Targeting iron metabolism has emerged as a novel therapeutic strategy for the treatment of cancer. As such, iron chelator drugs are repurposed or are 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 enzyme ribonucleotide reductase (RNR), responsible for DNA replication. Building on recent efforts to synergize intracellular Fe chelation with cytotoxic metals for anticancer therapy, this work aimed to develop the Fe dual chelator ligand DefNEtTrp, consisting of the Def and Trp moieties to exploit their respective hard and soft Lewis basicity for effective Fe(II/III) binding and redox modulation and to facilitate the formation of heterobimetal complexes. Using UV-Vis spectroscopy, MALDI-TOF mass spectrometry, and cyclic voltammetry analyses, DefNEtTrp is shown to generate a redox active Fe(III) complex Fe₃(DefNEtTrp)₂ featuring a reduction potential within the biological window to quench the RNR activating tyrosyl radical. The ligand is also used to synthesize the heterobimetallic complexes Ti(DefNEtTrp-Pt(II)-Cl)₂ and Ti(DefNEtTrp-Au(III)-Cl)₂. Proposed coordination structures are evaluated for insight into the optimal combination of metal ions for preparing specific heterobimetal compounds. Screened against different cancer cell line types, DefNEtTrp exhibits potent and broad spectrum antiproliferative behavior. As seen in Jurkat cell viability experiments, the cytotoxicity of DefNEtTrp is superior to that of unconjugated Def and Trp ligands in single-drug and combination drug treatments, and is assessed in the context of intracellular labile Fe binding.

Emilly Almánzar

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