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Reactive oxygen species (ROS) and reactive nitrogen species (RNS), saccharide (i.e. monosaccharide, disaccharide and polysaccharide), are continuously generated, transformed and consumed in the living systems. As a consequence of their significant value towards human health in aerobic life, it is very important and has drawn much attention in the chemical and biological sensing of the species. It is our long-standing interest in the recognition of monosaccharide (e.g. glucose) through exploration of various boronate-based fluorescence probes, thus, based on the previous work, we started on the design, synthesis and evaluation of novel fluorescent chemosensors for breakthrough discoveries in the detection of saccharide and ROS selectively and specifically, which are made up of different receptors and diverse singaling fluorophores, e.g. anthracene, coumarin, fluorescein, naphthalimine. Firstly, “integrated” and “insulated” boronate-based fluorescent probes (2-naphthylboronic acid and N-Methyl-o-(aminomethyl)phenylboronic acid) have been evaluated for the detection of hydrogen peroxide in the presence of saccharides (i.e. D-fructose). In the presence of D-fructose the initial fluorescence intensity of the “insulated” system is much higher and produces a blue visible fluorescence. Based on the experimental observation above in the boronate-based systems (i.e. B-N bond protection), a new water-soluble boronate-based fluorescent probe was designed and evaluated for the detection of peroxynitrite (much stronger oxidant) in the presence of D-fructose. The enhanced fluorescence of probe when bound with D-fructose was switched off in the presence of peroxynitrite. While, other reactive oxygen/nitrogen species led to only slight fluorescence decreases due to protection by the internal N-B interaction. The interaction of probe with D-fructose not only strengthens the fluorescence signal, but also protects the boronic acid to oxidation by other ROS/RNS. Therefore, under conditions generating various ROS/RNS, the boronate-based sugar complex preferentially reacts with peroxynitrite (ONOO−). The sensor displays good “on-off” response towards peroxynitrite both in RAW 264.7 cells and HeLa cells. A new ICT (internal charge transfer) sensing system was developed for the detection of hydrogen peroxide and peroxynitrite. The probe displayed an enhanced fluorescence change when bound with D-fructose due to the prolonged N-B distance. The fluorescence intensity of the probe dropped down both in the detection of H2O2 and ONOO− which was attributed to the oxidation of arylboronic acid even though in the presence of D-fructose. Using the self-assembly of aromatic boronic acids with Alizarin Red S (ARS), we developed a new chemo/biosensor for the selective detection of peroxynitrite. Phenylboronic acid, benzoboroxole and 2-(N, N-dimethylaminomethyl) phenylboronic acid were employed to bind with ARS to form the complex probes. In particular the ARS-NBA system with a high binding affinity can preferably react with peroxynitrite over hydrogen peroxide and hypochlorite due to the protection of the boron via the solvent-insertion B-N interaction. Our simple system produces a visible naked-eye colorimetric change and on-off fluorescence response towards peroxynitrite. By coupling a chemical reaction that leads to an indicator displacement, we have developed a new sensing strategy, referred to herein as RIA (Reaction-based Indicator displacement Assay). Next, we developed a novel class of simple materials for sensing monosaccharides by the functionalization of graphene oxide (GO) with boronate-based fluorescence probes. The composite materials were characterized by atomic force microscopy, Raman spectroscopy, and UV-vis/fluorescence spectroscopy. The strong fluorescence of the fluorescence probes is quenched in the presence of GO through fluorescence resonance energy transfer (FRET). The BA@GO composite sensors formed provide a useful platform for fluorogenic detection of monosaccharides based on the strong affinity between the boronic acid receptor and monosaccharides. The BA@GO composite sensor displayed a “turn-on” fluorescence response with a good linear relationship towards fructose over a range of other saccharides. Next, new water-soluble copper (II) complex fluorescence probes were developed and evaluated for the detection of nitric oxide and nitroxyl in a physiological condition. A significant fluorescence “off-on” response displayed by using the copper (II) complex for the detection of NO and HNO (Na2N2O3 as a donor). Under pathological conditions generating various ROS/RNS, the copper (II) complex fluorescent probe preferentially reacts with NO/HNO over other reactive oxygen species. The dual-analyte recognitions of the simple, sensitive probe were further applied in living cell for the exogenous NO/HNO. In the following work, we synthesised a phosphorous-based compound for the detection of HNO which derived from Angeli’s salt in a biological condition. Significantly, it displayed a high sensitivity and selectivity toward HNO over other various ROS species, especially NO since they have a similar chemical property. The underlying mechanism was attributed to the cleavage of C-O bond induced by Staudinger Ligation.

Glycoproteins have diverse and essential roles within biological systems. They are formed by enzymatic addition of saccharides to proteins during, or shortly after, translation. However, saccharides can also react with proteins non-enzymatically, a process termed glycation, which can cause impaired function and improper folding. Glycated proteins further react to form advanced glycation end-products, which have been implicated in the pathogenesis and progress of many diseases. Due to this pathological effect, glycation has been studied as a potential biomarker of these diseases. Photoaffinity labelling is a technique that is used to investigate the structure, and presence, of biological molecules; a precedent exists for its use in the study of carbohydrates in biological systems. Chapter 1 outlines the background of this thesis exploring previous studies of glycation, its effects, and methods used in recognition and photoaffinity labelling. Chapter 2 details the design and synthesis of a novel photoaffinity probe, and the optimisation of this synthesis. The target molecule was successfully produced and simpler alternatives to the initial synthetic route with similar yields are discussed. In Chapter 3 the use of the photoaffinity probe is studied. Labelling trials were performed on three proteins: human serum albumin (HSA), macrophage migration inhibitory factor (MIF), and casein. Mass spectrometry showed that the experiments with both HSA and MIF were successful, while the procedure appeared to lead to degradation of casein. Additionally, our work into developing techniques for identifying labelled samples is detailed. A diol-doped electrophoresis gel was not successful created, however, staining protein samples in polyacrylamide gel electrophoresis with curcumin showed promise. Chapter 4 explores the electrochemistry of the photoaffinity probe and details the use of the probe in functionalising a fluorine doped tin oxide (FTO) glass electrode. Cyclic voltammograms of Alizarin Red S (ARS), obtained using a treated electrode, suggest that surface functionalisation was successful.

Carbohydrates are known to play a large number of significant roles in various biological and pathological processes such as cancer metastasis and cellular communication. This is because of their ability to bind a wide range of hosts within the human body such as proteins and viruses. Due to these important interactions, carbohydrate sensing has long been a main focus of research. These research strategies have included the use of aptamers, non-covalent interactions, and boronic acid-based receptors. Boronic acid-based sensors are of particular interest due to their selectivity for 1,2- or 1,3-diols. Within these boronic acid-based studies, a large variety of techniques were employed for detection including different fluorescent, electrochemical, polymeric, and colorimetric studies, as well as various surface bound sensors. One type of technique that has rarely been applied is Surface Enhanced Raman Spectroscopy or SERS. This strategy would be beneficial as it provides information about functional groups, which would aid in the identification of the bound sugar. In this thesis, we present work based on the development of a boronic acid-based carbohydrate receptor that will be used to study carbohydrate binding through SERS. The receptor design includes an aryl boronic acid for carbohydrate recognition, a nitrogen atom in close proximity to the boron center to enhance binding, and a terminal thiol for attachment to a metal surface for SERS. This sensor will be used to study the binding of different saccharides for sensing applications.

It is well known that boronic acids can bind with diols and can be further applied as chemosensors for biomolecules such as carbohydrates and dopamine. Carbohydrates are known to mediate a large number of biological and pathological events. Small and macromolecules capable of carbohydrate recognition have great potentials as research tools, diagnostics, vectors for targeted delivery of therapeutic and imaging agents, and therapeutic agents.

Carbohydrates are known to play a large number of significant roles in various biological and pathological processes such as cancer metastasis and cellular communication. This is because of their ability to bind a wide range of hosts within the human body such as proteins and viruses. Due to these important interactions, carbohydrate sensing has long been a main focus of research. These research strategies have included the use of aptamers, non-covalent interactions, and boronic acid-based receptors. Boronic acid-based sensors are of particular interest due to their selectivity for 1,2- or 1,3-diols. Within these boronic acid-based studies, a large variety of techniques were employed for detection including different fluorescent, electrochemical, polymeric, and colorimetric studies, as well as various surface bound sensors. One type of technique that has rarely been applied is Surface Enhanced Raman Spectroscopy or SERS. This strategy would be beneficial as it provides information about functional groups, which would aid in the identification of the bound sugar. In this thesis, we present work based on the development of a boronic acid-based carbohydrate receptor that will be used to study carbohydrate binding through SERS. The receptor design includes an aryl boronic acid for carbohydrate recognition, a nitrogen atom in close proximity to the boron center to enhance binding, and a terminal thiol for attachment to a metal surface for SERS. This sensor will be used to study the binding of different saccharides for sensing applications.

<p> The ability of a never-dried paper web on a paper machine to resist breakage is commonly referred to as paper wet-web strength. Low wet-web strength can lead to frequent breaks which interrupt production and lower paper machine efficiency. Currently, no commercial products provide the function of enhancing wet-web strength. Boronic acid derivatized polyvinylamine (PVAm-PBA) showed high instantaneous wet adhesion to regenerated cellulose membranes. The objective of the research summarized in this thesis was to determine the factors and mechanisms dictating PVAm-PBA adhesion to wet cellulose. In addition, narrowly distributed PVAm microgel was prepared and the wet adhesion of boronate-microgels to cellulose is reported.</p> <p> The phase behavior and surface tension of PVAm-PBA were measured as functions of pH and the degree of PBA substitution. The pH ranges over which phase separation occurred increased with PBA substitution. 150 kDa PVAm-PBA with 4% derivatization phased separated at pH 8.5 to 9.5.The copolymer based on 51 % substitution was insoluble over most of the pH range. The hydrophobicity of copolymers was reflected in the significant lowering of surface tension particularly at high pH. Additionally, fructose, which binds to borate, influenced the titration curves but did not influence surface tension.</p> <p> Pairs of wet, regenerated cellulose films were laminated with PVAm-PBA and the forces required to delaminate the never-dried laminates, were measured as functions of adhesive structure and application conditions. The greatest wet adhesion was obtained with 150 kDa PVAm with 16% of the amines bearing phenylboronic moieties. The pH at which the PVAm-PBA was adsorbed onto the cellulose was the dominant process parameter. The specific role of the phenyl boronic groups was illustrated in two ways: a) replacing the B(OH)2 with OH (i.e. phenol) gave much lower adhesion; and, b) wet adhesion was greatly reduced by the presence of sorbitol which effectively competes with cellulose for boronate binding sites.</p> <p> The interaction of boronate and cellulose was studied. Owing to poor solubility of cellulose, two model polymers: dextran and hydroxyethyl cellulose (HEC) and two saccharides: glucose and cellobiose were measured by boron NMR measurement, tensile extension, fluorescence spectra, viscometer and peeling test methods. In conclusion, carbon-1, 2 diols at one end of cellulose chain can react with boronic acid. By contrast, carbon-2, 3 diols, which are abundant on cellulose chains, cannot react with boronic acid and the other diols, such as carbon-3, 4 diols and carbon-4, 6 diols cannot react with boronic acid. The high adhesion of boronate containing polymers to cellulose membranes was attributed to boronate ester formation with the cellulose end groups on the membrane surfaces. </p> <p> Finally, a simple and effective methodology was demonstrated for the preparation of polyvinylamine microgel with a narrow distribution. Boronate derivatives of PVAm microgels displayed very high wet adhesion to cellulose over a broad pH range.</p> / Thesis / Doctor of Philosophy (PhD)

<p> Synthesis of new biocompatible siloxane surfactants, where hydrophobic siloxanes are modified by biocompatible hydrophilic functional groups (e.g., triethoxysilane (TES), polyethylene glycol (PEO), and carboxylic acid) is a research area of increasing interest. In this research project we have developed a new class of these biocompatible surfactants, based on siloxanes, as the hydrophobic part, and boronic acids as the hydrophilic part. The reasons for choosing boronic acidlboronates as a modifying agents include: their pH sensitivity, biocompatibility, possible interactions with sugars, and because of a broader general utility in synthesis. The promise of these properties combined with the hydrophobicity, flexibility and many other important features of siloxanes encouraged us to initiate these syntheses. </p> <p> We have explored different synthetic strategies to prepare siloxane boronic acid surfactants, including Grignard reactions and metal-catalyzed hydroboration reactions. Nevertheless, the main approach that was investigated is metal-catalyzed hydrosilylation reactions of vinylphenylboronic acid. Two different approaches were developed to prepare the target compounds: (1) metal-catalyzed hydrosilylation using non-protected vinylphenylboronic acid and (2) metal-catalyzed hydrosilylation using protected vinylphenylboronic acid that can be removed under gentle conditions. The protected compounds underwent hydrosilylation smoothly, but led after separation using column chromatography to the unprotected compounds in moderate yield. The conversion of the hydrosilylation of unprotected boronic acids was quite good, but the compounds underwent decomposition during chromatography. Thus, the two approaches are complementary, depending on whether pure molecules are required for further synthetic elaboration, or a mixture of materials is suitable for practical application as surfactants. </p> <p> The amphiphilic nature of these siloxane boronic acid surfactants was studied and the compounds were found to be surface active. The limited solubility of our compounds in H20 prevented us from studying their surface tension properties. However, their solubility in chloroform enabled us to study their interfacial properties. </p> / Thesis / Master of Science (MSc)

In recent years, photoredox catalysis emerged as a privileged tool for small molecules activation via single-electron transfer mechanisms. Despite their ubiquity as reagents in organic synthesis, the use of boronic acid derivatives to generate carbon-centred radicals remains elusive. This dissertation explores the utilisation of photoredox catalysis to generate carbon radicals from boronic acid derivatives and subsequently engage them in C–C cross-coupling reactions. In the first chapter, an introduction to photoredox catalysis and organoboron reagents is provided, as well as a discussion on the key mechanistic aspects of photoredox catalysed C–C cross-coupling reactions. The second chapter presents our initial coupling strategy and how it evolved in understanding that pinacol boronic ester species can be used as a source of carbon radicals via single-electron oxidation from a photoredox catalyst. Coordination of the boronic esters with Lewis basic species was identified as a fundamental activating interaction. The synthetic utility of this discovery was highlighted by performing a wide range of photoredox catalysed arylations of pinacol boronic esters. The third chapter builds on our mechanistic understanding to identify a set of Lewis base catalysts that conveniently activates boronic esters and acids towards single-electron oxidation. The usefulness of this improved set of conditions was demonstrated by alkylating a wide range of boronic acid derivatives. The fourth chapter describes the application of this methodology in synthesising four active pharmaceutical ingredients from the GABA family. An emphasis was made on developing an efficient flow process and “transition metal free” conditions to survey the attractiveness of the method for the pharmaceutical industry. Finally, the fifth chapter describes the experimental procedures relevant to the results described in chapters 2 to 4.

Boronic acids are attractive synthetic intermediates and have been shown to be effective as inhibitors of various enzymes. In this project, the overarching goal is the selective inhibition of a protease present in the mitochondria known as human ClpXP. To study the potential selective inhibition of Human ClpXP using N-terminal peptidic boronic acid, we have designed a synthetic scheme that includes?-borylation of °,?-unsaturated carbonyl compounds using Cu(I) as catalyst, °-alkylation, saponification/hydrogenation, amidation, and oxidative removal of pinacolyl group with sodium periodate. A simple amidoboronic acid was also synthesized for stability studies. This compound, synthesized in 44% overall yield, could be used as a surrogate for N-terminal peptidic boronic acid to provide basic understanding of the stability of more elaborate N-terminal peptidic boronic acids. During the synthesis of this compound, published deprotection methods were not suitable to deprotect the pinacol group. A two-step protocol for pinacolyl boronic ester deprotection via a diethanolamine protected intermediate was successfully developed with the advantages of mild reaction conditions, tolerance to various functional groups, short reaction time and ease of product isolation. The current results will be useful for the deprotection of other boronic esters, such as pinanediol protected compounds, which are being used extensively in stereoselective synthesis. / Master of Science