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The general title given to this thesis represents the underlying ethos of my work that links most parts together, as well as being the motivation I now have for future work. The main scientific concern I present within is a more specific evolutionary theory on what has happened in land plants to a well known Calcium cell-signalling pathway found in mammals. Namely the Inositol triphosphate mediated Calcium release of ITPR channels in mammalian neural and muscle cells. This is discussed at length in Part ii, Chapters 2-3 of this thesis. Chapter 3 contains a detailed discussion surrounding an already known and characterised Calcium channel (TPC1) in Arabidopsis thaliana that was found to be related albeit very distantly to ITPR channels. Additional partner regulatory proteins are introduced and some justification is made that they interact directly with TPCl providing it with regulated gated activity specifically in guard cells. During the development of the theory presented in Part ii it became essential to understand the location and function of disordered protein regions in sequences over many species and genes, This lead to the production of a Database of Disordered Protein Predictions (D2P2 described in Part iii, as well as methods for visualizing multiple classes of protein annotations such as structural domains, post- translational modification sites, and regions of protein disorder that fold on contact, In Chapter 5 discussion surrounding major results from producing D2P2 and its implications on the evolution of disordered protein state are presented. Finally in Part iv I introduce some relatively unrelated work investigating the domain content of a new genome being sequenced at the King Abdullha University of Science and Technology for the Dinoflagellate species Symbiodinium microadriaticum. One of my main tasks in this collaboration was to identify proteins that mediate many endosymbiotic relationships carried out by Symbiodinium. Finding an example of a superfamily only found in a single clade of bacteria I identify a plausible target protein and mechanism for eluding Toll-like Receptors of host species. In the concluding Part v I summarise pieces of work that I have yet to finish, but include here to give some impression of the sorts of work I have been thinking about and hope to one day complete.

This thesis describes investigations into the use of tandem Prins Friedel-Crafts reactions to prepare the tricyclic core of natural products such as epicalyxin J and calyxin J. Model studies revealed that reaction of homoallylic alcohol 155 with anisaldehyde in the presence of TMSOTf gave the required tandem Prins Friedel-Crafts product 168 in modest yield (25%) along with further products including 172 formed via an oxonia-Cope rearrangement. Efforts to optimise the reaction by varying temperature, solvent and Lewis acid always led to complex mixtures. We propose that the ether oxygen in substrates such as 155 may be linked to the formation of the plethora of products. This hypothesis is supported by results of cyclisation studies with homoallylic acetals 25 and 273; with the phenethyl containing substrate 25 the tricyclic product 26 was isolated in 56% yield whereas with the ether side-chain 273, triflate 274 was the major product. Interestingly reaction of enol ether 300 with TMSOTf gave the novel product 301 which was we propose was formed via a neighbouring group participation of the ester group and cleavage of the methylene carbon-oxygen bond of the ether.

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This thesis is concerned with the synthesis of new anion receptors and describes the anion binding and anion transport properties of these compounds Ten squaramide receptors (A) based on a steroidal cholapod backbone have been synthesised. Association constants for the squaramide receptors with chloride anions were assessed in chloroform and were found to be exceptionally high, up to 1.2 x 1014 M-1 , and in most cases were higher than that of all chloride receptors previously published by the A. P. Davis group. The introduction of electron withdrawing aromatic groups led to increased association constants, as did the introduction of an additional hydrogen bond donor at position Z. The chloride transport properties of the squaramide receptors were also studied, however rates were disappointing. Six receptors based on a trans-decalin scaffold (B) have also been synthesised. These receptors feature two thiourea binding groups and have alkyl chains of varying lengths on the aromatic rings. Association constants of the decalin receptors for chloride were measured in DMSO-d6/O.5% H20 and in chloroform, and were found to be almost identical for each receptor. The chloride transport properties of the decalin receptors were also studied and it was found that as the length of the alkyl substituent R was increased, transport rates also increased up until R = n-hexyl, after which further increasing the length of the alkyl substituent caused transport rates to decrease. Some progress has also been made towards the synthesis of a novel tricyclic receptor (C).

The body of research in this thesis investigates the use of the Gallagher 3rd generation synthesis to make cytisine (i) and core variants of cytisine (ii) and (iii). A crucial step in the synthesis is the reduction of the lactam carbonyl, which can either be attempted before or after cyclisation. It was found that attempts to reduce the lactam carbonyl after cyclisation (iv) were unsuccessful, whereas reduction before cyclisation (v) was not reproducible. Alternative methodology to allow for the synthesis of a wider range of variants using a-arylation was developed. It was shown that the conditions used needed to be tailored to the system, making test systems not representative. By using a reduced number of equivalents of bromide in the reaction, diarylation, the main by-product isolated from a-arylation, could be supressed and only monoarylation (vi) was observed.

This thesis describes synthetic approaches directed towards the synthesis of the alkaloid natural products nitensidine D 213 and nitensidine E 214. The structurally less complex metabolite nitensidine D was prepared by the guanylation of commercially available geranylamine 254 whilst four synthetic approaches were attempted to prepare nitensidine E. Initially the 6-membered guanidines 225a-b, 256 and 257 were prepared via an iodocyclisation of the corresponding allylic 226a-b and homoallylic guanidines 255, whilst the guanidines 265a-b were prepared via a DMDO mediated epoxidation and acid catalysed cyclisation/ rearrangement reaction. Attempts to convert these to the desired metabolite were unsuccessful. FinallYl the cyclic guanidine 283 was prepared from the allylic acetate 281 via a palladium π-allyl cyclisation.

Macroalgal phlorotannins and peptides are increasingly being investigated for their health-promoting properties; however in-depth research into the occurrence, bioactivity, profiling and molecular properties of these components in Irish species is limited. The process by which bioactives are extracted and purified from their original biomass must be efficient and food-friendly to be applicable to the food industry. Two different extraction methods, solid-liquid extraction (SLE) and pressurised liquid extraction (PLE), were compared for the extraction of polyphenols from three brown macroalgae, Ascophyllum nodosum, Pelvetia canaliculata and Fucus spiralis, and a green macroalga, Ulva intestinalis. SLE was deemed to be a more industrially relevant technique for generating food-friendly antioxidant extracts than PLE as it requires less capital investment, is food-safe, and can be scaled up. Molecular weight cut-off (MWCO) fractionation and reverse-phase flash chromatography techniques were employed to enrich the polyphenol content of brown macro algal SLE extracts by removing predominantly sugars from the extracts. Furthermore, the use of bioassay-guided fractionation indicated that the observed antioxidant activities of the extracts could be attributed to the polar, medium-to-high molecular weight phlorotannins. The analytical quality control and standardisation of naturally-sourced functional extracts has become a requirement for their use in the food industry. In this work, a rapid ultra-performance liquid chromatography® (UP LC®) method was presented for the profiling of low molecular weight phlorotannin isomers for polymers up to 16 monomers in length from the three brown species. The predominant size ranges of the phlorotannins found in A. nodosum, P. canaliculata and F. spiralis were 6-11, 6-13 and 4-6 monomers, respectively. The identification of bioactive peptides has been largely unexplored. In this work, various peptides were isolated from a trypsin-digested Ascophyllum nodosum protein extract. A selection of peptides were synthesised and their in vitro antioxidant and antihypertensive activities assayed. The polypeptide EKTGLLNVVETAEKFL displayed the highest renin enzyme inhibition of 56.12 ± 2.66 % and this is the first report of renin inhibitory peptides identified from brown macro algae Computational chemistry may act as a support to natural products experiment, through the provision of data on the molecular properties of individual components and also on potential binding interactions between mixtures of bioactive components. Density functional theory was employed to theoretically determine the radical scavenging potential of various 7-phloroeckol conformers through the calculation of their O-H bond dissociation enthalpies. Furthermore, a molecular dynamics simulation approach was proposed for the investigation of binding interactions between a selected macro algal phlorotannin and a bioactive peptide from A. nodosum.

Intra- and inter-molecular hydrogen bonding greatly affects both physical and chemical properties for a wide variety of important molecules. This study focuses on intramolecular hydrogen bonding in polyhydroxy-1 ,4-naphthoquinones. The little known "bond counting rule", dictates that the global minimum will be comprised of a maximum number of highly stabilizing interactions. Hydrogen bonding was chosen for this work as the energy of the bond is typically 20-40 kJ mol-1, which is larger than computational error, allowing statistically significant energy differences between conformers to be determined. A series of interactions between neighbouring hydroxyl groups and each other, and between hydroxyl groups and neighbouring carbonyl groups were postulated. Quantification of the interaction energies was accomplished using a training set of several hundred unique isomers, allowing a quantitative bond counting rule to be developed. Harmonic vibrational spectroscopic and QTAIM analyses were performed for key interactions to aid in their characterisation as baseline, stabilising or destabilising. The effect of molecular conformation upon the wavelength and absorbance of electronic absorption spectra were also probed, highlighting the need to obtain low-energy conformations. Potential energy hypersurface (PES) for single and pairs of C-O bond rotation(s) not only indicate the presence of stationary points corresponding to maxima, minima and transition structures, but also any rotational barriers and reaction pathways for rotamer interconversion. To aid PES visualization, a set of custom Python-based tools were designed and constructed allowing creation of both graphic and haptic Web3D virtual models for teaching purposes. Increased topological perception and object manipulation were obtained using 3-D rapid prototyped models.

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