Date of Award

Winter 2024

Project Type

Thesis

Program or Major

Chemistry

Degree Name

Master of Science

First Advisor

Roy P Planalp

Second Advisor

Sean Edington

Third Advisor

Brittany White-Mathieu

Abstract

The study of iron within cells has advanced significantly since the Fenton reaction was proposed as a mechanism for ferroptosis. Various chemical probes have been developed for examining iron and reactive oxygen species (ROS), both of which are involved in the Fenton reaction. Iron, the most abundant transition metal in the human body, primarily exists as Fe(II) and Fe(III) in the cellular environment. The labile iron pool (LIP) is suspected to predominantly exist as Fe(II) due to endogenous reductants. Under ferroptotic conditions, Fe(III) produced in the Fenton reaction can be reduced back to Fe(II), even when chelated, re-inducing hydroxyl radical formation and further harming cells. Ferroptosis has been linked to cancers and injuries in the liver, kidney, heart, lung, pancreas, nervous system, and gastrointestinal system, as well as to conditions like endometriosis. Developing fluorescent iron probes for cellular studies poses considerable challenges. These probes must be selective for iron over other metals, stable, cell-permeable, and provide clear optical responses upon interaction. To address these challenges and the health concerns linked to ferroptosis, novel iron peptide probe components were synthesized and tested. These probes along with similar previously-synthesized probes are intended to pinpoint the location of free iron in cells. The effectiveness of the tested probes varied across cell types, with some appearing to show unexpected localization in lysosomes and others potentially localizing in other cellular compartments. Among the designs, the final peptide probe, P-1, is unique given its dual-detection towards iron and ROS simultaneously. In P-1, the fluorescein group emits upon reaction with ROS, while the fluorescence from the BODIPY group is quenched upon iron binding by an adjacent 8-hydroxyquinoline-7-carboxamide group. This innovative design offers a more nuanced optical response compared to traditional turn-on or turn-off probes.

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