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.

Chitosan gel film bandages: correlating structure, composition, and antimicrobial properties

Chitosan gel films were successfully obtained by evaporation cast from chitosan solutions in aqueous acidic solutions of organic acids (lactic and acetic acid) as gel film bandages, with a range of additives that directly influence film morphology and porosity. We show that the structure and composition of a wide range of 128 thin gel films, is correlated to the antimicrobial properties, their biocompatibility and resistance to biodegradation. Infrared spectroscopy and solid-state 13C nuclear magnetic resonance spectroscopy was used to correlate film molecular structure and composition to good antimicrobial properties against 10 of the most prevalent Gram positive and Gram negative bacteria. Chitosan gel films reduce the number of colonies after 24 h of incubation by factors of ∼105–107 CFU/mL, compared with controls. For each of these films, the structure and preparation condition has a direct relationship to antimicrobial activity and effectiveness. These gel film bandages also show excellent stability against biodegradation with lysozyme under physiological conditions (5% weight loss over a period of 1 month, 2% in the first week), allowing use during the entire healing process. These chitosan thin films and subsequent derivatives hold potential as low-cost, dissolvable bandages, or second skin, with antimicrobial properties that prohibit the most relevant intrahospital bacteria that infest burn injuries.

Exploring the relationship between patterns of physical activity, sedentary behaviour and cardiometabolic health in middle-aged Irish adults

Background and Study Rationale Being physically active is a major contributor to both physical and mental health. More specifically, being physically active lowers risk of coronary heart disease, high blood pressure, stroke, metabolic syndrome (MetS), diabetes, certain cancers and depression, and increases cognitive function and wellbeing. The physiological mechanisms that occur in response to physical activity and the impact of total physical activity and sedentary behaviour on cardiometabolic health have been extensively studied. In contrast, limited data evaluating the specific effects of daily and weekly patterns of physical behaviour on cardiometabolic health exist. Additionally, no other study has examined interrelated patterns and minute-by-minute accumulation of physical behaviour throughout the day across week days in middle-aged adults. Study Aims The overarching aims of this thesis are firstly to describe patterns of behaviour throughout the day and week, and secondly to explore associations between these patterns and cardiometabolic health in a middle-aged population. The specific objectives are to: 1 Compare agreement between the International Physical Activity Questionnaire-Short Form (IPAQ-SF) and GENEActiv accelerometer-derived moderate-to-vigorous (MVPA) activity and secondly to compare their associations with a range of cardiometabolic and inflammatory markers in middle-aged adults. 2 Determine a suitable monitoring frame needed to reliably capture weekly, accelerometer-measured, activity in our population. 3 Identify groups of participants who have similar weekly patterns of physical behaviour, and determine if underlying patterns of cardiometabolic profiles exist among these groups. 4 Explore the variation of physical behaviour throughout the day to identify whether daily patterns of physical behaviour vary by cardiometabolic health. Methods All results in this thesis are based on data from a subsample of the Mitchelstown Cohort; 475 (46.1% males; mean aged 59.7±5.5 years) middle-aged Irish adults. Subjective physical activity levels were assessed using the IPAQ-SF. Participants wore the wrist GENEActiv accelerometer for 7 consecutive days. Data was collected at 100Hz and summarised into a signal magnitude vector using 60s epochs. Each time interval was categorised based on validated cut-offs. Data on cardiometabolic and inflammatory markers was collected according to standard protocol. Cardiometabolic outcomes (obesity, diabetes, hypertension and MetS) were defined according to internationally recognised definitions by World Health Organisation (WHO) and Irish Diabetes Federation (IDF). Results The results of the first chapter suggest that the IPAQ-SF lacks the sensitivity to assess patterning of activity and guideline adherence and assessing the relationship with cardiometabolic and inflammatory markers. Furthermore, GENEActiv accelerometer-derived MVPA appears to be better at detecting relationships with cardiometabolic and inflammatory markers. The second chapter examined variations in day-to-day physical behaviour levels between- and within-subjects. The main findings were that Sunday differed from all other days in the week for sedentary behaviour and light activity and that a large within-subject variation across days of the week for vigorous activity exists. Our data indicate that six days of monitoring, four weekdays plus Saturday and Sunday, are required to reliably estimate weekly habitual activity in all activity intensities. In the next chapter, latent profile analysis of weekly, interrelated patterns of physical behaviour identified four distinct physical behaviour patterns; Sedentary Group (15.9%), Sedentary; Lower Activity Group (28%), Sedentary; Higher Activity Group (44.2%) and a Physically Active Group (11.9%). Overall the Sedentary Group had poorer outcomes, characterised by unfavourable cardiometabolic and inflammatory profiles. The remaining classes were characterised by healthier cardiometabolic profiles with lower sedentary behaviour levels. The final chapter, which aimed to compare daily cumulative patterns of minute-by-minute physical behaviour intensities across those with and without MetS, revealed significant differences in weekday and weekend day MVPA. In particular, those with MetS start accumulating MVPA later in the day and for a shorted day period. Conclusion In conclusion, the results of this thesis add to the evidence base regards an optimal monitoring period for physical behaviour measurement to accurately capture weekly physical behaviour patterns. In addition, the results highlight whether weekly and daily distribution of activity is associated with cardiometabolic health and inflammatory profiles. The key findings of this thesis demonstrate the importance of daily and weekly physical behaviour patterning of activity intensity in the context of cardiometabolic health risk. In addition, these findings highlight the importance of using physical behaviour patterns of free-living adults observed in a population-based study to inform and aid health promotion activity programmes and primary care prevention and treatment strategies and development of future tailored physical activity based interventions.