Anticancer diiron aminocarbyne complexes with labile N-donor ligands

The novel diiron amine complexes [Fe2Cp2(CO)(NH2R')(μ-CO){μ-CN(Me)(Cy)}]CF3SO3 [R' = H, 3; Cy, 4; CH2CH2NH2, 5; CH2CH2NMe2, 6; CH2CH2(4-C6H4OMe), 7; CH2CH2(4-C6H4OH), 8; Cp = η5-C5H5, Cy = C6H11 = cyclohexyl] were synthesized in 49–92 % yields from [Fe2Cp2(CO)2(μ-CO){μ-CN(Me)(Cy)}]CF3SO3,...

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Veröffentlicht in:European journal of medicinal chemistry 2025-03, Vol.286, p.117304, Article 117304
Hauptverfasser: Stocchetti, Sara, Vančo, Ján, Bresciani, Giulio, Biancalana, Lorenzo, Belza, Jan, Zacchini, Stefano, Dvořák, Zdeněk, Benetti, Sara, Biver, Tarita, Bortoluzzi, Marco, Trávníček, Zdeněk, Marchetti, Fabio
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Sprache:eng
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Zusammenfassung:The novel diiron amine complexes [Fe2Cp2(CO)(NH2R')(μ-CO){μ-CN(Me)(Cy)}]CF3SO3 [R' = H, 3; Cy, 4; CH2CH2NH2, 5; CH2CH2NMe2, 6; CH2CH2(4-C6H4OMe), 7; CH2CH2(4-C6H4OH), 8; Cp = η5-C5H5, Cy = C6H11 = cyclohexyl] were synthesized in 49–92 % yields from [Fe2Cp2(CO)2(μ-CO){μ-CN(Me)(Cy)}]CF3SO3, 1a, using a straightforward two-step procedure. They were characterized by IR and multinuclear NMR spectroscopy, and the structure of 7 was confirmed through X-ray diffraction analysis. Complexes 3–8 and the acetonitrile adducts [Fe2Cp2(CO)(NCMe)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (R = Cy, 2a; Me, 2b; Xyl = 2,6-C6H3Me2, 2c) were assessed for their water solubility, octanol-water partition coefficient and stability in physiological-like solutions. The in vitro antiproliferative activity of 2a-c and 3–8 was tested on seven human cancer cell lines (A2780, A2780R, PC3, A549, MCF7, HOS and HT-29), while the selectivity was evaluated using normal MRC-5 cells. Overall, the complexes exhibited variable cytotoxicity, with IC50 values reaching the low micromolar range for 3, 7 and 8 in A2780 and A2780R cells, along with significant selectivity. Targeted experiments covered cell cycle modification, induction of cell death, mitochondrial membrane potential, ROS production and interaction with DNA and bovine serum albumin (BSA) as a model protein. The interaction of 3 with BSA was further investigated through computational studies. Results showed a negligible increase in intracellular ROS levels (except for 2b) and insignificant changes in mitochondrial membrane potential. Diiron(I) bis-carbonyl complexes incorporating various N-donors (acetonitrile, ammonia, primary amines) exhibited moderate to strong cytotoxicity against a panel of cancer cell lines, demonstrating distinct cellular effects compared to their tris-carbonyl precursors. [Display omitted] •Novel diiron(I) complexes with amine ligands were synthesized.•They exhibited higher cytotoxic activity than cisplatin and tendency to selectivity.•They displayed distinct redox behavior compared to their tris-carbonyl precursors.•This behavior is linked to the lability of the N-ligand.
ISSN:0223-5234
1768-3254
1768-3254
DOI:10.1016/j.ejmech.2025.117304