One of the major hallmarks of cancer cells is their high iron and copper requirement for proliferation and metastasis. This makes attenuating the bioavailability of these essential metals within cancer cells an important anticancer drug target. Our laboratory has explored the use of iron chelators that have the capacity to transform Fe from the intracellular labile pool into functionally inert Fe(II/III) species and coupled these chelators with titanium(IV), to facilitate a multimodal cell death drug design. Ti(IV) complexes of a class of Fe(III) chelators that mimic serum transferrin coordination of Fe(III), termed chemical transferrin mimetic (cTfm) ligands, have been designed to operate by a transmetalation mechanism to deliver Ti(IV) intracellularly and scavenge Fe. One cTfm ligand, deferasirox, demonstrates a surprising ability to effectively bind Cu(II), with an affinity competitive with Fe binding, while also able to undergo a Ti(IV) for Cu(II) transmetalation with the Ti(deferasirox)2 complex. This chelator opens a new avenue for expanding the drug design template to simultaneously attack both Cu and Fe. In this work the Fe and Cu centered anticancer mechanism of action of Ti(deferasirox)2 is explored by examining the physiologically relevant Fe(III) and Cu(II) deferasirox species generated by transmetalation via mass spectrometry, UV-Vis spectroscopy, and single crystal X-ray diffraction, and cyclic voltammetry. Cell cycle, viability, and ROS assays are undertaken to delineate the biochemical effects of Ti(deferasirox)2 to understand the contributions of both the ligand and the Ti(IV) ion to the inhibition of the Fe-dependent enzyme ribonucleotide reductase, critical for DNA synthesis and cell replication, and to ultimately triggering apoptosis by the potential generation of cytotoxic redox-active Fe and Cu species.

Transmetalation as an anticancer approach to transform intracellular iron and copper into cytotoxic metals with titanium(IV) complexes

ACS Spring 2022

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