The palladium(II) chloro methyl complexes bearing the bidentate 6-R-C 5 H 3 N-2-CH 2 SR′ (RN-SR′; R ) H, Me, Cl; R′ ) Me, t-Bu, Ph) and the potentially terdentate 2,6-(CH 2 SR′) 2 -C 5 H 3 N (S-N-S(R′); R′ ) Me, t-Bu, Ph) pyridylthioethers as ancillary ligands were synthesized, characterized, and reacted with substituted alkynes ZCtCZ (Z ) COOMe, Z′ ) COOt-Bu, Z′′ ) COOEt). The reactions were followed under second-order conditions by 1 H NMR technique, and the reaction rates were determined. The corresponding vinyl derivatives were synthesized, and in the case of the complexes [PdCl(ZCdCZMe)(MeN-SPh)] and [PdCl(ZCd CZMe)(C1N-St-Bu)] (Z ) COOMe) reaction rates for alkyne insertion yielding the corresponding butadienyl complexes were also determined. The rate of insertion of the second alkyne on the vinyl complex is more than 3 orders of magnitude lower than the first insertion rate in both the studied complexes, thereby allowing easy separation between vinyl and butadienyl derivatives and an easy preparation of mixed butadienyl esters. Furthermore, the reaction rates are strongly dependent on the steric and electronic features of the ancillary ligands. In particular, the distortion of the complex main coordination plane, induced by the substituent in position 6 of the pyridine ring, was found to significantly influence the substrate reactivity. The structures of the mono-inserted vinyl [PdCl(ZCdCZMe)(MeN-St-Bu)] (1) and the bis-inserted butadienyl [PdCl((ZCdCZ) 2 Me)(MeN-St-Bu)] (2) complexes were determined by X-ray diffraction, and the persistence of a structural distortion of the complex skeleton was observed. Moreover, the distortion may be related to facile ancillary ligand displacement, a feature that can be exploited for the synthesis of substrates that would not be easily obtained otherwise.

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.

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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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The mechanochemical syntheses of allyl and indenyl palladate complexes are reported. All compounds were obtained in quantitative yields and microanalytically pure without the need of any workup. These complexes are stable in chlorinated and polar (DMSO or DMSO/H 2 O solutions) solvents. In chlorinated solvents, they appear as ionic pairs of which crystals suitable for single X-ray diffraction studies have been obtained. Bonding and solvation properties are rationalized through scalar relativistic DFT calculations. Moreover, most complexes showed excellent cytotoxicity towards ovarian cancer cell lines, with IC 50 values comparable or lower than cisplatin. The potent anticancer activity of two IPr Cl and IPr*-based palladate complexes was examined in a high-grade serous ovarian cancer (HGSOC) patient-derived tumoroid. Moreover, the inhibition of the antioxidant enzyme thioredoxin reductase (TrxR) was noticed, and structure-activity relationships could be derived, suggesting the ROS detoxifying system is involved in the mode of action.

The rate of insertion of methyl-substituted allenes into the Pd-Me bond in chelate pyridinethioether complexes [PdCl(Me)derivatives is remarkably enhanced by the presence of a methyl group in position 6 of the pyridine ring, which induces distortion on the main coordination plane, resulting in a metal substrate more prone to allene insertion. The flexibility of the sulfur-donor chelate ligand appears to be a paramount requisite.