DefNEtTrp: An Iron\nDual Chelator Approach for Anticancer\nApplication

Targeting iron metabolism has emerged as a novel therapeutic\nstrategy\nfor the treatment of cancer. As such, iron chelator drugs are repurposed\nor specifically designed as anticancer agents. Two important chelators,\ndeferasirox (Def) and triapine (Trp), attack the intracellular supply\nof iron (Fe) and inhibit Fe-dependent pathways responsible for cellular\nproliferation and metastasis. Trp, in particular, forms a redox active\nferrous complex that inactivates the Fe-dependent ribonucleotide reductase\n(RNR), responsible for DNA replication. Building on recent efforts\nto employ intracellular Fe chelation for anticancer therapy, this\nwork aimed to develop the Fe dual chelator ligand DefNEtTrp, consisting\nof the Def and Trp moieties, to exploit their high affinity Fe(II/III)\nbinding and redox modulation. Using UV–vis spectroscopy, EPR\nspectroscopy, ESI and MALDI-TOF mass spectrometry, and cyclic voltammetry\nanalyses, DefNEtTrp is shown to retain its Fe binding at both chelator\nmoieties and generate a redox active Fe(III) complex Fe<sub>3</sub>(DefNEtTrp)<sub>2</sub> featuring a reduction potential (<i>E</i><sub>1/2</sub> = +0.103 V vs normal hydrogen electrode)\nwithin the biological window. Screened against different cancer cell\nline types, DefNEtTrp exhibits potent and broad-spectrum antiproliferative\nand cell death behavior. Its cytotoxicity (IC<sub>50</sub> 0.77 ±\n0.06 μM) is superior to that of unconjugated Def and Trp ligands\n(IC<sub>50</sub> 2.6 ± 0.15 μM and 1.1 ± 0.04 μM,\nrespectively) in single-compound and combination treatments and is\nselective toward cancer cells. The cell death mechanism of the dual\nchelator is assessed in the context of intracellular labile Fe binding\nand was found to induce both apoptosis and ferroptosis.