Philosophiae Doctor - PhD / The abnormal death of neurons in the central nervous system of individuals suffering from neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, takes place by an intrinsic cell suicide programme known as apoptosis. This process is triggered by several stimuli, and consists of numerous pathways and cascades which lead to the death of neuronal cells. It is this multifactorial nature of neurodegenerative diseases that has over the years seen many researchers develop compounds that may serve as multi-target directed ligands (MTDLs) which could potentially confer neuroprotection by acting simultaneously on different receptors and target sites implicated in neurodegeneration. This study was aimed at developing MTDLs that may serve as neuroprotective agents by simultaneously (a) inhibiting N-methyl D-aspartate receptors (NMDAR) and blocking L-type voltage gated calcium channels (VGCC) thus regulating the Ca2+ influx mediated excitotoxic process; (b) inhibiting the monoamine oxidase enzymes A and -B (MAO-A/B) thus allowing increase in dopamine levels in the central nervous system and reducing the levels of the highly oxidative products produced by the activity of these enzymes; (c) possessing anti-apoptotic activity to halt the neuronal cell death process. In designing the compounds we focused on the structures of rasagiline and selegiline, two well-known MAO-B inhibitors and proposed neuroprotective agents, and of NGP1-01, a known VGCC blocker and NMDAR antagonist. The first series of compounds (reported in research article 1, Chapter 3), comprised polycyclic propargylamine and acetylene derivatives. Compounds 12, 15 and 16 from this series showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18 % to 59 % in micromolar concentrations, and compared favourably to the reference compounds. In the MAO-B assay, compound 10 exhibited weak MAO-B inhibition of 73.32 % at 300 μM. The rest of the series showed little to no activity on these target sites, despite showing significant anti-apoptotic activity. This suggested the compounds in this series to be exhibiting their neuroprotective action through some other mechanism(s) unexplored in this study.

Thesis advisor: Lawrence T. Scott / Chapter 1. The impact and growth of carbon nanotubes within the framework of nanotechnology is presented. Methods to produce single chirality nanotubes from template-mediated sources are evaluated. The concept of a nanotube endcap is introduced as a potential synthetic target toward the selective synthesis and growth of a single chirality carbon nanotube. Chapter 2. A modified synthesis of corannulene is presented, highlighting a selective imine based reaction protocol for the fuctionalization 4,7-dimethylacenaphthenequinone. Also reviewed is a cascade coupling approach toward the synthesis of corannulene, followed by an analysis of the thermochemistry of the two-component disconnection. Chapter 3. The synthesis of 6 different indenoannulated corannulene congeners derived from a single flash vacuum pyrolysis (FVP) is described. X-ray crystal structures for each indenoannulated corannulene are presented along with computational modeling. Spectroscopic comparison between observed and theoretical 1H NMR provides one of the largest complete and comparative data sets for a collection of PAHs. Chapter 4. The application of a palladium based indenoannulation reaction is presented as an alternative synthetic method to FVP. Heteroatom based derivatives of both tetraindenocorannulene and pentaindenocorannulene were both developed as potential solubilizing factors. The thermochemistry for each successive indenoannulation of 1,3,5,7,9-pentaphenylcorannulene leading to pentaindenocorannnulene has been calculated, providing an approximated energy landscape for the total transformation. Chapter 5. Several routes for the synthesis of 1,3,5,7,9-pentakis(2,6-dichlorophenyl)-corannulene are presented. The yield for this reaction has been improved through the use of a palladium based precatalyst. During this time we studied a five-fold palladium catalyzed borylation of corannulene using B2pin2. Finally development of a cascade coupling reaction towards a [5,5] SWNT endcap is highlighted by a 12 bond coupling reaction. Chapter 6. A nickel-promoted homo-coupling between the proximally situated aryl halides of 1,2,5,6-tetrakis(2-chlorophenyl)corannulene is used to complete the synthesis of diphenanthro[9,10-a:9′,10′-g]corannulene. X-ray quality crystal were grown of diphenanthro[9,10-a:9′,10′-g]corannulene, and the structure was solved. The crystals forms highly ordered arrays in a columnar fashion with each phenanthro segment aligned through a series of π - π stacking interactions. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Petroleum hydrocarbons are emitted into the environment via natural and anthropogenic activities. Once emitted, these hydrocarbons can be transported globally, persisting and accumulating in aquatic ecosystems. In the Alberta oil sands region (AOSR), mining activities have significantly altered and polluted the surrounding aquatic and terrestrial environments with heavy metals and various petroleum hydrocarbons including polycyclic aromatic hydrocarbons (PACs). Though PACs have been tracked through time using dated lake sediment cores, separating natural and anthropogenic PACs can be difficult. In the Peace Athabasca Delta (PAD) this task is especially difficult as this region has been receiving annual inputs of naturally eroded bitumen throughout history. Petroleum biomarkers are unique petrogenic compounds (i.e. derived from petroleum) which may provide a secondary proxy to track mining impacts. This thesis investigated the impacts of mining activities on the AOSR and the PAD using two different proxies, PAC and petroleum biomarkers. These two regions were compared to reference lakes to the south and northwest of the Athabasca oil sands formation, in order to provide a natural signal, with minimal oil sands mining contamination. Historically deposited PACs and petroleum biomarkers were analysed in radiometrically dated lake sediment cores from the AOSR and the PAD, Alberta. Sediment profiles in the AOSR (Saline Lake) showed increases in PAC fluxes for both alkylated and parent compounds coeval with mining activities. Alkylated PAC fluxes in reference lakes (Mariana Lake and BM11) increased at the height of oil sands development (1990s). PAD lakes showed no statistical increase in PAC flux through time due to high levels of naturally eroded bitumen entering the system. Parent PAC diagnostic ratios, however, showed clear shifts from pyrogenic (primarily wood burning) in pre-development sediments to petrogenically derived PACs in modern sediments, in both AOSR and PAD lakes, coeval with oil sands development. Petroleum biomarker diagnostic ratios in Saline Lake and PAD lakes remained stable through time, indicating a clear current and historical petroleum signal originating from the AOSR. Reference lakes (Mariana Lake and BM11) showed the greatest change in petroleum biomarkers. Historically, these lakes had signatures uncommon of petroleum sources, however, in recent years petroleum inputs from mining development were revealed by these petroleum biomarkers. This study compared the historical trends of several petroleum hydrocarbons in lake sediment to the historical emissions of these petroleum hydrocarbons from oil sands mining operations. Notably, we show the potential for petroleum biomarkers to trace petroleum hydrocarbon contamination in the environment.

1 / Yue Sun

Despite microbial degradation being the primary route of degradation of PAHs in soils, high molecular weight polycyclic aromatic hydrocarbons (such as benzo[a]pyrene) have consistently proven to e resistant to microbial attack. However, recent research has demonstrated the potential for bacterial-fungal co-cultures to achieve biodegradation of high molecular weight PAHs. The aim of this research was to determine the efficacy of co-culture bioaugmentation for the remediation of high molecular weight PAHcontaminated soils. PAH degrading bacteria were enriched on multiple PAHs and isolated on pyrene from both contaminated (soil from a former manufactured gas plant) and uncontaminated (agricultural soil, termite mound matrix and kangaroo faeces) sources. The bacterial isolates were identified using 16SrRNA analysis as Mycobacterium sp. Strain BS5, Mycobacterium sp. Strain KA5 and Mycobacterium sp. Strain KF4 or fatty acid methyl ester (FAME) analysis as Ralstonia pickettii and Stenotrophomonas maltophilia. The initial phase of assessment of PAH degradation by fungal and bacterial coculture components was undertaken using liquid media. Two fungal isolates from a previous investigation into the coculture process (Penicillium janthinellum) and the American Type Culture Collection (Phanerochaete chrysosporium) were assessed for their ability to degrade benzo[a]pyrene in minimal media and MYPD. The fungal isolates were found to be able to degrade benzo[a]pyrene cometabolically in MYPD. The bacterial isolates and two others from previous investigations were assessed for their ability to degrade single PAHs (fluorene, phenanthrene, fluoranthene, pyrene and benzo[a]pyrene) in liquid culture. This process was used as an initial screen to select the best bacterial isolates for further investigation of PAH degradation by axenic cultures and cocultures with the fungal isolates using a PAH mixture. Based on the results of these experiments four bacterial isolates (VUN 10,010, Mycobacterium 1B, Mycobacterium sp. Strain BS5 and Mycobacterium sp. Strain KA5) and the two fungal isolates were selected to investigate further using a PAH mixture composed of the previously mentioned PAHs. It was found that the use of a fungal bacterial coculture increased the degradation of the PAH mixture beyond that of axenic bacterial cultures. Based on these experiments, the coculture composed of P. janthinellum and VUN 10,010 was selected for assessment of its ability to degrade the same PAH mixture in spiked soil microcosm experiments. Natural attenuation, axenic P. janthinellum, axenic VUN 10,010 and a coculture of these two organisms were assessed for PAH degradation in soil microcosms over a 100 day period. Inoculation of microcosms with the coculture resulted in the removal of benzo[a]pyrene by 11 mg/kg (± 1.21 mg/kg) (30%) over the 100 day incubation period. Substantial PAH degradation was also observed in the microcosms assesing natural attenuation. Using an alternative sequential inoculation method, initially inoculating with P. janthinellum then 50 days later with VUN 10,010 significantly enhanced the removal of benzo[a]pyrene. After 100 days incubation, benzo[a]pyrene was degraded below detection limits in two of three microcosms, compared to a 4.95 mg/kg (± 4.64 mg/kg) (14.7 %) reduction in soil microcosms inoculated using an alternative inoculation process of VUN 10,010 followed by P. janthinellum. Attempts were made to optimise the process using sequential inoculation and soil amendments intended to enhance the performance of the fungal component using distilled water and 1% glucose. The addition of distilled water was not observed to substantially influence the ability of the coculture to degrade PAHs, whereas the addition of 1% glucose was found to inhibit PAH degradation.

Thesis (Ph. D.)--Oregon State University, 2007. / Printout. Includes bibliographical references. Also available on the World Wide Web.

Polycyclic aromatic hydrocarbons (PAH) have been identified as a serious environmental problem. In past research it has been proven that naphthalene, the simplest PAH, could be biodegraded using roller bioreactors and Pseudomonas putida. In this previous work it became apparent that the mass transfer rate of the hydrophobic naphthalene was the rate limiting factor in biodegradation, as the bacteria could degrade the naphthalene as fast as it entered solution. The challenge for the present research was to find a simple, inexpensive method for increasing the mass transfer rates within the framework of the previously successful reactor. <p>After some deliberation, the addition of inert particles (glass beads) was determined to be the preferred option to increase mass transfer. The inert particles visibly increased the turbulence in the reactor and significant increases in both mass transfer and bioremediation rates were achieved. The augmentation of mass transfer rates was found to be dependent on the type, size and relative loading of the particles. Two types of inert particles were investigated to increase mass transfer rates, spherical glass beads and Raschig rings. Glass beads were found to be far superior to Raschig rings for the intended purpose. Three sizes of spherical glass beads were then compared experimentally (1, 3, and 5mm). It was discovered that the 3mm beads were vastly superior to 1mm beads and 5 mm beads were slightly superior to 3mm beads. Different bead loadings (volume of particles / total working volume) were then explored with 10%, 25% and 50% bead loading investigated. Although slight increases in mass transfer were observed at higher bead loadings, the reduction in working volume for biodegradation meant that 50% was accepted as the optimum loading parameter. <p>The optimum conditions for maximum mass transfer occurred using 5 mm spherical glass beads at 50% loading. The increase in mass transfer and biodegradation rates compared to a traditional roller bioreactor were found to be 10 fold and 11 fold, respectively. The optimum mass transfer conditions were then applied to 2-methylnaphthalene with increases in mass transfer and biodegradation equal to 6 fold and 8 fold, respectively. The candidate bacteria used in this study was found incapable of degrading 1,5 dimethylnaphthalene although the mass transfer results demonstrate promise for the developed technology. To determine the effects of scale on the process, two larger reactors were finally studied. They were eight times and twenty-one times the size of the initial bioreactor. The process was shown to speed up at larger scale which shows great promise for future applications. The maximum degradation rate achieved in the larger reactor was 148 mgL-1h-1. This compares very well with the best result found in literature, 119 mgL-1h-1, which was achieved in a much more complex system. Clearly, the bead mill bioreactor designed during the present work is a simple concept that shows superior performance for the bioremediation of PAHs.

Polycyclic aromatic hydrocarbons (PAHs) and metals are co-contaminants of aquatic environments near industrial and urbanized areas. Mixtures could result in synergistic toxicity impairing macrophyte growth and potentially causing bioaccumulation and biomagnification throughout the ecosystem. In this study, combinations of 1,2-dihydroxyanthraquinone (1,2-dhATQ) and copper (Cu) at low concentrations synergistically inhibited Lemna gibba (duckweed) growth. Further analysis using fluorescence techniques showed an increase in reactive oxygen species (ROS) levels upon Cu exposures possibly through redox cycling in the chloroplasts. Pulse amplitude modulated (PAM) and fast repetition rate fluorometry (FRRF) indicated that plants exposed to 1,2-dhATQ had impaired photosynthetic electron transport that manifested as a decrease in the yield of photosynthesis and change in the redox status of the plastoquinone (PQ) pool. At the gene expression level acetyl coA carboxylase (ACC), a key enzyme in membrane repair, and serine decarboxylase (SDC), another enzyme needed for membrane repair were up-regulated in response to copper and 1,2-dhATQ, respectively. The mechanism for mixtures toxicity is thought to involve the reduced PQ pool which could serve as a source of electrons for copper redox cycling thereby increasing ROS production and causing synergistic growth inhibition. When the antioxidant glutathione (GSH) was added, copper toxicity was ameliorated but 1,2-dhATQ toxicity increased possibly through formation of reactive conjugates or suppression of the native antioxidant system. This study emphasizes that mixtures of toxicants at low concentrations can cause more biological damage than individual toxicants via alterations of the redox status and increases in ROS production.