Palladium(II)‐η 3 ‐Allyl Complexes Bearing N ‐Trifluoromethyl N ‐Heterocyclic Carbenes: A New Generation of Anticancer Agents that 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 (for the most part, IC 50 values fall in the range 0.02–0.5 μ m ). 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 η 3 ‐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.