Design and therapeutic landscape of copper ionophores: From coordination chemistry to cuproptosis modulation.

Copper ionophores have evolved from serendipitous discoveries into rationally designed therapeutics following the elucidation of cuproptosis. This review analyzes the core design principles that govern ionophore functions, focusing on the delicate balance between copper binding and membrane transport. Key physicochemical parameters, including binding affinity, reduction potential of Cu(II)/Cu(I) couple, lipophilicity, and coordination geometry, are examined as critical determinants of biological efficacy. We survey major structural classes from dithiocarbamates and tunable thiosemicarbazones to modular 8-hydroxyquinolines and flavonoid-derived motifs. Advanced strategies such as stimulus-responsive pro-ionophores, glycoconjugation, and organelle-targeted delivery are discussed as approaches to improve selectivity and reduce systemic toxicity. Beyond anticancer applications, we highlight the expanding therapeutic utility of copper ionophores in metabolic disorders, where controlled copper supplementation restores homeostasis. The emerging capacity of certain ionophores to target specific antioxidant proteins and to redistribute intracellular copper pools is also addressed. This review underscores the need for quantitative frameworks that link copper delivery parameters to cell fate, and identifies biomarker development as essential for clinical translation.