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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
Author(s) -
Scattolin Thomas,
Bortolamiol Enrica,
Visentin Fabiano,
Palazzolo Stefano,
Caligiuri Isabella,
Perin Tiziana,
Canzonieri Vincenzo,
Demitri Nicola,
Rizzolio Flavio,
Togni Antonio
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002199
Subject(s) - trifluoromethyl , chemistry , palladium , carboplatin , cisplatin , nucleophile , ligand (biochemistry) , stereochemistry , medicinal chemistry , selectivity , combinatorial chemistry , receptor , chemotherapy , alkyl , biochemistry , organic chemistry , biology , catalysis , genetics
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.