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Metallocene-based bioactive agents

Thesis type
(Thesis) Ph.D.
Date created
Metallocenes have demonstrated great potential as components of novel pharmaceuticals. Notable examples include ferrocene (Fc) compounds such as Ferrocifen and Ferroquine, which have shown clinical success as anticancer and antimalarial drugs respectively. In this work, metallocene conjugates have been developed to modify, enhance, and manipulate the activity of known drugs and biomolecules. The first study utilizes Fc as a bridge between two biologically-active molecules, biotin, a receptor targeting moiety, and chlorambucil, a chemotherapeutic, to give a novel trifunctional anticancer compound. Comparison of the activity of the resulting trifunctional molecule against the NCI-60 human-tumor cell-line screen with a series of control compounds, which had systematic absences of each of the three components, demonstrated that the Fc group increases anticancer activity. Furthermore, statistical analysis of patterns of activity in the NCI-60 data indicates that the Fc group likely exhibits activity due to the generation of reactive oxygen species (ROS). In the second study, Fc and receptor targeting moieties, biotin or estrone, were appended to an antimetastatic Ru(III) scaffold. The ligands of the compounds show promising cytotoxicity and selectivity, whereas the bimetallic complexes are less active, but still more cytotoxic than the parent Ru(III) complex. Spectroscopic and theoretical studies indicate a potential electrochemical interaction between the two redox-active metal centres. To further explore its ROS generating utility as a medicinal tool, Fc was also coupled to a series of uinolone-based antibiotics. Despite a design that aimed to allow the quinolone activity to be unencumbered by the Fc group, while allowing for ROS generation, the compounds showed little activity against a panel of bacterial pathogens. This suggested a fundamental harmacological issue with the compounds, possibly related to transport into cells. The fourth type of metallocene conjugate in this work installed ruthenocene-like tags to aromatic amino-acid side chains of human serum transferrin. These protein organometallics were studied for their ability to be transported into cancer cells, by comparing the tagged iron-loaded (holo) and iron-free (apo) forms of the protein. Circular Dichroism studies indicate that holo-transferrin maintains its secondary structure following modification, suggesting that the labelled protein could be transported via the transferrin receptor. Overall, the work in this thesis demonstrates the scope for diverse applications of metallocenes in medicinal chemistry.
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Supervisor or Senior Supervisor
Thesis advisor: Walsby, Charles
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