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.

The effect of complex workplace dietary interventions on employees dietary behaviours, nutrition knowledge and health status

Background The growing prevalence and associated burden of diet-related non-communicable diseases is a global public health concern. The environments in which people live and work influences their dietary behaviours. Aim The focus of this thesis was on the effectiveness of complex workplace dietary interventions. The comparative effectiveness of a complex workplace environmental dietary modification intervention and an educational intervention were assessed both alone and in combination relative to a control workplace setting. Methods The systematic review was guided by the PRISMA statement. In a cluster controlled trial, four workplaces were purposively allocated to control, nutrition education alone (Education), environmental dietary modification alone (Environment) and nutrition education and environmental dietary modification (Combined intervention). The interventions were guided by the MRC framework. In the control workplace, data were collected at baseline and follow-up. In the intervention related sub-study, the relationships between nutrition knowledge, diet quality and hypertension were examined. Results The systematic review provided limited evidence. In the FCW study, 850 employees aged 18-64 years were recruited at baseline with N(response rate %) in each workplace as follows: Control: 111(72%), Education: 226(71%), Environment: 113(91%), Combined intervention: 400(61%). Complete follow-up data was obtained for 517 employees (61%). There were significant positive changes in dietary intakes of saturated fat(p=0.013), salt(p=0.010) and nutrition knowledge(p=0.034) between baseline and follow-up at 7-9 months in the combined intervention versus the control workplace in the fully adjusted multivariate analysis. Small but significant changes in BMI(-1.2kg/m2 (p=0.047) were also observed in the combined intervention. In the sub-study, nutrition knowledge was positively significantly associated with diet quality and blood pressure but no evidence of a mediation effect of the DASH score was detected between nutrition knowledge and blood pressure. Conclusion This thesis provides critical evidence on the effectiveness of complex workplace dietary interventions in a manufacturing working population.

Alcohol consumption and related harm among university students in Ireland

Aim: Alcohol consumption is a leading cause of global suffering. The harms caused by alcohol to the individual, their peers and the society in which they live provokes public health concern. Elevated levels of consumption and consequences have been noted in those aged 18-29 years. University students represent a unique subsection of society within this age group. University authorities have attempted to tackle this issue throughout the past decade. However, the issue persists. Thus, the aim of this study is to contribute to the evidence base for policy and practice in relation to alcohol harm reduction among third-level students in Ireland. Methods: A mixed methods approach was employed. A systematic review of the prevalence of hazardous alcohol consumption among university students in Ireland and the United Kingdom from 2002 to 2014 was conducted. In addition, a narrative synthesis of studies of drinking types evidenced among youths in western societies was undertaken. A cross-sectional study focused on university students’ health and lifestyle behaviours with particular reference to alcohol consumption was undertaken using previously validated instruments. Undergraduate students registered to one university in Ireland were recruited using two separate modes; classroom and online. Studies investigated the impact of mode of data collection, the prevalence of hazardous alcohol consumption and resultant adverse consequences for mental health and wellbeing. In addition a study using a Q-methodology approach was undertaken to gain a deeper understanding of the cultural factors influencing current patterns of alcohol consumption. Data were analysed using IBM SPPS statistics 20, Stata 12, MPLUS and PQ Method. Results: The literature review focusing on students’ alcohol consumption found that there has been both an increase in hazardous alcohol consumption among university students and a convergence of male and female drinking patterns throughout the past decade. Updating this research, the thesis found that two-thirds of university students consume alcohol at a hazardous level, detailing the range of adverse consequences reported by university students in Ireland. Finally, the heterogeneous nature of this drinking was described in a narrative synthesis exposing six types of consumption. The succeeding chapters develop this review further by describing three typologies of consumption, two quantitative and one quali-quantilogical. The quantitative typology describes three types of drinking for men (realistic hedonist, responsible conformer and guarded drinker) and four types for women (realistic hedonist, peer-influenced, responsible conformer and guarded drinker). The quali-quantilogical approach describes four types of consumption. These are defined as the ‘guarded drinker’, the ‘calculated hedonist’, the ‘peer-influenced drinker’ and the ‘inevitable binger’. Discussion: The findings of this thesis highlight the scale of the issue and provide up-to-date estimates of alcohol consumption among university students in Ireland. Hazardous alcohol consumption is associated with a range of harms to self and harms to others in proximity to the alcohol consumer. The classification of drinkers into types signal the necessity for university management, health promotion practitioners and public health policy makers to tackle this issue using a multi-faceted approach.