Resource type
Thesis type
(Thesis) M.Sc.
Date created
2024-01-25
Authors/Contributors
Author: Kwan, Kalvin
Abstract
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).
Document
Extent
128 pages.
Identifier
etd22899
Copyright statement
Copyright is held by the author(s).
Supervisor or Senior Supervisor
Thesis advisor: Storr, Tim
Language
English
Member of collection
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