Dissertations / Theses on the topic 'Organic Chemistry not elsewhere classified'

Bacteria can cause many different types of infections. Virulence factors e.g. adherence proteins, biofilm formation, endotoxins and exotoxins allow invasion by bacteria and cause infections such as respiratory, urinary, and intestinal and blood stream infections. If left untreated they can lead to a condition known as sepsis. Sepsis is a whole body inflammatory response that can be fatal. The aim of this study is to develop biomimetic nanosponges from mammalian erythrocyte ghosts, as a potential treatment for toxin related sepsis.

The design of a novel photoelectrochemical sensor, the micro-optical ring electrode (MORE), is described. Based on a thin-ring microelectrode and using at fibre-optic light guide as the insulating material interior of the ring, the MORE has been deisigned, constructed and developed to permit electrochemical investigation of photochemically generated solution species. Initial characterisation of the electrode behaviour in the dark has been ccomplished by the use of ferricyanide in conjunction with predictive mathematical models of the time dependence of the current at micro ring electrode. The photocharacterisation of the MORE has been achieved looking at the photochemical response of tris (2,2'biyridine)ruthenium(II) in presence of the quenching agent Fe3+ . Subsequent application of the MORE has been in the electrochemical investigation of photoactive drugs employed in Cancer Therapy. In the following study, the microelectrochemistry of methylene blue, a dye commonly employed on Photodynamic Therapy (PDT), has been characterised in the dark using, in the first instance, gold disc microelectrodes. The electrochemical behaviour of MB+ on gold disc microelectrodes has than been compared to the results obtained when using the MORE. Exploration of the photoelectrochemical response of the MORE is reported, achieved via the interrogation of the photoelectrochemistry of MB+. Photocurrent signals obtained during cyclic voltammetric and chronoamperometric studies of MB\ conducted with the MORE under illuminated conditions and in the absence of any deliberately added reducing agent, are attributed to the formation and subsequent detection of 3 MB+ within the diffusion layer of the microring electrode. The data demonstrate that the use of the MORE for direct electrochemical detection of photogenerated species with lifetimes of < 9 x 5 10- s is possible. The electrochemistry of 3MB+ over the applied potential range from -0.4 to +1.0 V versus SCE is elucidated and discussed in the context of the behaviour of photoexcited MB+ in the presence of deliberately added reducing agent Fe3+. In order to investigate the production of singlet oxygen associated with cancer treatment, an attempt was made to study the MB+/02 system. This part of the project has not been completed, however a preliminary study of the electrochemistry of the MB.

This dissertation describes the development of a system for the automated, high-throughput screening of organic reactions. This system utilizes a liquid handling robot for reaction mixture preparation combined with desorption electrospray ionization mass spectrometry (DESI-MS) for reaction mixture analysis. With an analysis speed of ~1 second per reaction mixture, this system is capable of screening thousands of reactions per hour. Reaction mixtures are prepared in 384-well microtiter plates using a liquid handling robot. A sample of each reaction mixture (50 nL) is then transferred to a PTFE coated, glass slide using a pin tool. By offsetting the placement of the pin tool during each transfer, up to 6,144 unique reaction mixtures can be placed on each slide. The slide is then transferred to the DESI stage by a robotic arm, and the DESI-MS analysis begins, taking as little as 7 minutes for 384 reaction mixtures. We utilize a scheduling software to control each component of the system, which automates the entire process from reaction mixture preparation to DESI-MS analysis. In order to efficiently analyze and visualize the extremely large data sets generated by the system, we developed a custom software suite to automatically process each data set. We have used this system to screen several classes of industrially relevant reactions including Suzuki coupling, nucleophilic aromatic substitution, reductive amination, and Sonogashira coupling. We have validated both positive and negative results from the system using flow chemistry, and we have observed excellent agreement between the two methodologies. By being capable of screening thousands of reactions per hour, requiring only microliter quantities of reaction mixtures, and consuming less than a milliliter of solvent during the DESI-MS analysis, this system significantly reduces the time and costs associated with organic reaction screening.

Chemical science spans multiple scales, from a single proton to the collection of proteins that make up a proteome. Throughout my graduate research career, I have developed statistical and machine learning models to better understand chemistry at these different scales, including predicting molecular properties of molecules in analytical and synthetic chemistry to integrating experiments with chemo-proteomic based machine models for drug design. Starting with the proteome, I will discuss repurposing compounds for mental health indications and visualizing the relationships between these disorders. Moving to the cellular level, I will introduce the use of the negative binomial distribution to find biomarkers collected using MS/MS and machine learning models (ML) used to select potent, non-toxic, small molecules for the treatment of castration--resistant prostate cancer (CRPC). For the protein scale, I will introduce CANDOCK, a docking method to rapidly and accurately dock small molecules, an algorithm which was used to create the ML model for CRPC. Next, I will showcase a deep learning model to determine small-molecule functional groups using FTIR and MS spectra. This will be followed by a similar approach used to identify if a small molecule will undergo a diagnostic reaction using mass spectrometry using a chemically interpretable graph-based machine learning method. Finally, I will examine chemistry at the proton level and how quantum mechanics combined with machine learning can be used to understand chemical reactions. I believe that chemical machine learning models have the potential to accelerate several aspects of drug discovery including discovery, process, and analytical chemistry.

Since 1981, HIV/AIDS has affected over 70 million individuals worldwide. Due to the incorporation of Combination Antiretroviral Therapy (cART), this deadly virus has now become a manageable chronic illness with a reduction in mortality and morbidity rates. Combination therapy targets multiple stages of the HIV replication cycle including fusion, entry, reverse transcription, integration, and maturation. The HIV-1 protease enzyme is responsible for cleavage and processing of viral polyproteins into mature enzymes and is a common therapeutic target for inhibition of HIV. To date, there have been many protease inhibitors approved by the FDA and introduced into the market. However, mutations within the protease enzyme has rendered some of these inhibitors ineffective. This has led to an ever-growing need to develop novel protease inhibitors to combat drug resistance through mutations. Described herein is the design, synthesis, and biological evaluation of HIV-1 protease inhibitors featuring a novel hexahydropyrrolofuran (HPF) bicyclic scaffold as a P₂ ligand to target binding interactions with Asp29 and Asp30. The HPF ligand provides a molecular handle that allows for further structure-activity discoveries within the enzyme. The HIV-1 protease inhibitors discussed feature carbamate, carboxamide, and sulfonamide derivatives which displayed good to excellent activity.

Organic nitrogen compounds are important in environmental systems because they are prevalent in natural waters but are also components of polymers within membrane filters that are used for water treatment. In both of these cases, these compounds can be exposed to free chlorine during disinfection, which can trigger a set of reactions that can form a host of different halogenated by-products. When such by-products form during water treatment disinfection, these by-products, known as nitrogen-based disinfection by-products (N-DBPs), can be highly toxic and affect human and ecosystem health. Alternatively, when such reactions occur during membrane filtration, the organic nitrogen compounds, which are embedded within the upper layer polymer structure of the membrane filter, can degrade when free chlorine is applied. Therefore, this research was aimed at exploring the chemistry behind how specific types of organic nitrogen compounds which are found in these applications, such as tertiary amines and amides, react with free chlorine. It particularly focused on assessing the kinetics and by-product formation of these reactions under variable water quality conditions (e.g., pH, halide concentrations, and precursor doses).

More specifically, in the first phase of this work, the roles of tertiary amines in enhancing disinfection by-product (DBP) formation, such as trihalomethanes (THMs) and haloacetic acids (HAAs), during chlorination of aromatic compounds were studied. The results indicated that in synthetic solutions, chloroform (CHCl₃) and trichloroacetic acid (TCAA) were enhanced by up to 20× with tertiary amines at low dose ([tertiary amine]₀ = 0.5×[aromatic compound]₀). The enhancement effect was also dependent on the aromatic compound type, tertiary amine type and dose, and water conditions such as pH and bromide concentrations. Thus, THMs and HAAs were predicted to be enhanced when the aromatic compound reacted with R₃N-X⁺ (X=Br or Cl) and was not outcompeted by aromatic compound or tertiary amine reaction with free chlorine or bromine alone. In the second phase of this work, the reaction kinetics, by-product formation, and overall mechanisms of a polyamide-based monomer with chlorine were evaluated under varying water conditions. The current known mechanism, Orton Rearrangement, was reevaluated, and new mechanisms were proposed, where it was found that N-halogenation and ring halogenation were two independent pathways. The ability to choose either pathway was highly dependent on the water quality condition of the aqueous solution. The roles of different chlorinating/brominating agents were also investigated where certain species-specific rate constants were obtained. For the N-halogenation pathway, only chlorination and no bromination occurred in which the reactivity of the chlorinating agents likely decreased such that ClO^->HOCl. However, for the ring halogenation pathway, both chlorination and bromination occurred in which the reactivity of the chlorinating and brominating agents decreased such that Cl₂ >HOCl, and BrCl > BrOCl > Br₂ > Br₂O > HOBr, respectively. Overall, this study suggests that a number of unique reactions can occur for various types of organic nitrogen compounds which: (i) allow them to affect water quality by enhancing DBP formation, (ii) but, when integrated into a polymer matrix used for water treatment, can induce reactions that lead to permanent structural damage of the polymer. In all cases, the extent of these reactions is strongly governed by the surrounding water matrix.

Approximately 6.3 million bone fractures occur annually in the USA, resulting in considerable morbidity, deterioration in quality of life, loss of productivity and wages, and sometimes death (e.g. hip fractures). Although anabolic and antiresorptive agents have been introduced for treatment of osteoporosis, no systemically-administered drug has been developed to accelerate the fracture healing process. To address this need, we have undertaken to target a bone anabolic agent selectively to fracture surfaces in order to concentrate the drug’s healing power directly on the fracture site. We report here that conjugation of dasatinib to a bone fracture-homing oligopeptide via a releasable linker reduces fractured femur healing times in mice by ~60% without causing overt off-target toxicity or remodeling of nontraumatized bones. Thus, achievement of healthy bone density, normal bone volume, and healthy bone mechanical properties at the fracture site is realized after only 3-4 weeks in dasatinib-targeted mice, but requires ~8 weeks in PBS-treated controls. Moreover, optimizations have been implemented to the dosing regimen and releasing mechanisms of this targeted-dasatinib therapy, which has enabled us to cut the total doses by half, reduce the risk of premature release in circulation, and still improve upon the therapeutic efficacy. These efforts might reduce the burden associated with frequent doses on patients with broken bones and lower potential toxicity brought by drug degradation in the blood stream. In addition to dasatinib, a few other small molecules have also been targeted to fracture surfaces and identified as prospective therapeutic agents for the acceleration of fracture repair. In conclusion, in this dissertation, we have successfully targeted dasatinib to bone fracture surfaces, which can significantly accelerate the healing process at dasatinib concentrations that are known to be safe in oncological applications. A modular synthetic method has also been developed to allow for easy conversion of a bone-anabolic warhead into a fracture-targeted version for improved fracture repair.

In 2018, the World Health Organization (WHO) reported approximately 37 million people are living with the Human Immunodeficiency Virus (HIV). Suppressing replication of the virus down to undetectable levels was achieved by combination antiretroviral therapy (cART) which effectively reduced the mortality and morbidity rates of HIV positive individuals. Despite the improvements towards combatting HIV/AIDS, no successful treatment exists to eradicate the virus from an infected individual. Treatment regimens are lifelong and prompt less than desirable side effects including but not limited to; drug-drug interactions, toxicity, systemic organ complications, central nervous system HIV triggered disorders and most importantly, drug resistance. Current therapies are becoming ineffective against highly resistant HIV strains making the ability to treat long-term viral suppression a growing issue. Therefore, potent and more effective HIV inhibitors provide the best chance for long-term successful cART.

HIV-1 protease (PR) enzyme plays a critical role in the life cycle and replication of HIV. Significant advancements were achieved through structure-based design and X-ray crystallographic analysis of protease-bound to HIV-1 and brought about several FDA protease inhibitors (PI). Highly mutated HIV-1 variants create a challenge for current and future treatment regimens. This thesis work focuses on the design, synthesis, and evaluation of two new classes of potent HIV-1 PIs that exhibit a novel bicyclic oxazolidinone feature as the P2 ligand and a novel bis squaramide scaffold as the P2/P3 ligand. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Inhibitors 1.65g and 1.65h were further evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants and displayed antiviral activity similar to Darunavir. X-ray crystal structures of inhibitor 1.65a and inhibitor 1.65i were co-crystallized with wild type HIV-1 protease and solved at a 1.22 Å and 1.30 Å resolution and maintained strong hydrogen bond with the backbone of the PR enzyme.

Recent trends in materials science have exploited noncovalent monolayer chemistries to modulate the physical properties of 2D materials, while minimally disrupting their intrinsic properties (such as conductivity and tensile strength). Highly ordered monolayers with pattern resolutions <10 nm over large scales are frequently necessary for device applications such as energy conversion or nanoscale electronics. Scanning probe microscopy is commonly employed to assess molecular ordering and orientation over nanoscopic areas of flat substrates such as highly oriented pyrolytic graphite, but routine preparation of high-quality substrates for device and other applications would require analyzing much larger areas of topographically rougher substrates such as graphene. In this work, we combine scanning electron microscopy with polarization modulated IR reflection adsorption spectroscopy to quantify the order of lying down monolayers of diynoic acids on few layer graphene and graphite substrates across areas of ~1 cm². We then utilize these highly ordered molecular films for templating assembly of di-peptide semiconductor precursors at the nanoscale, for applications in organic optoelectronic device fabrication.

The necessity of cost effective, environmentally friendly technology has become increasingly important to remediate persistent organic pollutants in the environment. The emerging greener ultrasound technology has the potential to serve the remediation industry. In this study, the use of low power, high frequency (HF) ultrasound (1.6 MHz, 145 W/L) has been shown to effectively remediate DDT (90% of 8 mg/L) in water and sand slurries. Addition of iron powder accelerated DDT degradation in the sand slurry under ultrasonication. The potential of HF ultrasound (1.6 MHz, 160 W/L) in degradation of the non-volatile, polar model compound methylene blue (MB) was studied in MB spiked demineralised water and wastewater. A 70 % of 0.4 mg/L of MB was degraded in demineralised water whereas only 54% of MB degraded in MB spiked wastewater. There was a decrease in MB degradation rate with an increase in MB concentration. High power, low frequency (LF) ultrasound (20 kHz, 932 W/L) was used to desorb 400 mg/L of DDT added to three different natural soil slurries at 5, 10, 15 and 20 wt. % each. Each soil slurry was prepared in 0.1% v/v SDS surfactant solution, soaked for 30 min. and heated for another 30 min. at 40 oC before sonication. For the neutral pH soil slurry with higher dissolved organic carbon, the desorption efficiency achieved was over 80% in 30 s sonication. Alkaline soil with higher surface area than neutral soil indicated 60% desorption efficiency while the acidic soil, with the highest surface area and a higher amount of non-soluble organic matter, yielded 30% desorption efficiency under similar desorption conditions. Coconut fibre, used to biosorb the desorbed DDT in the decanted solution, was found to have over 25 g/kg of biosorption capacity for DDT. The surfactant SDS and associated DDT were completely separated from decanted liquid of the desorbed slurry with alum using adsorptive micellar flocculation in 60 min. settling. Acidic pH and molar concentration ratio of Al3+/SDS = 0.5 was used to completely remove the DDT. Using 20 kHz, 1125 W/L of sonication in an 80 mL reactor with air saturated 50 mg/L DDT at 20oC, the DDT removal efficiency achieved was 80% in 20 min. With zero valent iron addition, DDT removal efficiency in 15 min. is 100% with 15 and 22 mg/L of initial DDT concentrations. The settled DDT slurrywas remediated using 20 kHz at 240 W/L achieving DDT removal efficiency of 87% in 15 min. Also LF ultrasound was found to be effective in remediating chloroform (8 mg/L in 60 min) from spiked demineralised water and contaminated groundwater in both batch (120 W/L) and flow cell (6000 W/L) modes. Modeling and simulation of the ultrasonic reactor under 20 kHz ultrasonication was performed for various shape reactors using commercially available software. For almost all reactors, the highest ultrasonic intensity was observed near the transducer???s vibrating area. It was found that the highest acoustic pressure distribution, which is critical to the performance of the reactor, occurred in the conical reactor and flow cell configuration.
Thesis (PhD)--University of South Australia, 2010

High resolution tandem mass spectrometry (MSⁿ) coupled with various separation techniques, such as high-performance liquid chromatography (HPLC) and gas chromatography (GC), is widely used to analyze mixtures of unknown organic compounds. In a mass spectrometric analysis, analytes of interest are at first transferred into the gas phase, ionized (protonated or deprotonated) and introduced into the instrument. Tandem mass spectrometric experiments may then be used to gain insights into structure and reactivity of the analyte ions in the gas phase. The tandem mass spectral data are often compared to those reported in external databases. However, the tandem mass spectra obtained for protonated analytes may be markedly different from those in external databases because protonation site manifested during a mass spectrometric experiment can be affected by the ionization technique, ionization solvents and condition of the ion source. This thesis focuses on investigating the effects of instrumental conditions and analyte concentrations on the protonation sites of 4-aminobenzoic acid. Reactivities of radical species were also investigated. A modified bracketing method was developed and proton affinities of a series of mono- and biradicals of pyridine were measured. In another study, a para-benzyne analog was generated in both solution and the gas phase and its reactivities towards various neutral reagents in the gas phase were compared to those in solution.

Chapter 2 discusses the fundamental aspects of the instruments used in this research. In chapter 3, the effects of residual moisture in linear quadrupole ion trap on the protonation sites of 4-aminobenzoic acid are considered. Chapter 4 focuses on the use of gas-phase ion-molecule reactions with trimethoxymethylsilane (TMMS) for the identification of the protonation sites of 4-aminobenzoic acid. Further, the effects of analyte concentration on the protonation sites of 4-aminobenzoic acid are considered. Chapter 5 introduces a modified bracketing method for the experimental determination of proton affinities of a series of pyridine-based mono- and biradicals. In chapter 6, successful generation of para-benzynes in solution is discussed. The reactivity of a para-benzyne analog, 1,4-didehydrophenazine, is compared to its reactivity in the gas phase.

Infectious diseases caused by bacteria, fungi, and plasmodium parasites are a huge global health problem which ultimately leads to millions of deaths annually. The emergence of strains that exhibit resistance to nearly every class of antimicrobial agents, and the inability to keep up with these resistance trends has brought to the fore the need for new therapeutic agents (antibacterial, antifungal, and antimalarial) with novel scaffolds and functionalities capable of targeting microbial resistance. A novel class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically relevant strains of methicillin-resistant Staphylococcus aureus (MRSA). Synthesis, structure-activity relationship (SAR) studies, and biological investigations have led to lead molecules that exhibit anti-MRSA inhibitory activity as low as 1 – 2 µM. The most potent compounds have also been shown to have low toxicity against mammalian cells and exhibit in vivo efficacy in MRSA skin and thigh infection mouse models.

The novel aryl isonitriles have also been evaluated for antifungal activity. This study examines the SAR of aryl isonitrile compounds and showed the isonitriles as compounds that exhibit broad spectrum antifungal activity against species of Candida and Cryptococcus. The most potent derivatives are capable of inhibiting growth of these pathogens at concentrations as low as 0.5 µM. Notably, the most active compounds exhibit excellent safety profile and are non-toxic to mammalian cells up to 256 µM.

Beyond the antibacterial and antifungal activities, structure-antimalarial relationship analysis of over 40 novel aryl isonitrile compounds has established the importance of the isonitrile functionality as an important moiety for antimalarial activity. Of the many isonitrile compounds exhibiting potent antimalarial activity, two have emerged as leads with activity comparable to that of Artemisinin. The SAR details presented in this study will prove essential for the development new aryl isonitrile analogues to advance them to the next step in the antimalarial drug discovery process.

17-nor-Excelsinidine, a zwitterion monoterpene indole alkaloid isolated from Alstonia scholaris is a subject of synthetic scrutiny. This is primarily due to its intriguing chemical structure which includes a bridged bicyclic ammonium moiety, and its anti-adenovirus and anti-HSV activity. Herein we describe a six-step total synthesis of (±)-17-nor-Excelsinidine from tryptamine. Key to the success of this synthesis is the use of palladium-catalyzed carbonylative heck lactamization methodology which built the 6, 7-membered ring lactam in one step. The resulting pentacyclic product, beyond facilitating the easy access to (±)-17-nor-Excelsinidine, could also serve as a precursor to other related indole alkaloids.

The research described in this dissertation focuses on several areas: developing analytical methods to distinguish structural isomers, identifying the chemical compositions of aviation fuels and evaluating the effectiveness of organic dopants to swell aircraft o-ring seals. Chapter 2 discusses fundamental aspects of mass spectrometry, and ionization methods and the instrumentation used to complete this research.

Chapter 3 discusses and compares two activation methods used to distinguish ionized structural isomers. Ionized naphthene-containing aromatic structural isomers were subjected to collision-activated dissociation (CAD) in an ion trap (ITCAD) and to medium-energy collision-activated dissociation (MCAD) in an octupole collision cell, both in the energy-resolved mass spectrometry mode (ERMS). MCAD was shown to be superior over ITCAD at the structural differentiation of the ionized isomers.

Determination of the chemical compositions of petroleum-based jet and diesel fuels, potential alternative fuels and fuel blending components by using a GCxGC/(EI)TOF MS is discussed in chapter 4. The ability to determine the chemical compositions of fuels and to correlate the identified compounds and their concentrations to the physical and chemical properties and aircraft performance of the fuels is vital for the development of future resilient, alternative fuels. The chemical compositions of petroleum-based fuels were found to be different from potential alternative fuels.

Chapter 5 discusses the effectiveness of aromatic and nonaromatic compounds in swelling air craft o-ring seals, which prevents leaks in the fuel circulation systems. The aim of this study was to identify aromatic and nonaromatic compounds that most effectively swell o-ring seals. Steric effects were shown to decrease the efficiency of the compounds to swell seals. Ethylbenzene and indane were found to swell o-ring seals more effectively than any other compounds studied, including a currently approved alternative fuel.

Printing of 3-dimensional nanostructures with high-resolution by two-photon polymerization has gained significant attention recently. Isopropyl thioxanthone (ITX) has been studied and used as a photoinitiator because of its unique property in initiating and depleting polymerization, but to further improve the resolution of 3D structures, new photoinitiating materials are necessary to decrease the power requirements especially in industrial world. In this dissertation, different new types of thioxanthone-based photoinitiators were synthesized and our new initiators possessed a clear enhancement in terms of excitation over ITX. To clearly reveal the writing mechanism behind it, the behavior of the initiators was evaluated by several methods such as low temperature phosphorescence spectroscopy and density functional theory (DFT) calculations. The first type of new molecules with alkyne bridge will be discussed in chapter 2 and the further developed initiators with electron donating and withdrawing groups will be discussed in chapter 3. By modifying the structure of ITX, we have revealed and proposed an important pathway to guide future development of photoinitiators in direct laser writing.

Organic semiconductors have witnessed a prolific boom for their potential in the manufacturing of lightweight, flexible, and even biocompatible electronics. One of the fields of research that has yet to benefit from organic semiconductors is high temperature electronics. The lightweight nature and robust processability is attractive for applications such as aerospace engineering, which require high temperature stability, but little has been reported on taking such a leap because charge transport is temperature dependent and commonly unstable at elevated temperatures in organics. Historically, mechanistic studies have been bound to low temperature regimes where structural disorders are minimal in most materials. Discussed here is a blending approach to render semiconducting polymer thin films thermally stable in unprecedented operation temperature ranges for organic materials. We found that by utilizing highly rigid host materials, semiconducting polymer domains could be confined, thus improving their molecular and microstructural ordering, and a thermally stable charge transport could be realized up to 220°C. With this blending approach, all-plastic high temperature electronics that are extremely stable could also be demonstrated. In efforts to establish a universal route towards forming thermally stable semiconducting blends, we found that the molecular weight of conjugated polymer plays a crucial role on the miscibility of the blends. Finally, we found that the choice of the host matrix ought to consider the charge trapping nature of the insulator.

Various organic reactions, including important synthetic reactions involving C–C, C–N, and C–O bond formation as well as reactions of biomolecules, are known to be accelerated when the reagents are present in confined volumes such as sprayed or levitated microdroplets or thin films. This phenomenon of reaction acceleration and the key role of interfaces played in it are of intrinsic interest and potentially of practical value as a simple, rapid method of performing small-scale synthesis. This dissertation has three focusing subtopics in the field of reaction acceleration: (1) application of reaction acceleration in levitated droplets and mass spectrometry to accelerate the reaction-analysis workflow of forced degradation of pharmaceuticals at small scale; (2) fundamental understanding of mechanisms of accelerated reactions at air/solution interfaces; (3) discovery the use of glass particles as a `green' heterogeneous catalysts in solutions and systematical study of solid(glass)/solution interfacial reaction acceleration as a superbase for synthesis and degradation using high-throughput screening.

Reaction acceleration in confined volumes could enhance analytical methods in industrial chemistry. Forced degradation is critical to probe the stabilities and chemical reactivities of therapeutics. Typically performed in bulk followed by LC-MS analysis, this traditional workflow of reaction/analysis sequence usually requires several days to form and measure desirable amount of degradants. I developed a new method to study chemical degradation in a shorter time frame in order to speed up both drug discovery and the drug development process. Using the Leidenfrost effect, I was able to study, over the course of seconds, degradation in levitated microdroplets over a metal dice. This two-minute reaction/analysis workflow allows major degradation pathways of both small molecules and therapeutic peptides to be studied. The reactions studied include deamidation, disulfide bond cleavage, ether cleavage, dehydration, hydrolysis, and oxidation. The method uses microdroplets as nano-reactors and only require a minimal amount of therapeutics per stress condition and the desirable amount of degradant can be readily generated in seconds by adjusting the droplet levitation time, which is highly advantageous both in the discovery and development phase. Built on my research, microdroplets can potentially be applied in therapeutics discovery and development to rapidly screen stability of therapeutics and to screen the effects of excipients in enhancing formulation stabilities.

My research also advanced the fundamental understanding of reaction acceleration by disentangles the factors controlling reaction rates in microdroplet reactions using constant-volume levitated droplets and Katritzky transamination as a model. The large surface-to-volume ratios of these systems results in a major contribution from reactions at the air/solution interface where reaction rates are increased. Systems with higher surface-active reactants are subject to greater acceleration, particularly at lower concentrations and higher surface-to-volume ratios. These results highlight the key role that air/solution air/solution interfaces play in Katritzky reaction acceleration. They are also consistent with the view that reaction increased rate constant is at least in part due to limited solvation of reagents at the interface.

While reaction acceleration at air/solution interfaces has been well known in microdroplets, reaction acceleration at solid/solution interfaces appears to be a new phenomenon. The Katritzky reaction in bulk solution at room temperature is accelerated significantly by the surface of a glass container compared to a plastic container. Remarkably, the reaction rate is increased by more than two orders of magnitude upon the addition of glass particles with the rate increasing linearly with increasing amounts of glass. A similar phenomenon is observed when glass particles are added to levitated droplets, where large acceleration factors are seen. Evidence shows that glass acts as a ‘green’ heterogeneous catalyst: it participates as a base in the deprotonation step and is recovered unchanged from the reaction mixture.

Subsequent to this study, we have systematically explored the solid/solution interfacial acceleration phenomena using our latest generation of a high-throughput screening system which is capable of screening thousands of organic reactions in a single day. Using desorption electrospray ionization mass spectrometry (DESI-MS) for automated analysis, we have found that glass promotes not only organic reactions without organic catalysts but also reactions of biomolecules without enzymes. Such reactions include Knoevenagel condensation, imine formation, elimination of hydrogen halide, ester hydrolysis and/or transesterification of acetylcholine and phospholipids, as well as oxidation of glutathione. Glass has been used as a general `green' and powerful heterogeneous catalyst.

The thesis focuses on elastic polymer material that is biodegradable and compatible with human cells and tissues. The presented research describes polymer synthesis, material processing, physico-chemical investigation and biological tests performed on this novel biomaterial.

The development of solution-processable semiconducting polymers has brought mankind’s long-sought dream of plastic electronics to fruition. Their potential in the manufacturing of lightweight, flexible yet robust, and biocompatible electronics has spurred their use in organic transistors, photovoltaics, electrochromic devices, batteries, and sensors for wearable electronics. Yet, despite the successful engineering of semiconducting polymers, we do not fully understand their molecular behavior and how it influences their doping (oxidation/reduction) properties. This is especially true for donor-acceptor (D-A) p-systems which have proven to be very efficient at tuning the electronic properties of organic semiconductors. Historically, chain-length dependent studies have been essential in uncovering the relationship between the molecular structure and polymer properties. Discussed here is the systematic investigation of a complete D-A molecular series composed of monodispersed and well-defined conjugated molecules ranging from oligomer (n=3-21) to polymer scale lengths. Structure-property relationships are established between the molecular structure, chain conformation, and redox-active opto-electronic properties for the molecular series in solution. This research reveals a rod-to-coil transition at the 15 unit chain length, or 4500 Da, in solution. The redox-active optical and electronic properties are investigated as a function of increasing chain-length, giving insight into the nature of charge carriers in a D-A conjugated system. This research aids in understanding the solution behavior of conjugated organic materials.

The work presented in this thesis deals initially with the synthesis of rigid polyalicyclic dienes and dienophiles with pyrimidine moieties inbuilt in a rigid fashion (building BLOCKS). This work has allowed the production of a new class of ribbon molecules with precisely defined size, shape and position of the pyrimidine ring. In the second stage of the project, an assessment of their ability to participate in cycloaddition reactions as pyrimidine building BLOCK* components was investigated.

2,4-Dimethoxy-1,3-diazaanthracene (I) has acted as the pyrimidine transfer reagent for preparing building BLOCKs. The Diels-Alder adducts IV and V (Scheme I), prepared by reaction of I with norbomadiene, are new pyrimidine dienophilic BLOCKs. Both I and 2,4-dichloro-1,3-diazaanthracene (II) were active in photochemical [4π+4π] cycloaddition reactions with cyclopentadiene to form a second class of building BLOCKs VII and VIII (Scheme I). In addition, the photodimerisation of I and II was studied and structures IX-XII assigned on the basis of spectral and X-ray method.

The 2,4-dichloro-photoadduct VIII is of particular importance for this work since it is easily hydrolysed (2M NaOH, 60 °C, overnight) to the corresponding uracil XIII In contrast, thermal adducts IV and V were very difficult to hydrolyse (NaOH fusion) to uracils XIV and XV (Figure I).

The availability of pyrimidine BLOCKs which contain a reactive π-bond, e.g. (IV, V, VII and VIII) has enabled us to employ 3,6-di(2'-pyridyl)-s-tetrazine (XVI) and ACE (Alkene plus Cyclobutene Epoxide) coupling methods to obtain precisely functionalised ribbon molecules in a direct, convergent synthetic strategy.

The synthesis of the bis-pyrimidines by coupling norbornene reagents using 3,6-di(2'-pyridyl)-s-tetrazine is illustrated in Scheme II. In the first step, s-tetrazine XVI was reacted with pyrimidine BLOCK V under basic conditions to generate the dihydropyridazine XVII. This diaza-1,3-diene was reacted with a further equivalent of V under high pressure conditions to yield the bis-pyrimidines XVIII and XIX, which were separated by radial chromatography. The same procedure was used to link pyrimiclines to other effectors by using alternative alkenes in the second step.

The ACE coupling protocol is illustrated by the reaction of alkene VIII with the dimethoxynaphthalene-containing epoxide XX (Scheme III). The reaction can be conducted under thermal or photochemical conditions and is considered to proceed via 1,3-dipolar intermediate formed by ring-opening of the epoxide C-C bond of XX (See Chapter 4).

Each class of coupled adduct could be hydrolysed to the corresponding uracil by using either acid (XXII) or base (XXIII) hydrolysis conditions, the choice depending on the structure of the molecule in question and its substituents.

The work presented in this thesis involves a deal of new work and has been instrumental in the development of the Lego^®-based BLOCK assembly protocol for ribbon molecules construction.

For any drug candidate to be approved by the U.S. Food and Drug Administration, it must meet strict standards for safety and efficacy. While the field of nuclear medicine is over 100 years old, traditional methods such as external beams or systematic administration have rarely met these standards or have limited application. Ligand-targeted therapy and diagnostics, or “theranostics,” has emerged in the past several decades as an exciting field that offers new possibilities to design drugs that are both safe and effective. When applied to nuclear medicine, the field of ligand-targeted radioactive theranostics is younger still, with many critical lessons being discovered and applied currently. This dissertation outlines the necessary principles of radioactive theranostic drug design, then demonstrates the application of several more recent techniques to improve both the efficacy and safety of radioactive theranostics targeting two high priority oncological targets: fibroblast activation protein alpha and folate receptor.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage damage and loss in the joints that affects approximately 27 million adults in the US. Tissue that is damaged by OA is a major health concern since cartilage tissue has a limited ability to self-repair due to the lack of vasculature in cartilage and low cell content. Tissue engineering efforts aim towards the development of cartilage repair strategies that mimic articular cartilage and are able to halt the progression of the disease as well as restore cartilage to its normal function.

This study harnesses the biological activity of collagen type II, present in articular cartilage, and the superior mechanical properties of collagen type I by characterizing gels made of collagen type I and II blends (1:0, 3:1, 1:1, 1:3, and 0:1). The collagen blend hydrogels were able to incorporate both types of collagen and retain chondroitin sulfate (CS) and hyaluronic acid (HA). Cryoscanning electron microscopy images showed that the 3:1 ratio of collagen type I to type II gels had a lower void space percentage (36.4%) than the 1:1 gels (46.5%) and the complex modulus was larger for the 3:1 gels (G*=5.0 Pa) compared to the 1:1 gels (G*=1.2 Pa). The 3:1 blend consistently formed gels with superior mechanical properties compared to the other blends and has the potential to be implemented as a scaffold for articular cartilage engineering.

Following the work done to characterize the collagen scaffolds, we studied whether an aggrecan mimic, CS-GAHb, composed of CS and HA binding peptides, GAH, and not its separate components, is able to prevent glycosaminoglycan (GAG) and collagen release when incorporated into chondrocyte-embedded collagen gels. Bovine chondrocytes were cultured and embedded in collagen type I scaffolds with CS, GAH, CS and GAH, or CS-GAHb molecules. Gels composed of 3:1 collagen type I and II with CS or CS-GAHb were also studied. The results obtained showed CS-GAHb is able to decrease GAG and collagen release and increase GAG retention in the gels. CS-GAHb also stimulated cytokine production during the initial days of scaffold culture. However, the addition of CS-GAHb into the chondrocyte-embedded collagen scaffolds did not affect ECM protein expression in the gels. The incorporation of collagen type II into the collagen type I scaffolds did not significantly affect GAG and cytokine production and ECM protein synthesis, but did increase collagen release. The results suggest the complex interaction between CS-GAHb, the chondrocytes, and the gel matrix make these scaffolds promising constructs for articular cartilage repair.

Finally, we used Dunkin Hartley guinea pigs, a commonly used animal model of osteoarthritis, to determine if high frequency ultrasound can ensure intra-articular injections of the aggrecan mimic are accurately positioned in the knee joint. A high-resolution small animal ultrasound system with a 40 MHz transducer was used for image-guided injections. We assessed our ability to visualize important anatomical landmarks, the needle, and anatomical changes due to the injection. From the ultrasound images, we were able to visualize clearly the movement of anatomical landmarks in 75% of the injections. The majority of these showed separation of the fat pad (67.1%), suggesting the injections were correctly delivered in the joint space. The results demonstrate this image-guided technique can be used to visualize the location of an intra-articular injection in the joints of guinea pigs and we are able to effectively inject the aggrecan mimic into knee joints.

All of the work presented here suggests that the addition of the aggrecan mimic to collagen I and collagen I and II scaffolds has shown that this type of construct could be useful for treating cartilage damage in the future.

Gas phase studies of the secondary structure of peptides and proteins have become increasingly popular as they offer distinct advantages of small sample usage and experiment time. The mass spectrometer is key to performing these experiments as ions can be manipulated based on their mass to charge ratio. Combining mass spectroscopy with laser spectroscopy birthed a new method for determining gas phase structures, ion spectroscopy. This document begins with an overview of secondary structure analysis using several techniques in solid, liquid, and gas phases. It then describes how ion spectroscopy can also be utilized to obtain detailed fingerprint infrared spectra of ions which are then matched with density functional theory calculations to determine the 3D structure of an ion. After describing the instrumental apparatus, four examples of the use of ion spectroscopy to determine structure are presented. The first study looked to understand the effect of increased flexibility around a proline residue in the diastereomeric pair YAD/LPGA and how a simple switch to glycine can greatly affect beta turn formation in peptides. The next three studies describe an attempt to form a single turn alpha helix in the gas phase using a highly stable tethered peptide motif. Failure to form the single turn helix in the first study led to an interesting examination of the use of computational chemistry to lead the synthesis of peptides where a specific structure is required. After observing the single turn helix attention is then diverted to expanding and controlling its handedness via stereochemistry. In all, this document will guide the reader through the methods and experiments possible with ion spectroscopy.

Examines the problem of "identifying the configurations of molecular structures which correspond to the globally minimum potential energy for that structure".. This thesis addresses the problem of identifying configurations of molecular structures which correspond to the globally minimum potential energy for that structure. Molecular structures arise as a result of non-bonded and bonded atomic interactions and experimental evidence shows that, in the great majority of cases, the potential energy global minimum corresponds to the most stable configuration of the molecular structure. This configuration is of particular importance as it dictates most of the physical properties of the molecular structure. The potential energy of a molecular structure may be calculated, as a function of the atomic positions, using appropriate molecular models. However, as these give rise to potential energy functions that are typically nonconvex with many local minima, finding the global minima is an extremely difficult problem. For many years this problem has been investigated by chemists and physicists however, in more recent years, researchers from optimisation and computer science have also become involved and, in fact, the minimisation of non-convex potential energy functions arising from molecular conformation or protein folding problems has become one of the rnost important interdisciplinary problems [43]. This thesis develops and analyses a molecular structure global optimisation method using both deterministic local and stochastic global optimisation techniques within a genetic algorithm based environment. By incorporating different genetic operators, the one basic method was able to globally optimise a numlber of different types of molecular structures. From an experimental point of view, the method was particularly successful and found all currently accepted global minima for scaled Lennard-Jones atomic clusters of 2 to 80 atoms. two new global minima for 77 and 78 atom scaled Lennard-Jones atomic clusters . all currently accepted and some improved global minima for mixed argon-xenon atomic clusters of 7, 13 and 19 atoms. In addition, minima were determined for all remaining clusters in the 2, .... ,20 atom range. all currently accepted global minima for clusters of benzene molecules of 2 to 6 molecules and new minima for clusters of 8 to 12 molecules. all currently accepted global minima for a two-dimensional model molecular structure where the number of atoms ranged from 3 to 42. currently accepted global minima for a number of small molecules. Of particular importance is that, in determining these global minima, the method always started from randomly generated initial configurations and at no stage used any heuristic information to accelerate the search. From a theoretical point of view, this thesis presents an analytical comlparisonof the phenotype crossover operators used in the method with the more standard (genotype) crossover operators normally used in genetic algorithms. This analysis is confirmed with experimental results. In addition, a proof of convergence for the stochastic global optimisation technique used within the genetic algorithm environment and analytical evaluation of all potential energy gradients required by the deterministic local optimiser are presented. Chapter 1 of this thesis describes the molecular architecture problem and presents a review of local and global optimisation techniques. Chapter 2 describes the development of APSE, the stochastic global optimisation technique used in this study while the results obtained by applying APSE to the pure atomic cluster problem are presented in Chapter 3. Chapter 4 describes the development of GEM*, the major computational method used in this study. GEM* implements a combination of local optimisation and APSE probabilistic searches witrlin a genetic algorithm based environment. The results obtained by applying GEM* to the pure atomic cluster problem and a theoretical comparison of phenotype genetic crossover operators with rnore standard genetic crossover operators are presented in Chapter 5. The results obtained by applying GEM* to mixed argon-xenon atomic cluster problems are described in Chapter 6 while the optimisation of clusters of benzene and water molecules by GEM* is discussed in Chapter 7. Chapter 8 describes the GEM* optimisation results obtained for a model molecular structure and Chapter 9 presents the GEM* optimisation results for a number of small molecules. A summary and future research directions are presented in Chapter 10 while the appendices contain the analytical derivation of the potential energy gradients required for the implementation of the BFGS local optimiser and tables describing the structures obtained for mixed atomic clusters. Within this thesis Chapter 2 and Sections 3.3.1 and 3.4.1 appeared in the Australian Computer Journal, Vol. 28, No.4, November 1996. Chapter 6 has been accepted for publication by the Journal of Computational Chemistry. Sections 4.2, 5.2, 5.3 and 5.4 have been submitted to the Journal ofGlobal Optimization. Section 3.3.2 appeared as Technical Report 95 - 010, Department of Mathematics and Computing, Central Queensland University. Chapter 7 appeared as Technical Report 96 - 005, Department of Mathematics and Computing, Central Queensland University. Chapters 8 and 9 appeared as Technical Report 96 - 006, Department of Mathmatics and Computing, Central Queensland University.

The function of many biological processes depends on the structure and composition of the biomolecules involved. Both spectroscopy and mass spectrometry provide complimentary information regarding the three-dimensional conformation and the composition, respectively, as well as many other things. Here, double resonance conformer specific spectroscopy coupled with the latest ab inito computational methods is used to make structural assignments at the atomic resolution as well obtain information regarding propensities of intramolecular interactions. Additionally, rapid cooling in conjunction with IR excitation to modulate and measure the relative populations of conformers present in the expansion. Two different designer peptide systems are studied, including an achiral acylated 𝛼-aminoisobutryic acid dipeptide (Ac-AIB2-R) with various C-terminal protecting groups (R=NHBn, NHBnF, 𝛼-methylbenzylamine) and an acylated 𝛾4-phenylalanine (Ac-𝛾4Phe-NHMe) with the a methyl amine C-terminal protecting group. Mass spectrometry is used to determine the kinetics of gas-phase covalent tagging reactions used to enhance the sequence coverage. The covalent modification reactions utilize click chemistry between NHS or HOBt substituted sulfobenzoic acid tags with nucleophiles present on the residues of the amino acids composing the backbone. Effective temperatures are approximated using the Tolmachev model, which relates the statistical average internal energy of the molecule to a temperature.

Mass spectrometry is a versatile, powerful analytical tool for chemical and biomolecule identification, quantitation, and structural analysis. Tandem mass spectrometry is key component in expanding the capabilities of mass spectrometry beyond just a molecular weight detector. Another key component is the discovery of electrospray ionization allowing not only liquid samples to be ionized but also generation of multiply charged ions enabling mass spectrometry analysis of large biomolecules. The fragmentation pathway of ion during tandem mass spectrometry is highly dependent on the nature of the ion as well as the form of dissociation technique employed. To-date, no single form of ion or dissociation method can provide all the structure information needed; therefore, it is common to use multiple forms of ions, different charge carrier or modifications, with a variety of other dissociation techniques to generate complimentary information. Practically, it is not always easy to generate the desired form of ion via ionization methods and is one of the limitations. Gas-phase ion/ion reactions provide an easy approach in manipulation of ions, either through changing the ion type or covalent modifications, in the gas-phase with the goal of enhancing the capabilities of mass spectrometers for either molecular weight or structural analysis. In this dissertation, studies of new gas-phase ion/ion chemistry for biomolecules such as carbohydrates and phopho/sulfopeptides were performed, and exploration into mass spectrometry analysis of IgGs is discussed.