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

Abstract

The impact of methoxy and hydroxyl groups at the salicylidene moiety of chlorido[ N , N ′-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) complexes was evaluated on human MDA-MB 231 breast cancer and HL-60 leukemia cells. Methoxylated complexes ( C1 – C3 ) inhibited proliferation, migration, and metabolic activity in a concentration-dependent manner following the rank order: C2 > C3 > C1 . In particular, C2 was highly cytotoxic with an IC 50 of 4.2 μM which was 6.6-fold lower than that of cisplatin (IC 50 of 27.9 μM). In contrast, hydroxylated complexes C4 – C6 were almost inactive up to the highest concentration tested due to lack of cellular uptake. C2 caused a dual mode of cell death, ferroptosis, and necroptosis, whereby at higher concentrations, ferroptosis was the preferred form. Ferroptotic morphology and the presence of ferrous iron and lipid reactive oxygen species proved the involvement of ferroptosis. C2 was identified as a promising lead compound for the design of drug candidates inducing ferroptosis.

Transferrin Receptor-Mediated Cellular Uptake of Fluorinated Chlorido[N,N′-bis(salicylidene)-1,2-phenylenediamine]iron(III) Complexes

“…The values (see the Experimental Section) ranged from 5.70 to 5.89 μ B for C1 – C4 , respectively (Figures S17–S24), and indicated the formation of high spin iron(III) complexes ( S = 5/2). These results are consistent with those of previously reported iron(III) complexes. − As C1 – C4 bearing an iron(III) center with an odd number of unpaired electrons, they are detectable by electron paramagnetic resonance (EPR) measurement. These measurements revealed the expected g-values and signature for an iron(III) center (Figure S25).…”

“…The electrochemical behavior of the compounds was investigated by cyclic voltammetry (CV), according to a previously described method. , The resulting voltammograms of C1 – C4 are depicted in Figures S26–S29. The potential (vs ferrocene (Fc)) to reduce SP to [salophene]iron(II) amounted to E 1/2 = −728 mV and was shifted upon fluorine substitution to E 1/2 = −624 mV ( C1 ), −662 mV ( C2 ), −684 mV ( C3 ), and −616 mV ( C4 ).…”

“…We have recently shown that iron(III) complexes with an N , N ′-bis(salicylidene)ethylenediamine scaffold possess fluorescent properties . Therefore, fluorescence spectra were measured for C1 – C4 with the fluorescent dye coumarin 6 as positive control and SP as reference.…”

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

“…Unlike free Fe(II), the complexed Fe(II/III) central atom in SCs is not subject to rapid oxidation and incorporation into ferritin, the Fenton-inactive storage form of iron [ 88 ]. Less well understood is why SCs outperform other ferroptosis inducers, such as RSL3, and why different cell death programs are induced depending on the cell line and tumor type studied [ 28 , 29 , 31 , [33] , [34] , [35] , [36] , [37] , [38] , 40 , 41 ] and depending on small changes in SC structure [ [28] , [29] , [30] ]. The interplay of multiple redox-active mechanisms appears to be the key to understanding these favorable properties of SCs.…”

“…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 ].…”