DOI
https://doi.org/10.25772/588J-V825
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemistry
First Advisor
Nicholas Farrell
Abstract
Much of the current literature has focused on deciphering the intimate details of metal-DNA binding. Metalloglycomics, the study of metal-glycosaminoglycan (GAG) interactions, has been historically understudied. The highly sulfated GAG, heparan sulfate (HS), has emerged as an attractive medicinal target due to its role in cancer and viral infection. Polynuclear platinum complexes (PPCs), structurally distinct from current mononuclear complexes, bind to HS through interactions with the HS sulfate groups. However, PPC are susceptible to degradation by thiol-containing blood components. Here oxygen-donating species, loosely associating anions (LAAs) have been shown to delay metabolization of PPCs. Interactions of LAAs with PPCs are analogous to the PPC-HS interaction that lead to the formation of non-covalent Pt-O bonds, which effectively shield HS from enzymatic cleavage. Metalloglycomics also extends to examples of cobalt-ammine complexes. Recently, the biological activity of the iconic Werner’s Complex has been discussed, as the compound exhibits antiviral and anticancer activity. In order to elucidate the molecular details of this activity, a selection of mononuclear Co-ammine complexes were studied for their interactions with HS. Interestingly, pentaamminechlorocobalt (III), a staple of undergraduate inorganic laboratory curricula, was an effective inhibitor of bacterial heparinase enzyme activity and inhibited HSE-dependent cellular invasion through the extracellular matrix. This unexpected HS-metal interaction further emphasizes the potential of metalloglycomics for GAG-targeted drug design and possible therapeutic applications.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-11-2023