Investigations on the Influence of the Axial Ligand in [Salophene]iron(III) Complexes on Biological Activity and Redox Behavior

Abstract

The [N,N′-disalicylidene-1,2-phenylenediamine]iron(III) ([salophene]iron(III)) derivatives 1–4 with anionic axial ligands (A = Cl−, NO3−, SCN−, CH3COO−) and complexes 5 and 6 with neutral ligands (A = imidazole, 1-methylimidazole) as well as the μ-oxo dimer 7 inhibited proliferation, reduced metabolic activity, and increased mitochondrial reactive oxygen species. Ferroptosis as part of the mode of action was identified by inhibitor experiments, together with induction of lipid peroxidation and diminished mitochondrial membrane potential. No differences in activity were observed for all compounds except 4, which was slightly less active. Electrochemical analyses revealed for all compounds a fast attachment of the solvent dimethyl sulfoxide and a release of the axial ligand A. In contrast, in dichloromethane and acetonitrile, ligand exchange did not take place, as analyzed by measurements of the standard potential for the iron(III/II) redox reaction.

Design, Synthesis, Electrochemical, and Biological Evaluation of Fluorescent Chlorido[N,N′-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) Complexes as Anticancer Agents

“…Cyclic Voltammetry. Iron complexes are redox active and have the ability to form iron (III/II) pairs 35 S3).…”

“…Iron complexes are redox active and have the ability to form iron (III/II) pairs 35 that may participate in the Fenton reaction. Therefore, the electrochemical behavior was analyzed by cyclic voltammetry in DMSO, the solvent of the complexes.…”

Iron(III)-salophene catalyzes redox cycles that induce phospholipid peroxidation and deplete cancer cells of ferroptosis-protecting cofactors

“…The SCs 1 , 2 , and 3 (purity ≥95 %) and the μ-oxo derivatives μ-oxo- 1 , μ-oxo- 2 and μ-oxo- 3 (purity ≥95 %) were synthesized following previously published procedures [ 28 , 29 ], dissolved in DMSO (10 mM) or methanol (5 mM for EPR), and aliquots were stored at −20 °C under argon. The hydrophilic sulfonates 4 , 5 , 6 , and 7 (purity ≥95 %) were synthesized as recently described [ 29 , 53 ] and dissolved in H 2 O (2 mM) or DMSO (2 mM), and aliquots were stored at −20 °C under argon. Phospholipids and lipid standards were obtained from Merck (Darmstadt, Germany), dissolved in chloroform, aliquoted, and stored protected from light at −80 °C under argon.…”

“…Electrochemical measurements were performed as previously described [ 29 ]. In brief, the SP-150 potentiostat (BioLogic, Seyssinet-Pariset, France) was equipped with a conventional three-electrode cell, a glassy carbon working electrode, an Ag/AgCl reference electrode in saturated NaCl solution, and a 0.5 × 37 mm/1 mm × 37 mm platinum wire counter electrode (Alibaba Group, Shenzhen, China).…”

“…Typically, the most stable iron-salene and iron-salophene complexes (SCs) consist of a central Fe(III) ion coordinatively bound to N,N′-bis(salicylidene)ethylenediamine or N , N ′-bis(salicylidene)-1,2-phenylenediamine and an interchangeable axial ligand. Together with their dimeric μ-oxo complexes, they are potent inducers of ferroptosis in certain cancer cell lines [ [28] , [29] , [30] ], including leukemia cells [ 28 ]. However, depending on the system and experimental settings, they can also induce other cell death programs, such as apoptosis [ [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] ] and necroptosis [ 28 , 34 ] or interfere with cell cycle progression [ 31 , 38 ].…”