The accumulation of polychlorinated biphenyls (PCBs) into humans was described using CoZMoMAN, a mechanistic multimedia fate and transport model coupled to a human food chain model. Model results demonstrated that concentration-age relationships for population cross-sections and individuals over time are not equivalent and that, under steady-state conditions, the lipid-normalized concentration of PCBs in an individual does not monotonically increase with age. By considering the decades-long emission history of PCBs in the model simulations, it was shown that an individual’s concentration mostly depends upon when she/he was born relative to the peak in emissions. Similarly, the two most influential factors controlling the shape of cross-sectional concentration-age trends obtained in human biomonitoring studies are the time lapse between the peak in emissions and sample collection and chemical elimination half-life. As a result, it should be possible to deduce information on these two factors from the shape of cross-sectional concentration-age trend. Reproductive behaviours (parity, age at birth, breastfeeding) were shown to potentially have a significant impact on exposure (and can contribute substantially to the observed variability in biomonitoring studies) though the mother’s reproductive history has a greater influence on the prenatal and postnatal exposures of her children than it does on her own cumulative lifetime exposure. A case study of the influence of dietary transitions in a hypothetical Arctic community demonstrated that dietary transitions are an important factor underlying the variability in PCB body burdens within and between subpopulations in addition to partially explaining the observed temporal trends. Comparison of PCB partitioning to various lipid materials suggested that 1) triolein is a good surrogate for human storage lipids; 2) liposomes are not an appropriate surrogate for human storage tissues; and 3) that partitioning into human MCF-7 cells is dominated by the storage lipids rather than by membrane lipids. Finally, a new bioenergetically-balanced bioaccumulation (3B) fish model is presented. Comparison of results from the 3B model with that of existing models revealed that feeding and growth rates used by previous fish bioaccumulation models were not bioenergetically consistent. Differences in biomagnification factors with fish size and temperature as a result of differing energetic requirements demonstrated the importance of the assumptions regarding growth rate and feeding rate.

Mémoire numérisé par la Direction des bibliothèques de l’Université de Montréal. / Methodology was developed for synthesizing chemical libraries for discovering new peptide honnone receptor ligands. In particular, a combinatorial strategy was used for library synthesis of neruokinin and somatostatin receptor ligand candidates. This strategy was based on the design and synthesis of indolizidin-2-one amino acid scaffolds and their subsequent incorporation into a series of amido amides (88-140) using a novel solid-phase approach. Dipeptide mimic 7-benzylindolizidinone amino acid 48 was synthesized on a gram scale by a literature procedure and then introduced into a library of candidates (88-140) to discover new somatostatin and nemokinin receptor ligands. A combinatorial strategy was employed for their synthesis which featured oxime resin as solid support. 7-Benzylindolizidinone AL(BOC) amino acid 48 was coupled to oxime resin. The library members were then obtained by a sequence featuring deprotection of the BOC group, free basing and coupling to the amine with 5 different carboxylic acids, followed by displacement with 9 different primary amines to give amido amide targets. (J A second scaffold was conceived and synthesized in the second part of the thesis. Enantiopure 7^-(BOC)amino-7-[3-azidopropyl]mdolizidm-2-one acid 141 has been synthesized by displacement of the methanesulfonate of its 7- hydroxypropyl counterpart 151 with sodium azide and subsequent ester hydrolysis. ^V-(BOC)Amino-7-[3-hydroxypropyl]indolizidin-2-one ester 151 was obtained from a sequence commencing with the alkylation of (2S,SS)-di-tertbutyl 5-oxo-2,8-di-[^-(PhF)amino]azelate 75 (PhF = 9-(9-phenylfluorenyl)). Stereoselective allylation of 75, regioselective olefin hydroboration, selective primary alcohol protection as a silyl ether and oxidation of the secondary alcohol gave (2S,4R,SS)-di-tert-buty\ 4-[3-tër/-butyldimethylsiloxypropyl]-5-oxo-2,8-din [AL(PhF)amino]azelate 149 as a pure diastereomer in 33% overall yield. Linear ketone 149 was then converted into the indolizidinone heterocycle by a route featuring reductive amination, lactam cyclization and isolation by way of a silyl ether which provided the (6>S',7^?)-isomer of 151. Enantiopure 7V-(BOC)amino-7- (3-azidopropyl)indolizidin-2-one acid 141 was also achieved by converted 151 to its respective methanesufonate followed by displacement with sodium azide. In summary, this thesis provides first an introduction into the importance of the peptide hormones Substance P and somatostatin. The combinatorial strategy is then illustrated by the introduction of 7-benzylindolizidin-2-one 48 into a focused library. Finally, methodology is presented for preparing alternative 7-alkylindolizidin-2-one amino acid scaffolds. / Une méthodologie a été développée pour la synthèse d'une librairie de molécules dans le but de mettre au point de nouveaux ligands pour les récepteurs d'hormones peptidiques. En particulier, une stratégie combinatoire a été utilisée dans la synthèse d'une librairie de ligands potentiels aux récepteurs de la neurokinine et de la somatostatine. Cette stratégie est basée sur le design et la synthèse des acides aminés indolizidin-2-one comme squelettes et leur incorporation dans une série d'amido amides utilisant une nouvelle approche sur support solide. Le peptidomimétique 7-benzylindolizidinone 48 a été synthétisé sur une échelle multigramme selon un protocole de la littérature et a ensuite été incorporé dans une librairie de ligands potentiels aux récepteurs de la somatostatine et de la neurokinine. L'approche combinatoire utilisée pour la synthèse fait appel à la résine d'oxime comme support solide. L'acide aminé 7- benzylindolizidinone N-(BOC) 48 a été couplé à la résine. La librairie moléculaire a ensuite été obtenue par la déprotection du groupe BOC, l'obtention de la base libre et le couplage de l'amine avec cinq différents acides carboxyliques, suivi du déplacement avec neuf aminés primaires différentes pour donner les amido amides ciblés. Un deuxième squelette a été conçu et synthétisé dans la deuxième partie du projet. L'acide ^V-(BOC)amino-7-[3-azidopropyl]mdolizidm-2-one énantiopur 141 a été synthétisé par le déplacement du méthanesulfonate du 7-hydroxypropyl 151 avec l'azoture de sodium suivi de l'hydrolyse de l'ester. L'ester N- (BOC)amino-7-[3-hydroxypropyl]indolizidin-2-one 151 fût obtenu par une séquence de réactions commençant par l'alkylation du (25', SS)-di-tert-butyï-5- oxo-2,8-di-[^-(PhF)amino]azélate 75 (PhF = 9-(9-phénylfluorényl)). L'allylation stéréosélective de 75 , suivi de l'hydroboration régiosélective de l'oléfme, de la IV protection sélective de l'alcool primaire sous forme d'ether silylé puis de l'oxidation de l'alcool secondaire a donné le (25', 4R, SS)-di-tert-bvtyl-4-[3-tertbutyldiméthylsiloxypropyl]- 5-oxo-2,8-di-[AL(PhF)amino]azélate 149 comme seul diastéréoisomère dans un rendement global de 33%. La transformation de la cétone 149 en hétérocycle indolizidinone a par la suite été réalisée par une amination reductive, une cyclisation à la lactame et l'isolation sous forme d'ether silylé pour donner l'isomère (65, 77?) de 151. L'acide 7^-(BOC)amino-7-[3- azidopropyl]indolizidm-2-one 141 énantiopure a aussi été synthétisé par la conversion de 151 au méthanesulfonate correspondant suivi du déplacement avec l'azoture de sodiuni. En résumé, ce mémoire donne premièrement une introduction à l'importance des hormones peptidiques que sont la substance P et la somatostatine. La stratégie utilisée est ensuite illustrée par l'introduction du 7- beiizylindolizidin-2-one 48 dans une librairie de molécules. Finalement, la méthodologie pour préparer différents acides aminés 7-alkylindolizidin-2-one est présentée.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeröy / Co-crystallization allows the manipulation of physical properties of a given compound without affecting its chemical behavior. The ability to predict hydrogen bonding interactions, provides means to the rational design of supramolecular architectures. It also makes it possible to select with a degree of accuracy, a few co-formers that have a high probability of forming co-crystals with a compound of interest, instead of blindly screening against a large number of candidates. To study the effects of changing electronic environment on the ability to form co-crystals, five symmetric dioximes of different hydrogen bond donating ability were synthesized with different functional groups on the carbon α to the oxime moiety. It was shown that the supramolecular yield increase with the positive MEP value on the donor site. In order to further explore this relationship between calculated MEP values and supramolecular selectivity three asymmetric ditopic donors containing phenol carboxylic acid and aldoxime groups were screened against a series of asymmetric ditopic acceptors. Nine crystal structures show that the supramolecular outcome can be predicted according to Etter’s rules by ranking donors and acceptors according to calculated MEP values. To explore the possibility of using the same approach with other hydrogen bond donors, three asymmetric ditopic donor ligands containing cyanooxime groups were synthesized and screened against a series of asymmetric ditopic acceptors. Nine out of ten times the supramolecular outcome could be predicted by MEP calculations 1-deazapurine exists in two tautomeric forms (1H and 3H) in aqueous solution, which have very different hydrogen bonding environments. The 3H tautomer forms a self-complementary dimer involving a donor and an acceptor site leaving a second acceptor site vacant. In order to stabilize this tautomer the molecule was screened against a of series hydrogen and halogen bond donors. Four out of five structures obtained showed 3H tautomer. The 1H tautomer is the geometric complement of urea. Therefore the molecule was screened against a series of N,N-diphenylureas and all five structures showed the 1H tautomer.

Doctor of Philosophy / Department of Chemistry / Christopher J. Levy / The helix is an important chiral motif in nature, there is increasing development in field of helical transition metal complexes and related supramolecular structures. Hence, the goals of this work are to apply the principles of helicity in order to produce metal complexes with predictable molecular shapes and to study their properties as asymmetric catalysts. Computational studies suggest that the (1R,2R)-cyclobutyldiamine unit can produce highly twisted salen complexes with a large energy barrier between the M and P helical forms. To test this prediction, the tartrate salt of (1R,2R)-cyclobutyldiamine was synthesized and condensed with a series of saliclaldehydes to produce novel salen ligands. The salicylaldehydes chosen have extended phenanthryl or benz[a]anthryl sidearms to encourage formation of helical coordination complexes. These ligands were metallated with zinc, iron and manganese salts to produce salen metal complexes which were characterized by NMR analysis, high-resolution mass spectrometry, and IR spectroscopy. A second ligand type, neutral bis(pyridine-imine) has also been synthesized from (1R,2R)-cyclobutyldiamine and quinolylaldehydes. The synthesis of bis(pyridine-imine) ligands was conducted using greener method, solvent assisted grinding. These ligands, in-situ with nickel metal salts, showed good catalytic activity for asymmetric Diels-Alder reactions. The third ligand type studied was chiral acid-functionalized Schiff-base ligands. These were synthesized by the condensation of 3-formyl-5-methyl salicylic acid and (1R,2R)-cyclobutyldiamine. With this type of ligand, there is possibility of producing both mono and dinuclear metal complexes. In our studies, we were only able to synthesize mononuclear complexs. These were tested as catalysts for asymmetric direct Mannich-type reaction, but were found to be ineffective.

Introduction: Currently, there are no objective techniques to assess burn depth. An early assessment of burn depth would enable accurate management decisions, which would improve patient outcomes. Near infrared (NIR) technology has shown promise as a non-invasive monitor of oxygenation and perfusion, and its potential to assess the depth of burn injuries has been investigated clinically over the past five years. The purpose of the thesis was to determine the capacity of NIR technology to differentiate acute thermal injuries. Methods: Burn sites (n=5) and control sites (n=5) were created on the dorsum of sixteen animals with brass rods held at constant pressure and heated to 100°C and 37.5°C respectively. NIR data was collected from the burns and control sites pre-burn, immediately post-burn, and 1, 12, 24, 36, 48 and 96 hours after the burn injury. Biopsies of the burn and control sites were acquired at each time point and used to confirm the depth of injury. NIR data was processed for the content of water, oxy-, deoxy- and methemoglobin. Results: Oxyhemoglobin and total hemoglobin decreased as burn depth increased. The proportion of oxy- and deoxyhemoglobin to total hemoglobin showed that the ratio of oxy- to deoxyhemoglobin decreased as burn injury increased. Methemoglobin levels as a ratio of total hemoglobin also showed that as the severity of injury increased the proportion of methemoglobin also increased. Finally, superficial partial thickness injuries (3 s and 12 s) showed early peak levels of water, which rapidly declined towards baseline. The deep partial thickness injuries (20 s and 30 s) do not experience peak levels and retain water over the course of the experiment. The full thickness injuries water levels remain close or below baseline levels throughout the experiment. Conclusion: NIR spectroscopy could distinguish burn depth using water, oxy-, met- and total hemoglobin as separate entities. The presence of methemoglobin in the burn wounds is a novel finding that has not been described previously in burn literature.

Doctor of Philosophy / Department of Chemistry / Christopher J. Levy / A series of chiral titanium and manganese complexes with helix-directing salen ligands have been prepared, characterized and studied. Their structures displayed as a chiral helical motif as expected. And it was also found that all M(salen) units were exclusively M-helimeric in the solid state, except Ti(cyclohexyl-benz[a]anthryl) as P-helix. This may be due to the energy difference between P and M helice, which enables crystal packing forces to control and drive the molecular structure. This is also in agreement with the previous computational studies that the M configuration predominates in THF solution. All metal centers adopt a cis-β octahedral geometry except in Mn(binapthyl-phenanthryl-salen). Most of M(salen) complexes in this work afforded μ–oxo dinuclear helicates, instead of the expected monohelicate, except Mn(binapthyl-phenanthryl-salen), which is bridged by a third salen ligand. The titanium salt affected the complex solution behavior. In the presence of Cl[superscript]-, only mononuclear species was found by ESI-MS, while both di- and mononuclear species was found in MeOH in the presence of –O[superscript]iPr. The NMR spectra of Ti(salen) indicated one major species with cis-β geometry exist in most solution, which could be monomer or dimer, except Ti(binapthyl-salen). No counterions have been found in the solid state of Mn(salen) complexes in this work, but they affected the ligand decomposition in the solution in Mn(binapthyl-phenanthryl-salen). The Mn(salen) complexes could effectively and enatioselectively catalyze the asymmetric epoxidation of somoe trans, cis and terminal olefin, and various oxidants were employed.

Doctor of Philosophy / Department of Chemistry / Sundeep Rayat / Sundeep Rayat / This dissertation focused on the synthesis of 1-(2-ethynylphenyl)-4-phenyl tetrazole-5-thione derivatives 1 and evaluating their potential as a new class of photoactivated DNA cleaving prodrugs. We hypothesized that light activation of 1 would cause the decomposition of the tetrazolethione ring system to enyne-carbodiimide 2 with simultaneous loss of dinitrogen and sulfur via 1,3-triplet biradicals 1′, which would be spontaneously followed by Schmittel cyclization to indoloquinolines 3 via benzofulvene type biradicals 2′. The biradicals 1′ and 2′ would have the potential to cause DNA cleavage by abstracting hydrogens from its sugar phosphate backbone, analogous to the mechanism of action of naturally occurring enediyne antitumor antibiotics. Note that our proposed prodrugs contained a 1,4-diaryl tetrazolethione functionality and a direct synthetic route for their construction was lacking in the literature despite their wide spread applications. Therefore, our initial efforts were directed towards developing a general strategy to obtain these ring systems. We employed a highly versatile and efficient copper mediated N-arylation to first obtain a series of 1,4-diaryl tetrazol-5-ones which were thionated with Lawesson’s reagent to afford the corresponding 1,4-diaryl tetrazole-5-thiones in moderate yields. Specifically, the synthesis of 1 involved Sonogashira coupling of the obtained 1-(2-bromophenyl)-4-phenyl-1H-tetrazole-5(4H)-thione with the appropriate ethynyl compounds (Chapter 2). Since the tetrazole ring is an important structural component in many biologically and medicinally relevant compounds, we were interested in evaluating the anticancer activity of these compounds in the absence of photochemical activation. The moderate IC50 values against leukemia and breast cancer cell lines showed that the anticancer activity of these compounds prior to photoirradiation was minimal (Chapter 3). Independent studies have shown that the photodecomposition of tetrazolethiones gives carbodiimides via biradicals, and photocyclization of enyne-carbodiimide forms indoloquinoline also via biradicals. However, it was not known whether these two photoreactions could happen sequentially in one pot with one light source from a substrate like 1, generating biradicals 1′ and 2′ which could later be employed for DNA photocleavage as hypothesized. Therefere, we photolysed 1 in acetonitrile, and our results show clean formation of a mixture of enyne-carbodiimides and indoloquinolines via biradicals 1′ and 2′ (Chapter 4). Finally, we investigated DNA photocleavage by 1 at 350 nm and our results showed significant DNA cleavage in concentrations as low as 100 μM (Chapter 5).

Master of Science / Department of Chemistry / Kenneth J. Klabunde / The motivation for the preparation of gold nanoparticles includes their potential utility in sensors, nanoelectronics, and the vast basic knowledge we can gain from these novel materials. Colloids of gold nanoparticles are also one of the most stable and easiest to manipulate. Synthesizing gold nanoparticles with narrow size distribution, uniform shape, and good crystalline nature represents a significant challenge. Thiols were found to be very efficient capping ligands for the digestive-ripening process in our research group, during which a colloidal suspension in a solvent is refluxed at the solvent boiling temperature in the presence of a capping ligand to convert a highly polydispersed colloid into a nearly monodispersed one. The current thesis research focuses on using amines instead of thiols as the capping ligands, which were also found to have similar efficiency for this purpose. The major part of the work is devoted to understanding the digestive ripening of gold-amine colloids system, and the effect of the nature of the amine ligands. A noteworthy achievement of the current work is the ability to synthesize stable gold colloids with different sizes by using different amine ligands. A diverse set of instrumental techniques is used for the characterization of the gold nanoparticles.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first chapter of the thesis involves the design, synthesis, and anti-influenza activity of quercetin derivatives. Influenza viruses are important pathogens that cause respiratory infections in humans and animals. In addition to vaccination, antiviral drugs against influenza virus play a significant role in controlling viral infections by reducing disease progression and virus transmission. Plant derived polyphenols are associated with antioxidant activity, anti-carcinogenic, and cardio- and neuro-protective actions. Some polyphenols, such as resveratrol and epigallocatechin gallate (EGCG), showed significant anti-influenza activity in vitro. The antiviral effects of isoquercetin were greater than that of quercetin with lower IC[subscript]5[subscript]0 values and higher in vitro therapeutic index. Various phenolic esters, alkoxy and aminoalkoxy derivatives of quercetin were synthesized by functionalization of C3, C3’, and C5 hydroxyl groups. Antiviral activities of these synthesized compounds were tested against influenza virus (porcine H1N1 strain). Quercetin-3-gallate which is structurally similar to EGCG showed greater antiviral activity among the synthesized compounds. Its antiviral activity was comparable to that of EGCG with better in vitro therapeutic index. Second chapter in the thesis involves the progress towards the synthesis of mini graphenes like hexa-peri-benzocoronene cyclophane (HBCC). Bilayered graphenes are highly conducting materials with potential application in electronic devices and in lithium ion batteries. Despite great potential, bilayer graphenes with defined distance between the two layers have not been achieved through chemical synthesis. Chemical synthesis of hexa-peri-benzocorenene cyclophane (HBCC) from commercially available p-xylene was carried out. Final product, presumably compound 90 (the structure has not been completely characterized), is insoluble in all tested solvents including aqueous acids and organic solvents such as DMSO, DMF, benzene, 1,2-dichlorobenzene, dichloromethane, THF, hexanes and diethyl ether. The insoluble nature of the final product restricted the analysis to UV-visible spectroscopy. Synthesis of soluble analog incorporating the long chain ether groups is being investigated in Dr. Hua’s laboratory.

Doctor of Philosophy / Department of Chemistry / Ryszard J. Jankowiak / Low-temperature laser-induced fluorescence spectroscopy has various applications in analytical, physical, and biophysical chemistry. This technique provides information on the fluorescence origin band, zero-phonon lines and phonon-sidebands, inhomogeneous broadening, electron-phonon coupling strength, and ground- and excited-state vibrational frequencies of studied molecules. Examples discussed in this work include studies of DNA/metabolites and monoclonal antibody (mAb)/antigen interactions. The structural basis for the increased reactivity of BPDE towards guanines at 5-methylcytosine ([superscript]M[superscripte]eC):G sites in DNA was investigated by low temperature laser-based spectroscopy, studying the nature of physical complexes of benzo[a]pyrene tetraol in a series of 5-methylcytosine structural DNA analogs. We found that the presence of a C-5 substituent on cytosine and related structural modifications influences the conformation of BPT in DNA analogs, and could explain the increase in guanine reactivity at [superscript]M[superscript]eC:G sites of the p53 tumor suppressor gene that contains endogenenous 5-([superscript]M[superscript]eC. It has been demonstrated that various mAbs can bind a particular cross-reactant by adopting two distinct "red" and "blue" conformations of its binding sites. We showed that the blue conformation of pyrene in several mAbs (including 4D5 mAb) is consistent with [pi]-cation interactions, underscoring the importance of [pi]-cation interaction in ligand binding. We propose that considerable narrowing of the fluorescence origin band of the ligand in the protein environment could be regarded as a simple indicator of [pi]-cation interactions. It is also shown that time-resolved delta fluorescence line-narrowing ([delta]FLN) spectroscopy, using excitation within the (0,0)-transition band, provides more reliable information of the frequency dependence of the electron-phonon coupling (Huang-Rhys factor, (S < 1). Finally, analytical formulas were developed to describe FLN spectra with excitation energy transfer present. Our calculated FLN spectra are compared with spectra obtained by a simple convolution method (SC) and a more rigorous treatment using Redfield theory. We demonstrate that, under the condition of weak coupling between pigments (i.e., the coupling constant is smaller than the reorganization energy) and weak electron-phonon coupling strength (S < 1), our analytical formulas provide an excellent approximation of the SC and Redfield methodologies. We argued that our approach could also model FLN spectra obtained for very complex biological systems.