The following dissertation describes a collection of results that led to a successful formal total synthesis of a naturally-occurring antitumour antibiotic, (-)..echinosporin. To achieve that, various synthetic strategies were developed and examined, all of which relied on a cycloadditive event as a key step to prepare the [3.4.0J-bicyclic framework of (-)-echinosporin. The synthesis was eventually accomplished using the Padwa [3+2] cycloaddition-elimination of allenylphenylsulphone to a chiral sugar enone 6 as a key transformation. it provided the first recorded example of this reaction used in complex natural product total synthesis. Following a series of functional group interconversions on this cycloadduct, a mild new method for the C-carboxyalkylation of bromomagnesium ketone enolates was applied to install the C(11)~carboxylic group of (-)- echinosporin. The quaternary OH-bearing stereocentre was introduced via a substrate~directed osmylative dihydroxylation on a i3-keto ester enol 71 . The resulting ketone 77 was advanced into 70 via Barton deoxygenation. Following that, the crucial C(8)-C(9) unsaturation was introduced starting from the ketone 70 through a three-step sequence based on the Barton vinyl iodide synthesis and Pd(O)-mediated dehalogenation. Next, a TEMPO-based oxidation was used to bring the C(10)- position to a correct oxidation state. Following protection as the allyl ester, an E1cb silyloxy elimination installed the remaining C(4)-C(5) unsaturation. The allyl ester 90 was finally transformed into a primary amide and the C-2 ethyl glycoside was chemoselectively hydrolysed using aqueous HBF4 to reveal Smith's intermediate 1.

This thesis is concerned with the synthesis, characterisation and evaluation of novel ruthenium arene complexes for their application as anti-tumour agents.

The main body of this thesis comprises four chapters: Chapter One serves as an introduction. The first two thirds deals with cell signalling cascades, focusing particularly upon protein kinases and the roles that their dysfunction play in cancerous processes and upon the methods employed to inhibit them in a bid to counter these processes. Kinase inhibition by small molecules is a very active area of research and notable clinical successes have been achieved. The last portion of the chapter addresses some of the issues surrounding .drug discovery, and ends by stating the author's intention to utilise novel transition metal catalysis to access potential anticancer compounds, to test these compounds against cancer cell lines in vitro and to study their interactions with the active sites of cell signalling proteins known to be mutated in these same cancers in silica. After a brief introductory section dealing with relevant chemistry, Chapter Two describes the author's work with the arylallylation of purine derivatives via a 3-component palladium-catalysed cascade developed within the Grigg group, and the subsequent in vitro testing against the colon cancer cell line HCT116. Four of the synthesised compounds showed <10 uM IC50's. Chapter Three gives an account of the invention of a novel 3-component cascade synthesis of diindolylmethane compounds, three of which have demonstrated selectivity and < 10 uM activity against the LNCaP prostate cancer cell line in vitro. Derivatives of two of these. compounds in turn show enhanced selectivity and 0.5 - 2 uM activity against the LNCaP and PC3 prostate cancer cell lines. A short review of the relevant chemistry is given at the beginning of the chapter. Chapter Four furnishes full experimental details of the work carried out, together with appropriate data.

This thesis concerns the synthesis and characterisation of novel bis(diketonate) titanium dihalides. The compounds synthesised during the course of this work have been evaluated as potential anti-tumour agents. Chapter 1 comprises a brief review of the literature on of the role of titanium in transition metal anti-tumour agents as well comments on the industrial uses of the bis(diketonate) ligand. Chapter 2 compares the novel crystal structures of la 1,3-p-diketonatc molecules as well as the synthesis and characterisation of three novel bis(diketonatc) titanium isopropoxidc compounds. Chapter 3 concerns the synthesis and characterisation of 12 novel bis(diketonate) titanium dichlorides along with 8 novel crystal structures. In addition 5 novel mono(diketonate) titanium trichloridcs along with 4 novel crystal structures. Chapter 4 describes the synthesis and characterisation of 14 novel bis(dikctonate) titanium dibromides along with 8 novel crystal structures. Chapter 5 gives an account of the biological evaluation of a series of the bis(diketonate) titanium compounds including an SRB assay and DNA binding study. The SRB assay revealed one compound, 4.2, to show anti-tumour activity comparable to that of cisplatin in the A2780eis cell line. There is also a section on future work defining key features for further study. Chapter 6 represents experimental details and characterisation data for the compounds described in Chapters 1-5.

This thesis concerns the synthesis of a number of bis(phenyl-l ,3-~- diketonato )titanium dihalide complexes, and their subsequent evaluation as anticancer drugs in vitro. Mechanistic work has been carried out to determine the mode of anticancer activity exhibited by this class of drugs. Chapter 1 gives a summary of research into metal-containing anticancer drugs to date, with particular emphasis on the role of titanium. Chapter 2 describes the synthesis and characterisation of a series of phenyl-l,3-~- diketonate ligands, and the synthesis and characterisation of a bis(phenyl-l ,3-~- diketonato )titanium ethoxide complex. Chapter 3 describes the synthesis' and characterisation of six bis(phenyl-l ,3-~- diketonato)titanium dichloride complexes and SIX bis(phenyl-l,3-~- diketonato )titanium dibromide complexes. Chapter 4 describes in vitro testing carried out on a senes of bis(phenyl-l ,3-~- diketonato )titanium dihalide and dialkoxy complexes using the MTT assay with varying incubation times and oxygen concentrations. Several complexes are shown to exhibit cytotoxicity comparable to cisplatin. Chapter 5 describes a number of mechanistic studies carried out using the bis(phenyl-l ,3-~-diketonato )titanium complexes, and presents evidence for a cytotoxic species consisting of titanium with both diketonate and DMSO ligands. Chapter 6 gives experimental details and characterisation data for the compounds described in Chapters 2-5.

Cancers preference for glycolysis, with down-regulation of mitochondrial respiration, also known as the 'Warburg effect', provides a unique cancer target by modulation of mitochondrial respiration. We have examined the key regulators of glycolysis and mitochondrial respiration in colorectal cancers (CRC), to investigate its influence on outcome, and identify novel targets for anti-cancer therapy. METHODS: Antibody specificity was confirmed by western blotting. Tissue micro-arrays incorporating 280 GRG were constructed using archival colorectal tissue from the medical research council (MRC) CLASICC trial, and probed by immunohistochemistry for markers of glycolysis (HIF1a, LDH5, HK2), and oxidative phosphorylation (PDK isoforms 1-4, PDC subunits E1a, E2). SPDPK1 was also investigated due to its key role in the PISK-Akt pathway. Expression levels were scored semi-quantitatively, and compared to clinicopathological and 5-year survival data. RESULTS: Poorly differentiated tumours showed a significantly higher expression of HIF1 a (p=0.028). Higher levels of HIF1α associated significantly with lymph nodal involvement (p=0.027). High PDKS (p=0.008, HR=2.16, 95% Cl: 1.22, S.82), low PDHE1 a (p<0.001, HR=2.46, 95% Cl: 1.57, S.86) and high HIF1 a (p=0.001 , HR=2.61 , 95% Cl: 1.49,4.57) levels were independent predictors of worse 5-year disease free survival. High PDKS (p=0.OS7, HR=S.04, 95% Cl: 1.07, 8.62) and HIF1 a (p=0.041, HR=2.69, 95% Cl: 1.04, 6.9S) levels also predicted for increased 5-year distant recurrence, DISCUSSION: CRC demonstrating Warburg effect display aggressive biology, and are associated with significantly worse survival. The PDH/PDK system, which is integral to the Warburg effect, associates significantly with cancer survival and spread. The study identifies the potential for further investigation into PDKS as an attractive anti cancer target.

Synthetic ether analogues (prototypes: miltefosine, perifosine and cdelfosine) of natural phospholipids are a family of anti-cancer drugs with a wide range of pharmacological behaviour. There is a growing interest in anti-cancer ether phospholipids owing to their seleC;!1vity against tumours which has resulted in a much lower toxicity, as compared with other classical anti-cancer chemotherapeutic agents. However, due to the presence of the phosphate diester, these compounds can be quickly biodegraded by enzymes of phospholipid metabolism. Consequently, the aims of this research project were to synthesise isosteric analogues of miltefosine, perifosine and edelfosine by replacing the two phosphorus-oxygen bonds with phosphorus-carbon bonds. Several methodologies for the preparation of phosphorus-carbon bonds were investigated and phosphinic acid analogues of miltefosine, perifosine and edelfosine were efficiently synthesised in good overall yields. The first phosphorus-carbon bond of miltefosine and edelfosine analogues was prepared by a radical hydrophosphorylation addition reaction, and the second by conversion to the P(III) silyloxy intermediate, followed by Michael-type addition to acrylonitrile and acidic hydrolysis of the silyl groups. Miltefosine analogue was synthesised in a total of six steps from hexadecene, in 69% overall yield, and edelfosine analogue was synthesised in a total of ten steps from hexadecanol, in 8.5% overall yield. Perifosine analogue was successfully synthesised by a double radical hydrophosphorylatipn process, in a total of six steps, in 50% overall yield from hexadecene.

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