Stereochemical Aspects in the Context of the Structure–Activity Relationship of Chlorido[ N , N ′-bis(chloro/bromosalicylidene)-1,2-diphenyl-1,2-diaminoethane]iron(III) Complexes

In this structure-activity relationship study, chlorido[N,N'-bis(chloro/bromosalicylidene)-1,2-diphenyl-1,2-diaminoethane]iron(III) complexes differing in (i) the configuration of the 1,2-diphenylethane backbone ((RS), (RR/SS), or (SS)) and (ii) the halogen substituents at the salicylidene residue in positions 5 (Cl (1a-c) or Br (2a-c) or 3-Br,5-Cl (3a-c)) were investigated. All complexes were fully characterized and showed high stability with regard to ligand racemization. The antitumor activity was dependent on the configuration and the substitution pattern of the salicylidene moieties. (RS)-Configured complexes were nearly inactive, whereas (RR/SS)- or (SS)-configured complexes displayed almost identical efficacies. 1a-c induced oxidative stress, but only 1b and 1c caused extensive lipid oxidation and ferroptosis as part of the mode of action. Exchange of the 3-Cl substituents for 3-Br only marginally changed the biological effects, whereas the introduction of 3-Br, 5-Cl substituents led to a loss of activity. The differences in effectiveness result from the spatial structure caused by the 1,2-diphenylethane skeleton.