Iron iii chelators and heterobimetallic systems as the novel approach for targeted chemotherapy and photocytotoxicity

Abstract

The strategic design of iron(III) chelators and metal-based anticancer agents that can selectively trigger ferroptosis or photodynamically induce cytotoxicity in cancer cells marks a major breakthrough in contemporary cancer research and therapy. My thesis centers on two strategic directions: (i) the design of tris-catecholate-based siderophore mimics for iron(III) sequestration to induce ferroptosis, and (ii) the engineering of red-light-activable hetero-bimetallic complexes for targeted photodynamic therapy (PDT). These approaches collectively address the dual need for controlled oxidative damage and cancer cell specificity. The siderophore mimic H6-T-CATL, synthesized through peptide coupling, was designed to mimic natural iron-chelating motifs and selectively extract Fe(III) from mitochondrial metalloproteins like Fe-TPP-Cl. The resulting [Fe(III)- T-CATL] 3- complex showed high affinity (Krel and#8776; 1014) for Fe(III) and underwent glutathione (GSH)- mediated reduction to Fe(II), enabling Fenton-type chemistry and ROS generation. In vitro studies demonstrated that H6-T-CATL induced substantial ROS production, GSH depletion, and lipid peroxidation in cancer cells, ultimately leading to mitochondrial dysfunction, DNA damage (evidenced by and#947;H2AX activation), and apoptosis. Cytotoxicity assays showed that H6-T-CATL was selectively toxic to cancer cells (A549 and MDA-MB-231) while exhibiting significantly lower toxicity in normal cells (HEK293 and AC16). Flow cytometry analysis further confirmed the induction of early and late apoptosis, supporting the ferroptotic mechanism. However, due to the lack of tumor-targeting capability, H6-T-CATL required further modification to improve cancer selectivity. newline