Total synthesis of furospongolide and related furanolipid analogues as potential anti-tumour agents

This thesis details the design, development and execution of innovative methodology in the total synthesis of the terpene-derived marine natural product, furospongolide. It also outlines the synthetic routes used to prepare a novel range of furanolipids derivatives and subsequent evaluation of their potential as antitumour agents. The first chapter is a review of the literature describing efforts undertaken towards the synthesis of biologically active furanosesterterpenoid marine natural products. A brief discussion on the sources and biological activity exhibited by furan natural products is also provided. In addition, a concise account of the role of hypoxia in cancer, and the increasing interest in HIF-1 inhibition as a target for chemotherapeutics is examined. The second chapter discusses the concise synthesis of the marine HIF-1 inhibitor furospongolide, which was achieved in five linear steps from (E,E)-farnesyl acetate. The synthetic strategy features a selective oxidation reaction, a Schlosser sp3-sp3 cross-coupling, a Wittig cross-coupling and an elaborate one-pot selective reduction, lactonisation and isomerization reaction to install the butenolide ring. The structure-activity relationship of furospongolide was also investigated. This involved the design and synthesis of a library of structurally modified analogues sharing the same C1-C13 subunit. This was achieved by exploiting the brevity and high level of convergence of our synthetic route together with the readily amenable structure of our target molecule. Exploiting the Schlosser cross-coupling allowed for replacement of furan with other heterocycles in the preparation of various furanolipid and thiophenolipid derivatives. The employment of reductive amination and Wittig chemistry further added to our novel library of structural derivatives. The third chapter discusses the results obtained from the NCI from biological evaluation From a collection of 28 novel compounds evaluated against the NCI-60 cancer cell array, six drug candidates were successfully selected for further biological evaluation on the basis of antitumour activity. COMPARE analysis revealed a strong correlation between some of our design analogues and the blockbuster anticancer agent tamoxifen, further supporting the potential of furanolipids in the treatment of breast cancer. The fourth chapter, details the full experimental procedures, including spectroscopic and analytical data for all the compounds prepared during this research.

Modelling and control of a floating oscillating water column

A novel numerical model of a Bent Backwards Duct Buoy (BBDB) Oscillating Water Column (OWC) Wave Energy Converter was created based on existing isolated numerical models of the different energy conversion systems utilised by an OWC. The novel aspect of this numerical model is that it incorporates the interdependencies of the different power conversion systems rather than modelling each system individually. This was achieved by accounting for the dynamic aerodynamic damping caused by the changing turbine rotational velocity by recalculating the turbine damping for each simulation sample and applying it via a feedback loop. The accuracy of the model was validated using experimental data collected during the Components for Ocean Renewable Energy Systems (CORES) EU FP-7 project that was tested in Galway Bay, Ireland. During the verification process, it was discovered that the model could also be applied as a valuable tool when troubleshooting device performance. A new turbine was developed and added to a full scale model after being investigated using Computational Fluid Dynamics. The energy storage capacity of the impulse turbine was investigated by modelling the turbine with both high and low inertia and applying three turbine control theories to the turbine using the full scale model. A single Maximum Power Point Tracking algorithm was applied to the low-inertia turbine, while both a fixed and dynamic control algorithm was applied to the high-inertia turbine. These results suggest that the highinertia turbine could be used as a flywheel energy storage device that could help minimize output power variation despite the low operating speed of the impulse turbine. This research identified the importance of applying dynamic turbine damping to a BBDB OWC numerical model, revealed additional value of the model as a device troubleshooting tool, and found that an impulse turbine could be applied as an energy storage system.