Palladium organometallic compounds bearing N-Heterocyclic Carbene ligands as promising anticancer agents

Despite the appearance in the market of platinum compounds with minor side effects than cisplatin (i.e. carboplatin and oxaliplatin), they did not solve the ineffectiveness on some types of tumors, having the same mechanism of action proposed for cisplatin (DNA platination). For this reason, many research groups have focused their attention on the synthesis and determination of the anticancer properties of compounds with metals different from platinum. Among the most investigated metals there are certainly ruthenium and gold and, only recently, palladium. The latter, despite belonging to the same group of platinum, has some rather different features: \u2022Better water solubility of its complexes. \u2022Structure-activity relationships and mechanisms of action generally different from platinum compounds. However, the fast dissociation pattern of palladium complexes compared to platinum represents a problem since the speciation, which heavily affects the biological activity and the pharmacokinetic properties, could be increased. To remedy this contraindication the most direct option is the introduction of ligands firmly anchored to the metal such as N-Heterocylic Carbenes (NHCs), which are known to give strong s-bonds with most of the transition metals. Moreover, several NHC-palladium complexes have already exhibited an interesting cytotoxic activity in vitro and tumour growth suppression even in vivo. In this PhD thesis, the synthesis and characterization of new palladium compounds stabilized by different types of N-Heterocyclic Carbenes and important organometallic fragments such as h3-allyl-Pd(II), palladacyclopentadienyl and h2-olefin-Pd(0) will be exposed. The reactivity and the importance in many catalytic processes of the fragments reported in Fig. A1 are well known, on the contrary, their biological activity is almost unexplored. Starting from these premises, it was decided to test the synthesized compounds toward different tumor lines, particularly on ovarian carcinoma, and human fibroblasts (healthy cells). From the antiproliferative activity data collected for about one hundred compounds, emerges that, regardless of the nature of the selected carbene ligand, the most active compounds bear the allyl fragment. For these species the evaluation of their activity in vivo and experiments aimed at identify the primary biological target, in order to propose the possible mechanism of action, are planned. A class of compounds generally slightly less active than that containing the allyl residue is represented by the palladacyclopentadienyl complexes and their derivatives. Nevertheless, for some of the synthesized compounds, an excellent antiproliferative and proapoptotic activity has been shown on ovarian cancer cell lines (CisPt sensitive and CisPt resistance), accompanied by a poor activity against normal cells. For the compound 40a a thorough investigation on the main biological target, which was found to be DNA, and on the degree of uptake in tumor cells was also carried out. Due to the high stability imparted by the palladaciclopentadienyl fragment and the chelatig biscarbene ligand, this compound does not undergo substitution reactions when reacted with reduced glutathione (GSH), which is a potential coordinating species present in abundance in the biological environment. It is therefore reasonable to suppose that the interaction with the DNA occurs through non-covalent interactions with the polynucleotide chain. Finally, the class of compounds decidedly less active than those described so far is represented by the Pd (0) derivatives stabilized by olefinic ligands. For these complexes the antiproliferative and proapoptotic activity was evaluated only in ovarian carcinoma lines, observing only in very few cases IC50 values comparable to those of cisplatin

Synthesis and characterization of palladacyclopentadiene complexes with N-heterocyclic carbene ligands

New palladacyclopentadiene compounds containing different chelate NHC-thioether and NHC-pyridine ligands have been prepared by transfer of the functionalized carbenes from the respective silver complexes to the polymeric precursors [PdC-COOR)4]n (R = Me, t-Bu). Their dynamic behaviour in solution was discussed and the solid-structure of 2c was determined by X-ray crystallography. The treatment of [Pd(C-COOCH3)4]n with two equivalents of the carbene silver complexes led to the (NHC)2Pd(C4-COOCH3)4 derivatives (3cei), a new class of compounds with only PdeC bonds. A serious limitation to this synthetic procedure is an excessive steric crowding around the metal centre. The complexes 3 are present in solution as a mixture of two atropoisomers, due to restricted rotation around the CarbeneePd bond. The kinetics of equilibration between the two configurational isomers was studied for complex 3c, which was also structurally defined by X-ray crystallography (anti isomer). Finally a synthetic protocol was set up for the synthesis of mixed NHC-Phosphine and NHC-Isocyanide palladacyclopentadiene complexes. In this procedure the order of addition of the reactants is of great importanc

Halogen metathesis in Pd(II) σ-butadienyl complexes

4reservedmixedSCATTOLIN, THOMAS; VISENTIN, Fabiano; CANOVESE, Luciano; SANTO, ClaudioScattolin, Thomas; Visentin, Fabiano; Canovese, Luciano; Santo, Claudi

Gold(I)-N-Heterocyclic Carbene Synthons in Organometallic Synthesis

The prominent role of gold-N-heterocyclic carbene (NHC) complexes in numerous research areas such as homogeneous (photo)catalysis, medicinal chemistry and materials science has prompted organometallic chemists to design gold-based synthons that permit access to target complexes through simple synthetic steps under mild conditions. In this review, the main gold-NHC synthons employed in organometallic synthesis are discussed. Mechanistic aspects involved in their synthesis and reactivity as well as applications of gold-NHC synthons as efficient pre-catalysts, antitumor agents and/or photo-emissive materials are presented

Computational investigations on the unexpected extrusion of molecular iodine in Pd(II) σ-butadienyl complexes

4reservedmixedSCATTOLIN, THOMAS; VISENTIN, Fabiano; CANOVESE, Luciano; SANTO, ClaudioScattolin, Thomas; Visentin, Fabiano; Canovese, Luciano; Santo, Claudi

Reactions of palladium(0) olefin complexes stabilized by some different hetero- and homo-ditopic spectator ligands with propargyl halides

Several new allenyl and propargyl complexes have been obtained by oxidative addition with propargyl chlorides of palladium (0) olefin complexes stabilized by N−N, P−P, N−P, N−S. and N−C homo− and hetero−ditopic spectator ligands. The oxidative addition of some of the isolated palladium(0) olefin derivatives with 3−chloro−1−propyne and 3−chloro−1− phenyl−propyne has been investigated and the ensuing tautomeric mixtures bearing propargyl and allenyl fragmenst η1− coordinated isolated. As a consequence of a detailed kinetic study, we have analyzed the influence of the electronic and steric parameters of the involved reactants and hypothesized the mechanism of reaction. The tautomeric rearrangement of one allenyl isomer into its propargyl counterpart was also investigated and in this case the complete determination of all the rate constants involved has been obtained. Beside these studies, two very rare η3−propargyl palladium derivatives have been isolated and characterized

Reactivity of N-heterocyclic carbene-pyridine palladacyclopentadiene complexes toward halogen addition. the unpredictable course of the reaction

As an extension of a previously published work we have reacted some palladacyclopentadiene complexes stabilized by bidentate N-heterocyclic carbene-pyridine or monodentate N-heterocyclic carbene-pyridine and isocyanide ligands with the halogens I2 and Br2. All the bidentate and monodentate complexes react with halogens to give at first the expected Ï\u83-coordinated butadienyl fragment. However, two of the less hindered NHC carbene-pyridine bidentate butadienyl iodo derivatives undergo a further rearrangement and novel Pd(ii) complexes characterized by a ten term coordinative ring were isolated and characterized. In the most favorable case we were able to carry out the kinetics of rearrangement and measure its reaction rate. Moreover, we have surmised a plausible mechanism on the basis of a dedicated computational approach and in one case the surprising structure characterized by the ten term coordinative ring was resolved by X-ray diffraction

Combined Treatment of Cancer Cells Using Allyl Palladium Complexes Bearing Purine-Based NHC Ligands and Molecules Targeting MicroRNAs miR-221-3p and miR-222-3p: Synergistic Effects on Apoptosis

Combined treatments employing lower concentrations of different drugs are used and studied to develop new and more effective anticancer therapeutic approaches. The combination therapy could be of great interest in the controlling of cancer. Regarding this, our research group has recently shown that peptide nucleic acids (PNAs) that target miR-221 are very effective and functional in inducing apoptosis of many tumor cells, including glioblastoma and colon cancer cells. Moreover, in a recent paper, we described a series of new palladium allyl complexes showing a strong antiproliferative activity on different tumor cell lines. The present study was aimed to analyze and validate the biological effects of the most active compounds tested, in combination with antagomiRNA molecules targeting two miRNAs, miR-221-3p and miR-222-3p. The obtained results show that a “combination therapy”, produced by combining the antagomiRNAs targeting miR-221-3p, miR-222-3p and the palladium allyl complex 4d, is very effective in inducing apoptosis, supporting the concept that the combination treatment of cancer cells with antagomiRNAs targeting a specific upregulated oncomiRNAs (in this study miR-221-3p and miR-222-3p) and metal-based compounds represents a promising therapeutic strategy to increase the efficacy of the antitumor protocol, reducing side effects at the same time

Isocyanide insertion across the Pd–C bond of allenyl and propargyl palladium complexes bearing phosphoquinoline as a spectator ligand. Synthesis of a palladium complex bearing a coordinated cyclobutenyl fragment

We have studied the insertion of p-toluenesulfonylmethyl isocyanide (TosMIC) on selected allenyl and propargyl complexes of palladium bearing diphenylphosphine quinoline as a spectator ligand. The fast process gives different products depending on the tautomer involved in the reaction. Thus, the unsubstituted allenyl species yields an insertion complex with the isocyanide coordinated between the metal and the first allenyl carbon. On the other hand, a mixture of phenyl substituted allenyl and propargyl palladium complexes yields a novel species characterized by a cyclo-butenyl fragment directly coordinated to palladium. The solid state structure of such a complex together with an exhaustive kinetic study of the whole process is reported