Implementing the design cues of dissociation dynamics and transmetalation in gallium(iii) complexes to promote the anti-proliferative activity of ligands targeting intracellular iron(ii) trafficking

Abstract

Designing ligands for cancer has traditionally overlooked complex dissociation and transmetalation in enhancing efficacy. Another neglected criterion is the ligands' ability to intercept the labile Fe(II) pool released after transferrin endocytosis and reduction of transferrin-bound Fe(III). Given iron's essential role in cancer proliferation, disrupting metal homeostasis offers a promising therapeutic strategy. Herein, we introduce a new class of Fe(II)-selective ligands and their Ga(III) complexes for cancer therapy, guided by insights into their dissociative dynamics and transmetalation behavior. Unlike prior approaches focused on static metal coordination, this work integrates dissociation and transmetalation as design features, enabling selective interception of intracellular Fe(II) trafficking. Relative to the ligand, Ga(III) complexation led to a pronounced (p < 0.001–0.0001) enhancement in anti-proliferative activity, with up to a 70-fold increase in potency. This result was in contrast to the modest increase in potency (up to 2.4-fold) observed for the Cu(II) or Zn(II) complexes. Mechanistic dissection demonstrated that, unlike the complete dissociation of the Ga(III) complexes, the relative Zn(II) and Cu(II) complexes underwent only partial dissociation. This difference facilitates complete ligand and Ga(III) release from the complex and may account for the superior cytotoxicity of the Ga(III) complexes versus their Zn(II) and Cu(II) counterparts. Furthermore, their potency was linked to Fe(II) ligation rather than Fe(III), despite electronic similarity to Ga(III). This study introduces three underexplored design principles for anti-cancer ligand engineering: (i) dynamic complex dissociation; (ii) selective intracellular transmetalation using NNO-containing ligands; and (iii) interception of labile Fe(II) generated after endosomal Fe(III) reduction.