Palladium(II)-η3-allyl complexes bearing N-trifluoromethyl N-heterocyclic carbenes:a new generation of anticancer agents which restrain the growth of high grade serous ovarian cancer tumoroids.

The first palladium organometallic compounds bearing N-trifluoromethyl N-heterocyclic carbenes have been synthesized. These η 3 -allyl complexes are potent antiproliferative agents against different cancer lines (the most part of IC 50 falls in the range of 0.02-0.5 μM) and by choosing PTA as co-ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2-methyl substituents generally slightly reduces the antitumor activity. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, therefore revealing a behavior substantially different from that of cisplatin and derivatives. We assume that the specific mechanism of action of these organometallic compounds involves the nucleophilic attack on the η 3 -allyl fragment. The effectiveness of the representative complex 4c has been verified on ovarian cancer tumoroids derived from patients. The results are promising: contrary to carboplatin, our compound resulted very active and showed a low toxicity toward normal liver organoids.