Fluorescent chlorido[N,N′-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) complexes as anticancer agents

Metal complexes in cancer therapy are well-established. Since iron complexes have also shown potential, the effect of chlorido[N,N′-disalicylidene-1,2-bis(4- methoxyphenyl)-ethylenediamine]iron(III) complexes with methoxy groups (C1–C3) or hydroxy groups (C4–C6) at positions 3, 4, or 5 of the salicylidene moieties was evaluated on human MDA-MB 231 breast cancer and HL-60 leukemia cells. Methoxylated complexes (C1-C3) demonstrated concentration-dependent inhibition of proliferation, migration, and metabolic activity, with C2 exhibiting the highest potency, followed by C3 and C1. Notably, C2 displayed remarkable cytotoxicity (IC50 of 4.2 μM), outperforming even cisplatin (IC50 of 27.9 μM) by 6.6-fold. In contrast, hydroxylated complexes C4-C6 exhibited minimal activity even at the highest concentrations, attributed to a lack of cellular uptake. C2 induced a dual mode of cell death, involving ferroptosis and necroptosis, with ferroptosis dominating at higher concentrations. Alterations in cellular morphology, intracellular ferrous iron, and increased concentration of lipid reactive oxygen species  confirmed the involvement of ferroptosis. Accordingly, C2 could be identified as a promising lead compound for the development of drug candidates capable of inducing ferroptosis.