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Bacterial resistance to many current antibiotics continues to spread globally which is a disturbing phenomenon which can lead to serious medical implications. In order to combat this, new compounds from both synthetic and/or natural sources are being investigated. Curcumin is a compound of interest due to its wide range of biological properties but although readily available suffers from a number of disadvantages, particularly solubility, and bioavailability. In this study twenty-four curcumin analogues (CAs) were synthesised using a Claisen-Schmidt condensation reaction prior to characterisation and four were subsequently identified as novel compounds. The antibacterial activity of each was assessed against a panel of relevant Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) and their cytotoxicity evaluated against both HeLa and HaCaT cells. Enhancements to the CAs' initial poor solubility were performed using solid dispersion techniques in combination with bovine serum albumin prior to reassessment of the antibacterial activity. The Minimum Inhibitory Concentration (MIC) results showed that seventeen CAs displayed activity against both Gram-positive and Gram-negative strains with the remaining seven showing selective activity towards one strain, all in the MIC range of 5-20 µg/mL. No CAs were found to elicit cytotoxicity towards the cell lines up to 100 µM and although the solubility was significantly enhanced, the level of antibacterial activity remained the same. Lastly, CA nanoparticles were synthesised as a pilot study to investigate their effect on antibacterial activity. The initial work in this study indicates that a number of these CAs have potential as antibacterial agents, however further work including mechanistic studies and a full in vitro nanoparticle study need to be conducted prior to investigating possible applications such as integration into burn/wound dressings.

G-quadruplex ligands, which can intercalate the G-quadruplex structures, have been studied as a strategy for indirect inhibition of telomerase activity, alongside targeting other G-quadruplexes found in other genes, including oncogenes. The scope of G-quadruplex ligands as cancer targeting drugs is particularly high as there more than 350000 DNA sequences within the human genome that can be targeted. In light of this, several small molecules have been introduced, which can induce and stabilise G-quadruplexes, which are classified as new drug agents for cancer therapy. This thesis looks at the synthesis of suitably functionalised polyaromatic compounds to achieve this stabilisation. Deoxyribonucleic acid (DNA) in our cells contains the instructions for all aspects of life, from cell division to immune responses. The discoveries and structural determination of DNA, leading to the human genome project, provides a great resource for genetic understanding. The pairing of nuclear bases is typically represented as Watson-Crick. When DNA is chemically changed, disruption to cell processes occurs. Cancer is one outcome of this damage, where DNA is damaged to a point where cell cycle control is incapacitated. One key aspect of cancer is that cells lose the ability to undergo apoptosis. Telomeres are integral structures present in the DNA of eukaryotic cells. They consist of regions of DNA motifs that are repeated throughout the structure. These conserved motifs contain an abundance of Guanine in sequences of 3-4 repeat units. These Guanine units make up the Guanine tetrad structures that allow the telomere to function as genomic stabiliser and protective agent against DNA damage or cross chromosome fusion such that all telomeres have a single stranded Guanine motif overhang at the 3' end of the chromosome. Telomere length will usually dictate the lifespan of a cell, however in cancer cells we see this mechanism for programmed cell death, hijacked by the expression of telomerase, which extends telomere length and inhibits programmed cell death. The well-established principle behind the development of G quadruplex ligands is that inhibition of telomerase, which isn't expressed in healthy cells, can selectively facilitate apoptosis of cancerous cells. G-quadruplexes are structures that have shown the potential as therapeutic targets through 5 their propensity to associate with themselves and structures that are similar which will intercalate. Because of this, small molecules that intercalate within the structure and stabilise them within DNA have targeted G-quadruplexes. This stabilised DNA G-quadruplex structure will then inhibit the division of the cell through prevention of unwrapping and recognition of regulation regions and telomeric regions, which are normally cleaved off . In this research we aimed to make a number of G-quadruplex ligands to specifically target this inhibition and show activity against the HeLa cancer cell line. Throughout the research we synthesised several G-quadruplex ligands with different synthetic methodologies. Our success with these ligands was mainly achieved with imine couplings and these compounds showed cytotoxicity to HeLa cells. Compounds that showed cytotoxicity were further analysed for drug G-quadruplex interaction by 1D, 1H NMR titration experiments. Five of the compounds that showed cytotoxic effect demonstrated drug G-quadruplex interactions.

Pathogenic neovascularization underlies a number of degenerative ocular diseases, which together are the most common causes of blindness in children and adults. Novel therapies are sorely needed to treat these diseases as even the newer, highly expensive, anti-vascular endothelial growth factor (VEGF) drugs, such as ranibizumab, can have acute, systemic side effects. Natural product chemistry involves the extraction of potentially pharmacologically active phytochemicals from plants. Homoisoflavonoids are a class of active compounds isolated from the Scilloideae sub-family of the Asparagaceae family. Homoisoflavonoids are frequently extracted from the Scilloideae sub-family and are considered promising pharmacological candidates due to their anti-bacterial, anti-mutagenic, anti-oxidant and anti-inflammatory effects. Cremastranone is a homoisoflavonoid extracted from an orchid used in traditional medicine, Cremastra appendiculata, and has an anti-proliferative effect on blood vessels. This compound has been shown to be effective in treating pathogenic neovascularisation in premature mice. A synthetic method, which can be used to produce a wide variety of homoisoflavonoid compounds, is reported here with the goal to synthesise the most promising homoisoflavonoid candidates extracted in this work for in vivo studies. The sub-family Scilloideae contains the tribes Ornithogaleae, Hyacintheae, Urgineeae and Oziroëeae. Seven plant species from the Hyacintheae, Urgineeae and Oziroëeae tribes were investigated in this work. This is the first report of the phytochemical investigation of Rhodocodon cryptopodus, R. rotundus, Massonia (Whiteheadia) bifolia and Oziroë arida. Rhodocodon cryptopodus (Baker) and Rhodocodon rotundus (H. Perrier) bulbs were investigated, producing six known compounds identified as triterpenoids, cinnamic acid derivatives and a homoisoflavonoid and four novel compounds. From R. cryptopodus one novel coumarin was extracted and from R. rotundus, two novel bufadienolides and one novel 3S-homoisoflavonoid were extracted Plants within the Eucomis (L'Her) genus are known to contain many homoisoflavonoids. E. autumnalis (Mill. Chitt.), E. bicolor (Baker) and E. comosa (Hort ex. Wehrh) were investigated. These species have been investigated previously. They were reinvestigated using bulbs from a commercial bulb supplier as large quantities were available and large amounts of extracted compounds were required for screening purposes. Phytochemical investigations yielded a spirocyclic nortriterpenoid, phenolic compounds, a chromanone, a purine nucleoside and homoisoflavonoids. One novel homoisoflavonoid was extracted from E. autumnalis and two novel homoisoflavonoids were extracted from E. comosa. The phytochemistry of Massonia (Whiteheadia) bifolia ((Jacq.) J.C. Manning & Goldblatt) was investigated. Analysis of the bulbs of M. bifolia yielded four known compounds including a spirocyclic nortriterpenoid and three homoisoflavonoids. Novel compounds included a xanthone and two homoisoflavonoid compounds. A phytochemical analysis of Oziroë arida (Raf.) bulbs yielded six known compounds, identified as two phytosterols, a cinnamic acid derivative, a purine nucleoside and two homoisoflavonoids. Extracted and synthetic homoisoflavonoids were tested for their anti-proliferative activities in cell-based assays. Active compounds were also tested for their anti-angiogenic activities in vitro. Results indicated that several homoisoflavonoids are very active at stopping the proliferation, migration and tube formation of cultured endothelial cells. Selected promising compounds will be taken on for in vivo studies in the future.