Deferasirox is an orally delivered iron chelator that is used in the treatment of iron overload diseases. We have repurposed it in synergism with Ti(IV) for an anticancer purpose. Ti(deferasirox)<sub>2</sub> operates intracellularly to decrease the levels of functional Fe by reacting with the labile iron pool via transmetalation. In this process, deferasirox binds Fe(III), creating a highly stable Fe(III) complex that makes Fe functionally inert. Simultaneously, the Ti(IV) is released into the cytosol, able to bind to Fe free biomolecular sites including the enzyme ribonucleotide reductase (RNR), responsible for producing the building blocks for DNA replication. RNR has a diiron binding site and it depends on the redox activity of Fe to become activated. In an effort to evolve the Ti(deferasirox)<sub>2</sub> compound into a specific inhibitor of RNR we have designed and synthesized a novel ligand based on the conjugation of the Fe(II)/(III) chelator, triapine, with deferasirox because triapine has the capacity to bind at the diiron site of RNR. We used ultraviolet-visible (UV-Vis) spectroscopy and mass spectrometry techniques to explore the ligands iron chelation properties and its coordination to Ti(IV). Through cyclic voltammetry analysis we reveal that our ligand can form a redox active species with a reduction potential capable of quenching the tyrosyl radical of RNR. We also evaluated the cytotoxicity/antiproliferative activity of the ligand against the leukemia Jurkat cell line where it displays a superior cytotoxic behavior versus the combination of the separate molecules. This work serves to improve the cancer cell selectivity of our Ti(IV) compound and the specificity of its activity.

Design, synthesis, and evaluation of a novel bifunctional iron chelator as a potential inhibitor of ribonucleotide reductase

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