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Modern synthetic chemistry is unimaginable without transition metal catalysis. Yet the often high cost, toxicity and scarcity of many transition metals is driving attempts to find sustainable alternatives. Thus, the development of catalytic processes using main-group catalysts is now of broad interest. This thesis reports the development of a facile protocol for the aluminium-catalysed hydroboration of alkynes, alkenes and polar bonds using commercially-available catalysts. The catalytic hydroboration is proposed to occur by hydroalumination followed by product release through σ-bond metathesis with pinacol borane. An alternative route to alkenyl boranes is the 1,1-carboboration of alkynes using stoichiometric B(C6F5)3. A zwitterionic intermediate in the Piers' borane-catalysed hydroboration and 1,1-carboboration of alkynes with B(C6F5)3 has been characterised and its divergent reactivity identified. This has led to the development of a B(C6F5)3 - catalysed hydroboration of alkynes using HBpin.

Surface-enhanced Raman scattering (SERS) spectroscopy is a powerful analytical technique for ultrasensitive detection of chemicals and biomolecules. As the high sensitivity of SERS requires analytes to be in close contact with a plasmonic substrate, the detectionof analyte molecules with low chemical affinity towards the substrate is thus limited. Cucurbit[n]uril (CB[n]) exhibits strong and selective encapsulation of various guest molecules into its barrel-shaped cavity. In addition, it can function as a precise rigid spacer between metallic nanoparticles (NPs). The larger homologue CB[8] can simultaneously sequester two guest molecules to form ternary complexes, allowing for tailoring of the chemical environment of its cavity to trap specific analytes. CB[n] aggregated metallic NPs provide a powerful platform for the detection of a wide variety of molecules. However, the colloidal instability of this system requires the measurement to be finished within 60 min after the preparation of the substrate. In addition, in situ measurements may involve environments that affect such self-assembly processes. For example, the possible displacement of analytes in the nanogap by non-analyte moieties can give rise to fluctuating backgrounds. Therefore, a SERS substrate that can provide the same levels of detection and functionality but eliminates the need for aggregation is of great demand. This thesis mainly focuses on the preparation and characterisation of CB[n]-engineered nanostructures as SERS substrates with great colloidal stability, high SERS enhancements and sensitivities. Other applications of the prepared nanostructures such as peptide separation and high-performance catalysis are also discussed. In the first chapter, the historical development and the remaining challenges in the field of SERS are discussed. Three types of the most commonly used SERS substrates are introduced, followed by the introduction of rationally designed nanoplatforms for molecules with low chemical affinity towards metallic surfaces. In addition, CB[n] host guest complexation, examples of CB[n]-engineered nanostructures and the application of these nanostructures in SERS sensing are also discussed. The second chapter demonstrates the preparation of surface-bound CB[8] catenanes on silica NPs, where CB[8] is employed as a tethered supramolecular "receptor" to selectively capture target guest molecules. More specifically, CB[8] is threaded onto a methyl viologen (MV2+) axle and immobilised onto silica NPs with a surface density up to 0.56 nm$^{−2}$. Its use as an efficient and recyclable nanoplatform for peptide separation is demonstrated. The peptides captured by the catenanes can be released by reversible single-electron reduction of MV$^{2+}$. The entire process demonstrates high recoverability. Continued in the third chapter, a highly stable free-standing molecular sensor that exploits a catenane-engineered nanostructure is described. CB[8] is tethered onto spiky γ-Fe2O3@Au NPs in a similar approach, to collect target analytes from aqueous media. These target analytes can be detected with high sensitivities, on account of the high SERS enhancement (on the order of 10$^{8}$) of the spiky NPs. This CB[8] catenane-based molecular sensor provides a powerful SERS substrate that shows great promise in the detection of versatile chemicals, biomolecules, controlled substances and auxiliary diagnostics of various diseases. The fourth chapter introduces a facile preparation of monodispersed γ-Fe2O3@Au magnetic nanoraspberry NPs using a one-pot seeded growth method. The obtained nanoraspberry NPs show excellent colloidal stability and high SERS enhancement factors (on the order of 10$^{10}$). By immobilising a dense layer of CB[n]s onto the surface of nanoraspberry NPs, a new type of CB/Au NP SERS substrate is obtained. CB[n]s are located perpendicularly to the NP surface and their cavity maintain the capability to sequester guest molecules from aqueous media. More versatile molecules (both electron rich and electron deficient molecules) can thus be detected with high sensitivities. We envisage that this nanoraspberry-based molecular sensor will provide a powerful platform for SERS detection in various fields, such as chemical and biomolecule analysis, illegal drug detectionand pre-clinical/clinical diagnosis. The fifth chapter focuses on the preparation of CB[7]-based catalytic microreactors, where metallic NPs are immobilised onto microchannels via supramolecular interaction of methyl viologen@CB[7]. This microreactor exhibits remarkable catalytic activity on account of the high surface area to volume ratio of the microchannels and metallic NPs. Superior to most conventional heterogeneous catalytic reactions, separation post reaction and complicated recycling steps of the catalysts are not required. Moreover, CB[7] can complex a variety of metallic NPs onto its portal (e.g. gold, silver, palladium, quantum dot), providing a multifunctional in situ catalysis platform. In the end, a concluding chapter summarises the presented work, also giving a brief outlook of the potential future work.

Aliphatic polyesters prepared by the ring opening polymerization of lactones and lactides, are versatile polymers having good hydrolyzability, mechanical properties and biocompatibility. These characteristics make them a leading material in biomedical and pharmaceutical industries as a resorbable implant and a vehicle for controlled drug delivery. An extensive research effort has been made to develop new initiators, catalysts for the ring opening polymerization of cyclic esters. Many effective initiators based on alkali metals, metal oxides have been developed for anionic polymerization of lactones. The main objectives of this project were to develop a novel catalyst by utilizing fully biocompatible and non-toxic reagents for the synthesis of polycaprolactone (PCL) by ring opening polymerization of cyclic esters at reasonably low temperature and a synthesis of hybrid silica nano-composite for biomedical applications and its characterization. Silica and dry calcium hydride reagents were used to successfully prepare heterogeneous catalysts for the ring opening polymerization of cyclic ester monomer å-caprolactone at reasonably low temperature of 100 oC. Two kinds of catalyst were prepared with non-functionalized and silane functionalized silica. The GP silane functionalized silica catalyst showed higher activity and higher product yield as compared to non-functionalized catalyst during polymerization at the same temperature. The in-situ polymerization kinetics of both reactions was studied using Raman spectroscopy. A silica based nano-composite was also synthesized which has a potential application in bone tissue engineering and possible drug delivery. The synthesized polyester and hybrid silica nano-composite were characterized with different analytical techniques to confirm required product formation.

Chemotherapeutics are potent molecules capable of systematically treating cancer. As healthy tissues contain features also inherent to cancer cells, treatment often results in unwanted sideeffect. As chemotherapeutic side-effect produces significant harm and often limits optimal drug dosing, new strategies must be developed to improve treatment selectivity. A prodrug strategy provides one option to improve the selectivity of an established chemotherapeutic. By modifying a pharmaceutically active drug, interaction with biology may be functionally masked. Subsequent ‘un-masking’ the prodrug exclusively at the intended treatment site may direct treatment only to where the anticancer effect is required. This thesis progresses the novel approach of bioorthogonal organometallic (BOOM) prodrug activation. A metal catalyst and masked chemotherapeutic constitute reaction partners to provide a new strategy for intratumoural prodrug activation. Whereby the prodrug and metal catalyst are independently non-cytotoxic, in combination the prodrug undergoes catalytic activation to deliver an anticancer affect. By positioning the metal catalyst within a tumour (i.e. by microsurgery), an administered masked prodrug sensitive to catalyst-mediated activation could allow for ‘targeted’ chemotherapy localised to the tumour site. The design, synthesis and study of new BOOM prodrug candidates are reported herein. Novel protecting groups are developed to enhance drug masking to biology and subsequent catalyst-mediated activation. Prodrug screening studies are carried out in cancer cell culture models, with zebrafish and in ex vivo rodent model tumour explants. The catalyst, a palladium (Pd0) functionalised bead system, is optimised for enhanced activation, drug release and in vivo implantation. The potentially infinite generation of active chemotherapeutics exclusively in tumour would increase the efficacy of treatment whilst reducing harmful effect on healthy tissue.

The goal of this research was to develop alternate economic routes for the synthesis of functionalised triarylphosphines. Such species are employed as catalysts ligands in chemical synthesis and can be incorporated into designed-ylides for olefination reactions. The synthesis of the SHOP ligand, the key constituent of the Shell Higher Olefins Process for making linear alpha olefins via ethylene oligomerisation and olefin metathesis, is described using four totally new approaches. These include a Directed Ortho Metalation (DOM) approach, Copper iodide catalyzed cross-coupling, Halogen-Magnesium Exchange reaction and Diazonium salt approaches. The efficiency, in terms of overall yield and mild process conditions, make some of the routes potentially commercialisable. Additionally, a series of ortho-substitued triarylphosphines were derived to probe and modulate the reactivity of the Wittig reaction. We report that non-stabilized ortho-P-alkoxy-substituted ylides react with aromatic and aliphatic aldehydes providing (E)-olefins with high stereocontrol employing an intramolecular phenoxy and alkoxy substituent to promote (E)-olefination through betaine interconversion. In one particular case; removal of phosphoine oxide was also achieved. Extension of this methodology was also carried out on semi-stabilized benzylic ylides, which are known for producing 1:1 mixtures of (E):(Z) olefins under classical condition. Potential applications of the methodology are also described. / Thesis / Master of Science (MSc)

Yes / This study investigated adsorption kinetics, adsorption equilibrium, and adsorption isotherm of three dyes [i.e., methylene blue (MB), rhodamine-B (RB), and safranin T (ST)] onto polyacrylonitrile (PAN) and ethanolamine (EA) grafted PAN nanofibers (NFs) membranes (EA-g-PAN). The membranes were characterized by field emission scanning electron microscopy (FE-SEM), Fourier-transform infrared spectroscopy (FT-IR) spectroscopy, and Brunauer–Emmet–Teller (BET). FE-SEM showed a smooth morphology for the NFs before and after grafting, while FT-IR confirmed EA grafting into the nitrile group of PAN. The grafting percentage with no change in the physical nature of the membrane was 12.18%. The nitrogen adsorption–desorption isotherms for PAN and EA-g-PAN NFs membranes were similar and classified as a Type IV according to the International Union of Pure and Applied Chemistry. The surface area, pore-volume, and pore size of the EA-g-PAN increased to 21.36 m2 g−1, 0.16 cm3 g−1, and 304.93 Å, respectively. The pores were cylindrical mesopores with bimodal openings, which means that pores were open at both ends. The adsorption of the MB, RB, and ST dyes onto the PAN and EA-g-PAN NFs membranes leveled off at ~ 60 min. The adsorption kinetics showed good fitting to pseudo-second-order kinetic model and multi-step diffusion process. The order of the dye adsorption was PAN / the Deanship of Scientific Research, King Saud University [RG-1440-060]

The overall aim of this project was to study 'functionalised' calcium carbonates (FCCs) for use as a carrier for the controlled release of 'actives,' by permeation and diffusion, and is being proposed as an environmentally friendly and non-toxic pharmaceutical excipient, nutraceutical, and flavour carrier. The delivery of a drug to its target site in the appropriate amount and time-frame in order for it to have a controlled release effect whilst achieving the maximum therapeutic effect remains a topic of design and development for novel drug delivery systems. FCCs encompass a family of new pharmaceutical excipients in which the conditions of manufacture follow strict process regulations with respect to the grade of reagents that are employed and the microbiological environment under which they are produced, and include freedom from organic polymers. Adjustments to the FCC production process can be used to produce a wide range of different morphologies, and raise the possibility of tailoring the void structures of the particles to provide controlled release delivery vehicles for actives across many fields, including drugs and flavours. However, such tailoring can only be fully optimised by a fundamental characterisation of the way in which a drug, loaded into an FCC, then flows and diffuses out over a period of time to provide the delayed release. It was found that adsorption on the FCC surface is selective, for example, saccharin does not become adsorbed from 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES) buffer solution, and neither does anethole from ethanol. FCC also does not adsorb the cationic probe benzyltrimethylammonium bromide (BTMAB) or the anionic probe sodium 2-naphthalenesulphonate (Na2NS). However, it was found that vanillin adsorbs onto the FCC in an amount of 2.00 ± 0.59 mg g^-1. Aspirin and vanillin adsorption from ethanolic solutions with various additions of water onto FCC TP was investigated and fitted with the Tóth isotherm. It was estimated that vanillin adsorbed onto around 17 %, and aspirin onto around 39 %, of the overall FCC TP surface area without the addition of any water. An equation was formulated in order to approximate the adsorption as a function of the FCC's surface coverage by the water. This is discussed in Chapter 4 and has also been published in a peer-reviewed academic journal (Levy et al., 2017). Chapter 5 discusses the preliminary steps of the loading of vanillin and saccharin into FCC, and the results were inconclusive for a majority of samples, concluding that the loading and analysis methods need refining. The modelling of the diffusion profiles of vanillin loaded FCC S07 and S10 was successful, and resulted in diffusion coefficients of 231.9 x 10^-16 m^2 s^-1 and 248.44 x 10^-16 m^ s^-1, respectively. This is outlined in Chapter 6. Chapter 7 describes the 'zero length column' (ZLC) technique, which was used as a way to characterise the diffusivity of the intraparticle pores of each FCC grade. However, it was established that there are many experimental artefacts present with such a method. This work outlines the development of the novel 'finite length column' (FLC), which was developed as a means to overcome the limitations of the ZLC (Levy et al., 2015). Effective diffusivity coefficients in the long-term region of the diffusion curves of the FCC samples range from 1.06-106 x 10 ^-16 m ^2 s^-1. The FLC was then used in preliminary trials to dilute FCC with an inert solid in order to further refine the ZLC technique, and is discussed in Chapter 8. Two mathematical methods were also developed to aid in the refinement. The reported effective diffusivity coefficient for FCC 03 in the long-term region of the diffusion curve is 49.5 x 10^-16 m^2 s^-1. In conclusion, this work confirms that FCC has potential for use as a carrier for the controlled release of 'actives' by diffusion. The utilisation of mathematical modelling in conjunction with experimental methods in the study of drug release and delivery is steadily increasing due to its enormous future potential; it will enable the optimisation of novel dosage forms and the elucidation of release mechanisms at a major reduction in cost and time compared with the number of experimental studies required to do so.

Tumour necrosis factor-stimulated gene-6 (TSG-6) is a protein expressed in a wide range of cell types and tissues, predominantly in response to inflammatory stimuli. The expression of TSG-6 is believed to be associated with the protection of tissues from the damaging effects of inflammation. In animal models treatment with TSG-6 protein has been found to reduce inflammatory damage in myocardial infarction, corneal injury and arthritis. Endogenous TSG-6 production has been suggested to play a protective role in inflammatory arthritis and has been implicated in bone homeostasis. The expression of TSG-6 is also essential in the process of cumulus matrix formation that occurs around the oocyte in the periovulatory period and is necessary for successful ovulation and fertilisation. In many cases the mechanism underlying a particular TSG-6 function is not fully understood. TSG-6 has numerous binding partners including the serum glycoprotein inter-alpha-inhibitor (IαI), the growth factor bone morphogenetic protein-2 (BMP-2) and the extracellular matrix protein fibronectin, as well as glycosaminoglycans (GAGs) such as hyaluronan and heparan sulphate (HS). The TSG-6 protein is mostly composed of contiguous Link and CUB domains, with the majority of ligand binding sites identified within the Link module. The CUB domain of TSG-6 has been less extensively studied. Here biophysical techniques have been used to investigate the TSG-6 interactome including both the Link module and CUB domain. Intrinsic fluorescence spectroscopy was used to establish the metal-ion binding properties of the CUB domain, which was established to have a high affinity Ca2+-binding site. Using surface plasmon resonance (SPR), a novel metal-ion dependent interaction was found for the CUB domain of TSG-6 and the heavy chains (HCs) of IαI. Investigation using mutants of both the CUB domain of TSG-6 and HC of IαI established that the metal-ion binding sites within each protein are involved in the interaction. SPR analysis was also used to define the affinities and binding sites for TSG-6 interactions with fibronectin and BMP-2. High affinity interactions between TSG-6 ligands were also revealed (e.g. BMP-2 and HC, fibronectin and HC) and their binding sites defined. The discovery of the novel interactions between these TSG-6 ligands suggests crosstalk within the TSG-6 interactome, with the potential for ternary complex formation or indeed hierarchical orders of binding. Thus work was undertaken to develop a passivated lipid bilayer platform for use with surface sensitive techniques. This platform was used to investigate the hierarchy of protein and GAG interactions using quartz crystal microbalance with dissipation monitoring (QCM-D) and dual polarisation interferometry (DPI). The investigation revealed a novel role for the Link module of TSG-6 in heparin condensation, potentially via protein dimerisation and/or oligomerisation which could affect heparin/HS functions within the extracellular matrix (ECM). Thus the biophysical analysis of TSG-6 presented here has identified novel interactions and functions of TSG-6 which may provide mechanisms for the protective functioning of TSG-6 in inflammation and its ECM structuring role in ovulation.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-23T12:13:09Z No. of bitstreams: 2 Dissertação - Eli José Miranda Ribeiro Júnior - 2015.pdf: 709119 bytes, checksum: baa5cef4451e6bd53886e3cc249f19df (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-23T12:15:43Z (GMT) No. of bitstreams: 2 Dissertação - Eli José Miranda Ribeiro Júnior - 2015.pdf: 709119 bytes, checksum: baa5cef4451e6bd53886e3cc249f19df (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-10-23T12:15:43Z (GMT). No. of bitstreams: 2 Dissertação - Eli José Miranda Ribeiro Júnior - 2015.pdf: 709119 bytes, checksum: baa5cef4451e6bd53886e3cc249f19df (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-01-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Laccase is a poliphenoloxidase enzyme that catalyzes the oxidation of phenolic compounds in the corresponding quinones. The current obtained in this redox process can be used for quantitative analysis. In this work, a carbon paste biosensor modified gluteraldehyde functionalized silica and an enzymatic extract of the “Pycnoporus sanguineus” fungi as a lacase source is proposed for phenol determination. The effect of carbon paste and electrolyte composition, pH from 3,0 to 8,0, start potential from 0,55 to 0,25mV, scan rate from 5 to 25 mV s-1 and potential pulse amplitude from 10 to 60mV on the differential pulse voltammetric response was investigated. A linear correlation of R² = 0,9946 was obtained for the phenol content (catechol) in the concentration range from 50 to 500nMol L-1, with a detection limit of 30nMol L-1. This biosensor was used for the determination of different kinds of phenolic compounds, presenting a better response for catechol. / A lacase é uma enzima poliphenoloxidase que catalisa a oxidação de compostos fenólicos nas correspondentes quinonas. A corrente obtida neste processo redox pode ser usada para a análise quantitativa da concentração dos fenóis na água. Neste trabalho, é proposto o uso de um biossensor modificado para a determinação de fenol. O biossensor de pasta de carbono com sílica funcionalizada foi modificado com glutaraldeído e um extrato enzimático de fungos “Pycnoporus sanguineus” como uma fonte de lacase. O efeito da pasta de carbono e da composição de electrólito, permite trabalhar com pH compreendido entre 3,0 - 8,0, e um potencial inicial entre 0,55 - 0,25mV. A velocidade de varrimento foi de 5 a 25mV s-1 e amplitude de pulso de 10 a 60mV, estudando-se na resposta voltamétrica de pulso diferencial .Uma correlação linear de R2 = 0,9946 foi obtida para o teor de fenol (catecol) na gama de concentrações de 50 a 500nMol L-1, com um limite de detecção de 30nMol L-1. Este biossensor foi utilizado para a determinação de diferentes tipos de compostos fenólicos, apresentando uma melhor resposta para o catecol.