Chelation therapies using small-molecule scavengers of metal ions have been employed clinically for decades in the treatment of accidental metal overexposure and genetic disorders associated with metal accumulation. Recently, evidence on the alteration of metal homeostasis and metabolism in several pathological conditions has prompted the evaluation of chelation approaches in multiple contexts. For instance, chelating agents have been investigated in clinical trials for the treatment of neurodegenerative diseases, parasitic infections and cancer. Such applications, targeting metal dysregulation rather than overload, will necessarily require a higher level of molecular design when compared to those involving chelating system for indiscriminant metal scavenging. In this context, we are designing and investigating intracellular activation strategies in pro-chelator systems for iron sequestration. We describe the incorporation of disulfide/thiol switches in thiosemicarbazone binding units that coordinate iron ions following reduction of the disulfide mask. The formation of low-spin iron(III) complexes is documented both in vitro and intracellularly. In addition, the redox behavior of the metal-bound chelators, which could be involved in the generation of reactive oxygen species, is investigated along with the cytotoxicity of the new chelating systems in cultured cells. Current approaches to the molecular design of metal scavengers are expected to enhance the selectivity of chelation therapy and extend its reach beyond metal overload disorders to neurodegenerative conditions and cancer.

Molecular strategies for intracellular iron sequestration

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.