Defense Date

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Dr. Nicholas Farrell

Abstract

Heparan sulfate (HS), a type of glycosaminoglycan (GAG), has been identified as a ligand for interactions with polynuclear platinum complexes (PPCs). HS is involved in numerous biological processes, and often considered to be extracellular DNA. PPCs interact with HS through the formation of a “sulfate clamp”, where multiple anionic sulfate groups cluster around the cationic PPC. The masking of HS results in the inhibition of enzymatic activity, protein-HS interactions, and other biological processes. PPCs use HS proteoglycans as an method of cellular internalization. By targeting sulfated-GAGs, PPCs can offer precision medicine not currently observed with the FDA approved platinum therapies. Additionally, a patient’s sulfated-GAG level can be used as a biomarker prior to treatment. In an effort to delineate the structural requirements needed to obtain high affinity binding with HS, focused libraries were synthesized to determine the effects of charge, nuclearity (number of Pt centers), charge dispersion, and hydrogen bonding ability of PPC-HS binding. The libraries were then probed in biophysical assays with Fondaparinux (FPX), a commonly used model for HS. As a generality, compounds with increased number of platinum centers, and higher overall charges exhibited higher affinities towards FPX. Additional assays determined the hydrogen bonding abilities and charge dispersion of the PPCs greatly influenced the system. The lead compounds were used in vivo to determine overall efficacy and maximum tolerated dose.

Rights

© Eric Ginsburg

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-7-2020

Available for download on Tuesday, May 06, 2025

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