Affiliation:
1. Department of Organic Chemistry, Faculty of Chemical Engineering and Technology University of Zagreb Zagreb Croatia
2. Laboratory for Solid‐State and Complex Compounds Chemistry, Division of Materials Chemistry Ruđer Bošković Institute Zagreb Croatia
3. Laboratory for Physical Chemistry of Traces, Division for Marine and Environmental Research Ruđer Bošković Institute Zagreb Croatia
4. Laboratory for the Computational Design and Synthesis of Functional Materials, Division of Organic Chemistry and Biochemistry Ruđer Bošković Institute Zagreb Croatia
5. Laboratory for Cell Biology and Signalling, Division of Molecular Biology Ruđer Bošković Institute Zagreb Croatia
Abstract
Bis(2‐picolyl)amine (bpa), iminodiacetamide (imda), and bis‐1,2,3‐triazole (bta) ferrocene ligands (L) with and without an aliphatic linker were prepared by multi‐step synthesis. The cis‐fac, trans‐fac, or mer stereochemistry of their ML2 complexes with Ni(II), Cu(II), Cd(II), and Zn(II) was studied in the solid state (infrared [IR] and single‐crystal X‐ray diffraction [SC‐XRD]), in solution (nuclear magnetic resonance [NMR] and cyclic voltammetry [CV]) and by density functional theory (DFT) calculations. Crystal structures were determined for bpa ligand 7, and complexes [Ni(1)2](NO3)2 (1Ni), [Cu(8)2]OTf2 (8Cu), [Ni(10b)2](NO3)2 (10bNi), and [Cu(10b)2]OTf2 (10bCu). The bond strength of the central metal ion to the ligand amine nitrogen atom was studied by NMR, electrochemistry, and DFT. The information on redox‐active centers, electron transfer properties of ferrocene ligands (L), and their in situ complexation with zinc(II) and nickel(II) ions were obtained by voltammetric analysis. In addition, DFT calculations showed that the electron ionization in ML2 complexes occurs from one of the ferrocene units, leaving the electronic structure of the other ligand intact, while some of the expelled electron density is recovered by the adjacent amine through resonance. This effect is more pronounced in the free ligands, because the eventual amine resonance in ML2 needs to balance its Zn(II) coordination participation, which justifies why they show higher ionization energies over free ligands. Moreover, due to lower steric hindrance, the N(amino)–Zn(II) coordination is additionally stronger in 1:1 ML complexes, which makes their electron depletion further more demanding. If compared with the clinical drug cisplatin, complexes of bpa 1Ni and imda 2Ni showed a better effect on the viability of different tumor cell lines and better selectivity towards normal cells. Treatment with 1Ni and 2Ni causes an increase of cells in the S phase of the cell cycle and leads to the accumulation of cells in G0/G1. A decrease in the expression level of anti‐apoptotic marker Bcl‐2 upon treatment with both compounds together with increased amount of Annexin V‐FITC positive cells implied apoptosis as the mode of cell death.