Palladium(0) and Juglone: a new alliance in the fight against ovarian cancer Giovanni Tonon, Anna Rafaniello, Matteo Mauceri, Nicola Demitri, Thomas Scattolin, et al. Dalton Transactions, 2026 Four Juglone-based Pd(0) complexes with varied ligands were synthesized and characterized. They showed strong cytotoxicity and cancer selectivity. The most promising complex inhibited the PIN1 oncoprotein, as confirmed by Western Blot.
Synthesis and Anticancer Activity of Palladium-Butadienyl Complexes Bearing Picolyl-NHC and Phosphine Ligands Thomas Scattolin, Matteo Mauceri, Nicola Demitri, Flavio Rizzolio, Fabiano Visentin European Journal of Inorganic Chemistry, 2024 This work presents the synthesis and full characterization of Pd(II)‐butadienyl complexes incorporating picolyl‐NHC or phosphine ligands (PPh3 or PTA). These complexes were evaluated against four different cancer cell lines and human lung fibroblasts. Our findings indicate a slightly lower antiproliferative activity of picolyl‐NHC Pd(II)‐butadienyl complexes compared to recently published ones featuring N−N, P−P, and C−C ligands but, above all, they exhibited selectivity for ovarian cancer cells. Additionally, trans‐[PdX (phosphine)2C4(COOMe)4Y)] derivatives (X=Br, Cl and Y=CH3, Br) proved excellent anticancer activity across all tested cancer cell lines, especially the bisPTA complexes. Importantly, the IC50 values suggest minimal impact from the halide coordinated to palladium or that present in the butadienyl terminal position. Furthermore, the low activity observed towards non‐cancerous cells underscores the potential of these synthesized Pd(II)‐butadienyl compounds as promising candidates for further investigation in anticancer research.
Palladium(II)-Indenyl Complexes Bearing N-Heterocyclic Carbene (NHC) Ligands as Potent and Selective Metallodrugs toward High-Grade Serous Ovarian Cancer Models Enrica Bortolamiol, Matteo Mauceri, Rachele Piccolo, Enrico Cavarzerani, Nicola Demitri, et al. Journal of Medicinal Chemistry, 2024 In this study, we synthesized novel Pd(II)-indenyl complexes using various N-heterocyclic carbene (NHC) ligands, including chelating NHC-picolyl, NHC-thioether, and diNHC ligands, and two monodentate NHCs. Transmetalation reactions between a Pd(II)-indenyl precursor and silver-NHC complexes were generally employed, except for chelating diNHC derivatives, which required direct reaction with bisimidazolium salts and potassium carbonate. Characterization included NMR, HRMS analysis, and single-crystal X-ray diffraction. In vitro on five ovarian cancer cell lines showed notable cytotoxicity, with IC50 values in the micro- and submicromolar range. Some compounds exhibited intriguing selectivity for cancer cells due to higher tumor cell uptake. Mechanistic studies revealed that monodentate NHCs induced mitochondrial damage while chelating ligands caused DNA damage. One chelating NHC-picolyl ligand showed promising cytotoxicity and selectivity in high-grade serous ovarian cancer models, supporting its consideration for preclinical study.
Rational Design of Palladium(II) Indenyl and Allyl Complexes Bearing Phosphine and Isocyanide Ancillary Ligands with Promising Antitumor Activity Enrica Bortolamiol, Eleonora Botter, Enrico Cavarzerani, Matteo Mauceri, Nicola Demitri, et al. Molecules, 2024 A new class of palladium–indenyl complexes characterized by the presence of one bulky alkyl isocyanide and one aryl phosphine serving as ancillary ligands has been prepared, presenting high yields and selectivity. All the new products were completely characterized using spectroscopic and spectrometric techniques (NMR, FT-IR, and HRMS), and, for most of them, it was also possible to define their solid-state structures via X-ray diffractometry, revealing that the indenyl fragment always binds to the metal centre with a hapticity intermediate between ƞ3 and ƞ5. A reactivity study carried out using piperidine as a nucleophilic agent proved that the indenyl moiety is the eligible site of attack rather than the isocyanide ligand or the metal centre. All complexes were tested as potential anticancer agents against three ovarian cancer cell lines (A2780, A2780cis, and OVCAR-5) and one breast cancer cell line (MDA-MB-231), displaying comparable activity with respect to cisplatin, which was used as a positive control. Moreover, the similar cytotoxicity observed towards A2780 and A2780cis cells (cisplatin-sensitive and cisplatin-resistant, respectively) suggests that our palladium derivatives presumably act with a mechanism of action different than that of the clinically approved platinum drugs. For comparison, we also synthesized Pd-ƞ3-allyl derivatives, which generally showed a slightly higher activity towards ovarian cancer cells and lower activity towards breast cancer cells with respect to their Pd-indenyl congeners.
Early Warnings by Liver Organoids on Short-and Long-Chain PFAS Toxicity Stefano Palazzolo, Isabella Caligiuri, Andrea Augusto Sfriso, Matteo Mauceri, Rossella Rotondo, et al. Toxics, 2022 Short-chain per-fluoroalkyl substances (PFAS) have replaced long-chains in many applications, however the toxicity and its mode of action and interactions due to the large number of these compounds and their mixtures is still poorly understood. The paper aims to compare the effects on mouse liver organoids (target organ for bioaccumulation) of two long-chain PFAS (perfluorooctane sulfonate -PFOS-, perfluorooctanoic acid -PFOA) and two short-chain PFAS commonly utilized in the industry (heptafluorobutyric acid -HFBA-, Pentafluoropropionic anhydride-PFPA) to identify the mode of action of these classes of contaminants. Cytomorphological aberrations and ALT/GDH enzyme disruption were identified but no acute toxicity endpoint neither apoptosis was detected by the two tested short-chain PFAS. After cytomorphological analysis, it is evident that short-chain PFAS affected organoid morphology inducing a reduction of cytostructural complexity and aberrant cytological features. Conversely, EC50 values of 670 ± 30 µM and 895 ± 7 µM were measured for PFOS and PFOA, respectively, together with strong ALT/GDH enzyme disruption, caspase 3 and 7 apoptosis activation and deep loss of architectural complexity of organoids in the range of 500–1000 µM. Eventually, biochemical markers and histology analysis confirmed the sensitivity of organoid tests that could be used as a fast and reproducible platform to test many PFAS and mixtures saving time and at low cost in comparison with in vivo tests. Organoids testing could be introduced as an innovative platform to assess the toxicity to fast recognize potentially dangerous pollutants.
New PIN1 inhibitors identified through a pharmacophore-driven, hierarchical consensus docking strategy Giulio Poli, Miriana Di Stefano, Joan Arias Estevez, Filippo Minutolo, Carlotta Granchi, et al. Journal of Enzyme Inhibition and Medicinal Chemistry, 2022 PIN1 is considered as a therapeutic target for a wide variety of tumours. However, most of known inhibitors are devoid of cellular activity despite their good enzyme inhibitory profile. Hence, the lack of effective compounds for the clinic makes the identification of novel PIN1 inhibitors a hot topic in the medicinal chemistry field. In this work, we reported a virtual screening study for the identification of new promising PIN1 inhibitors. A receptor-based procedure was applied to screen different chemical databases of commercial compounds. Based on the whole workflow, two compounds were selected and biologically evaluated. Both ligands, compounds VS1 and VS2, showed a good enzyme inhibitory activity and VS2 also demonstrated a promising antitumoral activity in ovarian cancer cells. These results confirmed the reliability of our in silico protocol and provided a structurally novel ligand as a valuable starting point for the development of new PIN1 inhibitors.
