The application of Ti (IV) based compounds in cancer therapy is currently being explored because of their improved stability and wider spectrum of activity compared to anticancer platinum-based drugs. Although the development of iron chelators in human health is primarily focused on the treatment of secondary iron (Fe) overdose, Ti(IV) complexes containing iron chelators such as deferasirox have shown to be effective in inhibiting the bioavailability of intracellular labile Fe (III) and induce cell death via apoptosis. Deferasirox, a chemical transferrin mimetic ligand, has the ability to bind, deliver and release Ti(IV) into the cell through a transmetalation mechanism with intracellular Fe(III). However, the potency of this drug is limited to only targeting the Fe(III) labile pool. Combinatorial studies using Ti(deferasirox)2 and the Fe(II)/Fe(III) chelator triapine against various cancer cell lines reveals an enhanced dose response effect. These findings prompted us to incorporate triapine into the structure of Ti(deferasirox)2 and evaluate its cytotoxic properties.Herein, a novel drug design strategy is presented in which triapine is incorporated into the structure of deferasirox through an amide bond conjugation to enhance the potency and spectrum of activity of the Ti(deferasirox)2 complex. Triapine is a promising chemotherapeutic compound with great success in phase I and II clinical trials because of its related bioactivity as an inhibitor of the ribonucleotide reductase, a key enzyme in DNA synthesis. The carbodiimide-mediated coupling reaction of deferasirox and triapine was achieved as shown by nuclear magnetic resonance. MALDI-TOF/TOF, powder X-ray diffraction, energy dispersive X-ray spectroscopy, and Ultraviolet-visible spectroscopy were also used to fully characterize the newly synthesized ligand and identify its metal binding capacity.

Synthesis of a deferasirox-triapine conjugate as a bifunctional iron-chelating ligand for the development of novel Ti(IV) complexes with enhanced anticancer potency

ACS Spring Meeting 2021

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