The research in this thesis is centred on the synthesis of novel organic molecules of intrinsic microporosity (OMIMs), dendrimers of intrinsic microporosity (DIMs) and sulfur-based polymers of intrinsic microporosity (sPIMs). OMIMs are a new class of discretely amorphous microporous materials, synthesised by the combination of functionalised cores and termini that share awkward molecular geometries exploited to generate microporosity in polymers of intrinsic microporosity (PIMs). OMIMs presented in this thesis are prepared by the combination of fluorinated biphenyl or terphenyl cores with dihydroxy (catechol) based benzene, naphthalene or triptycene termini. Through a systematic study of substituted termini, a structure-property relationship is established and applied to generate highly soluble OMIMs possessing apparent BET surface areas within the range of 7 – 726 m2 g-1, as measured by nitrogen sorption at 77 K. The second section on DIMs is an expansion of the work on OMIMs. By isolating tri-substituted biphenyl cores (branch units), first generation dendrimers are afforded by the reaction of a branch unit with a suitably functionalised core. DIMs in this thesis centre around the 9,10-diethyltriptycene-2,3,6,7,13,14-hexaol core, and give rise to apparent BET surface areas within the range of 300 – 722 m2 g-1, as measured by nitrogen sorption at 77 K. The final section of this thesis focuses around the monomer synthesis and subsequent polymerisations of three spirobisindane based sPIMs (sPIM-0, sPIM-1 and sPIM-2). Whereas typical PIMs exploit catechol containing monomers to generate dibenzodioxane containing polymers, sPIMs employ dithiol containing monomers to generate thianthrene containing polymers. These thianthrene units could lead to enhanced gas separation properties of the polymer before or after post-polymerisation oxidation to sulfones or sulfoxides. All three sPIMs were found to be microporous, possessing apparent BET surface areas within the range 438 – 510 m2 g-1, as measured by nitrogen sorption at 77 K.

This thesis presents an investigation of the hydrogen transfer reactions between dihydrofolate (H2F) and NADPH that are catalysed by the dihydrofolate reductase (DHFR) isolated from Geobacillus stearothermophilus (BsDHFR) as well as an artificial hybrid originating from the DHFRs from mesophilic Escherichia coli (EcDHFR) and hyperthermophilic Thermotoga maritima (TmDHFR). A broad spectrum of studies, focusing on the relationship between structure, thermostability and kinetics, showed that the catalytic behaviour of BsDHFR is generally similar to other monomeric DHFRs, including ones found in the mesophile Escherichia coli and the psychrophile Moritella profunda, but significantly different from the dimeric TmDHFR. The fact that all monomeric DHFRs display similar catalytic behaviour, regardless of their widely different optimal temperatures, suggests that thermostability does not directly relate to catalytic efficiency. The biophysical differences between monomeric DHFRs and TmDHFR are likely derived from the dimeric nature of the hyperthermophilic enzyme. An artificial dimeric variant of EcDHFR, Xet-3, was prepared by introducing residues at the dimer interface of TmDHFR. While thermostability of this variant is enhanced, it showed a great decrease in its steady-state and pre-steady-state rate constants. Given that the corresponding rate constants did not increase when the loops are released in the monomeric variant of TmDHFR, the lowered catalytic ability in Xet-3 is likely a consequence of geometric distortion of the active site and loss of loop flexibility that is catalytically important in EcDHFR. In contrast, the relatively poor activity of TmDHFR is not simply a consequence of reduced loop flexibility; the dimer interface of TmDHFR plays a rather complicated role in catalysis.

Two projects are involved in this thesis; both of them are about the synthesis and applications of new poly(alkylene sulfide)s. The objective of the first project is the development of new polymeric borane reagents. The goal of second project is to introduce a new strategy for the synthesis of novel photochromic poly(alkylene sulfide)s. Chapter One Chapter One is an introductory chapter about borane chemistry. It involves a definition of the borane reagents, their uses in the most important applications and their development. Generally, this chapter shows the importance of borane reagents and the needs to develop convenient ones. Chapter Two Chapter Two includes a brief introduction about methods of synthesis of poly(alkylene sulfide)s. It shows how by following the most convenient procedure a number of poly(alkylene sulfide)s have been produced and from those polymers a couple of borane complexes were prepared. It also shows the stability, uses in different applications (reduction, hydroboration-oxidation and more sophisticated reaction) and the recycling of the polymeric material. In this chapter we report new poly(propylene sulfide)–borane complexes as convenient and versatile reagents for organic synthesis. Chapter Three Chapter Three is about photochromism and diarylethenes. It shows the reported synthetic strategies for the production of diarylperfluorocyclopentenes and their uses in the production of the different types of photochromic polymers which are very interesting materials that are used in a wide range of advanced applications. Chapter Four Chapter Four describes our attempt to develop a new route for the production of poly(alkylene sulfide)s bearing photochromic units. It shows the synthesis of a novel photochromic diarylperfluorocyclopentene aldehyde and the use of such material in the production of a model that resembles the target polymers. The synthesis of a novel photochromic oligomeric material is presented in this chapter.

The calcium activated cysteine protease calpain-I has a pivotal role in a variety of physiological processes within the human body. In particular calpain-I enables the cell spreading and subsequent chemotaxis behaviour of neutrophils in response to tissue damage. Neutrophils are linked to the pathological condition rheumatoid arthritis and so calpain-I is considered be a valuable therapeutic target. Many inhibitors of calpain-I are highly non-selective with the exception of two small molecule synthetic inhibitors. A phenyl and an indole-based α-mercaptoacrylic acid have shown a slight selectivity towards calpain-I over other cysteine proteases. In this work 24 novel monohalogenated α-mercaptoacrylic acid inhibitors were prepared based on these lead structures using Vilsmeier-Haack chemistry followed by Knoevenagel condensation of the resulting aromatic aldehydes as key steps. The thiols within the α-mercaptoacrylic acid moiety demonstrated a tendency to form disulfide bridges in solution. Analysis of this disulfide formation through 1H NMR spectroscopy, UV-Vis spectrophotometry and HPLC showed that the monomeric form was active under the reducing conditions used in subsequent assays. The analogues were tested as inhibitors of calpain-I revealing that bromoindole based inhibitors were the most potent. Selected compounds showed ~10 fold selectivity towards calpain-I versus calpain-II. In live neutrophils they were capable of slowing the cell spreading process by up to 70%. When live neutrophils containing the inhibitor were irradiated with 410 nm light, the cells completely lost the ability to spread. To show that these compounds were allosteric inhibitors the calcium binding domain PEF(S) was expressed in E. coli and purified using anion exchange chromatography and size exclusion chromatography. Solution of X-ray co-crystal structures of the calpain PEF(S) domain with two different inhibitors revealed that they bind to the protein in a similar fashion as an α-helical domain of calpastatin, the endogenous inhibitor of calpain.

No description available.

Polarization is an often - neglected term in molecular modelling, and this is particularly the case in docking. However, the growing interest in fragment - based drug design, coupled with the small size of fragments that makes them amenable to quantum mechanical treatment, has created new opportunities for including polarization, anisotropic electrostatics and realistic repulsion potentials in docking. We have shown that polarization implemented as induced charges can offer in the region of a 10-15% improvement in native docking results, as judged by the percentage of poses within a rather tight threshold of 0.5 or 1.0 Å, where accurate prediction of binding interactions, are more likely. This is a significant improvement given the quality of current commercial docking programs (such as Glide use d here). This improvement is most apparent when the correct pose is known a priori, so that the extent of polarization is correctly modelled, and scoring is based on force - fields that do not scale the electrostatics. The introduction of specific active - sit e water molecules was shown to have a far greater effect than the polarization, probably because of the introduction of 3 additional full charges, rather than introduction of smaller charge perturbations. With active site waters , polarization is more likely to improve the docking when the water molecule is carefully orientated using quantum mechanical/molecular mechanics (QM/MM) methods. The placement of such water molecules is a matter of great current interest; we have shown that the water molecule can be placed with some degree of reliability simply by docking with the ligand present, provided that the water makes good hydrogen bonding interactions (these are the very conditions under which it is desirable to include the specific active-site water). Anisotropic electrostatics and exponential repulsion for rigid fragments was investigated using Orient and compared to QM/MM methods, all methods merited further research. The general hierarchy is that native docking using Glide (with polarization) > QM/MM (with MM polarization)> Orient-based methods. Thus, we expanded the Glide (with polarization) dataset to include more realistic crossdocking experiments on over 5000 structures. RMSD analysis resulted in many examples of clear improvement for including polarization.

No description available.

Conjugated polymers for application in optoelectronic devices have been an increasingly popular topic of research over the past two decades, with photovoltaic devices incorporating conjugated polymers now nearing large-scale commercialisation. This work focuses on the structure-property relationships of conjugated polymers. Firstly, the difference in backbone structure between an alternating copolymer and its statistical counterpart are investigated, the differences in backbone sequence is elucidated by kinetic and microscopic techniques. The resulting polymers are found to be more gradient or block-like and form better BHJ blends with the PC61BM acceptor and have deeper HOMOs resulting in the observed increase in PCE. Subsequently, alterations to the catalytic system for the synthesis of statistical copolymer by Stille polycondensation are investigated. Variations in the ligands electronic and steric effects are shown to have a profound effect on the relative rates of monomer conversion. Changing the catalyst directly effects the backbone sequence of the polymer. Polymers synthesised using various catalysts are investigated and their optoelectronic and morphological properties are discussed related to the monomer sequence. Finally, well-defined all-conjugated block copolymers are investigated. Electron deficient PTBT and electron rich PTBnDT blocks are synthesised and characterised. Each of the homoblocks demonstrate distinctly different miscibility and film morphology with the PC61BM electron acceptor. When coupled, the resulting block copolymers show signs of micro-phase separation and the viability of block copolymers as a means of domain size control is investigated.

The development of novel efficient catalytic materials to improve the efficiency of industrial processes has been the driving force for many academic and industrial studies. The general approach adopted to enhance the activity of a given catalytic formulation is usually based on enhancing the structural and structural properties (e.g. crystal size and surface area) by adopting new synthesis methods, by supporting the active phase or by modifying the reactivity of the parent materials by adding dopants. However, in a less studied approach, it has been shown that the presence of interstitial species such as carbon or nitrogen can modify the electronic structure of parent metals apparently conferring, in the case of systems such as molybdenum carbide, properties akin to precious metals. This approach allows not just improvement of the catalytic activity in an incremental manner but also the design entirely new catalytic formulations. In this context, the effect of the interstitial elements carbon and nitrogen upon the activity of a range binary and ternary molybdenum based materials for ammonia synthesis and methane cracking has been investigated within this thesis. The performance of Co3Mo3N, Co3Mo3C, and Co6Mo6C for ammonia synthesis has been compared. Depending on the chemical composition, significant difference in catalytic activity was apparent. In contrast to Co3Mo3N, which is active at 400 °C, Co3Mo3C was found to be only active at a reaction temperature of 500 °C. Furthermore, in-situ NPD revealed that the catalytic activity of ternary cobalt molybdenum systems is associated with the presence of N in the 16c Wyckoff crystallographic site. Co6Mo6C was found to be inactive under the conditions tested. The same comparison between the chemical composition and the catalytic activity has been made in the context of methane cracking. Although all the prepared materials (i.e. Co3Mo3N, Co6Mo6N, Co3Mo3C, and Co6Mo6C) displayed catalytic activity, differences as a function of chemical composition were observed. Among the evaluated catalysts, the Co6Mo6N sample showed the highest activity. However, in-situ and post-reaction analysis revealed a significant phase transformation during reaction which explains the differences in terms of catalytic reactivity. In summary, this thesis details a comparison between the catalytic performance of a range of binary and ternary molybdenum based materials presenting different chemical compositions. Particular attention has been directed towards the role of, and the interconversion between, lattice C and N species with the intention of elucidating their influence upon catalytic behaviour.

While ultraviolet (UV) radiation is essential for sustaining life, it can also be destructive for biological systems. In humans, for example, UV radiation initiates production of vitamin D, while also being the primary external source of skin cancer. Despite the skin's melanin providing natural protection against radiative stress, and despite the wide range of commercially available photoprotective lotions, i.e. sunscreens, skin cancer incidence has risen in recent years. The urgent need for more effective sunscreens is, therefore, obvious. However, the sunscreen industry is currently challenged with limited availability of suitable and photostable sunscreen active ingredients. The work presented in this thesis aims to address these challenges by presenting an innovative approach to sunscreen molecular design based on the unique insight provided by laser femtochemistry. The ideal sunscreen should dissipate excess energy via fast, efficient and safe relaxation mechanisms, which typically occur on ultrafast timescales. The studies presented in this thesis focus on two categories of sunscreens, the cinnamates and the anthranilates, and employ ultrafast laser spectroscopy techniques to map and understand the photoprotection mechanisms that afford these sunscreens their photoprotective capabilities. As such, this thesis constitutes a significant contribution to the field of research whose primary concern is to unveil the mechanisms of action of photoprotection in sun screen molecules: the results reported have identified key photophysical photoprotective mechanisms and raised important questions regarding the effects of a sunscreen molecule's environment on its photodynamics. Based on the insight provided by the research herein presented, a rationale for sun screen molecular design may be developed for which the molecular structure of sunscreen active ingredients can be manipulated in order to either enhance the desired energy redistribution mechanisms or hinder any relaxation pathways that may lead to harmful side photochemistry. In reaching its full potential, this innovative approach to sunscreen development has the potential to create a new generation of high-performance sunscreens to be incorporated in commercial sunscreen formulations, in an attempt to disrupt the rise in skin cancer incidence.