Cancer is the second biggest global killer,[1,2] with cancers of the brain and central nervous system accounting for a disproportionately high number of deaths.[3] The most prolific cancer of the central nervous system is glioblastoma, for which prognosis is still very poor. In this project, analogues of two lead compounds with known activity against glioblastoma cell lines (compounds 4 and 5, Figure 1) were produced in order to develop structure-activity relationships and discover compounds with superior activities against glioblastoma. Figure 1 - The structures of the lead compounds 4 and 5 Analogues of compound 4 were the result of a rigorous similarity search of the ZINC database,[4,5] as well as using chemical intuition to identify potential analogues. A scaffold-hopping approach was undertaken, through which two new compound classes were identified as potentially superior lead compounds for future work (Figure 2). Figure 2 - The structures of two analogues of compound 4 with different scaffolds and superior activity, compounds 168 and 214 Compound 4 is known to induce cell death through the induction of elevated levels of cellular reactive oxygen species (ROS),[6] which may be formed via the radical form of compound 4 and its analogues. The connection between the anticancer activity of 4 and its analogues with the propensity of these compounds to form radicals was also investigated. Enthalpic values relevant to radical formation (BDE, AIP, PDE, PA and ETE) were calculated using a density functional theory (DFT) approach. Although no strong correlation was found for the whole series of compounds, the data indicates that correlations may exist within certain structural classes. The anticancer activity of compound 5, a prodrug, was compared against 11 analogues of both the prodrug and active form of the compound (Scheme 1). It was found that compound 9 has superior activity to that of the prodrug 5. Substitutions at the N-position of 5 were also found to have a significant effect on activity, with an N-tosyl analogue having significantly improved activity against glioblastoma cell lines and short term cultures. The results obtained suggest that future work on this series should therefore be based around compound 9, a subclass of indoles that have wide ranging anticancer activity, but have not yet been reported against glioblastoma. Scheme 1 - The degradation of 5 into its suspected active form (9) In conclusion, analogues were discovered within this project which improved upon the anticancer activity of both compounds 4 and 5. For compound 4, two alternative scaffolds were identified as superior and novel lead compounds against glioblastoma, and there is some indication that there may be a correlation between radical formation and anticancer activity within specific structural classes of this functional class of compounds. For prodrug 5, substituents at the N positon were found to have a significant effect on activity, and the activity of the active form (9) was found to be superior to the activity of the prodrug.

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SMAC (Secondary Mitochondria-derived Activator of Caspases) mimetics have generated significant interest as potential chemotherapeutic compounds via their ability to promote apoptosis in cancer cells. These molecules target several Inhibitor of Apoptosis Proteins (IAPs) whose elevated expression is ubiquitous with tumorigenesis. We report several novel SMAC based peptidomimetics which appear to mirror the anti-IAP activity of SMAC in vitro. Elements of reported SMAC mimetics were combined with unique structural features to design novel, efficacious IAP antagonists. Our approach included modifications to the 2nd and 4th residues of the AVPI peptide sequence, the motif responsible for SMAC 's interaction with IAPs. Cell-based compound testing against MDA-MB-231 breast cancer cells identified several promising leads possessing nanomolar cytotoxic effects. Apoptotic activity was confirmed via capsase-3/7 activation, a hallmark of regulated cell death. Our experimental data suggests we have developed selective, potent anti-cancer compounds to be further developed in the pursuit of new anti-cancer therapeutics.

Covalent bond-forming reactions between small molecules and proteins are ubiquitous. These reactions play a central role in the diversification and functionalization of proteins, enabling normal cell growth and life. Scientists routinely employ electrophilic compounds to modify proteins by exploiting the intrinsic nucleophilicity found on amino acid side-chains. These modifications permit a wide variety of experiments and allow for new insights and a deeper understanding of the chemistry and biology of living systems. The three research projects described in this thesis employ electrophilic, protein-modifying agents to meet unique goals. The first study (Chapter 2) details the development of a novel class of compounds that enhance the efficacy of therapeutic oncolytic viruses specifically in cancer cells. A medicinal chemistry-based approach was used to understand, measure and improve physicochemical and pharmacological properties of these small molecules. Inspired by the unique scaffold identified in Chapter 2, the second study of this thesis (Chapter 3) explores the bioactivity of the structurally related armeniaspirole natural products. Chemical synthesis enabled the uncovering of structure-activity relationships and ultimately allowed for the design of an activity-based probe. The final study (Chapter 4) details investigations of the terminal thioesterase involved in the biosynthesis of valinomycin. Small molecules substrates for the enzyme were synthesized and used to reveal details of the enzymatic mechanisms.

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Tuberculosis (TB) is a life-threatening infectious disease caused by Mycobacterium tuberculosis (Mtb). Globally, TB is a major public health burden with an estimated 10.4 million new cases and 1.8 million deaths reported in 2015. Although TB is curable, the treatment options currently available are beset by numerous shortcomings such as lengthy and complex treatment regimens, drug-drug interactions, drug toxicities, as well as emergence of widespread multi-drug resistance. Therefore, there is an urgent and compelling need to develop new, more effective, safer drugs with novel mechanisms of action, and which are capable of shortening treatment duration. This study focused on hit-to-lead optimization of two new classes of compounds with potential anti-TB properties: 2-aminoquinazolinones (AQZs) and benzoxazole-based oximes (BZOs). A hit compound for each of these classes with low micromolar antimycobacterial activity had previously been identified through phenotypic whole-cell in vitro screening.