Carbon tetrachloride (CCl4) is a hepatotoxicant known to elevate alanine aminotransferase (ALT) and other liver enzyme levels, and cause lipid peroxidation, as well as centrilobular necrosis. A number of poly ADP-ribose polymerase (PARP) inhibitors were administered via intraperitoneal (i.p.) injections to male ICR mice as cotreatments at various time intervals relative to the CCl4. Aminophylline, a water soluble complex consisting of two molecules of theophylline bridged by ethylene diamine, was administered one-half hour, one hour and two hours after CCl4. The levels of ALT in the serum, as well as malondialdehyde and its equivalent markers of oxidative damage in the liver, were significantly reduced by aminophylline, relative to those in mice receiving only CCl4. The hepatoprotective effects of aminophylline were confirmed via the examination of histopathologic samples from the livers of mice receiving aminophylline in conjunction with CCl4 as opposed to those administered CCl4 alone. The potential benefit to society as a result of this research is that aminophylline, which has already been approved by the Food and Drug Administration (FDA), could potentially be administered in the event of an overexposure to CCl4 or similar halocarbons to minimize the free radical-mediated hepatotoxicity resulting from overexposure.

The cortistatins are a recently identified class of marine natural products that were found to exhibit potent and selective inhibition of human umbilical vein endothelial cells (HUVECs), making them promising leads for the development of anti-angiogenic drugs. In our synthesis, we envisioned that natural cortistatins and unnatural analogs could be prepared by late-stage introduction of isoquinolines to 17-keto precursors, and that these differentially substituted precursors could all be derived from a common key intermediate 112. We developed a robust synthetic route to prepare gram quantities of key intermediate 112 starting from readily available benzylzinc reagent 116 and enol triflate 117. Key intermediate 112 was next converted to cortistatin precursors 108, 109, 110, and 111 in three to eight steps, representing each of the four natural cortistatin ABC-ring substitution patterns. Subsequently, a generally applicable method was developed to introduce the isoquinoline moiety. After complexation to N,N,N',N'-tetramethylethylenediamine (TMEDA), 7-lithio-isoquinoline added to 17-keto precursors to provide the corresponding 1,2-addition products; the resulting tertiary alcohols underwent radical deoxygenation via their trifluoroacetates to afford the desired (17S)-products. This organolithium-addition-deoxygenation sequence provided cortistatins A (1, on a 20-mg scale), J (9), K (10), and L (11) in good overall yields. We also synthesized cortistatin primary amines (176 and 186) and used them to prepare several cortistatin based affinity reagents. By employing these reagents in pull-down experiments, we identified a 55-kD membrane kinase as a putative protein target of cortistatins. We wanted to prepare cortistatin analogs with isoquinoline modifications due to the importance of this ring for the biological activity of cortistatins. This led us to develop a novel and versatile synthesis of substituted isoquinolines. In our method, lithiated o-tolualdehyde tert-butylimines were condensed with different nitriles to generate eneamido anion intermediates, which were trapped in situ with various electrophiles at the C4-position, affording a wide range of substituted isoquinolines. Further diversification was achieved by modification of the work-up conditions and by subsequent transformations. / Chemistry and Chemical Biology

Two-photon absorption is the process in which a molecule absorbs two photons simultaneously. The two key advantages of two-photon processes over one-photon processes are the possibility of excitation of materials with high three-dimensional spatial resolution and deep light-penetration into absorbing materials. Based on bond-cleavage reactions activated by photon-induced intramolecular electron transfer, two-photon activatable acid and radical initiators and two-photon removable protecting groups have been successfully designed and synthesized for photopolymerization and three-dimensional microfabrication and for biomedical photo-triggers. The optical and chemical properties of synthesized molecules, such as quantum yield of acid generation, initiation efficiency of photopolymerization, and photolysis efficiency, have been studied by using a variety of physical and analytical techniques under one-photon conditions. The two-photon characteristics and applications of these molecules are being investigated in collaboration with other groups.

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.

A new treatment technology, called Advanced Reduction Process (ARP), was developed by combining UV irradiation with reducing reagents to produce highly reactive species that degrade contaminants rapidly. Vinyl chloride (VC) and 1,2-dichloroethane (1,2-DCA) pose threats to humans and the environment due to their high toxicity and carcinogenicity. In this study, batch experiments were conducted under anaerobic conditions to investigate the degradations of VC and 1,2-DCA with various ARP that combined UV with dithionite, sulfite, sulfide or ferrous iron. Complete degradation of both target compounds was achieved by all ARP and the reactions were found to follow pseudo-first-order decay kinetics. The effects of pH, sulfite dose, UV light intensity and initial contaminant concentration on the degradation kinetics were investigated in the photochemical degradation of VC and 1,2-DCA by the sulfite/UV ARP. The rate constants were generally promoted by raising the solution pH. The optimal pH conditions for VC and 1,2-DCA degradation were pH 9 and pH 11,respectively. Higher sulfite dose and light intensity were found to increase the rate constants linearly for both target contaminants. A near reciprocal relation between the rate constant and initial concentration of target compounds was observed in the degradation of 1,2-DCA. The rate constant was observed to be generally independent of VC concentration, but with a slight increase at lower concentrations. A degradation mechanism was proposed that described reactions between target contaminants and reactive species such as the sulfite radical and hydrated electron that were produced in the photolysis of sulfite solution. A mechanistic model that described major reactions in the ARP system was developed and explained the dependence of the rate constant on those experimental factors. Chloride ion and chloroethane were detected as the major degradation products at acid and neutral pH. An increase in pH promoted the extent of dechlorination with complete dechlorination being observed at pH 11 for both VC and 1,2-DCA. Due to the rapid degradation kinetics in these ARPs, this new treatment technology may be applied to remove various contaminants in water and wastewater.

In the last decade processes known as living/controlled radical polymerizations (L/CRP) have been developed which permit the synthesis of high-value specialty polymers. Currently, the three processes that have demonstrated the most potential are: reverse addition fragmentation chain transfer polymerization (RAFT), atom transfer radical polymerization (ATRP) and stable free radical polymerization (SFRP). While each process has their strengths and weaknesses with regard to specific polymers and architecture, the viability of these systems to industrial scale production all lie in the ability to perform the polymerization in a water based system because of process, environmental and economic advantages. The most effective method of controlling the polymerization of vinyl acetate in bulk has been RAFT. We have developed a miniemulsion RAFT polymerization using the xanthate methyl (ethoxycarbonothioyl)sulfanyl acetate. The miniemulsion is stabilized with 3 wt% sodium lauryl sulfate, initiated with the azo-based water-soluble VA-060. The main focus of this research was adapting ATRP to a miniemulsion system. It was determined that ionic surfactants can be successfully employed in emulsion-based ATRP. The cationic surfactant cetyltrimethylammonium bromide provides excellent stability of the latex over a range of surfactant loadings (allowing the particle size to be easily manipulated), at temperatures up to 90 C, for a wide variety of ATRP formulations. A new method of initiation was developed for reverse ATRP, using the redox pair hydrogen peroxide/ascorbic acid. This nearly eliminated the induction period at the start of the polymerization, increased the polymerization rate 5 fold and, surprisingly, enabled the formation of well-controlled polymers with a number-average molecular (Mn) weight approaching 1 million (typically ATRP is limited to ~200 000). The ability to control the particle size and the number of polymer chains (through the target Mn) over a wide range of values allowed us to determine that ATRP is influenced by compartmentalization effects. The knowledge gained from our work in L/CRP was used to develop the surfactant-free SFRP of styrene. A multi-stage approach was adopted starting from dilute styrene/water solutions to favor the formation of the alkoxyamine and short chain SG1-oligomers (stage one) before the addition of the majority of the styrene (stage two). / Thesis (Ph.D, Chemical Engineering) -- Queen's University, 2007-09-14 12:09:32.266

Acrylic free radical polymerization at high temperature proceeds via a complex set of mechanisms, with many rate coefficients poorly known and difficult to determine experimentally. This problem is compounded by the large number of monomers used in industry to produce coatings and other materials. Thus, there is a strong incentive to develop a methodology to estimate rate coefficients for these systems. This study explores the application of computational chemistry to estimate radical addition rate coefficients for the copolymerization of acrylates, methacrylates and styrene. The software package Gaussian is used to calculate heats of reaction (ΔHr) values for monomer additions to monomeric and dimeric radicals, using minimum energy structures identified and characterized for the reactants and products. The Evans-Polanyi relationship is applied to estimate reactivity ratios from the relative differences in ΔHr. The validity of this methodology is tested through a comparison of calculated monomer and radical reactivity ratios for acrylate, methacrylate, vinyl acetate, ethene and styrene systems to available experimental data for copolymerization systems. The methodology is found to work for some systems while there is computational breakdown in others due to steric crowding and/or breakdown of the Evans-Polanyi relationship. / Thesis (Ph.D, Chemical Engineering) -- Queen's University, 2008-04-25 16:13:12.091 / NSERC

Background: We evaluated the validity of a set of 11 quality indicators for prostate cancer radiotherapy and radical prostatectomy by examining their association with outcomes. The selected indicators were: hospital volume, pre-treatment risk assessment, patient consultation with a radiation oncologist, appropriate follow-up care, leg immobilization during radiotherapy, bladder filling during radiotherapy, portal film target localization, use of nerve sparing surgery, operative blood loss, margin status and pelvic lymph node dissection. The selected outcomes were: cause-specific survival, disease-free survival, late morbidity (urinary incontinence, gastrointestinal and genitourinary morbidity), change in node stage from clinical N0 to pathologic N1, and margin status. Methods: Our study sample consisted of 1570 prostate cancer patients who were diagnosed in Ontario between January 1, 1990 and December 31, 1998 who received radical prostatectomy within 6 months of diagnosis (n=646), or curative radiotherapy within 9 months of diagnosis (n=924). Quality of care, outcomes, and potential confounders were measured using patient chart and administrative data. Regression techniques were used to evaluate the associations between quality indicators and relevant outcomes. Results: For patients treated surgically, hospital volume met our test of validity. Patients treated in the lowest volume hospital (0-1 RP/month) were at greater risk of prostate cancer death than patients treated in the highest volume hospitals (7+ RP/month) (HR=5.37 95% CI=1.23-23.46). For patients treated with radiotherapy, leg immobilization and bladder filling during radiotherapy met our test of validity. Patients treated without leg immobilization were more likely to experience urinary incontinence (RR=2.18, 95% CI=1.23-3.87) and genitourinary late morbidities (RR=1.72, 95% CI=1.16-2.56) than patients who received leg immobilization. Patients who were treated with an empty bladder were more likely to experience GU late morbidities (RR=1.98, 95% CI=1.08-3.63) than those treated with a full bladder. The remaining indicators did not meet our test of validity. Conclusion: Our results support the validity of one surgical quality indicator and two radiotherapy quality indicators. Explanations for our non-significant findings, including limited study power, data quality, our definition and measurement of indicators, and a true failure to predict outcome(s) are discussed, and recommendations for further research are presented. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2011-09-07 20:26:34.461

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.

This thesis applies the radical feminist perspective set out by MacKinnon (1993) and Dworkin (1995), to analyze the construction of female sexuality within popular Canadian men’s pornographic magazines and non-pornographic magazines. A mixed methods approach was used to analyze the images and text within the feature articles of the selected magazines. Results revealed that women continue to be constructed as sexual objects within both categories of magazines, but the earlier link identified by MacKinnon and Dworkin between violence and sexuality was on longer apparent. Instead, women were a sexual puzzle that the magazines attempted to unpack. Rather than a strict dichotomy between pornographic and non-pornographic magazines, a continuum of grey emerged whereby the level of explicitness between the two magazines increased as the continuum progressed from left to right, thereby demonstrating the pornographication of mainstream media, as per McNair (2002).