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The growing sustainability movement within the chemical industries endeavours to forge cleaner manufacturing processes which integrate the key principles of Green Chemistry. At the forefront of these initiatives are solvent replacement strategies, driven, in part, by increasingly stringent regulations surrounding the use of solvents of concern. A group of solvents which have fallen under particular scrutiny are polar aprotic solvents, such as DMF, NMP and DMAc. This solvent class is characterised by high polarity and superior solvating abilities, which has firmly established their use within synthetic organic and medicinal chemistry. However, they are also associated with reproductive toxicity and are regarded as teratogens. As such, their continued use within industry is becoming increasingly discouraged. Direct replacement of polar aprotics using existing solvents often fails and, as such, novel alternatives are required. In this regard, the use of biomass feedstocks in the development of new solvents is an expanding area within Green Chemistry which aims to minimise the dependence on petroleum-based chemicals Cyrene and dimethyl isosorbide (DMI) are two emerging solvents derived from cellulose. However, their application within organic chemistry is under explored and, as such, their use within industry is currently limited. This research programme aims to investigate the use of these alternative solvents in synthetic transformations commonly utilised within the context of drug discovery in the pharmaceutical industries. Robust and general condition sets have been developed and thoroughly evaluated in the application of Cyrene as a medium for the Sonogashira and Suzukia-Miyaura cross-couplings, and amide bond formation. In addition, the methodology developed for the Sonogashira cross-coupling was extended to enable the efficient synthesis of pharmaceutically relevant heterocycles. Cyrene exhibited a pronounced base sensitivity, the effect and limitations of which were studied within organic reactions. Additionally, the utilisation of DMI as an alternative solvent within prominent Pdcatalysed transformations was also evaluated. Accessible conditions for the Suzukia-Miyaura, Mizorokia-Heck and Sonogashira cross-coupling reactions were developed and the scope of the reactions investigated. Ultimately, it is hoped that exemplifying the use of these solvents within organic synthesis and highlighting their limitations will influence their uptake by industrial practitioners.

The airway epithelium forms a continuous barrier from the nose to the alveoli and serves a variety of functions. Multiple functionally distinct cell types are involved in these processes. The innate defence functions require a patent airway epithelium, with infections often associated with epithelial defects and phenotypic alterations that are themselves associated with multiple lung diseases. Non-typeable Haemophilus influenzae (NTHi) and respiratory syncytial virus (RSV) are frequently identified in the airways in a range of respiratory diseases These pathogens often trigger exacerbations and worsening symptoms that often result in hospitalisation. This is particularly true in paediatric populations. Although mortality for NTHi and RSV infections alone are themselves low it remains unclear what role these infections play in mortality rates in complex chronic respiratory infections. These studies aimed to establish NTHi and RSV infections within airway epithelium models, and use them as tools to study pulmonary innate defence mechanisms in order to understand the role of these infections in respiratory disease. In vitro airway models were established using lung derived cell lines, undifferentiated primary human bronchial epithelial (uHBE) cells and air-liquid interface (ALI) differentiated uHBE cell cultures. Following establishment of differentiation we validated ALI cultures using a number of markers, including for the putative innate defence PLUNC family proteins, gel-forming mucins and tubulin. These markers are representative of different epithelial cell types within the cultures. Cultures were infected with NTHi or RSV for periods of time ranging from 1 hour to 7 days with a view to establishing chronic infections and allowing biofilm formation. Monolayer cultures showed an enhanced susceptibility to both infections. Cytokine array profiling showed enhanced pro-inflammatory cytokine profiles in response to NTHi and RSV infections in ALI cells resulting in an ability to manage infections compared to monolayer cultures. Expression analysis indicated that both infections altered the transcription of a number of pro-inflammatory genes. Neutrophil products and trypsin were shown to degrade PLUNC proteins in ALI cell secretions. NTHi also appeared to cause degradation of PLUNC proteins suggesting that infection may impair the innate defence shield of the airway epithelium. Our data showed that differential ALI cultures of human airway cells are a useful model for the study of respiratory pathogens.