A Chemoselective and Modular Post-Synthetic Multi-Functionalization of NHC-Platinum Complexes

Article abstract of DOI:10.1002/ejic.201500116

We report oxime ligation in combination with metal ligand exchange as a novel orthogonal and practical approach to the multifunctionalization of NHC-platinum complexes. This strategy, which enables strong diversity enhancement of metallodrug candidates, could also be applied to selective bioconjugation. We report oxime ligation in combination with metal ligand exchange as a novel orthogonal and practical approach to the multi-functionalization of NHC-platinum complexes.

Full text of DOI:10.1002/ejic.201500116

SHORT COMMUNICATION
DOI:10.1002/ejic.201500116
A Chemoselective and Modular Post-Synthetic Multi-
Functionalization of NHC–Platinum Complexes
[a]
[a]
[b]
Georges Dahm, Etienne Borré, Gilles Guichard, and
Stéphane Bellemin-Laponnaz*[
a,c]
Keywords: Platinum / N-heterocyclic carbenes / Functionalization / Coordination chemistry
We report oxime ligation in combination with metal ligand
exchange as a novel orthogonal and practical approach to
the multifunctionalization of NHC–platinum complexes. This
strategy, which enables strong diversity enhancement of
metallodrug candidates, could also be applied to selective
bioconjugation.
Introduction
their selectivity profile, and the demonstration of their effi-
[
9]
cacy in vivo. In vivo, the molecule should be inert towards
the biological environment to avoid potential interference
and deactivation before reaching the target cells. Parameters
such as solubility and stability in aqueous solution thus be-
come crucial in this respect. Ideally, NHC–metal complexes
should also exhibit high selectivity towards cancer cells and
rapid clearance from non-targeted cells. Active targeting by
linking the anticancer agent to a suitable ligand that dis-
plays a high affinity for a specific receptor is thus needed.
All these requirements should be pre-evaluated and possibly
modulated by means of simple and highly modular syn-
The unique properties of metal ions can be used for the
treatment of acute illnesses.[ In this way, the serendipitous
discovery of cisplatin by Rosenberg led to the most widely
used anticancer drug, and this mainly paved the way for a
new field of research that is medicinal inorganic chemis-
try.[ Although widely used, cisplatin treatment is ac-
companied by several toxic side effects and tumor resis-
1]
2]
[
3]
tance. Thus, chemists have tried to find alternative drugs
in particular with potentially different mechanisms of ac-
[
4]
tion. Nevertheless, the clinical success of the cisplatin
drug still remains a driving force for the development of
new platinum complexes with reduced side effects and/or
[
10]
thetic pathways.
The post-synthetic functionalization of organometallic
complexes has long been understudied, mainly because
these compounds, by their very nature, were thought to be
incompatible with and too sensitive for such chemical trans-
formations. Today, this concept is being revisited in light
of the fast development of click chemistry and the copper-
(acquired) resistance. As such, organometallic complexes
have been the subjects of exciting studies and offer many
opportunities in the design of new drugs, not only as anti-
cancer agent but also as antimicrobial, antimalarial and di-
[
5]
agnostic agents.
N-heterocyclic carbene (NHC) metal complexes are a
[
11]
catalyzed azide-alkyne cycloaddition (CuAAC). The high
orthogonality, reliability and experimental simplicity of the
CuAAC was exploited recently to access various transition
class of organometallic complexes that have received recent
interest in the context of cancer therapy.[
6,7]
In particular,
several NHC-containing platinum compounds have shown
[
12,13]
metal conjugates including NHC complexes.
efficacy in vitro against various cancer cell lines with cyto-
toxicities significantly higher than cisplatin.[8] However, the
However, creating a covalent and irreversible bond by
azide-alkyne cycloaddition necessitates the insertion of po-
tentially cleavable functionalities for an efficient release of
the drug into the cancer cell. The reaction has also other
limitations that have been noted in particular when con-
sidering post-functionalization of organometallic com-
(pre)clinical development of these new molecules as anti-
cancer agents still faces multiple challenges, including the
clarification of their mode of action, the investigation of
[
a] Institut de Physique et Chimie des Matériaux de Strasbourg
[
13]
Université de Strasbourg-CNRS UMR 7504
plexes.
2
3 rue du Loess, BP 43, 67034 Strasbourg cedex 2, France
With such issues in mind, we describe here an efficient
strategy for preparing multifunctionalized NHC–Pt com-
plexes either by iterative assembly or by using orthogonal
ligation reactions (Figure 1).
Among click-type reactions, the carbonyl condensation
reactions, such as imine-, hydrazine- and oxime-bond for-
mation, recently received considerable attention for ac-
E-mail: bellemin@unistra.fr
http://www.ipcms.unistra.fr
[
[
b] Univ. Bordeaux, CBMN, UMR 5248, Institut Européen de
Chimie et Biologie (IECB),
2
rue Robert Escarpit, 33607 Pessac, France
c] Institute for Advanced Study, Université de Strasbourg
5
allée du Général Rouvillois, 67083 Strasbourg, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201500116.
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SHORT COMMUNICATION
benzyloxime and the benzylamino ligand, thus confirming
directional chemical reactivity.
The molecular structure of a related compound was con-
firmed by X-ray diffraction analysis. Figure 2 displays the
molecular structure of the Pt complex 3 obtained by reac-
tion with cyclohexylamine and O-benzylhydroxylamine.
The platinum centre features the typical square-planar ar-
rangement with a carbene–platinum bond length of
1
1
.970(7) Å and the oxime in (E) configuration [C(11)–N(3)
.385(9) Å].
Figure 1. Schematic representation of a selective post-synthetic
functionalization of NHC–platinum complexes by using possibly
reversible reactions (exemplified with C=N-bond formation).
cessing bioconjugates.[11a,14,15] In addition of such post-syn-
thetic functionalization, we envisioned that the introduction
of additional functionalities through the coordination of a
secondary relevant ligand would greatly enhance the diver-
sity of the compounds. Such combination of chemoselective
and orthogonal click techniques should considerably facili-
tate the preparation of Pt complexes that display multiple
ligands.
Results and Discussion
It is known that oximes display a much higher stability
compared to imines; thus, hydroxylamine derivatives (rather
than amine derivatives) preferentially react with an alde-
hyde moiety. On the other hand, we found that in a compet- Figure 2. Molecular structure of complex 3. Selected bond lengths
[
Å] and angles [°]: Pt(1)–C(1) 1.970(7), Pt(1)–N(4) 2.5901(6), Pt(1)–
itive experiment with benzylamine and benzyl hydroxyl-
amine an (NHC)(pyridine)platinum complex [(NHC)(pyr-
I(1) 2.6012(6), Pt(1)–I(2) 2.5901(6), C(11)–N(3) 1.283(12), N(3)–
O(1) 1.385(9); I(1)–Pt(1)–I(2) 177.70(2), C(1)–Pt(1)–N(4) 177.7(3).
idine)PtI ] reacts preferentially with the amine in a ratio
2
of 3:1 (see Supporting Information for details). This result
suggests that the combination of oxime ligation with ligand
exchange on the metal center could be exploited to access
orthogonal bifunctionalized NHC complexes. To validate
this hypothesis, we conducted the two reactions concur-
rently in a one-pot dual experiment with an (NHC)(pyr-
idine)platinum complex bearing a benzaldehyde moiety (e.g.
Sequential assembly by varying the order of addition of
the reactants (Scheme 2) was also investigated to further
[16]
optimize the process.
By introducing the amine first
(
pathway a), it was found that better conversion could be
obtained in the presence of excess of amine reagent, thus
giving the corresponding imine product as intermediate.
Further treatment with wet silica led to the hydrolysis of
the imine giving the aldehyde product in good yield. The
hydroxylamine-functionalized compound could then be ef-
ficiently introduced. Alternatively, oxime ligation can be
first done selectively (pathway b). Interestingly, the oxime
ligation was found to be highly selective when the oxime
1) by just mixing all components (Scheme 1). NMR analy-
sis showed the formation of a major product in ca. 50%,
which was found to be the Pt complex 2 containing the
was formed from the ammonium salt RONH Cl, whereas
3
addition of a base such as triethylamine resulted in an unse-
lective functionalization. Introduction of the amine after-
wards resulted in a selective pyridine ligand exchange giving
the expected product.
Scheme 3 displays two representative examples of such
chemoselective molecular assembly. NHC–Pt complex 1
was first treated with an excess of d-phenylalanine benzyl
ester followed by treatment with wet silica to give the corre-
sponding aldehyde-containing amino complex in 82% iso-
lated yield. Then, reaction with 1 equiv. of O-benzylhydrox-
ylamine gave the expected Pt complex 4 in 62% yield. By
Scheme 1. One-pot chemoselective functionalization of NHC–Pt
complex 1 by oxime ligation and ligand exchange, complex 2 indi-
cating a self-sorting behaviour out of an eight-component dynamic
combinatorial library (yield determined by NMR).
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modification, thus offering an additional level of chemical
diversity. For example, the NHC–platinum complex 6 con-
taining the protected l-Boc-Tyr-OtBu residue was obtained
by oxime ligation in 60% yield under mild conditions. A
selective deprotection of the N-Boc protecting group could
then be achieved by treatment with formic acid in dichloro-
methane to give complex 7 in quantitative yield (Scheme 4).
Scheme 4. Selective N-Boc deprotection of an NHC–Pt complex 6
following chemoselective oxime bond functionalization.
Imine ligation shows lower stability than oxime or
hydrazone ligations, in particular they are not stable at
[
14]
physiological pH. Nevertheless, they can be used as inter-
mediates and in situ reduced to generate the corresponding
secondary amine. For example, doubly functionalized plati-
num complex 8 with l-glutamic acid di-tert-butyl ester was
obtained by treatment of NHC–Pt complex 1 with an excess
Scheme 2. The two possible pathways for double modification of
NHC–Pt complex 1 by sequential oxime ligation/ligand exchange.
of the protected amino acid followed by NaHB(OAc) (75%
3
yield, two steps), featuring now an irreversible ligation with
one glutamic acid derivative (Scheme 5). Due to the coordi-
nation of amino groups being thermodynamically stable, it
is also possible to functionalize Pt complexes with two dif-
ferent nitrogen-containing ligands akin to previous complex
using pathway b, complex 1 was first treated with O-benzyl-
hydroxylamine leading quantitatively to oxime ligation.
Then, in a second step, the pyridine ligand could be selec-
tively exchanged by l-glutamic acid di-tert-butyl ester to
give complex 5 in 54% isolated yield.
6. As an example, complex 9 was treated with l-Phe-OBn
followed by NaHB(OAc) to give complex 10 in 65% over-
3
all yield.
Scheme 3. Examples of one-pot double modification of NHC–Pt
complex 1 by sequential oxime ligation and ligand exchange (path-
ways a and b). Reaction conditions: (i) NEt
ii) BnONH Cl, NEt ; CH Cl ; (iii) CH Cl
acid di-tert-butyl ester hydrochloride, EtOH.
3
, MeOH then wet SiO
2
;
(
3
3
2
2
2
2
; (iv) NEt , l-glutamic
3
Scheme 5. Post-modification of NHC–Pt complexes by tandem im-
ine ligation/reduction. Reaction conditions: (i) l-glutamic acid di-
tert-butyl ester hydrochloride (5 equiv.), K CO ; (ii) NaHB(OAc)
2 3 3
The double functionalization by oxime ligation and
metal ligand exchange offers products of remarkable sta-
bility that are potentially amenable to further chemical (3 equiv.); (iii) l-Phe-OBn (1.1 equiv.).
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[
6] a) A. Gautier, F. Cisnetti, Metallomics 2012, 4, 23; b) K. M.
Hindi, M. J. Panzner, C. A. Tessier, C. L. Cannon, W. J.
Youngs, Chem. Rev. 2009, 109, 3859; c) L. Mercs, M. Albrecht,
Chem. Soc. Rev. 2010, 39, 1903; d) W. Liu, R. Gust, Chem.
Soc. Rev. 2013, 42, 755.
Conclusions
Altogether these results demonstrate the efficiency of
combining ligand substitution with oxime ligation to en-
hance the chemical diversity of (N-heterocyclic carbene)-
platinum complexes. Although the directional chemical re-
activities of amines and hydroxylamines allow the bis-func-
tionalization of the (carbene)metal complex to be carried
out in a one-pot process, we found it more practical to pro-
ceed sequentially in either way. The compatibility of the
newly formed NHC–platinum complexes with further
chemical transformations (e.g. Boc deprotection, reductive
amination) brings added value. The examples reported
herein thus validate a synthetic method that may prove use-
ful in biology, allowing the cell targeting properties and
cytotoxic activities and of NHC–metal complexes to be
finely tuned.
[
7] Recent general reviews on NHC complexes: a) M. N. Hopkin-
son, C. Richter, M. Schedler, F. Glorius, Nature 2014, 510, 485;
b) S. Bellemin-Laponnaz, S. Dagorne, Chem. Rev. 2014, 114,
8
747; c) K. Riener, S. Haslinger, A. Raba, M. P. Högerl, M.
Cokoja, W. A. Herrmann, F. E. Kühn, Chem. Rev. 2014, 114,
5215; d) S. Díez-González, N. Marion, S. P. Nolan, Chem. Rev.
2009, 109, 3612.
[
8] a) M. Skander, P. Retailleau, B. Bourrie, L. Schio, P. Mailliet,
A. Marinetti, J. Med. Chem. 2010, 53, 2146; b) M. Chtchigrov-
sky, L. Eloy, H. Jullien, L. Saker, E. Ségal-Bendirdjian, J. Pou-
pon, S. Bombard, T. Cresteil, P. Retailleau, A. Marinetti, J.
Med. Chem. 2013, 56, 2074; c) E. Chardon, G. Dahm, G.
Guichard, S. Bellemin-Laponnaz, Chem. Asian J. 2013, 8, 1232;
d) E. Chardon, G. Dahm, G. Guichard, S. Bellemin-Laponnaz,
Organometallics 2012, 31, 7618; e) E. Chardon, G. L. Puleo, G.
Dahm, S. Fournel, G. Guichard, S. Bellemin-Laponnaz, Chem-
PlusChem 2012, 77, 1028; f) E. Chardon, G. L. Puleo, G.
Dahm, S. Fournel, G. Guichard, 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, C.-M. Che, Chem. Sci. 2011, 2,
Acknowledgments
728.
[
9] Pharmaceutical Perspectives of Cancer Therapeutics (Eds.: Y.
The authors gratefully acknowledge the Centre National de la Re-
cherche Scientifique (CNRS) (France) and the Ministère de l’En-
seignement Supérieur et de la Recherche (MESR) for a PhD grant
to G. D. The authors also thank Dr. Corinne Bailly and Dr. Lydia
Karmazin for X-ray diffraction studies and Dr. Thierry Achard
and Mathilde Bouché for technical assistance. This work was sup-
ported by La Ligue contre le Cancer – Région Grand Est.
Lu, R. I. Mahato), Springer, New York, 2009.
10] A. Monney, M. Albrecht, Coord. Chem. Rev. 2013, 257, 2420.
11] For reviews, see: a) W. Tang, M. L. Becker, Chem. Soc. Rev.
[
[
2
014, 43, 7013; b) P. Thirumurugan, D. Matosiuk, K. Jozwiak,
Chem. Rev. 2013, 113, 4905; c) M. Meldal, C. W. Tornøe,
Chem. Rev. 2008, 108, 2952; d) J. E. Moses, A. D. Moorhouse,
Chem. Soc. Rev. 2007, 36, 1249.
[
12] See, for example: a) S. Gauthier, N. Weisbach, N. Bhuvanesh,
J. A. Gladysz, Organometallics 2009, 28, 5597; b) D. Urankar,
J. Ko sˇ mrlj, Inorg. Chim. Acta 2010, 363, 3817; c) J. D. White,
M. F. Osborn, A. D. Moghaddam, L. E. Guzman, M. M.
Haley, V. J. DeRose, J. Am. Chem. Soc. 2013, 135, 11680.
[
1] Medicinal Inorganic Chemistry (Eds.: J. L. Sessler, S. R. Doc-
trow, T. J. McMurry, S. J. Lippard), ACS Symposium Series,
Washington, DC, 2005.
[
[
2] B. Rosenberg, L. Van Camp, T. Krigas, Nature 1965, 205, 698.
3] M. A. Fuertes, C. Alonso, J. M. Pérez, Chem. Rev. 2003, 103,
[13] F. Cisnetti, C. Gibard, A. Gautier, J. Organomet. Chem. 2014,
DOI: 10.1016/j.jorganchem.2014.10.012.
6
45.
4] a) L. Ronconiand, P. J. Sadler, Coord. Chem. Rev. 2007, 251,
633; b) P. C. A. Bruijnincx, P. J. Sadler, Curr. Opin. Chem.
[14] S. Ulrich, D. Boturyn, A. Marra, O. Renaudet, P. Dumy, Chem.
Eur. J. 2014, 20, 34.
[
1
[15] a) W. H. Ang, E. Daldini, L. Juillerat-Jeanneret, P. J. Dyson,
Inorg. Chem. 2007, 46, 9048; b) Y. Q. Tan, P. J. Dyson, W. H.
Ang, Organometallics 2011, 30, 5965; c) D. Y. Q. Wong,
C. H. F. Yeo, W. H. Ang, Angew. Chem. Int. Ed. 2014, 53, 6752.
[16] The sequential rather than the one-pot assembly was found to
give better overall yields. Moreover, one-pot assembly generates
several possible products so that it is more difficult to purify
the desired target.
Biol. 2008, 12, 197; c) S. H. van Rijt, P. J. Sadler, Drug Discov-
ery Today 2009, 14, 1089.
[
5] a) G. Gasser, N. Metzler-Nolte, Curr. Opin. Chem. Biol. 2012,
16, 84; b) G. Gasser, I. Ott, N. Metzler-Nolte, J. Med. Chem.
2011, 54, 3; c) M. M. Jellicoe, S. J. Nichols, B. A. Callus, M. V.
Baker, P. J. Barnard, S. J. Berners-Price, J. Whelan, G. C. Yeoh,
A. Filipovska, Carcinogenesis 2008, 29, 1124; d) S. Ray, R. Mo-
han, J. K. Singh, M. K. Samantaray, M. M. Shaikh, D. Panda,
P. Ghosh, J. Am. Chem. Soc. 2007, 129, 15042.
Received: February 3, 2015
Published Online: March 6, 2015
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