"IRON CHELATOR AND FLUOROPHORE PEPTIDE BIOCONJUGATES FOR THE STUDY OF C" by Leonid I. Povolotskiy

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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