Palladium(II)-η³-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

Graphical Abstract

Atypical target: Palladium organometallic compounds bearing N-trifluoromethyl N-heterocyclic carbenes have been synthesized. These η³-allyl complexes are potent antiproliferative agents toward different cancer lines (IC₅₀ values mostly fall in the 0.02–0.5 μM range), and their primary cellular target is not DNA but mitochondria. Their effectiveness has been verified on ovarian cancer tumoroids derived from patients.

Abstract

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.