Synthesis and comparative study of the anticancer activity of η3-allyl palladium(II) complexes bearing N-heterocyclic carbenes as ancillary ligands
Graphical abstract
Fifteen new Pd(II) allyl complexes containing at least one N-heterocyclic carbene ligand and others previously published by our research group, have been tested against different tumor lines (ovarian cancer, lung cancer, colon cancer and malignant melanoma) and normal cells (human lung fibroblasts). Most of the tested compounds exhibit a much powerful antitumor activity than cisplatin on all tumor cell lines examined.
Moreover, a selected number of compounds among those reported are particularly promising since exhibit a markedly lower activity toward normal cells than to cancer cells.
Introduction
Since the discovery of the first stable N-heterocyclic carbene by Arduengo and coworkers [1], they have received a growing interest as ancillary ligands in numerous transition metal-mediated catalytic reactions [2]. The low toxicity, high thermal stability and resistance to oxygen and moisture are the basis of success of metal-NHC complexes. All these favorable features are basically ascribable to the strength of the metal–carbene bond [3].
Moreover, the possibility of changing the N-substituents, ring type and heteroatoms has allowed the synthesis of a great variety of NHC-based compounds [2], [4].
A further opportunity is represented by the incorporation of the carbene moiety into ligands containing other “classical” donor groups. In this respect, the synthesis of Pt, Pd, Ru, Ir and Rh complexes stabilized by chelating N-functionalized NHCs with substituted imines, pyridines, ethers and alkyl/arylsulfides has allowed the modulation of the electron density on the metal center of interest [5].
Furthermore, in the last decade, also complexes containing two carbene ligands have been extensively employed in homogeneous catalysis [6]. In particular, chelating bisNHCs, beside imparting a very high stability to their complexes, allows the fine-tuning of the steric and electronic properties by choosing the wingtips substituents, backbone and linker [7].
Many examples of bis-carbene Pd(halide)2 complexes, generally obtained by reaction between bisimidazolium salts with Pd(OAc)2 at high temperatures, are reported in the literature [8]. On the other hand, there are very few examples of Pd(II) bis-carbene complexes containing organometallic fragments able to promote efficiently and selectively catalytic processes or interactions with biological systems. Within this context, examples of bis-carbene species with palladacyclopentadienyl [9a,b], η3-allyl-Pd(II) [9c,d] and η2-olefin-Pd(0) [9e] fragments have recently been reported.
The palladacyclopentadienyl fragment, which is known to be involved in the formation and stereoselective extrusion of conjugated dienes [10], has been extensively studied by our research group using different categories of ligands [11]. In particular, it has been observed that palladacyclopentadienyl complexes bearing chelating bisNHCs exhibit a high antiproliferative activity towards ovarian cancer cell lines, with DNA as the primary biological target [9], [9](a).
With reference to the η3-allyl fragment, the first example of a palladium(II) complex with a chelating bis-carbene ligand was instead reported in 2013 by Elsevier and coworkers, in which the semihydrogenation of 1-phenyl-1-propyne was also explored [9], [9](c). More usually, allyl complexes are utilized in many homo- and hetero-cross coupling processes [12], including the Tsuji-Trost reaction, which involves the functionalization of allyl substrates [12c,d]. The crucial step of this last process is the nucleophilic attack on the terminal allyl carbon of the Pd (II)-η3-allyl intermediate. The reaction rate, as reported in numerous studies, is sometimes heavily affected by the presence of substituents on the allyl residue. In particular, the presence of a methyl group in the central allyl carbon makes the nucleophilic attack slower by about one order of magnitude with respect to the unsubstituted substrates [13].
Conversely, the behavior of this class of important organometallic substrates in a biological environment has been much less explored. Recently we have published an article showing the interesting cytotoxicity against some ovarian cancer cell lines of allyl palladium(II) complexes stabilized by purine-based NHCs [14].
Encouraged by these first promising results, we report in this new work the synthesis and the anticancer activity of new allyl palladium(II) complexes containing at least one N-heterocyclic carbene ligand. Moreover, we propose an extensive analysis of the influence of both spectator ligands and the type of allylic fragment on the cytotoxicity of this class of molecules toward six different tumor lines and human lung fibroblasts (normal cells).
As shown in Fig. 1, the palladium(II) compounds described in this paper can be divided into four broad categories: (A) monodentate bisNHC and chelating bisNHC complexes; (B) chelating phosphino- picolyl- or arylsulfide-NHC complexes; (C) mixed NHC/L complexes (L = triphenylphosphine, PPh3; 1,3,5-triaza-7-phosphaadamantane, PTA or 2,6-dimethylphenylisocyanide, DIC) and (D) chelating NS or NP complexes. These latter species, previously synthetized by our research group, allow to extend the analysis of spectator ligand effects on the antiproliferative activity of palladium(II) allyl derivatives.
Section snippets
Synthesis of η3-allyl palladium(II) complexes bearing chelating bisNHCs
The synthesis of cationic η3-allyl palladium(II) compounds containing chelating bis-carbene ligands (3a-f and 5e) was carried out by reacting the silver complexes 2a-f [8](g), [15] with the allyl palladium(II) precursors 1 or 4 [16], according to the conditions reported in Scheme 1.
These reactions are favored by the presence of a labile pyridyl-thioether ligand in the palladium(II) precursor and by the precipitation of silver bromide as a consequence of the transmetallation process.
Complexes
Conclusions
We have synthesized fifteen new Pd(II) allyl complexes bearing bidentate or monodentate N-heterocyclic carbenes with the phosphines triphenylphosphine and 1,3,5-triaza-7-phosophaadamantane (PTA) as co-ligands.
All the complexes were fully characterized by NMR and IR spectroscopy and elemental analysis.
Some of the synthesized species were obtained as mixtures of atropoisomers, and for those with the most sterically demanding ancillary ligands the interconversion between isomers is hindered even
Materials and characterization techniques
All syntheses of complexes were carried out using standard Schlenk techniques under an atmosphere of dry nitrogen. Solvents were dried and distilled according to standard methods: CH2Cl2 was firstly treated with 3 Å molecular sieves and then distilled over P2O5. All other chemicals were commercially available grade products and were used as purchased.
The palladium(II) precursors 1 and 4 [16], the silver compounds 2a-f [23], [28], 6a-d [29], and 8 [30] and the palladium(II) complexes 7c-d [22],
Authorship statement
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Conception and design of study: Thomas Scattolin and Fabiano Visentin.
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Acquisition of data: Thomas Scattolin, Enrica Bortolamiol, Isabella Caligiuri, Nicola Demitri.
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Analysis and/or interpretation of data: Thomas Scattolin, Enrica Bortolamiol, Isabella Caligiuri, Nicola Demitri, Flavio Rizzolio and Fabiano Visentin.
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Drafting the manuscript: Thomas Scattolin.
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Revising the manuscript critically for important intellectual content: Fabiano Visentin and Flavio Rizzolio.
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