DOI: 10.1002/ejic.201600296 Full Paper Cytotoxic Carbene Complexes Selective Formation of cis-N-Heterocyclic Carbene-Pt II -Pnictogen Complexes and in vitro Evaluation of Their Cytotoxic Activities toward Cancer Cells Mathilde Bouché, [a] Georges Dahm, [a] Aline Maisse-François, [a] Thierry Achard,* [a] and Stéphane Bellemin-Laponnaz* [a,b] Abstract: A series of heterotopic platinum complexes combin- ing N-heterocyclic carbene (NHC) and pnictogen-based ligands [Pn = P(nBu) 3 , PPh 3 , AsPh 3 and SbPh 3 ] has been synthesized and fully characterized. Use of an excess of Pn ligand led to the formation of cationic bis-Pn platinum-NHC complexes in high yield, with both Pn ligands being arranged trans to each other. Several representative complexes could be characterized by X- Introduction Since the isolation of the first stable N-heterocyclic carbene by Arduengo, [1] the chemistry of NHCs has become rich and is still a very fertile field of investigation for both homogeneous catal- ysis and organometallic chemistry. [2,3] Despite this rapid devel- opment, application in other fields remains marginal, although in the last few years interest in investigating NHCs in underex- plored fields has grown. [4] For example, the unique properties of NHC metal complexes make them attractive for the develop- ment of metallodrugs. [5] In particular, the strong carbene–metal bond enhances the stability of the entire system in the blood- stream. [6] Interesting antimicrobial properties have also been reported for various NHC metal complexes. [6] Of late, for exam- ple NHC-copper, [7] gold, [8] palladium, [9] platinum, [10] and silver complexes [11] were highlighted as auspicious anticancer agents. [12] Among these investigations, the development of new platinum-based complexes to overcome severe side effects and cell-resistance phenomena encountered with cisplatin is of great importance. [13] In addition, the poor selectivity of this world bestselling drug and its efficiency toward a limited num- ber of cancers remains an issue. In the development of NHC-platinum anticancer drugs, Mari- netti and co-workers nicely showed that neutral mono- and [a] Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), DMO, Université de Strasbourg-CNRS UMR 7504, 23 rue du Loess, BP 43, 67034 Strasbourg, France E-mail: bellemin@unistra.fr achard@ipcms.unistra.fr http://www.ipcms.unistra.fr/ [b] University of Strasbourg Institute for Advanced Study (USIAS), 5 allée du Général Rouvillois, 67083 Strasbourg, France Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under http://dx.doi.org/10.1002/ejic.201600296. Eur. J. Inorg. Chem. 2016, 2828–2836 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2828 ray crystallographic studies thus confirming the ligand arrange- ment around the metal. This simple approach allows the gener- ation of diversity in metallodrug candidates. Biological activities on various human cancer cells have been studied and com- pared with those of cisplatin. The results confirmed the high cytotoxicity of these NHC-platinum complexes bearing pnicto- gen ligands. bimetallic trans-(NHC)PtX 2 (amine) complexes are active mol- ecules against several types of cancer, including cisplatin-resist- ant cancer cell-lines. [10] Cationic NHC-Pt II complexes also exhib- ited high cytotoxicity against HeLa (cervical cancer) and HepG 2 (hepatocellular carcinoma) cell lines. [14] The easily available [(NHC)Pt II X 2 ] unit has been established as a useful molecular building-block to generate libraries of anticancer analogues ei- ther by postfunctionalization [15] or by ligand exchange. [16] Pnictogen ligands (Pn), and more precisely phosphine, are ubiquitous in coordination chemistry of platinum(II) complexes. Nevertheless, the number of pnictogen-containing Pt com- plexes described decreases upon going down group 15 of the periodic table. [17] Only a few examples of NHC-Pt complexes combined with P, [18–20] As, [18] and Sb [21] ligands have been de- scribed. Arsenic and antimony derivatives have been known for decades for their biological activities and are still investigated for medical applications. [22] Accordingly, a combination of the (NHC)Pt molecular building-block and pnictogen ligands would be an interesting system with which to investigate possible syn- ergetic effects. [22a,23] Such an effect has recently been observed by O'Halloran and co-workers while studying anticancer proper- ties of a platinum/arsenic compound (arsenoplatin); in this case, higher cytotoxicity than either cisplatin or As 2 O 3 was noted in both colon cancer and glioblastoma. [24] The use of tertiary arsine ligands in combination with platinum is also known to induce interesting biological activities against tumor cells. [25] We report herein the synthesis of platinum(II) complexes combining N-heterocyclic carbene (NHC) and pnictogen-based ligands [Pn = P(nBu) 3 , PPh 3 , AsPh 3 and SbPh 3 ] (Figure 1). Syn- theses were conducted under very mild reaction conditions and provided a large library of NHC-Pt II -Pn complexes, all as single stereoisomers with cis-configuration. [26] A series of cationic platinum complexes was also synthesized, thus increasing the