300, CDCl3, 25 °C): d 8.81 (d, JH,H = 6.30 Hz, 2H, py) 7.90
3
(d, JH,H = 6.30 Hz, 2H, py), 5.94 (s, 1H, pz), 5.34 (–CH2). Anal. Calc.
for C11H13AuCl3N3: C, 26.93; H, 2.67; N, 8.57. Found: C, 26.60; H,
2.60; N, 8.00%.
Appendix A. Supplementary material
4.5.6. Synthesis of trichloro[4-(3,5-diphenylpyrazol-1-
ylmethyl)pyridine]gold(III) (10)
CCDC 697852, 697857, 697856, 697858, 697855, 697853 and
697854 contain the supplementary crystallographic data for L6,
2, 2 ꢀ NCMe, 3, 3a, 8 and 10. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.ica.2009.02.046.
Compound 10 was prepared from L6 (0.05 g, 0.17 mmol) and
H[AuCl4] ꢀ 4H2O (0.07 g, 0.17 mmol). The product was precipitated
by addition of small amounts of water. Product was obtained as
yellow solid. Yellow crystals of 10 suitable for X-ray structure
determination were obtained by slow evaporation of acetonitrile
solution at room temperature. Yield = 0.07 g, 64%. 1H NMR
3
(300 MHz, CD3CN, 25 °C): d 8.57 (d, JH,H = 6.60 Hz, 2H, py), 7.88
References
3
3
(d, JH,H = 6.60 Hz, 2H, py), 7.61 (d, JH,H = 6.60 Hz, 2H, Ph-pz),
7.45 (m, 8H, Ph-pz), 6.91 (s, 1H, pz), 5.67 (s, 2H, –CH2). 13C{1H}
NMR (75 MHz, CD3CN, 25 °C): d 147.6 (C4-py), 143.2 (C2,6-py),
134.0 (C3,5-py), 130.3 (Ph), 130.1 (Ph), 130.0 (Ph), 129.9 (Ph),
129.8 (Ph), 129.2 (Ph), 129.1 (Ph), 126.5 (Ph), 126.4 (Ph), 105.3
(C4-pz), 53.2 (–CH2) ppm. Anal. Calc. for C21H17AuCl3N3: C, 41.03;
H, 2.79; N, 6.84. Found: C, 41.64; H, 2.78; N, 6.77%.
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