Altering relative metal-binding affinities in multifunctional metallochaperones for mutant p53 reactivation

Over 50% of cancer diagnoses can be attributed to p53 malfunction. p53 incorporates a structural Zn2+ site that is required for proper protein folding and function, and in many cases point mutations can result in loss of Zn2+, destabilization of the tertiary structure, and eventual amyloid aggregation. Many zinc metallochaperones (ZMCs) have been shown to generate intracellular reactive oxygen species (ROS), likely by chelating redox-active metals such as Fe2+/3+ and Cu+/2+ and undergoing Fenton-like chemistry. High levels of ROS can result in off-target effects and general toxicity, and thus, careful tuning of the ligand's metal-binding affinity for other endogenous metals is important for selective mutant p53 targeting. This thesis explores small molecule design strategies to change the relative Zn2+/Cu2+ binding ability in a series of ligands and investigates the impact of donor group changes on metallochaperone activity and overall cytotoxicity in two mutant p53 cancer cell lines (NUGC3 and SKGT2).