DefNEtTrp: An Iron Dual Chelator Approach for Anticancer Application

Targeting iron metabolism has emerged as a novel therapeutic strategy for the treatment of cancer. As such, iron chelator drugs are repurposed or specifically designed as anticancer agents. Two important chelators, deferasirox (Def) and triapine (Trp), attack the intracellular supply of iron (Fe) and inhibit Fe-dependent pathways responsible for cellular proliferation and metastasis. Trp, in particular, forms a redox active ferrous complex that inactivates the Fe-dependent ribonucleotide reductase (RNR), responsible for DNA replication. Building on recent efforts to employ intracellular Fe chelation for anticancer therapy, this work aimed to develop the Fe dual chelator ligand DefNEtTrp, consisting of the Def and Trp moieties, to exploit their high affinity Fe(II/III) binding and redox modulation. Using UV-vis spectroscopy, EPR spectroscopy, ESI and MALDI-TOF mass spectrometry, and cyclic voltammetry analyses, DefNEtTrp is shown to retain its Fe binding at both chelator moieties and generate a redox active Fe(III) complex Fe₃(DefNEtTrp)₂ featuring a reduction potential (<i>E</i> _1/2 = +0.103 V vs normal hydrogen electrode) within the biological window. Screened against different cancer cell line types, DefNEtTrp exhibits potent and broad-spectrum antiproliferative and cell death behavior. Its cytotoxicity (IC₅₀ 0.77 ± 0.06 μM) is superior to that of unconjugated Def and Trp ligands (IC₅₀ 2.6 ± 0.15 μM and 1.1 ± 0.04 μM, respectively) in single-compound and combination treatments and is selective toward cancer cells. The cell death mechanism of the dual chelator is assessed in the context of intracellular labile Fe binding and was found to induce both apoptosis and ferroptosis.