Click chelators for platinum-based anticancer drugs

Article abstract of DOI:10.1002/ejic.200700849

Triazoles from "click chemistry" are convenient ligands for the formation of platinum complexes bearing combined triazole-amine or triazole-carboxylate moieties. Striking differences in the chelation modes are observed between the two series. One of the triazole-amine platinum complexes exhibits selective cytotoxicity against breast cancer cells lines. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejic.200700849

FULL PAPER
DOI: 10.1002/ejic.200700849
Click Chelators for Platinum-Based Anticancer Drugs
Aurélie Maisonial,[a] Patrycja Serafin,[a] Mounir Traïkia,[a] Eric Debiton,*[b]
Vincent Théry,[a] David J. Aitken,*[c] Pascale Lemoine,*[d] Bernard Viossat,[d] and
Arnaud Gautier*[a]
Keywords: Click chemistry / Platinum / Chelates / Cancer
Triazoles from “click chemistry” are convenient ligands for
the formation of platinum complexes bearing combined tri-
azole–amine or triazole–carboxylate moieties. Striking differ-
ences in the chelation modes are observed between the two
series. One of the triazole–amine platinum complexes exhib-
its selective cytotoxicity against breast cancer cells lines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Platinum anticancer drugs have enjoyed a long history
since the discovery of cisplatin by Rosenberg et al. in the
1960s.[1] Most of the well-known platinum based anticancer
compounds share the general formula cis-[PtX2(NH2R)2] or
cis-[PtX2(NHR2)2], in which R is an organic fragment and
X is a leaving group such as chloride. Some other antitu-
mour PtII compounds have appeared recently, as exem-
plified by the trinuclear (1),[2] binuclear (2)[3] and mononu-
clear (3)[4] complexes (Figure 1).
Flexible polynuclear compounds 1 were found to chelate
at the N7 site of DNA guanines in long-range inter- and
intrastrand crosslinks.[5] Binuclear azoles 2 (pyrazole and
triazole) are able to create intrastrand crosslinks that cause
Figure 1. Recently developed anticancer complexes 1–3.
a minor kink in the DNA double helix.[6] AMD473 (3) is a solid-phase synthesis,[7] the production of biologically active
sterically hindered PtII complex designed to overcome the platinum complexes has remained within the confines of in-
resistance caused by thiols such as gluthatione and metall- organic and organometallic chemistry. Modern approaches
othionein[4c,4d] that entered clinical trials in 1997.
for drug discovery Ϫ such as parallel and combinatorial
With the exception of the seminal work of Reedijk et syntheses Ϫ have not yet been applied to transition-metal
al., who reported metal–peptide and metal–oligonucleotide complexes.
The recent emergence of “click chemistry” as a new para-
digm for organic synthesis invokes only simple, high-yield-
ing and easily workable transformations. It has facilitated
an extraordinary expansion in the number of molecules
available for medicinal chemistry.[8] Among these click reac-
tions, the copper-catalysed Huisgen [2+3] cycloaddition has
received unrivalled attention and has furnished an impres-
sive array of new biologically relevant compounds.[8c,8d] The
technique has been used to facilitate in situ target-guided
selection of lead drug compounds.[9] Other recent develop-
ments include the formation of palladium ligands for Su-
zuki–Miyaura coupling, Tsuji–Trost allylation or amination
of aryl chlorides.[10] In general, triazole has proven itself
useful for metal binding and it is not surprising that multi-
dentate N,N and N,P ligands find use in metal-based cataly-
sis.[11] A very recent publication relates the behaviour of 1,4-
[a] Laboratoire SEESIB, CNRS-UMR 6504, Université Blaise Pas-
cal, Clermont-Ferrand II,
24, Ave des Landais, 63177 Aubiere cedex, France
Fax: +33-4-73407717
E-mail: arnaud.gautier@univ-bpclermont.fr
[b] Université Clermont 1, UMR 484, Laboratoire de Pharmacog-
nosie/Biotechnologies, U.F.R. Pharmacie, INSERM and Centre
Jean Perrin,
Clermont-Ferrand, 63005, France
E-mail: debiton@inserm484.u-clermont1.fr
[c] Laboratoire SOM – ICMMO, CNRS-UMR 8182, Université
Paris-Sud XI, Bât. 420,
15, rue Georges Clemenceau, 91405 Orsay cedex, France
E-mail: david.aitken@icmo.u-psud.fr
[d] Laboratoire de Cristallographie et RMN Biologiques UMR
8015 – CNRS, Faculté des Sciences Pharmaceutiques et Biolo-
giques, Université René Descartes – Paris V,
4 avenue de l’Observatoire, 75270 Paris cedex 06, France
Fax: +33-1-53739925
E-mail: pascale.lemoine@univ-paris5.fr
298
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Click Chelators for Platinum-Based Anticancer Drugs
disubstituted 1,2,3-triazoles as chelators of rhenium and
technetium for the radiolabelling of biomolecules.[12]
Prompted by the interest in azole structures 2, we de-
cided to investigate the copper-catalysed Huisgen [2+3] cy-
cloaddition reaction with the intention to generate a small
library of 1,2,3-triazole ligands for platinum complexes. It
is of note that most of the synthesis of PtII N,N or N,O
complexes of biological interest are conducted in water. In-
deed, most of the criteria relevant to click chemistry apply
to the preparation of such compounds: complex formation
is modular and has a large scope, whereas reactions take
place in ecologically benign solvents such as water and gen-
erate inoffensive byproducts. Moreover, product isolation is
usually simple (e.g., by filtration), processes are insensitive
to oxygen and yields are usually good. Thus, we consider
that not only triazole formation but also metal complex-
ation fall within the confines of click chemistry.
The targeted structures, depicted in Figure 2, are PtII
chelates that coordinate through one triazole nitrogen atom
and one exocyclic functionality (amine or carboxylate). The
ligands can be classified into two categories: “regular” click
ligands, in which the C4 substituent chain participates with
N3 for chelation, and the isomeric counterparts, “inverse”
click ligands, in which the chelation involves N2 and the
substituent chain at N1. The regular and inverse ligands are
expected to form five- and six-membered complexes, respec-
tively.
Scheme 1. Triazole ligands 7–12 synthesised in this work.
Figure 3. Selected click catalysts.
An aqueous stock solution of the precatalyst CuSO4/5
(0.10 ) was prepared (this solution is stable for months at
room temperature), and the active species was generated in
situ by adding ascorbic acid. NHC–copper(I) catalyst 6
presents two advantages: (1) it is a stable copper(I) species
that does not require a reducing reagent to generate the
active species and (2) its activity is conserved in neat condi-
tions if the components of the reaction are liquids.
Results of ligand syntheses are shown in Table 1. We
were pleased to find that catalysts 4 and 5 behaved equally
well and produced the expected triazoles in good yields and
high purities (Ͼ95%). The activity of NHC–copper(I) cata-
lyst 6 was comparable for alkynes functionalised by amines
and acids under neat conditions (Table 1, Entries 3 and 6)
and gave the same regioisomeric product as that obtained
in the reactions involving 4 and 5, which provides evidence
for a catalysed process.[15] In contrast, the catalytic activity
of 6 was not retained with amine- and acid-functionalised
azides (Table 1, Entries 9 and 12); it was restored, however,
with 3-azidopropanol (Table 1, Entries 15 and 18). Coordi-
nation of the azide to copper is known to be one of the key
Figure 2. Retrosynthetic analysis for target triazoles and complexes.
Results and Discussion
Synthesis of the Ligands
We began by screening several catalyst systems for the steps of the catalytic process.[16] A bifunctional coordinative
preparation of the library of target triazole ligands by using ligand such as azido–acetic acid or azido–ethylamine might
the Huisgen [2+3] cycloaddition reaction (Scheme 1). The form a “copper clamp” that saturates the coordination
catalysts examined were: the known CuSO4/TBAT (4)/ sphere of the copper centre and thus blocks its catalyst ac-
ascorbic acid;[13] CuSO4/hydrosoluble ligand 5/ascorbic tivity. In the case of 3-azidopropanol, a “clamp” does not
acid;[13] and the newly-reported N-heterocyclic carbene form because the alcohol has a weaker coordinating ca-
(NHC) copper(I) complex [(SIMes)CuBr] (6)[14] (Figure 3). pacity; thus, the catalytic activity is retained.
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E. Debitton, D. J. Aitken, P. Lemoine, A. Gautier et al.
FULL PAPER
Table 1. Synthesis of triazoles 7–12 by using three different catalytic
systems.
Table 2. Structures subjected to natural population analysis (NPA).
Entry
Compound
Catalyst[a]
Yield [%]
1
2
3
4
5
6
7
8
7[b]
7[b]
7[b]
8
4
5
6
4
5
6
4
5
6
4
5
6
4
5
6
4
5
6
75
85
90
60
67
68
57
55
0
78
83
0
78
74
91
97
99
95
Atom
13
14
15
16
8
N1
N2
N3
C4
C5
–0.206
–0.077
–0.278
0.090
–0.204
–0.067
–0.216
–0.042
0.014
–0.236
–0.133
–0.254
0.012
–0.201
–0.071
–0.264
0.078
8
9[b]
9[b]
9[b]
10
9
–0.067
–0.050
–0.041
10
11
12
13
14
15
16
17
18
10
10
11[b]
11[b]
11[b]
12
Complex Formation
We selected two platinum sources, K2PtCl4 and
KPtCl3·dmso (Kukushkin’s salt),[18] for the formation of
metal complexes. The anion of the latter reagent is known
to exhibit a strong trans effect, and the presence of the
dmso ligand offers convenient stoichiometry determination
of the platinum complexes formed therefrom through sim-
12
12
[a] Loading of 1 mol-%. [b] Isolated as its hydrochloride salt.
Overall, this reaction allowed us to build a representative
selection of regular ligands classified as N,N (7 and 11) and
N,O (8 and 12) chelators and two inverse ligands classified
as N,N (9) and N,O (10) chelators.
1
ple H NMR spectroscopic signal integration.[19]
DFT Calculations
Behaviour of Five-Membered Regular Chelate Ligands
The designation of regular and inverse ligand chelation
modes depends on which triazole nitrogen atom is involved
in metal bonding. Among the regulars, N,O ligands consti-
tute a subset, in which the conjugation of the carboxylate
functionality can influence the electron density at N2 and
N3. It is noteworthy that previous DFT calculations sug-
gested that the highest electron density in the triazole is at
the N3 position and consequently regular click ligands are
reported to be better chelators.[12] To delineate the influence
of the substitution pattern, calculations were carried out by
using density functional theory (DFT, Gaussian 03) at the
B3LYP/6-311G(d,p) level of theory.[17] The geometries of
the model compounds 1,4-dimethyl-1,2,3-triazole, (13), 1-
methyl-1,2,3-triazole-4-carboxylic acid, (14), 1-methyl-
1,2,3-triazole-4-carboxylate, (15) and 1-methyl-4-phenyl-
1,2,3-triazole (16) were optimised, and the NPA electron
density around the triazole heterocycle was calculated
(Table 2).
Complexation of regular N,N ligand 7 with the two se-
lected platinum sources in aqueous solution gave a five-
membered chelate in each case, as illustrated in Scheme 2.
The presence of base to release the amine was necessary;
blank experiments in the absence of NaOH showed that no
precipitation occurred. Neutral and cationic complexes 17
and 18 were obtained in average yields. Their structures
were supported by 195Pt NMR spectroscopy: 17 resonated
at δ = –2143 ppm (N2Cl2 coordination) and 18 at δ =
–2835 ppm (typical of a N2ClS coordination).[20] Only one
of the two possible cis and trans isomers of 18 was ob-
1
tained, as shown by the H, 13C, and 195Pt NMR spectra,
but we were not able to determine its exact structure by
X-ray diffraction as a result of unsatisfactory crystals.
These calculations revealed that N3 possesses the highest
electron density, regardless of the nature of the substituents.
Compound 13, as a model for the regular N,N ligands, dis-
plays the highest electron density at N3, which is the posi-
tion expected to be involved in chelation. Compounds 14
and 15, as models for the N,O regular ligands, also dis-
played high electron density at N3, although in the case of
conjugate base 15, the electron density also increased at N2.
In contrast, 16, which is a model for inverse ligands, is po-
Scheme 2. Synthesis of regular N,N complexes.
A single crystal of 17 suitable for X-ray diffraction was
orly populated at the N2 position. This phenomenon was grown by slow diffusion of ethanol into a saturated dmf
recently suggested as the reason for weak inverse ligand solution of the complex over one week at 35 °C. Figure 4
chelation to technetium.[12]
presents a perspective view of the molecule.
300
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Click Chelators for Platinum-Based Anticancer Drugs
Figure 5. New compound 17 and some related platinum–heterocy-
clic complexes.
1
trometry. Inspection of the H and 13C NMR spectra re-
vealed a mixture of cis/trans isomers (ratio 3:1, presumably
in favour of trans-19 for steric and thermodynamic reasons,
according to Farrell[22]). Reaction of 8 with Kukushkin’s
salt afforded 20, as only one of the two possible cis or trans
isomers, in average yield. 195Pt NMR spectroscopy (δ =
–3001 ppm, NOSCl coordination) and mass spectrometry
confirmed the structure but here again we were not able to
determine its exact structure by X-ray diffraction because
of unsatisfactory crystals.
Figure 4. CAMERON plot (50% thermal probability ellipsoids) of
17.
The X-ray structure proved unambiguously the forma-
tion of a five-membered chelate. Bond lengths and angles
of interest are summarised in Table 3. The PtII centre pres-
ents a square-planar geometry, and the metal centre bond
lengths and angles fall into their usual ranges. The diagonal
bonds are not equivalent, however, as N1–Pt is shorter than
N8–Pt [1.999(5) and 2.042(4) Å, respectively] and Pt–Cl2 is
shorter than Pt–Cl1 [2.277(2) and 2.306(1) Å, respectively].
Table 3. Selected bonds lengths and angles of 17.
Distances [Å]
N1–Pt
N8–Pt
1.999(5)
2.042(4)
Cl1–Pt
Cl2–Pt
2.306(1)
2.277(2)
Angles [°]
N8–Pt–Cl2
N8–Pt–Cl1
N8–Pt–N1
90.8(1)
177.1(1)
81.4(2)
N1–Pt–Cl1
N1–Pt–Cl2
Cl1–Pt–Cl2
96.4(1)
172.1(1)
91.40(6)
Torsions [°]
Scheme 3. Synthesis of regular N,O complexes.
N1–C9–C10–N8 15.1(7)
C9–C10–N8–Pt –17.3(6)
C10–N8–Pt–N1 12.2(4)
N8–Pt–N1–C9
Pt–N1–C9–C10
–3.7(4)
–5.7(7)
To gain more information about the reasons for the for-
mation of L2Pt-type complexes 19, we took advantage of
the aqueous solubility of ligand 12. A mixture of 12,
K2PtCl4 and NaOH (1:1:1 in water) afforded a solution,
in which only one 195Pt NMR signal was detected at δ =
–1626 ppm, which is typical for a NOCl2 coordination
A comparison with related heterocyclic platinum com-
plexes is interesting (Figure 5). As a result of the strain ef-
fect, 17 differs significantly from AMD473 (3); the picoline
plane with respect to the Pt square plane is tilted by 50° in
the latter, whereas for 17 the triazole is almost coplanar
with the metal centre (angle between the two planes is 3.7°).
Thus, the geometrical structure of 17 is closer to cis-
1
sphere. In the H NMR spectrum, the H5 signal of free
ligand 12 (sodium salt) in D2O appeared at δ = 8.35 ppm.
A 1:1 ratio of 12/K2PtCl4 showed a shift of H5 to 8.41 ppm
and a broadening of the signal, whereas a 2:1 ratio of 12/
K2PtCl4 showed two sharp signals at δ = 8.21 and 7.65 ppm
(ratio 75:25, respectively). On the basis of the 195Pt NMR
signal, structure 21 was proposed for the main product
(Scheme 4). Thus, we concluded that the formation of bis(li-
gand) complexes 19 (Scheme 3) was accelerated by their
precipitation from the reaction medium.
Cl2Pt(amp) [amp
=
2-pyridylmethylamine] and cis-
Cl2Pt(pea) [pea = 2-pyridylmethylamine], in which the pyr-
idine rings lie at an angle of about 8° from the metal coordi-
nation plane.[21a] Interestingly, cis-Cl2Pt(amp) displays cyto-
toxicity in the cisplatin range against the hormone-indepen-
dent human mammary carcinoma cell line MDA-MB
231.[21b]
The behaviour of regular N,O ligand 8 was rather dif-
ferent, as shown in Scheme 3. Complexation of an equi-
molar ratio of 8 and K2PtCl4 in water afforded neutral
product 19 in low yield (12%). By using a 2:1 ratio of 8/
K2PtCl4, the yield of 19 increased to 43%. The L2Pt stoichi-
ometry was confirmed by 195Pt NMR spectroscopy (δ =
–1416 ppm, typical for N2O2 coordination) and mass spec- Scheme 4. A water-soluble regular N,O complex.
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301

E. Debitton, D. J. Aitken, P. Lemoine, A. Gautier et al.
FULL PAPER
Behaviour of Six-Membered Inverse Chelate Ligands
The results of this prescreening (Table 4) show that the
complexes containing N2SCl (18), N2O2 (19) and NOSCl
(20) coordinations displayed no interesting activity, which
is in accordance with the accepted structure–activity rela-
tionships of platinum drugs.[23] In contrast, N2Cl2 coordina-
tion complex 17 displayed significant cytotoxicitiy toward
PA1 and MCF7 line cells.
The IC50 values of 17 and of cisplatin against all four cell
lines are given in Table 5. The neutral cis dichloro diamino
complex 17 exhibited cytotoxicity against the MCF7 breast
carcinoma cell line comparable to that of cisplatin. In con-
trast, it is less active than cisplatin against PA1 ovarian car-
cinoma and poorly active against the A549 nonsmall cell
lung cancer. Interestingly, it is almost inactive against nor-
mal fibroblast, an argument supporting a favourable thera-
peutic index in vivo.
Efforts to coordinate ligand 9 with each of the two plati-
num sources in aqueous solution are summarised in
Scheme 5. The complexation of 9 with K2PtCl4 was unsuc-
cessful: only small amount of an undefined white material
was formed after 5 h at 60 °C. Reaction with Kukushkin’s
salt also failed to give an identifiable complex.
Table 5. IC50 values (µ) values of 17 and cisplatin against different
cell lines.
Scheme 5. Attempted syntheses of inverse N,N complexes.
Similarly, we were unable to obtain any tractable product
from the reaction of 10 with either of the platinum sources,
even after an extended reaction time or by increasing the
reaction temperature (Scheme 6).
Compound
PA1
MCF7
A549
Fibroblast
17
Cisplatin
6.7
0.4
27.0
16.5
Ͼ50
5.6
Ͼ50
23.9
Conclusions
We showed that click chemistry is a useful tool for the
facile construction of a series of potentially chelating tri-
azole ligands for platinum. Among these, only regular li-
gands give good complexation through the formation of
five-membered chelates. Complex 17 displays an interesting
cytotoxicity against breast cancer cells, which is comparable
to cisplatin. Extension of the synthetic methodology to
more structurally diverse motifs is currently under investi-
gation.
Scheme 6. Attempted syntheses of inverse N,O click complexes.
Cytotoxicity
Experimental Section
Four platinum complexes were submitted to prescreening
at 50 and 25 µm concentrations on three cancer cells lines
(MCF7: breast, PA1: ovarian and A549: lung) and a fibro-
blast lane as a blank. To evaluate the influence of the li-
gand, the platinum complexes selected were: N2Cl2 (17),
N2SCl (18), N2O2 (19) and NOSCl (20).
General Methods
Chemistry: The following general procedures were used in all reac-
tions unless otherwise noted. Reactions were stirred with a Teflon-
covered magnetic stirring bar. Solvents were removed with a Buchi
rotary evaporator (water bath 40 °C). All commercially available
Addition of the test compound to the cellular medium reagents were used as received, unless otherwise indicated. TLC
was performed with 250-µm silica gel 60 plates with 254 nm fluo-
rescent indicator.
was performed from a dmf stock solution, rather than dmso
because of the chelating properties of the latter. The final
concentration of dmf did do not exceed 0.05% v/v owing
to the inherent cytotoxicity of this solvent.
Spectroscopy: Solution NMR spectra were recorded in Fourier
Transform mode at 25 °C with a Bruker AVANCE 400 (1H at
Table 4. Percentage of inhibition of cell growth at 50 and 25 µ concentrations of 17, 18, 19 and 20 in comparison to that of cisplatin.
PA1 MCF7 A549 Fibroblast
50 µ
25 µ
50 µ
25 µ
50 µ
25 µ
50 µ
25 µ
17
100
95
50
40
100
98
75
40
40
100
80
45
20
15
95
76
20
0
5
75
45
35
23
30
100
40
35
17
27
100
40
25
20
10
95
35
20
10
5
18
19
20
Cisplatin
92
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Click Chelators for Platinum-Based Anticancer Drugs
400 MHz, 13C at 100 MHz) or a Bruker AV 500 (195Pt at 107 MHz)
spectrometer. Data are reported as chemical shifts (δ) in ppm with
respect to the standard reference compounds tetramethylsilane (1H,
13C) or Na2PtCl6 (195Pt). Spin multiplicity is described by the fol-
lowing abbreviations: s = singlet, d = doublet, t = triplet, q = quar-
tet, m = multiplet, dd = doublet of doublets and br. = broad. Coup-
ling constants (J) are reported in Hz. IR spectra were obtained as
solid KBr pellets with a Paragon 500 Perkin–Elmer FTIR and data
are reported in cm–1. High-resolution mass spectra were recorded
with a Q-TOF micro apparatus (Waters). Samples were dissolved
in dmf (2 mg·mL–1), 10 or 20 µL of the dmf solution were diluted,
respectively, in 990 or 980 µL of water and injected by syringe at a
flow rate of 5 µL·min–1. The high-resolution measurements were
obtained with a lock mass: leucine–enkephalin (m/z = 556.2771).
suspended in water at a concentration of 1.5 . Sodium azide
(1.05 equiv.) and ammonium chloride (2.0 equiv.) were added, and
the reaction was heated at 70 °C for 48 h with vigorous stirring.
The aqueous layer was extracted with diethyl ether, dried with
MgSO4 and the solvent was evaporated to yield pure azide. Benzyl
azide: 97%; 3-azido-propane-1-ol: 93%; azido–acetic acid: quanti-
tative after 48 h at room temperature followed by acidification
(conc. HCl) to give pH = 2, then extraction with diethyl ether.
General Procedure for the Synthesis of Ligands by Using Catalyst 4
or 5: To a solution of azide (3.76 mmol) and alkyne (3.76 mmol) in
H2O/tBuOH (1:1, 10 mL) was added 4 (20 mg, 38 µmol, 1.0 mol-
%) and CuSO4·7H2O (11 mg, 38 µmol, 1.0 mol-%) or precatalyst 5
(0.1 , 380 µL, 38 µmol, 1.0 mol-%) and a fresh solution of ascor-
bic acid (0.1 , 1.14 mL, 0.114 mmol, 3 mol-%). The solution was
stirred at room temperature for 10 h. When the 1,2,3-triazole prod-
uct had precipitated from the reaction medium, the solid was fil-
tered, washed with diethyl ether and dried in air. In other cases,
the 1,2,3-triazole was extracted from the medium with EtOAc, and
the extract solution was dried with MgSO4 and evaporated.
Electron Density Calculations: All calculations were conducted by
using density functional theory (DFT) as implemented in the
Gaussian 03 program.[17] Geometry optimisations and vibrational
frequency calculations were performed by using the restricted
B3LYP exchange and correlation functional and the triple-ζ 6-
311G(d,p) basis sets for all atoms. Harmonic frequency analysis
based on analytical second derivatives was used to characterise the
optimised geometries as local minima.
General Procedure for the Synthesis of Ligands by Using Catalyst
6: In a screw-capped vial, neat alkyne (2.0 mmol, 1.0 equiv.), neat
azide (2.0 mmol, 1.0 equiv.) and 6 (9.0 mg, 0.02 mmol, 1 mol-%)
were mixed. The resulting mixture was stirred for 1 h at room tem-
perature to give a solid that was filtered, washed with hexane or
ether (2 mL) and dried in air.
Cell-Growth Inhibition Assay: Normal human fibroblasts were pur-
chased from Promocell (Heidelberg, Germany). Breast cancer ade-
nocarcinoma (MCF7), lung nonsmall cell carcinoma (A549) and
ovary adenocarcinoma (PA1) human cell lines were purchased from
the European Collection of Cell Cultures (ECACC; Salisbury,
UK). Stock cell cultures were maintained as a monolayer in 75 cm2
culture flasks in Glutamax Eagle’s Minimum Essential Medium
with Earle’s salts (MEM; Invitrogen, Cergy–Pontoise, France) sup-
plemented with 10% fetal calf serum (Sigma, St Quentin Fallavier,
France), 1 m sodium pyruvate (Invitrogen), 1X vitamins solution
(Invitrogen), 1X nonessential amino acids solution (Invitrogen) and
4 µg·mL–1 of gentamicine (Invitrogen). Cells were grown at 37 °C
in a humidified atmosphere containing 5% CO2. Cells were plated
at a density of 5ϫ103 cells per well in 96-well microplates (Nun-
clon, Nunc, Roskilde, Denmark) in 150 µL of culture medium and
were allowed to adhere for 16 h before treatment with the test com-
pound. Stock solution of each compound was prepared in dimeth-
ylformamide (dmf) and kept at –20 °C until use. The percentage of
dmf was kept at 0.05% (v/v) regardless of the concentration tested;
this quantity of dmf did not modify cellular growth. 50 µL of a
4X solution in MEM was then added and a 48 h continuous drug
exposure protocol was used. After this time, the cytotoxic effect
of compounds on tumour cells was assessed by using a resazurin
reduction assay.[24] Briefly, plates were rinsed by 200 µL PBS
(37 °C, Invitrogen) by using a multichannel dispenser (Labsystems,
Helsinki, Finland) and emptied by overturning on absorbent towel-
ling. 150 µL of a 25 µg·mL–1 solution of resazurin in MEM (with-
out SVF nor phenol red) was added to each well. The plates were
incubated 1 h at 37 °C in a humidified atmosphere with 5% of CO2
for fluorescence development by living cells. Fluorescence was then
measured on the automated 96-well plate reader Fluoroskan As-
cent FL (Labsystems) by using an excitation wavelength of 530 nm
and an emission wavelength of 590 nm. Fluorescence is pro-
portional to the number of living cells in the well and IC50 values
(drug concentration required to decrease final cell population by
50%) were calculated from the curve of concentration-dependent
cell number decrease, defined as the fluorescence in experimental
wells as a percentage of that in control wells, with blank values
subtracted.
(1-Benzyl-1H-[1,2,3]triazol-4-yl)methylammonium Chloride (7·HCl):
A minimum amount of cold ethanol was used to dissolve the crude
reaction product and a few drops of conc. HCl (12 ) were added.
A white precipitate formed immediately. The suspension was cooled
to 0 °C for 1 h and was filtered and washed with ice-cold ethanol
and diethyl ether. The white solid was dried in air. M.p. 229–
230 °C. 1H NMR (400 MHz, D2O): δ = 4.31 (s, 2 H), 5.65 (s, 2 H),
7.35–7.38 (m, 2 H), 7.42–7.45 (m, 3 H), 8.13 (s, 1 H) ppm. 13C
NMR (100 MHz, D2O): δ = 34.0, 54.0, 125.4, 128.1, 128.8, 129.2,
134.7, 139.9 ppm. IR (KBr): ν = 3469 (br.), 3069, 3001, 2568, 2364,
˜
1587, 1496, 1458, 1225, 1177, 1141, 1087, 1054, 1028, 967, 872,
717, 694 cm–1. C10H13ClN4 (224.69): calcd. C 53.46, H 5.83, N
24.95; found C 53.90, H 5.84, N 24.47.
1-Benzyl-1H-[1,2,3]triazole-4-carboxylic Acid (8): M.p. 177–179 °C.
1H NMR (400 MHz, [D6]dmso): δ = 5.64 (s, 2 H), 7.33–7.38 (m, 5
H), 8.77 (s, 1 H), 13.10 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]-
dmso): δ = 57.4, 128.1, 123.3, 128.0, 128.8, 135.6, 139.9, 161.7 ppm.
IR (KBr): ν = 3413, 3116, 1683, 1546, 1430, 1341, 1236, 1049, 945,
˜
895, 785, 716, 688, 554 cm–1. C10H9N3O2 (203.20): calcd. C 59.11,
H 4.46, N 20.68; found C 58.98, H 4.61, N 20.79.
2-(4-Phenyl-1H-[1,2,3]triazol-1-yl)ethylammonium Chloride (9·HCl):
A mixture of 2-chloroethylammonium chloride (2.00 g, 17 mmol)
and sodium azide (1.17 g, 18 mmol) in water (17 mL) was heated at
80 °C for 2 d to provide a 1.0  solution of 2-azidoethylammonium
chloride. The evolution and completion of the reaction was fol-
lowed by sampling the reaction mixture, adding a few drops of D2O
then recording the 13C NMR spectrum [product data: 13C NMR
(D2O): δ = 48.1, 38.9 ppm]. As the azide intermediate is unstable
in neat conditions, the 1.0  stock solution was used directly. To
the stock solution (2.0 mL, 2.0 mmol, 1.0 equiv.) was added tert-
butyl alcohol (2.0 mL), phenyl acetylene (214 mg, 2.1 mmol,
1.05 equiv.), precatalyst 5 (0.1 , 200 µL, 20 µmol, 1.0 mol–%) and
a fresh solution of ascorbic acid (0.1 , 600 µL, 0.60 mmol, 3 mol-
%). The reaction was left overnight, and then the solvent was evap-
orated. Water (5 mL) was added, and the aqueous solution was
extracted with diethyl ether. The aqueous layer was evaporated to
yield 206 mg of a white powder. (55%). 1H NMR (400 MHz, D2O):
General Procedure for the Synthesis of Azides: Unless otherwise
specified, the alkyl or benzyl chloride or bromide (1.0 equiv.) was
Eur. J. Inorg. Chem. 2008, 298–305
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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303

E. Debitton, D. J. Aitken, P. Lemoine, A. Gautier et al.
FULL PAPER
δ = 3.04 (t, J = 5.8 Hz, 2 H), 4.36 (t, J = 5.8 Hz, 2 H), 7.4–7.3 (m,
tate was filtered and washed with water (2 mL), methanol (1 mL)
3 H), 7.63 (d, J = 7.0 Hz, 2 H), 8.10 (s, 1 H) ppm. 13C NMR and diethyl ether (2 mL) to give 73.0 mg (0.12 mmol, 50%) of a
(100 MHz, D2O): δ = 40.5, 52.3, 122.2, 125.5, 128.7, 129.1, 129.4,
green solid. M.p. Ͼ230 °C. 1H NMR (400 MHz, [D6]dmso): δ =
5.61 (s, 1.33 H, minor isomer), 5.77 (s, 0.6 H, major isomer), 7.50–
5.0 (m, 10 H), 8.60 (s, 0.6 H, minor isomer), 9.0 (s, 1.33 H, major
isomer) ppm. 13C NMR (100 MHz, [D6]dmso): δ = 55.3, 55.4,
127.9, 128.3, 128.3, 128.4, 128.6, 128.7, 128.8, 128.9, 133.9, 134.0,
166.9 ppm (carbonyl not found). 195Pt NMR (107 MHz, [D7]dmf):
143.4 ppm. IR (KBr): ν = 3500–2500 (br.), 1603.9, 1508.4, 767.7,
˜
691.3 cm–1. C10H13ClN4 (224.69): calcd. C 53.46, H 5.83, N 24.95;
found C 53.65, H 6.02, N 25.21.
2-(4-Phenyl-1H-[1,2,3]triazolyl)acetic Acid (10): M.p. 198–200 °C.
1H NMR (400 MHz, [D6]dmso): δ = 5.38 (s, 2 H), 7.34 (s, 1 H),
7.40 (s, 2 H), 7.88 (m, 2 H), 8.57 (s, 1 H), 13.01 (br. s, 1 H) ppm.
13C NMR (100 MHz, [D6]dmso): δ = 50.7, 122.7, 125.1, 127.9,
δ = –1416 ppm. IR (KBr): ν = 3406, 1599, 1404, 1288, 1048, 810,
˜
534 cm–1. HRMS (ES): calcd. for C20H16N6O4Pt 599.0938; found
599.0818.
128.8, 130.6, 146.4, 168.6 ppm. IR (KBr): ν = 1734, 1102 cm–1.
˜
C10H9N3O2 (203.20): calcd. C 59.11, H 4.46, N 20.68; found C
59.14, H 4.54, N 20.7.
20: To a solution of 8 (50.0 mg, 0.25 mmol, 1.0 equiv.) in water
(300 µL) was added KOH (1.0 , 250 µL, 0.25 mmol) and
KPtCl3·dmso (100.0 mg, 0.25 mmol, 1.0 equiv.) in water (1.2 mL).
The solution was stirred at room temperature for 12 h. A precipi-
tate appeared during this time; it was filtered and washed with
water (2 mL), ethanol (1 mL) and diethyl ether (2 mL) to give
69.4 mg (0.14 mmol, 55%) of a white solid. M.p. 177–178 °C. 1H
NMR (400 MHz, [D7]dmf): δ = 3.71 (s, 6 H), 5.94 (s, 2 H), 7.44
(m, 3 H), 7.55 (m, 2 H), 9.04 (s, 1 H) ppm. 13C NMR (100 MHz,
[D7]dmf): δ = 46.0, 57.0, 129.3, 129.8, 130.1, 130.1, 135.2, 143.4,
166.7 ppm. 195Pt NMR (107 MHz, [D7]dmf): δ = –2838 ppm. IR
1-(3-Hydroxypropyl)-1H-[1,2,3]triazol-4-ylmethylammonium Chlo-
ride (11·HCl): M.p. 130–132 °C. 1H NMR (400 MHz, [D6]dmso):
δ = 1.93 (q, J = 7.8 Hz, 2 H), 3.39 (t, J = 7.2 Hz, 2 H), 4.01 (br. s,
2 H), 4.44 (t, J = 7.2 Hz, 2 H), 8.23 (s, 1 H), 8.64 (br. s, 3 H) ppm.
13C NMR (100 MHz, [D6]dmso): δ = 30.9, 31.7, 44.6, 55.1, 122.5,
137.9 ppm. IR (KBr): ν = 3500–2500 (br.), 1591.9, 1485.3, 1117.1,
˜
879.4, 710.2, 701.2, 534.4 cm–1. C6H13ClN4O (192.65): calcd. C
37.41, H 6.80, N 29.08; found C 37.22, H 7.12, N 29.34.
(KBr): ν = 3462, 3015, 1705, 1560, 1267, 1165, 1034, 723 cm–1.
1-(3-Hydroxypropyl)-1H-[1,2,3]triazole-4-carboxylic Acid (12): M.p.
149–151 °C. 1H NMR (400 MHz, [D6]dmso): δ = 2.00 (t, J =
6.5 Hz, 2 H), 3.40–3.34 (m, 2 H), 4.45 (t, J = 6.5 Hz, 2 H), 4.60
(br. s, 1 H), 8.66 (s, 1 H), 13.00 (br. s, 1 H) ppm. 13C NMR
(100 MHz, [D6]dmso): δ = 32.5, 47.0, 57.3, 128.9, 139.5, 161.7 ppm.
˜
HRMS (ES): calcd. for C12H14Cl2N3PtO3S 510.0156; found
510.1056. C12H14Cl2N3O3PtS (510.85): calcd. C 28.21, H 2.76, N
8.23, S 6.28; found C 28.41, H 2.72, N 8.27, S 5.98.
X-ray Crystallographic Study of Compound 17: Diffraction intensity
data were collected at T = 293 K with an Oxford-Diffraction XCA-
LIBUR diffractometer [Mo-Kα radiation (λ = 0.7107 Å)] with data
collection and reduction by using the CrysAlis program package.[25]
Data were corrected for Lorentz-polarisation effects and empirical
absorption corrections by using SCALE3 ABSPACK.[26] The struc-
ture was solved by direct methods with SIR-92[27] and refined by
least-squares methods on F2 with SHELXL-97[28] incorporated in
the WinGX package.[29] Hydrogen atoms were inserted at calcu-
lated positions with isotropic thermal parameters constrained to be
1.2 times the Ueq of the carrier atoms. The molecule was drawn by
using CAMERON.[30] Crystal data, data collection parameters and
convergence results are listed in Table 6. CCDC-647393 contains
IR (KBr): ν = 3700–3200 (br.), 1705, 1558, 1433, 1242, 1048,
˜
759 cm–1. C6H9N3O3 (171.15): calcd. C 42.10, H 5.30, N 24.55;
found C 42.05, H 5.41, N 24.89.
Platinum Complexes
17: To a solution of 7·HCl (50.0 mg, 0.22 mmol, 1.0 equiv.) in water
(600 µL) was added KOH (1.0 , 220 µL, 0.22 mmol) and K2PtCl4
(92.0 mg, 0.22 mmol, 1.0 equiv.) in water (1 mL). The solution was
stirred 12 h at room temperature in the dark. The precipitate was
filtered and washed with water (2 mL), ethanol (2 mL) and diethyl
ether (2 mL) to give 65.5 mg of a pale yellow solid (0.14 mmol,
1
65%). M.p. Ͼ230 °C. H NMR (400 MHz, [D7]dmf): δ = 3.53 (s,
2 H), 5.80 (s, 2 H), 7.35–7.50 (m, 5 H), 8.46 (s, 2 H) ppm. 13C
NMR (100 MHz, [D7]dmf): δ = 43.7, 56.2, 123.6, 129.6, 129.8,
130.1, 136.0 ppm. 195Pt NMR (107 MHz, [D7]dmf): δ = –2143 ppm.
IR (KBr): ν = 3470, 3204, 3112, 1576, 1451, 1256, 1143, 710 cm–1.
Table 6. Crystal data and structure refinement for 17.
˜
C10H12Cl2N4Pt (454.21): calcd. C 26.44, H 2.66, N 12.33; found C
26.66, H 2.72, N 12.33.
Empirical formula
Mw
C10H12Cl2N4Pt
454.23
Crystal system
Space group
a [Å]
b [Å]
monoclinic
P121/a 1
10.732(1)
9.415(1)
12.696(1)
95.49(1)
1276.9(1)
4
2.363
848
11.389
2.88/32.19
13597
4252
2327
IϾ2σ(I)
0.035
0.057
0.836
–1.46 and 2.93
18: To a solution of 7·HCl (50.0 mg, 0.21 mmol, 1.0 equiv.) in water
(760 µL) was added KOH (1.0 , 213 µL, 0.21 mmol) and
KPtCl3·dmso (89.0 mg, 0.21 mmol, 1.0 equiv.) in water (1.8 mL).
The solution was stirred 12 h at room temperature in the dark.
The precipitate was filtered and washed with water (2 mL), ethanol
(2 mL) and diethyl ether (2 mL) to give 47.9 mg of a white solid
c [Å]
β [°]
V [Å3]
1
(90 µmol, 42%). M.p. Ͼ230 °C. H NMR (400 MHz, [D7]dmf): δ
Z
ρcalcd. [gcm–3]
F(000)
= 3.36 (s, 6 H), 3.51 (s, 2 H), 5.79 (s, 2 H), 7.40–7.50 (m, 5 H), 8.42
(s, 2 H) ppm. 13C NMR (100 MHz, [D7]dmf): δ = 31.0, 43.7, 57.0,
123.6, 129.6, 129.8, 130.1, 136.0, 154.6 ppm. 195Pt NMR
µ [mm–1]
θ range [°]
(107 MHz, [D ]dmf): δ = –2964 ppm. IR (KBr): ν = 3470, 3204,
˜
7
Measured reflections
Independent reflections
Observed reflections
Selection criterion
R1
3112, 1576, 1451, 1256, 1143, 710 cm–1. HRMS (ES): calcd. for
C12H18Cl2N4OPtS 495.0516; found 495.0435.
cis/trans-19: To a solution of 8 (97.0 mg, 0.48 mmol, 2.0 equiv.) in
water (1 mL) was added NaOH (1.0 , 500 µL, 0.50 mmol) and
K2PtCl4 (100.0 mg, 0.24 mmol, 1.0 equiv.) in water (1.0 mL). The
solution was heated at 60 °C for 4 h. The solution was stirred over-
night at room temperature and a precipitate appeared. The precipi-
wR2
Goodness-of-fit
Residual electron density [eÅ–3]
304
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Eur. J. Inorg. Chem. 2008, 298–305

Click Chelators for Platinum-Based Anticancer Drugs
Bell, B. Wüstenberg, S. Kaiser, F. Menges, T. Netscher, A.
Pfaltz, Science 2006, 311, 642; f) P. J. Guiry, C. P. Saunders,
Adv. Synth. Catal. 2004, 346, 497.
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] T. L. Mindt, H. Struthers, L. Brans, T. Angelov, C.
Schweinsberg, V. Maes, D. Tourwe, R. Schibli, J. Am. Chem.
Soc. 2006, 128, 15096–15097. To the best of our knowledge
these authors are the first to introduce the terms “regular” and
“inverse” for ligands.
[13] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett.
2004, 6, 2853–2855.
[14] S. Díez-González, A. Correa, L. Cavallo, S. P. Nolan, Chem.
Eur. J. 2006, 12, 7558–7564.
[15] Thermal (uncatalysed) reactions are known to yield mixture of
1,4 and 1,5 regioisomers.
Acknowledgments
The PAC (Plan Auvergne Cancer) is gratefully acknowledged for
support of this work. P. S. thanks the Erasmus network for an ex-
change grant. We also thank Prof. V. Kukushkin (St. Petersburg
State University, The Russian Federation) for helpful discussions
and Prof. S. Nolan and Dr. S. Díez-González (ICIQ, Tarragona,
Spain) for a generous gift of NHC–copper bromide catalyst.
[16] V. O. Rodionov, V. V. Fokin, M. G. Finn, Angew. Chem. Int.
Ed. 2005, 44, 2210–2215.
[1] B. Rosenberg, L. van Camp, T. Krigas, Nature 1965, 205, 698–
699.
[17] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morok-
uma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzew-
ski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K.
Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V.
Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, re-
vision D.01, Gaussian, Inc., Wallingford, CT, 2004.
[18] Y. N. Kukushkin, Y. E. VyazЈmenskii, L. I. Zorina, Russ. J. In-
org. Chem. 1968, 13, 1573–1576.
[2] N. Farrell, Y. Qu, L. Feng, B. van Houten, Biochemistry 1990,
29, 9522–9531.
[3] S. Komeda, S. Bombard, S. Perrier, J. Reedijk, J. Kozelka J.
Inorg. Biochem. 2003, 96, 357–366.
[4] a) F. I. Raynaud, F. E. Boxall, P. M. Goddard, M. Valenti, M.
Jones, B. A. Murrer, M. Abrams, L. R. Kelland, Clin. Cancer
Res. 1997, 3, 22063–22074; b) L. R. Kelland, S. Y. Sharp, C. F.
O’Neill, F. I. Raynaud, P. J. Beale, I. R. Judson, J. Inorg. Bi-
ochem. 1999, 77, 111–115; c) J. Holford, F. Raynaud, B. A.
Murrer, K. Grimaldi, J. A. Hartley, M. Abrams, L. R. Kelland,
Anti-Cancer Drug Des. 1998, 13, 1–18; d) M. Hay, Curr. Opin.
Oncol. Endocr. Metab. Invest. Drugs 1999, 1, 443–447; e) T.
Okada, I. M. El-Mehasseb, M. Kodaka, T. Tomohiro, K. I.
Okamoto, H. Okuno, J. Med. Chem. 2001, 44, 4661–4667.
[5] U. Bierbach, M. Sabat, N. Farrell, Inorg. Chem. 2000, 39, 1882–
1890.
[6] S. Komeda, M. Lutz, A. L. Spek, M. Chikuma, J. Reedijk, In-
org. Chem. 2000, 39, 4230–4236.
[7] a) M. S. Robillard, A. R. P. M. Valentijn, N. J. Meeuwenoord,
G. A. van der Marel, J. H. van Boom, J. Reedijk Angew. Chem.
Int. Ed. Engl. 2000, 39, 3096–3099; b) K. S. Schmidt, D. V. Fil-
ippov, N. J. Meeuwenoord, G. A. van der Marel, J. H.
van Boom, B. Lippert, J. Reedijk Angew. Chem. Int. Ed. Engl.
2000, 39, 375–377.
[19] a) S. Ongeri, D. J. Aitken, H.-P. Husson, J. Kozelka, B. Viossat,
Inorg. Chem. 2000, 39, 6131–6133; b) D. J. Aitken, H.-P. Hus-
son, D. Nguyen-Huy, S. Ongeri, F. Vergne, B. Viossat, Inorg.
Chem. Commun. 1998, 1, 314–316.
[8] a) H. C. Kolb, M. Finn, K. B. Sharpless, Angew. Chem. Int.
Ed. 2001, 40, 2004–2021; b) H. C. Kolb, K. B. Sharpless, Drug
[20] P. S. Pregosin, Annu. Rep. NMR Spectrosc. 1986, 17, 285–349.
Discovery Today 2003, 8, 1128–1137; c) W. G. Lewis, L. G. [21] a) V. P. Munk, C. I. Diakos, L. T. Ellis, R. R. Fenton, B. A.
Green, F. Grynszpan, Z. R. Radic, P. R. Carler, P. Taylor,
M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41,
1050–1057; d) L. V. Lee, M. L. Mitchell, S. J. Huang, V. V.
Fokin, K. B. Sharpless, C. H. Wong, J. Am. Chem. Soc. 2003,
125, 9588–9589; e) V. P. Mocharla, B. Collason, L. V. Lee, S.
Röper, K. B. Sharpless, C. H. Wog, H. C. Kolb, Angew. Chem.
Int. Ed. 2005, 44, 116–120; f) T. S. Seo, X. Bai, H. Ruparel, Z.
Li, N. J. Turro, J. Ju Proc. Natl. Acad. Sci. USA 2004, 101,
5488–5493; g) M. Sawa, T. L. Hsu, T. Itoh, M. Sugiyama, S. R.
Messerle, T. W. Hambley, Inorg. Chem. 2003, 42, 3582–3590; b)
H. Brunner, M. Schmidt, H. Schönenberger, Inorg. Chim. Acta
1986, 123, 201–207.
[22] Farrell has proposed the trans configuration in the case of pyr-
idine–carboxylate complexes, see: S. M. O. Quintal, Y. Qu,
A. G. Quiroga, J. Moniodis, H. I. S. Nogueira, N. Farrell, In-
org. Chem. 2005, 44, 5247–5353.
[23] a) M. J. Cleare, J. D. Hoeschele, Bioinorg. Chem. 1973, 2, 187–
210; b) J. Reedijk, Inorg. Chim. Acta 1992, 873, 198–200.
Hanson, P. K. Vogt, C. H. Wong, Proc. Natl. Acad. Sci. USA [24] E. Debiton, J. C. Madelmont, J. Legault, C. Barthomeuf, Can-
2006, 103, 12371–12376.
cer Chemother. Pharmacol. 2003, 51, 474–482.
[25] CrysAlis RED, Oxford Diffraction Ltd., Version 1.171.31.5 (re-
lease 28-08-2006 CrysAlis171.NET) (compiled Aug 28 2006,
13:05:05).
[9] a) R. Manetsch, A. Krasinski, Z. Radic, J. Raushel, P. Taylor,
K. B. Sharpless, H. C. Kolb, J. Am. Chem. Soc. 2004, 126,
12809–12818; b) A. Krasinski, Z. Radic, R. Manetsch, J. Rau-
shel, P. Taylor, K. B. Sharpless, H. C. Kolb, J. Am. Chem. Soc.
2005, 127, 6686–6692; c) M. Whiting, J. Muldoon, Y. C. Lin,
S. M. Silverman, W. Lindstrom, A. J. Olson, H. C. Kolb, M. J.
Finn, K. B. Sharpless, J. H. Elder, V. V. Fokin, Angew. Chem.
Int. Ed. 2006, 45, 1435–1439.
[26] N. Walker, D. Stuart, Acta Crystallogr., Sect. A 1983, 39, 158–
166.
[27] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi,
M. C. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr.
1994, 27, 435–436.
[10] R. J. Detz, S. A. Hears, R. de Gelder, P. W. N. M. van Leeuwen,
H. Hiemstra, J. N. H. Reek, J. H. van Maarseveen, Org. Lett.
2006, 8, 3227–3230.
[11] For N,N ligands: a) A. Pfaltz, Acc. Chem. Res. 1993, 26, 339–
345; b) A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron:
Asymmetry 1998, 9, 1–45; c) J. S. Johnson, D. A. Evans, Acc.
Chem. Res. 2000, 33, 325–335; d) B. M. Trost, I. Hachiya, J.
Am. Chem. Soc. 1998, 120, 1104–1945. For N,P ligands: e) S.
[28] G. M. Sheldrick, SHELXL-97: Program for Crystal Structure
Refinement, University of Göttingen, Germany, 1997.
[29] WinGX-version1.63.02: L. J. Farrugia, J. Appl. Crystallogr.
1999, 32, 837–838.
[30] D. J. Watkin, C. K. Prout, L. J. Pearce, CAMERON, Chemical
Crystallography Laboratory, Oxford, UK, 1996.
Received: August 15, 2007
Published Online: October 31, 2007
Eur. J. Inorg. Chem. 2008, 298–305
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
305