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Iron is an essential element for tumor progression and metastasis. High iron demand is observed in cancers to accommodate their rapid growth rate since iron plays a vital role in DNA biosynthesis. This aberrant iron homeostasis is a hallmark of cancer, motivating the development of iron chelation approaches in cancer chemotherapy. Although iron-binding molecules have demonstrated promising antiproliferative effects in clinical trials, side effects were observed during iron chelator treatments. The off-target toxicity is attributed to indiscriminate metal-binding and induction of oxidative stress. As such, this dissertation aims to provide novel strategies to address these issues. We utilized prochelation and bioconjugation approaches to inactivate the iron-binding molecules in the extracellular environment so that thebinding ability can only be restored intracellularly and preferentially in cancer cells. These prochelators and bioconjugated prochelators demonstrated an improved specificity in cultured cells when compared to traditional chelation-based compounds.Chapter 1 of this dissertation provides a brief overview of the iron uptake mechanism in humans. Common diseases associated with iron are discussed, including iron overload and neurodegeneration. Next, the roles of iron in cancer biology are discussed, such as malignant initiation, metathesis, and drug resistance. Moreover, we provide an overview of clinically investigated iron chelators and reported metal prochelators.Chapter 2 focuses on two newly synthesized thiosemicarbazone prochelators, in which a binding thiolate donor is masked by a disulfide bond, requiring intracellular reduction to release active chelators that readily bind intracellular iron. The prochelator series in this study features methyl-substituted thiosemicarbazone or imidazole-2-thione moieties to increase lipophilicity for better membrane permeability. Interestingly, these new prochelators covalently modify bovine serum albumin through