Strategic design and development of a siderophore mimic: pioneering anticancer therapy ROS generation and ferroptosis

We designed a tris-catecholate-based siderophore mimic, H 6 - T-CATL , to selectively chelate iron( iii ) from mitochondrial cytochromes and other iron-containing proteins within cellular matrices. This strategic sequestration aims to trigger apoptosis or ferroptosis in cancer cells through the glutathione (GSH)-dependent release of reduced iron and subsequent ROS-mediated cytotoxicity. Synthesis of H 6 - T-CATL involved precise peptide coupling reactions. Using the Fe( iii )-porphyrin model (Fe-TPP-Cl), akin to cytochrome c , we studied H 6 - T-CATL 's ability to extract iron( iii ), yielding a binding constant ( K rel ) of 10 14 for the resulting iron( iii ) complex (Fe III -T-CATL) 3− . This complex readily underwent GSH-mediated reduction to release bioavailable iron( ii ), which catalyzed Fenton-like reactions generating hydroxyl radicals (&z.rad;OH), confirmed by spectroscopic analyses. Our research underscores the potential of H 6 - T-CATL to induce cancer cell death by depleting iron( iii ) from cellular metalloproteins, releasing pro-apoptotic iron( ii ). Evaluation across various cancer types, including normal cells, demonstrated H 6 - T-CATL 's cytotoxicity through ROS production, mitochondrial dysfunction, and activation of ferroptosis and DNA damage pathways. These findings propose a novel mechanism for cancer therapy, leveraging endogenous iron stores within cells. H 6 - T-CATL emerges as a promising next-generation anticancer agent, exploiting iron metabolism vulnerabilities to induce selective cancer cell death through ferroptosis induction. The article reports a remarkable anticancer activity through iron( iii ) chelation and ferroptosis by a newly developed catecholate-based siderophore mimic.