Towards a dual copper(II) and iron(III) transmetalation strategy for an anticancer application with the deferasirox...

Copper and iron are redox-active essential metals that are disproportionately required by cancer cells to sustain proliferation, survival, and metastasis. Their intertwined biology represents a universal metabolic vulnerability that could be therapeutically exploited. Here, we investigate the possibility of a dual-metal targeting strategy using deferasirox (Def), a clinically approved iron chelator, and its titanium(IV) complex, Ti(Def)₂, to disrupt Cu and Fe homeostasis through intracellular transmetalation. Solution speciation and metal competition studies reveal an unexpectedly strong affinity for Cu(II) that exceeds predictions based on HSAB theory. UV Vis, EPR, and mass spectrometric analyses suggest that Cu(II) Def species predominate as square-planar monomers at low micromolar concentrations and undergo salt-dependent dimerization at higher concentrations, supported by X-ray diffraction of the dimeric [Cu(Def)(py)]₂ complex. Cell-based studies indicate that intracellular Cu(II) binding by Def may contribute to the apoptotic cytotoxicity of Ti(Def)₂. In A549 lung cancer cells, transmetalation with labile Cu(II) complements previously reported Fe(III) transmetalation, generating redox-active Cu(II) Def species (Ec = 0.0398 V) alongside redox-active Fe(III) Def species. In the reducing intracellular environment, these complexes can undergo reductive dissociation, increasing cellular Cu(I) and Fe(II) levels and likely perturb metal homeostasis. Ti(Def)₂ itself is redox inert, implicating Cu- and Fe-Def intermediates as the primary sources of reactive oxygen species, including superoxide, leading to oxidative stress and apoptotic cell death. Minimal off-target transmetalation with serum Cu carrier proteins supports the intracellular selectivity of this approach. Together, these findings establish the framework for Cu and Fe transmetalation-driven redox dysregulation as an anticancer strategy.