Date of Award

Spring 2023

Project Type

Dissertation

Program or Major

Chemistry

Degree Name

Doctor of Philosophy

First Advisor

Roy P Planalp

Second Advisor

Glen Miller

Third Advisor

Richard P Johnson

Abstract

Bifunctional Szeto-Schiller (SS) peptides provide new tools for the study of cellular processes and drug delivery at the organelle level. SS-peptides have been shown to localize to the inner mitochondrial membrane (IMM), which holds a large fraction of intracellular labile iron. Dysregulation of iron has been linked to a variety of disorders ranging from neurodegeneration to cancer. Previous studies have employed the hydroxypyridinone and catechol chelating families which fail to inhibit Fenton-style redox cycling of iron. It has been shown independently, that tripodal 8-hydroxyquinoline (8HQ) structures can prevent Fenton chemistry. SS-peptide variants containing 8HQ as the iron-chelating group along with a fluorescent reporter were prepared. It was determined that the peptide backbone does not interfere with iron binding and there is a fluorescent response to increasing iron concentrations. Additionally, the iron-peptide complexes were shown to prevent the generation of hydroxyl radicals when compared to an EDTA-iron complex. These conjugates were successfully targeting to mitochondria in an ovarian cancer cell model and cellular experiments are ongoing. The synthesis of a linkable 8HQ tripodal structure has been completed but final deprotection conditions remain elusive. The effect of the fluorophore was also examined through substitution of the dansyl group to a rhodamine B analogue. The new conjugates were subjected to the same cellular localization studies but failed to colocalize with commercially available mitochondrial stains.

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