Exploration of the iron chelator deferasirox : a multifaceted platform for the development of antineoplastic agents and water-soluble sensors

Chelators have gained considerable interest due to the wide range of potential applications for this class of molecules, including as therapeutics and chemosensors. Over recent decades, a number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against cancer in vitro, in vivo and in preliminary clinical trials. Considering these promises, during my dissertation I have explored the strategic derivatization of the clinical iron chelator deferasirox with focus on the preparation of chelators that show enhanced activity against cancer cells. In addition, I have investigated the optimization of deferasirox as chemosensor for Fe³⁺ in water samples. In chapter 1, an overview on the recent progress in the use of transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics is provided. This chapter focuses on the reported agents that are able to coordinate iron, copper, and zinc. Chapter 2 describes the design, synthesis, and biological evaluation of strategically functionalized derivatives of the FDA approved iron chelator deferasirox. Preparative efforts focused on derivatives containing organelle-targeting moieties and their in vitro activity against A549 lung cancer cells is discussed. In contrast to the parent chelator deferasirox, several of the new derivatives could be traced inside cells through fluorescent cell imaging. One of the derivatives exerted improved antiproliferative activity relative to deferasirox and was revealed to preferentially localises within the lysosome. Chapter 3 discusses the evaluation of deferasirox as colorimetric chemosensor for the detection and quantification of Fe³⁺ in aqueous samples. The optimization of deferasirox and the water-soluble, non-toxic derivative ExSO₃H are discussed. In addition, ExSO₃H was identified as potential chelator for uranyl (UO₂²⁺) in water and the interaction between these two species was investigated. Chapter 4 discusses the observation that a fluorescent turn-on response was produced when a water-soluble deferasirox derivative was allowed to interact with human serum albumin (HSA). This fluorescence was quenched in the presence of Fe³⁺, thus permitting the monitoring of the presence of this biologically important metal cation with a protein-bound chelator.