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The first palladium organometallic compounds bearing N‐trifluoromethyl N‐heterocyclic carbenes have been synthesized. These η3‐allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC50 values fall in the range 0.02–0.5 μm). By choosing 1,3,5‐triaza‐7‐phosphaadamantane (PTA) as co‐ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2‐methyl substituents generally reduces the antitumor activity slightly. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, thus revealing a behavior substantially different from that of cisplatin and its derivatives. We assume that the specific mechanism of action of these organometallic compounds involves nucleophilic attack on the η3‐allyl fragment. The effectiveness of a representative complex, 4 c, was verified on ovarian cancer tumoroids derived from patients. The results are promising: unlike carboplatin, our compound turned out to be very active and showed a low toxicity toward normal liver organoids.

A series of new palladium allyl complexes bearing purine-based carbenes derived from caffeine, theophylline and theobromine have been prepared and characterized by NMR spectroscopy, and elemental analysis and in two cases by single crystal X-ray diffraction. The cytotoxic and proapoptotic activities of compounds have been determined in vitro on human ovarian cancer A2780 and SKOV-3 cell lines. These experiments have shown that the palladium-allyl fragment induces a general cytotoxicity, but the choice of the supporting ligands is of paramount importance for achieving the best results. In particular complexes 4c, 4d and 5d exhibit a higher antiproliferative effect (IC50: 0.09, 0.81 and 0.85 μM respectively) than cisplatin (IC50: 1.5 μM) on A2780 cells, and 4d (IC50: 1.7 μM vs. 5.94 μM) on SKOV-3 cell line. Moreover in many cases it has been proved that the cytotoxicity of our complexes is associated with the induction of apoptosis.

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