Post-functionalization of platinum-NHC complexes by oxime ligation for ligand targeted therapy

Article abstract of DOI:10.1039/c5nj03104d

Carbonyl condensation reactions such as imine, hydrazine, and oxime-bond formation have been successfully used for accessing N-heterocyclic carbene platinum bioconjugate complexes. Among all the synthesized compounds, oxime-containing complexes were found to display a high hydrolytic stability and were found to be stable on silica gel or in wet solvents. As a proof of concept, the Pt NHC complexes were finally functionalized with three selective ligand-targeting moieties using oxime ligation. Preliminary results of the biological effects on various human cancer and non-cancer cells are also reported.

Full text of DOI:10.1039/c5nj03104d

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New J. Chem.
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DOI: 10.1039/C5NJ03104D
Post-functionalization of platinum-NHC complexes by oxime ligation for ligand targeted therapy.
by
Etienne Borré,a Georges Dahm,a Gilles Guichard,b,c Stéphane Bellemin-Laponnaz*a,d
a
Institut de Physique et Chimie des Matériaux de Strasbourg, Université de Strasbourg-CNRS
UMR7504, 23 rue du Loess, BP 43, 67034 Strasbourg Cedex 2, France
E-mail: bellemin@unistra.fr
b Université de Bordeaux, CBMN, UMR 5248, Institut Européen de Chimie et Biologie , UMR5248, 2 rue
Robert Escarpit, 33607 Pessac, France
cCNRS, CBMN, UMR 5248, 33600, Pessac, France
d
University of Strasbourg Institute for Advanced Study (USIAS), 5 allée du Général Rouvillois, 67083
Strasbourg, France
1

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Abstract
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DOI: 10.1039/C5NJ03104D
Carbonyl condensation reactions such as imine, hydrazine, and oxime-bond formation have been
successfully used for accessing N-heterocyclic carbene platinum bioconjugate complexes. Among all
synthesized compounds, oxime-containing complexes were found to display a high hydrolytic stability
and were found to be stable on silica gel or in wet solvents. As a proof of concept, the Pt NHC complexes
were finally functionalized with three selective ligand-targeting moieties using oxime ligation.
Preliminary results of the biological effects on various human cancer and non-cancer cells are also
reported.
2

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Introduction
Since the discovery of cisplatin by Rosenberg,1 the scientific community has paid
much attention to the use of metal ions for the treatment of acute illnesses.2 Indeed, this
discovery led to the most widely used anticancer drug and paved the way for current
development in medicinal inorganic chemistry. Although very successful, cisplatin including
some of its close analogues is associated with various severe toxic side effects as well as
potential tumor resistance,3 suggesting a need for new platinum-based anti-cancer agents.
N-heterocyclic carbenes (NHC) have emerged as a privileged class of metal ligands
due to various attractive features including the ease of synthetic preparation or the strong
binding to transition metal thus generating highly stable species. In addition, their modularity,
i.e. their steric and/or electronic properties can be easily tuned, was found to be essential in
the development of efficient catalysts for example.4,5 More recently, N-heterocyclic carbene
complexes have been considered for the development of metal-based drug candidates.6
Several NHC platinum compounds have be found to exhibit high cytotoxicity against various
cancer cell lines and to compare favorably with cisplatin.7 These first generation NHC
platinum compounds showed promise, yet various optimizations are still needed to address
issues related to stability, solubility or cell permeability. As a molecule moves further toward
the development phase, the concept of post-functionalization provides an easy way to tune the
properties of the drug candidate.8 The high stability of the NHC Pt complexes offers various
possibilities of post-functionalization, via for example azide-alkyne cycloaddition,6e,6f
nucleophilic substitution or ligand exchange6c,6d which have all been explored successfully.
More recently, we have introduced carbonyl condensation reactions to access NHC platinum
bioconjugates.9 The imine/oxime ligation in combination with metal ligand exchange is a
novel orthogonal approach that allows rapid multifunctionalization NHC Pt complexes.
Herein, we now describe our efforts aimed at conjugating cytotoxic NHC platinum complexes
3

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to various ligands, including suitable cell-targeting agents, as a first step towards the design of
DOI: 10.1039/C5NJ03104D
ligand targeted Pt NHC therapeutics. The successful synthesis and characterization of several
Pt NHC bioconjugates along with their biological activities against various cancer cell lines
are reported.
Results and Discussion
Imine, hydrazone, and oxime ligation
N-heterocyclic carbene Pt(II) complexes of general formula [(NHC)PtI2(L)] (L=
nitrogen-containing ligand) are known to display high cytotoxic activity.6 Because the
biological activities of these complexes are likely to be sensitive to small chemical
modifications, it was critical to verify that the installation of an aldehyde moiety for
imine/oxime ligation would not impair the overall potency and effectiveness against cancer
cells. The active platinum complexes comprise the monodentate N-heterocyclic carbene
ligand and three potential leaving groups in the form of two halides and a nitrogen-based
ligand. For this reason, we sought to introduce the aldehyde moiety onto the NHC ligand.
Ideally, the coordination sphere of the complex should remain as unperturbed as possible; we
thus examined the use of the aldehyde functionality in para position of the benzene ring as
shown on Figure 1. Platinum complexes 1 and 2 were easily prepared from the corresponding
imidazolium salt and platinum(II) salt in the presence of an excess of NaI and K2CO3 in
pyridine or cyclohexylamine as solvent. The molecular structure of complex 1 was confirmed
by X-ray diffraction studies (Figure 2). The complex displays the coordination of the pyridine
ligand trans to the NHC ligand with the expected square-planar geometry at the Pt center. The
iodine ligands adopt the trans geometry and point almost perpendicularly toward the carbene
4

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ligand plane, which is a common feature for such complexes. The bond lengths and angles
DOI: 10.1039/C5NJ03104D
offal in the typical range (Pt-C bond length of 1.981 Å).7
Both complexes were found to inhibit cancer cell growth in vitro in the same order of
magnitude as unmodified Pt complexes (vide infra), thus showing that the aldehyde
functionality does not alter the biological activity of the NHC-Pt entity.
O
O
H
H
N
N
I
Me
N
N
I
C
Me
C
I Pt
N
I Pt
H2N
1
2
Figure 1. Molecular structure of the aldehyde-functionalized NHC Pt complexes 1 and 2.
Figure 2. ORTEP view of complex 1 with partial atom labelling. Thermal ellipsoids drawn at
50% probability; hydrogen atoms have been omitted for clarity [except for C(11)]. Selected
5

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bond distances (Å) and angles (deg): C(1)-Pt(1), 1.981(6); N(3)-Pt(1), 2.091(4); I(1)-Pt(1),
DOI: 10.1039/C5NJ03104D
2.5918(4); I(1)-Pt(1), 2.6031(4); C(11)-O(1), 1.210(9); C(1)-Pt(1)-I(2), 88.98(15); I(1)-Pt(1)-
I(2), 176.944(16); C(1)-Pt(1)-N(3), 178.2(2); N(2)-C(1)-N(3)-C(13), 35.44(15).
Next, we examined the use of the aldehyde functionality to tether the cyclohexylamine
(CHA) molecule via imine coupling reactions. The NHC platinum complex 1 quantitatively
reacted with the amine (used as solvent) to form the desired imine-containing complex 3
(Scheme 1), in which the amine also reacted at the platinum center to give the CHA adduct.
Alternatively, complex 3 could be directly obtained from the CHA adduct 2 in quantitative
yield as well. The imine formation was easily followed by proton NMR thanks to typical
signals at δ 10.0 ppm and 8.3 ppm for CH=O and CH=N, respectively.10
Not surprisingly, the imine functional group in 3 displays a low stability. Upon
exposure to humidity, the complex 3 may be hydrolyzed back to the starting material 2.
Consequently, the imine is not robust enough for bioconjugation applications. In addition, the
labile character of the pyridine ligand prompted us to use afterwards the amine adduct 2 rather
than the pyridine adduct 1.11
C6H11
N
Na2SO4
cyclohexylamine
hydrolysis
N
N
Me
1 (or 2)
2
C
r.t., overnight
I Pt I
H2N
3 (quant.)
Scheme 1. Reaction of NHC Pt complexes 1 or 2 with cyclohexylamine.
Hydrazones and oximes usually possess greater hydrolytic stability than imines.12
Since these functions are prompt to hydrolysis underacidic conditions, this would guaranty a
higher stability of the Pt conjugates as well as possible more efficient release of the active Pt
6

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7
core in the cell. The phenylhydrazone Pt complex 4 was obtained quantitatively after reaVcietwioArnticle Online
DOI: 10.1039/C5NJ03104D
in CH2Cl2 overnight at room temperature and in the presence of Na2SO4 drying agent (Scheme
2). However, this product was found to be sensitive to water: after one night in wet CDCl3, a
mixture of 4 and 2 was observed in a ratio of 3 to 1. On the other hand, oxime species were
more easily accessed under very mild conditions and no drying agent was required. For
example, the reaction with benzyl hydroxylamine gave the expected product 5 in 92% isolated
yield whereas reaction with anthracenylmethyl hydroxylamine gave the corresponding Pt
complex 6 in 98% yield. More interestingly, the two oxime-containing Pt complexes 5 and 6
possess a good hydrolytic stability and were found to be stable on silica gel or in wet solvents.
The formation of 5 could even be performed in dimethylformamide/water 90/10 without any
loss of activity.
The functionalization by oxime ligation affords Pt complexes of remarkable stability,
yet that are potentially susceptible to further chemical modification. For example, the reaction
of Pt complex 2 with tert-butyl 6-(aminooxy)hexanoate gave the oxime product 7 in 88%
isolated yield. A deprotection of the ester moiety was successfully achieved with formic acid
in CH2Cl2 giving complex 8 in quantitative yield. Overall, these examples of chemoselective
oxime ligation show the versatility and relatively ease of derivatization of the platinum NHC
complexes.
7

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DOI: 10.1039/C5NJ03104D
H
N
N
PhNHNH2
Na2SO4
N
N
I
Me
C
I Pt
H2N
4 (quant.)
O
N
O
N
N
I
Me
C
I Pt
H2N
N
N
I
Me
C
Bn-ONH3Cl
NEt3
I Pt
H2N
5 (92%)
2
O
N
Napht-CH2-ONH3Cl
N
N
C
Me
NH2OC5H10CO2tBu
I
I Pt
H2N
NEt3
6 (98%)
O
O
N
N
N
N
I
OtBu
Me
N
N
C
O
OH
O
C
Me
HCO2H
I Pt
H2N
I
I Pt
H2N
7 (88%)
8 (quant.)
Scheme 2. Reaction of Pt NHC complex 2 with various hydrazines and
hydroxylamines.
Crystals suitable for X-ray diffraction studies were obtained for the oxime-
functionalized complex 6 by slow diffusion of pentane into a dichloromethane solution of the
complex. Figure 2 displays the molecular structure of the anthracene NHC Pt conjugate 6,
along with selected bond distances and angles. In particular, the analysis confirmed the E-
geometry at the oxime bond [C-N bond length of 1.289(8) Å].
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Figure 3. ORTEP view of complex 6 with partial atom labelling. Thermal ellipsoids drawn at
50% probability; hydrogen atoms have been omitted for clarity [except for N(4) and the
oxime]. Molecular structure of Pt conjugate complex 6. Selected bond distances (Å) and
angles (deg): C(1)-Pt(1), 1.970(5); Pt(1)-I(1), 2.6022(4); Pt(1)-I(2), 2.6077(4); Pt(1)-N(4),
2.127(4); C(12)-N(3), 1.289(8); N(3)-O(1), 1.397(6); N(2)-C(1)-N(1), 106.0(5); C(1)-Pt(1)-
N(4), 178.33(18); C(1)-Pt(1)-I(1), 90.53(14); C(12)-N(3)-O(1), 110.7(5); N(4)-Pt(1)-I(1),
90.51(14); C(1)-Pt(1)-I(2), 90.22(14); N(4)-Pt(1)-I(2), 88.73(14); I(1)-Pt(1)-I(2), 179.003(15);
C(12)-N(3)-O(1)-C(13), 176.3(5).
Derivatization with ligand targeting moieties
The selective delivery of anticancer drugs to cancer cells can be increased by
associating the drugs with molecules that bind to receptors that are overexpressed on the
target cells. Such ligand-targeted therapies may lead to less toxic treatments and allow to
carry higher dosages of anticancer drug to tumor tissue. Most efforts have focused on
monoclonal antibodies (MAbs) as targeting agents, yet chemically synthesized and
biocompatible targeting ligands have been reported for active tumor-targeting drug delivery.
We have selected three different families of such small targeting ligands and studied their
conjugation with the NHC platinum complex 2 (Figure 4). Metronidazole derivatives are
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DOI: 10.1039/C5NJ03104D
known to target hypoxic cells. During the tumor growth, the hypoxic cell number increases
since the tumor microenvironment is significantly deprived of oxygen. This characteristic
represents a clear difference between tumor and normal cells and is potentially exploitable in
cancer treatment. Thus, the metronidazole derivative 9 featuring a hydroxylamine has been
synthesized for that purpose. We also selected a positively charged pyridinium moiety 10,
which is known to target proteoglycans via an electrostatic interaction between the pyridinium
and the negatively charged sulphate and carboxyl groups in proteoglycans. It was found
recently that the proteoglycan’s concentration increases in a noticeable way in the tumor
environment. Moreover, proteoglycans play a key role in tumoral progression rendering them
attractive for cancer treatment.14 Finally, we decided to investigate the introduction of a
prostate-tumor target.15 The urea derivative 11 shown in Figure 4 is known to target and
inhibit the glutamate carboxypeptidase II also known as Prostate Specific Membrane Antigen
(PSMA). This glycoprotein, made of 750 amino acids, is overexpressed in prostate cancer and
thus is an attractive target for prostate cancer imaging and treatment.16 The hydroxylamine
functionalities required for subsequent oxime ligation were easily introduced using
hydroxyphtalimide route (see supporting information for synthetic details).
O
NH2
O
Br
NO2
HN
NH2
NH2
N
O
N
N
O
COOH
COOH
11
10
9
O
pyrimidium
derivative
metronidazole
derivative
HOOC
N
N
H
H
cartilaginous cells target
urea
derivative
hypoxic cells target
prostate cells target
Figure 4. Ligand targeting moieties 9-11 synthesized and used for bioconjugation with Pt
NHC complexes.
10

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The oxime ligation with compound 9 was successfully performed in dichloromethane at room
temperature overnight, showing a 69% conversion as deduced from NMR. The resulting Pt-
metronidazole conjugate 12 was isolated in 41% yield after purification by chromatography
on silica gel. Using the same procedure, the platinum pyrimidium conjugate 13 could also be
isolated and purified on silica gel to afford the product in 45% yield (70% conversion in the
crude mixture as deduced from NMR measurement). In both cases, addition of aniline as
catalyst did not improve the conversion and the main side products in both cases remained
unreacted reagents.17
O2N
N
N
O
N
9
N
N
I
Me
C
CH2Cl2, RT
I Pt
H2N
12 (41%)
69% conv.
O
O
N
N
H
10
Br
N
N
Me
N
N
I
C
Me
C
CH2Cl2, RT
70% conv.
I
I Pt
H2N
I Pt
H2N
13 (45%)
O
2
NH
COOH
COOH
O
O
N
11.HTFA
HOOC
N
N
H
H
N
N
C
Me
CH2Cl2, RT
40% conv.
I
I Pt
H2N
14 (35%)
Figure 5. Synthesis of platinum NHC conjugates 12-14.
The ligation of the urea-based ligand of PSMA 11 with Pt NHC complex 2 was
1
conducted in a mixture of dichloromethane/methanol/water. Analysis of the crude by H
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NMR revealed a conversion of 40%. The oxime reaction was highly selectiDvOeI: 1s0i.1n0c3e9/Cn5NoJ03104D
additional byproducts were observed, however the complete purification of the Pt-
peptidomimetic conjugate was not possible by conventional techniques. Purification by C18-
SiO2 using methanol as eluent finally gave the conjugate 14 in 90% purity together with 10%
of peptidomimetic 11 as deduced from NMR, HPLC and mass spectrometry analyses. As
alternative, we investigated the ligation of the fully tBu-protected peptidomimetic 14 with 2.
Whereas the fully tBu-protected platinum conjugate could be isolated and purified, it
appeared that the cleavage of the ester functions was unselective or lead to decomposition,
although various reaction conditions have been investigated.
In vitro biological evaluation
The antiproliferative activity of a selection of metal–NHC complexes was evaluated
against a panel of 4 cancer cell lines, namely MCF7 (breast carcinoma), HCT-116 (colon
cancer cells), PC3 (prostate adenocarcinoma), SKOV3 (ovarian cancer cells) and 2 noncancer
cell lines, MRC5 (human fetus lung cells) and EPC (endothelial progenitor cells) (IC50, Table
1). Cisplatin was used as reference for the studies. However, due to the instability of cisplatin
in DMSO, it was used as a stock solution in water.18
Cisplatin
1
2
5
7
8
12
13
14
MCF7[a]
HCT116[b]
PC3[c]
19.8±0.6 0.49±0.07 0.78±0.05 0.35±0.03 1.10±0.05 9.74±0.66 0.94±0.03
75.5±4.1
17.1±2.4
60.4±2.3
87.7±8.0
18.8±1.5
41.7±1.8
78.2±6.3
23.7±3.9
52.2±9.0
62.1±12.5
80.1±8.1
84.6±8.0
6.4±0.2
10±1
4±3
0.93±0.03 0.79±0.06 0.28±0.02 1.11±0.12 9.93±0.07 5.13±0.24
1.5±0.4 0.55±0.09 0.19±0.01 0.66±0.03 6.44±0.35 1.20±0.01
0.17±0.07 0.13±0.02 0.44±0.02 1.85±0.14 0.11±0.01
SK-OV3[d]
MRC5[e]
EPC[f]
18±2
12.5±0.1 0.60±0.02 0.30±0.07 0.14±0.01 0.65±0.04
76±10 1.8±0.2 1.08±0.03 0.33±0.07 1.47±0.16
7.3±2.5
0.44±0.12
1.17±0.07
26.8±3.0
[a] MCF7, breast carcinoma. [b] HCT116, colon cancer cells. [c] PC3, prostate adenocarcinoma. [d] SK-OV3, human ovarian
cancer cells. [e] MRC5, human fetus lung cells. [f] EPC, endothelial progenitor cells.
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DOI: 10.1039/C5NJ03104D
Table 1. In vitro cytotoxic activity (IC50 values in µM) of platinum complexes against several
cell lines (after 72 h of incubation; stock solutions in DMSO for all complexes; stock solution
in H2O for cisplatin).
Overall, these biological assays revealed that the aldehyde-functionalized platinum
complexes 1 and 2 maintain a high cytotoxic activity (at the micromolar range). For example,
the IC50 values range from 0.17 µM (HCT116 cells) to 1.08 µM (EPC cells) for the
cyclohexylamine adduct 2, values that are comparable to unfunctionalized NHC Pt
complexes.7 The introduction of
a
benzyl hydroxylamine or
a
tert-butyl 6-
(aminooxy)hexanoate did not change this biological activity. For example, the Pt NHC oxime
complex 5 displays IC50 values from 0.13 (HCT116 cells) to 0.35 µM (MCF7 cells) whereas
complex 7 exhibits IC50 values from 0.44 (HCT116 cells) to 1.47 µM (EPC cells). Notably,
the acid deprotected complex 8 demonstrates a significant decrease of biological activity of
one order of magnitude when compared to protected compound 7, a feature that has been
previously observed with related complexes.7h
The functionalization of 2 with the neutral metronidazole derivative gave somewhat
the same order of magnitude (0.11 to 1.20 µM, compound 12) with the exception of PC3 cells
(IC50 of 5.13 µM). On the other hand, clear differences with the pyridinium or urea-
functionalized complexes were observed. Much lower activities were observed with charged
complexes such as the platinum cationic conjugate 13 (17.7 to 87.7 µM) and the platinum
peptidomimetic conjugate 14 (23.7 to 84.6 µM).19 This may be due to the low aptitude of
these positively or potentially negatively charged compounds to cross the cell membrane7h
even upon engagement of their extra cellular target, as successful delivery would then depend
on targeted receptor internalization and intracellular trafficking
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Summary - Conclusion
In this study, we have shown that N-heterocyclic carbene platinum complexes can be
easily functionalized by imine type ligation. Amines or hydrazines could be ligated to
platinum NHC complexes under drying conditions, however the resulting imine or hydrazone
bioconjugates displayed limited stability in the presence of humidity. On the other hand,
model hydroxylamines reacted smoothly with the Pt complex either under aqueous or non-
aqueous conditions to give the corresponding oximes which were isolated in good yields. The
scope of the method was examined with success for three cell targeting moieties. The new
platinum-based compounds have demonstrated in vitro efficacy. Functionalization of the
platinum complex by a neutral ligand does not alter this activity. However, the potency of the
bioconjugates may be reduced by the introduction of a positively or negatively charged
ligand. Future studies may concentrate on conjugates targeting receptors that are readily
internalized into the cells to allow proper release of the cytotoxic NHC metal complex into the
cell. The examples reported herein thus validate the oxime methodology that may prove
useful for future developments in anticancer NHC metal complexes.
Experimental
General comments
All manipulations were performed under inert atmosphere (argon) by using standard vacuum
line and Schlenk tube techniques. Glassware was dried at 120 °C in an oven for at least three
hours. Toluene, CH2Cl2 and THF were dried using an SPS system and water content was
quantified by Karl Fischer titration. Ethanol and acetonitrile were deoxygenated by bubbling
argon for 30 min and stored over activated 4Å molecular sieves. Cyclohexylamine, pyridine
and NEt3 were distilled over CaH2 and stored under argon. NaI and K2CO3 were dried over
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two days under reduced pressure at 200 °C. All other reagents were commerciaDllOyI: 1a0v.1a03il9a/Cb5lNeJ03104D
and used as received. Complexes 1 and 2 were synthesized according to our previous report.
The syntheses of compounds 9, 10 and 11 are described in the supplementary information.
NMR spectra were recorded on Bruker AV300 spectrometer. Chemical shifts are reported in
ppm (δ) compared to TMS (1H and 13C) using the residual peak of deuterated solvent as
internal standard. MS spectra were performed by the mass spectrometry service of the
“Institut de Chimie de Strasbourg” on microTOF, Bruker Daltonics. Elemental analyses were
performed by the ‘service d’analyse élémentaire’ of the Strasbourg chemistry department.
X-ray analyses
X-ray diffraction data collection was carried out on a Nonius Kappa-CCD diffractometer
equipped with an Oxford Cryosystem liquid N2 device, using Mo-Kα radiation (λ = 0.71073
Å). The crystal-detector distance was 36mm. The cell parameters were determined (Denzo
software)20 from reflections taken from one set of 10 frames (1.0° steps in phi angle), each at
20s exposure. The structures were solved by direct methods using the program SHELXS-
2013.21 The refinement and all further calculations were carried out using SHELXL-2013.22
The H-atoms were included in calculated positions and treated as riding atoms using
SHELXL default parameters. The non-H atoms were refined anisotropically, using weighted
2
full-matrix least-squares on F . A semi-empirical absorption correction was applied using the
MULscanABS routine in PLATON.23 Crystallographic data were deposited at The Cambridge
Crystallographic Data Centre CCDC at numbers 1435135 and 1435136.
Syntheses
Complex 3. To 0.025 mmol of platinum complex 1 (or 2), oven-dried Na2SO4 and dry
cyclohexylamine (ca. 1 mL) were added under inert atmosphere. The resulting solution was
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then stirred overnight at room temperature. The solution was filtered off over a ceDliOteI: 1p0.l1u03g9/aCn5NdJ03104D
volatiles were removed under vacuum. The crude reaction mixture was purified by flash
chromatography (SiO2 deactivated by NEt3, gradient CH2Cl2/pentane 1/1 to CH2Cl2) to give
complex 3 as a yellow solid in quantitative yield. 1H-NMR (CDCl3, 300 MHz, 20 °C): δ 1.00-
1.87 (m, 10H, CHA), 2.24 (d, J= 12.0Hz, 2H, CH2), 2.48 (m, 2H, CH2), 2.92 (m, 2H, NH2),
3.18 (m, 2H, 2CHCHA), 3.86 (s, 3H, N-CH3), 5.59 (s, 2H, N-CH2), 6.53 (d, J= 2.1Hz, 1H,
CH=), 6.77 (d, J= 2.1H, 1H, CH=), 7.45 (d, J=8.1Hz, 2H, Har), 7.68 (d, J=8.1Hz, 2H, Har),
13
8.28 (s, 1H, CH=N). C-NMR (CDCl3, 75 MHz, 20 °C): δ 24.8 25.3 25.7 34.3 36.6 (CHA),
38.1 (N-CH3), 50.5 (CHA), 54.8 (N-CH2), 69.9 (CHA), 119.8 (CH=), 122.4 (CH=), 128.4
(CHAr), 129.1 (CHAr), 136.7 (CAr), 137.5 (CAr), 140.3 (C-Pt), 157.9 (CH=N). Elemental
analysis calcd (%) for C24H36I2N4Pt (MW = 829.46): C 34.75, H 4.37, N 6.75, found: C 34.57,
H 4.33, N 6.36.
Complex 4. To 18.0 mg (0.024 mmol) of platinum complex 2, oven-dried Na2SO4,
phenylhydrazine (17 µL, 7 equiv.) and dry dichloromethane (2 mL) were added under inert
atmosphere. The resulting solution was then stirred overnight at room temperature. The
solution was filtered off over a celite plug and volatiles were removed under vacuum. The
crude reaction mixture was purified by flash chromatography (SiO2 deactivated by NEt3,
gradient CH2Cl2/pentane 1/1 to CH2Cl2) to give 20.0 mg of complex 4 (yellow solid, quant.).
1H-NMR (CDCl3, 300 MHz, 20 °C): δ 1.01-1.86 (m, 8H, 8H, CHA), 2.21 (m, 2H, 2H, CHA),
2.94 (m, 2H, NH2-Pt), 3.25 (m, 1H, CH, CHA), 3.89 (s, 3H, N-CH3), 5.60 (s, 2H, N-CH2),
6.58 (d, J=2.1Hz, 1H, CH=), 6.78 (d, J=2.1Hz, 1H, CH=), 6.78-7.76 (m, 11H, 9Har, NH,
13
CH=N). C-NMR (CDCl3, 75 MHz, 20 °C): δ 24.7 (CHA), 25.2 (CHA), 35.9 (CHA), 38.4
(N-CH3), 53.8 (CHA), 54.7 (N-CH2), 120.1 (CH=), 122.5 (CH=), 128.1, 128.5, 129.6, 130.1,
131.5, 136.2, 136.5, 140.9 (C-Pt), 142.2, 141.7 (CH=N). MS (positive ESI) [M+Na]:
16

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calculated for C24H31I2N5PtNa 861.02, found 861.02. Elemental analysis caDlcOdI: 10(.%103V)9ie/wCf5AoNrtriJc0le3O10nl4inDe
C24H31I2N5Pt (MW = 838.43): C 34.38, H 3.73, N 8.35, found: C 34.07, H 3.34, N 8.16.
Complex 5. Complex 2 (10 mg, 13.4 µmol), ClNH3OBn (2.1 mg, 13.4 µmol) and
triethylamine (1.8 µL, 14 µmol) in anhydrous dichloromethane was stirred overnight at room
temperature. The solution was filtered off over celite plug and volatiles were removed under
reduced pressure. The crude product was purified by chromatography (SiO2,
1
CH2Cl2/cyclohexane) to afford the product as a yellow solid (10.6 mg, 92%). H-NMR
(CDCl3, 300 MHz, 20 °C): δ 1.05-1.35 (m, 5H, CHA), 1.55-1.87 (m, 3H, CHA), 2.22 (d, J=
11.7Hz, 2H, CH2), 2.85 (m, 2H, NH2), 3.27 (m, 1H, CHCHA), 3.89 (s, 3H, N-CH3), 5.21 (s,
2H, O-CH2), 5.61 (s, 2H, N-CH2), 6.56 (d, J= 2.4Hz, 1H, CH=), 6.79 (d, J= 2.4Hz, 1H, CH=),
7.26-7.64 (m, 9H, Har), 8.12 (s, 1H, CH=N). 13C-NMR (CDCl3, 75 MHz, 20 °C): δ 24.8
(CHA), 25.3 (CHA), 26.9 (CHA), 35.9 (N-CH3), 54.0 (CHA), 54.9 (N-CH2), 77.2 (O-CH2),
119.8 (CH=), 122.4 (CH=), 127.5 (CAr), 127.9 (CAr), 127.9 (CAr), 128.0 (CAr), 128.3 (CAr),
128.4 (CAr), 128.4 (CAr), 129.3 (CAr), 132.3 (CAr), 137.1 (CAr), 137.5(CAr), 140.3 (C-Pt), 148.4
(CH=N). 1H-NMR (Acetone, 300 MHz, 20 °C): δ 1.15-1.35 (m, 3H, CHA), 1.55-1.87 (m, 2H,
CHA), 2.31 (m, 2H, CHA), 2.90 (m, 2H, CH2), 3.28 (m, 1H, CHCHA), 3.45 (m, 2H, NH2), 3.86
(s, 3H, N-CH3), 5.18 (s, 2H, O-CH2), 5.64 (s, 2H, N-CH2), 6.93 (d, J= 2.4Hz, 1H, CH=), 7.16
13
(d, J= 2.4Hz, 1H, CH=), 7.26-7.45 (m, 5H, Har), 7.59 (m, 4H, Har), 8.21 (s, 1H, CH=N). C-
NMR (Acetone, 75 MHz, 20 °C): δ 24.7 (CHA), 25.3 (CHA), 29.0 (CHA hide by solvent),
35.2 (N-CH3), 53.3 (CHA), 54.7 (N-CH2), 76.0 (O-CH2), 120.2 (CH=), 122.9 (CH=), 127.0
(CAr), 127.7 (CAr), 128.3 (CAr), 129.2 (CAr), 132.2 (CAr), 138.0 (CAr), 140.0 (C-Pt), 148.4
(CH=N). MS (positive ESI) [M-I]: calculated for C25H32I1N4O1Pt1 726.127, found 726.130,
[M-I+CH3CN]: calculated for C25H32IN4OPtCH3CN 767.153, found 767,153, [M+Na]:
calculated for C25H32I2N4OPtNa 876.021 found 876.023.
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DOI: 10.1039/C5NJ03104D
Complex 6. Complex 2 (10 mg, 13.4 µmol), O-(anthracen-9-ylmethyl)hydroxylamine (3.0 mg,
13.4 µmol) and triethylamine (1.8 µL, 14 µmol) in anhydrous dichloromethane was stirred
overnight at room temperature. The solution was filtered off over celite plug and volatiles
removed under reduced pressure. The crude product was purified by chromatography (SiO2,
1
CH2Cl2/cyclohexane) to afford the product as a yellow solid (12.5 mg, 98%). H-NMR
(CDCl3, 300 MHz, 20 °C): δ 1.05-1.35 (m, 5H, CHA), 1.55-1.84 (m, 3H, CHA), 2.27 (m, 2H,
CHA), 2.94 (m, 2H, NH2-Pt), 3.24 (m, 1H, CHCHA), 3.90 (s, 3H, N-CH3), 5.60 (s, 2H, N-
CH2), 6.22 (s, 2H, O-CH2), 6.55 (d, J= 2.1Hz, 1H, CH=), 6.79 (d, J= 2.1Hz, 1H, CH=), 7.40-
7.62 (m, 8H, 2Har+ 6Hantr), 8.02 (d, J=8.1Hz, 2H, 2Har), 8.08 (s, 1H, CH=N or 1Hantr),
8.74 (s, 1H, CH=N or 1Hantr), 8.50 (s, 2H, 2Hantr). 13C-NMR (CDCl3, 75 MHz, 20 °C): δ
24.8 (CHA), 25.5 (CHA), 35.9 (CHA), 38.1 (N-CH3), 54.0 and 54.8 (CHCHA and N-CH2),
68.7 (O-CH2), 119.8 (CH=), 122.4 (CH=), 124.4 125.0 126.4 127.3 127.4 128.9 129.0 129.3
131.2 131.4 132.2 137.0 (Car), 140.2 (C-Pt), 148.4 (CH=N). Elemental analysis calcd (%) for
C33H36I2N4OPt (MW = 953.56): C 41.57, H 3.81, N 5.88, found: C 41.34, H 3.59, N 5.23.
UV/Vis (CH2Cl2) λmax (nm) (ε, M−1 cm−1): 273 (7833), 367 (6812), 392 (6788); luminescent
properties: λexc=368 nm; λem= 400-470 nm. Crystals suitable for X-ray diffraction studies
were obtained from CH2Cl2/pentane.
Complex 7. Complex 2 (50 mg, 0.068 mmol) and NH2OC5H10CO2tBu (14 mg, 0.068 mmol)
in anhydrous dichloromethane was stirred overnight at room temperature. The volatiles were
removed under reduced pressure and the crude product was purified by chromatography
1
(SiO2, CH2Cl2/cyclohexane) to afford 7 as a yellow solid (56 mg, 88%). H-NMR (CDCl3,
300 MHz, 20 °C): δ 1.13-1.43 (m, 15H), 1.61-1.76 (m, 9H), 2.20-2.28 (m, 4H), 2.92 (bd, J =
6.4 Hz, 2H), 3.18-3.32 (m, 1H), 3.88 (s, 3H), 4.15 (t, J = 6.6 Hz, 2H), 5.59 (s, 2H), 6.56 (d, J
18

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= 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz,V2iewHA)rt,icle Online
DOI: 10.1039/C5NJ03104D
13
8.05 (s, 1H). C-NMR (CDCl3, 75 MHz, 20 °C): δ 24.8, 24.9, 25.3, 25.4, 28.1, 28.8, 35.5,
35.9, 38.1, 54.0, 54.8, 74.1, 80.0, 119.8, 122.4, 127.3, 129.2, 132.4, 136.9, 140.2, 147.7,
173.1. HRMS (positive ESI) [M-I]: calculated for C28H44IN4O3Pt 806.2106, found 806.2100.
Complex 8. Complex 7 (20 mg, 0.021 mmol) was stirred 30 minutes at room temperature in
anhydrous dichloromethane with few drops of formic acid. The volatiles were removed under
reduced pressure and the crude product was purified on silica chromatography (DCM/MeOH
96/4) to afford 8 as a yellow solid (19 mg, quantitative). 1H-NMR (CDCl3, 300 MHz, 20 °C):
δ 1.12-1.38 (m, 11H), 1.39-1.52 (m, 4H), 1.61-1.79 (m, 9H), 2.26-2.29 (m, 2H), 2.39 (t, J =
7.0 Hz, 2H), 2.94 (bd, J = 7.0 Hz, 2H), 3.18-3.32 (m, 1H), 3.90 (s, 3H), 4.17 (t, J = 6.6 Hz,
2H), 5.61 (s, 2H), 6.57 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H),
7.58 (d, J = 8.1 Hz, 2H), 8.06 (s, 1H). 13C-NMR (CDCl3, 75 MHz, 20 °C): δ 24.4, 24.8, 25.4,
28.7, 29.7, 33.7, 35.9, 38.1, 53.9, 54.8, 74.0, 119.8, 122.4, 127.3, 129.2, 132.4, 136.9, 140.1,
147.7, 178.5. MS (positive ESI) [M+H]: calculated for C25H36I2N4O3Pt 878.06, found 878.05.
Complex 12. Complex 2 (40 mg, 54 µmol) and 9 (15 mg, 0.82 mmol) in anhydrous
dichloromethane was stirred overnight at room temperature. The volatiles removed under
reduced pressure and the crude product was purified by chromatography (SiO2,
1
CH2Cl2/cyclohexane) to afford 10 as a yellow solid (20 mg, 41%). H-NMR (CDCl3, 300
MHz, 20 °C): δ 1.06-1.35 (m, 6H), 1.61-1.79 (m, 5H), 2.24-2.29 (m, 2H), 2.47 (s, 3H), 2.90-
2.98 (m, 2H), 3.21-3.26 (m, 1H), 3.90 (s, 3H), 4.47 (t, J = 4.5 Hz, 2H), 4.66 (t, J = 4.5 Hz,
2H), 5.62 (s, 2H), 6.60 (d, J = 2.1 Hz, 2H), 6.82 (d, J = 2.1 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H),
7.52 (d, J = 8.3 Hz, 2H), 7.98 (s, 1H), 8.01 (s, 1H). 13C-NMR (CDCl3, 75 MHz, 20 °C): δ
14.5, 24.8, 25.2, 35.8, 38.1, 46.0, 53.9, 54.8, 72.4, 119.8, 122.4, 127.5, 128.9, 129.3, 131.3,
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133.2, 137.7, 140.4, 149.4, 151.2. HRMS (positive ESI) [M+Na]: calculatedViewfAortricle Online
DOI: 10.1039/C5NJ03104D
C24H33I2N7O3PtNa 939.0280, found 939.0287.
Complex 13. Complex 2 (30 mg, 41 µmol) and 10 (9.5 mg, 41 µmol) in anhydrous
dichloromethane was stirred overnight at room temperature. The volatiles removed under
reduced pressure and the crude product was purified by chromatography (SiO2,
1
CH2Cl2/cyclohexane) to afford 11 as a yellow solid (15 mg, 39%). H-NMR (MeOD, 300
MHz, 20 °C): δ 0.97-1.42 (m, 10H), 1.67-1.71 (m, 1H), 1.80-1.84 (m, 2H), 2.32-2.35 (m, 2H),
2.57 (quint, J = 9.4 Hz, 2H), 3.26-3.33 (m, 1H), 3.47-3.65 (m, 2H), 3.93 (s, 3H), 4.36 (t, J =
5.5 Hz, 2H), 5.69 (s, 2H), 6.95 (d, J = 2.1 Hz, 2H), 7.16 (d, J = 2.1 Hz, 2H), 7.59 (s, 4H), 7.98
(s, 1H), 8.14 (t, J = 7.0 Hz, 2H), 8.60 (t, J = 7.9 Hz, 1H), 9.12 (d, J = 5.5 Hz, 2H). 13C-NMR
(MeOD, 75 MHz, 20 °C): δ 24.6, 25.2, 30.1, 35.2, 36.9, 53.2, 54.5, 59.7, 70.5, 120.0, 122.5,
126.9, 127.9, 128.8, 129.0, 131.5, 138.4, 144.9, 145.5, 148.9. HRMS (positive ESI) [M+]:
calculated for C26H36I2N5OPt 883.0652, found 883.0595.
Complex 14. Complex 2 (65 mg, 88 µmol), 11.TFA (45 mg, 80 µmol) and NEt3 (11 µL, 80
µmol) in methanol was stirred overnight at room temperature. The volatiles removed under
reduced pressure. NMR of the crude revealed a conversion of 38%. Purification by C18-SiO2
1
using methanol finally gave the compound 12 in 90% purity. Selected NMR data: H-NMR
(MeOD, 300 MHz, 20 °C): δ 3.92 (s, 3H), 4.21 (t, J = 6.5 Hz, 2H), 4.27-4.44 (m, 2H), 5.68 (s,
2H), 6.90 (d, J = 2.1 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.50-7.72 (m, 4H), 8.15 (s, 1H). 13C-
NMR (MeOD, 75 MHz, 20 °C): δ 51.7, 52.1, 52.8, 54.0, 73.1, 119.4, 121.9, 126.2, 128.5,
131.7, 137.3, 140.6, 147.3, 158.2, 173.9, 174.3, 174.5, 174.6 HRMS (positive ESI) [M+Na]:
calculated for C36H55I2N7O9PtNa 1201.1696, found 1201.1705.
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Acknowledgments
The authors gratefully acknowledge the CNRS and the Ministère de l’Enseignement
Supérieur et de la Recherche (MESR) for a PhD grant to G.D. The authors also thank Dr. C.
Bailly and Dr. L. Brelot for X-Ray diffraction studies (Strasbourg) and Dr Delphine Felder-
Flesch for fruitful discussions. This work was supported by La Ligue contre le Cancer –
Région Grand Est.
References and Notes
[1] B. Rosenberg, L. Van Camp and T. Krigas, Nature, 1965, 205, 698.
[2] Medicinal Inorganic Chemistry (Eds.: J. L. Sessler, S. R. Doctrow, T. J. McMurry, S. J.
Lippard), ACS Symposium Series, Washington, DC, 2005.
[3] M. A. Fuertes, C. Alonso and J. M. Pérez, Chem. Rev., 2003, 103, 645.
[4] Recent general reviews on NHC complexes: a) M. N. Hopkinson, C. Richter, M. Schedler
and F. Glorius, Nature, 2014, 510, 485; b) S. Bellemin-Laponnaz and S. Dagorne, Chem.
Rev., 2014, 114, 8747; c) K. Riener, S. Haslinger, A. Raba, M. P. Högerl, M. Cokoja, W. A.
Herrmann and F. E. Kühn, Chem. Rev., 2014, 114, 5215; d) S. Díez-González, N. Marion, S.
and P. Nolan, Chem. Rev., 2009, 109, 3612.
[5] For the synthesis of carbene precursors, see: L. Benhamou, E. Chardon, G. Lavigne, S.
Bellemin-Laponnaz and V. César, Chem. Rev., 2011, 111, 2705.
[6] a) A. Gautier and F. Cisnetti, Metallomics, 2012, 4, 23; b) K. M. Hindi, M. J. Panzner, C.
A. Tessier, C. L. Cannon and W. J. Youngs, Chem. Rev., 2009, 109, 3859; c) L. Mercs and M.
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Chem., 2010, 53, 2146; b) M. Chtchigrovsky, L. Eloy, H. Jullien, L. Saker, E. Ségal-
Bendirdjian, J. Poupon, S. Bombard, T. Cresteil, P. Retailleau and A. Marinetti, J. Med.
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Chem. Asian J., 2013, 8, 1232; d) E. Chardon, G. Dahm, G. Guichard and S. Bellemin-
Laponnaz, Organometallics, 2012, 31, 7618; e) E. Chardon, G. L. Puleo, G. Dahm, S.
Fournel, G. Guichard and S. Bellemin-Laponnaz, Chem-PlusChem, 2012, 77, 1028; f) E.
Chardon, G. L. Puleo, G. Dahm, S. Fournel, G. Guichard and S. Bellemin-Laponnaz, Chem.
Commun., 2011, 47, 5864; g) R. W.-Y. Sun, A. L.-F. Chow, X.- H. Li, J. J. Yan, S. S.-Y. Chui
and C.-M. Che, Chem. Sci., 2011, 2, 728; h) G. Dahm, C. Bailly, L. Karmazin and S.
Bellemin-Laponnaz, J. Organomet. Chem. 2015, 794, 115; i) T. Zou, C.-N. Lok, Y. M. E.
Fung and C.-M. Che, Chem. Commun 2013, 49, 5423; j) R. W.-Y. Sun, A. L.-F. Chow, X.-H.
Li, J. J. Yan, S. S.-Y. Chui, C.-M. Che, Chem. Sci. 2011, 2, 728.
[8] A. Monney and M. Albrecht, Coord. Chem. Rev., 2013, 257, 2420.
[9] G. Dahm, E. Borré, G. Guichard and S. Bellemin-Laponnaz Eur. J. Inorg. Chem., 2015,
1665.
[10] The imine formation was easily followed by proton NMR thanks to typical signals at
10.0 ppm and 8.3 ppm for CH=O and CH=N, respectively. For all herein presented
1
complexes, only one signal was observed by H and 13C-NMR spectroscopy for the imine
group CH=N indicating the presence of only one isomer (i.e. E isomer).
[11] The imine ligation in combination with metal ligand exchange has been recently used by
us as a novel orthogonal and practical approach to multifunctionalization of NHC-platinum
complexes, see reference [9].
[12] J. Kalia and R. T. Raines, Angew. Chem. Int. Ed., 2008, 47, 7523.
[13] a) X. Zhang , Z-F. Su , J. R. Ballinger , A. M. Rauth , A. Pollak and J. R. Thornback,
Bioconjugate Chem., 2000, 11, 401; b) M. B. Mallia, A. Mathur, S. Subramanian, S.
Banerjee, H. D. Sarma and M. Venkatesh, Bioorg. Med. Chem. Lett., 2005, 15, 3398.
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Mignot, R. Antoine, P. Dugourd, F. Redini, L. Sancey, F. Lux, P. Perriat, M. Janierae and O.
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[18] Due to the low solubilities of Pt NHC complexes in water, we prepared and used stock
solutions in DMSO. The stability of the complexes in DMSO solution was confirmed by
NMR and UV-vis studies.
[19] The peptidomimetic 11 did not display any cytotoxic activity. The IC50 values were
calculated taken into account 90% purity and the presence of 10% of peptidomimetic 8.
[20] “Kappa CCD Operation Manual”, Nonius B. V., Ed.; Delft: The Netherlands, 1997.
[21] G. M. Sheldrick, Acta Cryst.,1990, A46, 467.
[22] G. M. Sheldrick, Acta Cryst., 2008, A64, 112.
[23] A. L. Spek, J. Appl. Cryst., 2003, 36, 7.
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Table of content
Carbonyl condensation reactions have been used for accessing N-heterocyclic carbene (NHC)
platinum bioconjugate complexes.
Graphical Abstract
O
O
NH
N
I
N
I
Me
C
COOH
COOH
O
NH2
O
H
Pt
O
C
O
HN
N
H2N
HOOC
N
N
COOH
H
H
N
I
N
I
Me
C
O
Pt
Targeting Platinum Anti-Cancer Agent?
HOOC
N
N
COOH
H2N
H
H
Prostate Cancer Cell Target
1