The objective of this thesis is to examine the photophysical and structural properties of Cu(I) complexes of 2-(2’-pyridyl)benzimidazolyl based ligands and Cu(I), Pd(II) and Pt(II) complexes of 2-(2’-pyridyl)indolyl based ligands, for possible use as phosphorescent emitters in OLEDs. The discovery of the atropisomeric 3,3’-bis(2-(2’-pyridyl)indolyl based ligands led to the examination of C-C coupling reactions and the investigation of the new chiral ligands with transition metal ions. Cu(I) complexes of 2-(2’pyridyl)benzimidazolyl-benzene with varying phosphine ligands were prepared. The structures were studied with X-ray crystallography and NMR. Experimental and computational results established that steric and electronic properties of the phosphine ligands influence the photophysical properties of the Cu(I) complexes. Polynuclear Cu(I) complexes with 2-(2’-pyridyl)benzimidazolyl based ligands and two PPh3 ancillary ligands were synthesized, the photoluminescent and electroluminescent properties were examined. A series of 2-(2’-pyridyl)indolyl based ligands; 2-(2’-pyridyl)indolyl-benzene (pib), 1,4-bis[2-(2’-pyridyl)indolyl]benzene (bib) and 1,3,5-tris[2-(2’-pyridyl)indolyl]benzene) (tib) and the corresponding C-C coupled dimers bis[3,3’(2-(2’-pyridyl)indolyl-benzene)] (bpib), bis[3,3’(1,4-bis[2-(2’-pyridyl)indolyl]benzene (bbib) and bis[3,3’(1,3,5-tris[2-(2’-pyridyl)indolyl]benzene)] (btib) were synthesized in a one-pot reaction with the formation of both C-N and C-C bonds. The photophysical properties of these new molecules were investigated. The dimers display intramolecular exciplex formation. The rotation barrier around the C-C bond in the 3 position of the bis-indole was calculated using DFT which support that bpib is an atropisomeric ligand. Cu(I), Pd(II) and Pt(II) complexes were synthesized with pib and bpib. [Cu(pib)(PPh3)2]+ contains a three-coordinate Cu(I) ion and doesn’t display MLCT but rather 3π-1π phosphorescence. In Pd(pib)(acac) and Pt(pib)(DMSO)Cl the pib ligand forms C,N chelated neutral complexes that display red emission in frozen solution and in solid state. The X-ray crystal structure for [Cu(bpib)2]+ revealed a homo-chiral crystal and for Pd(bpib)Cl2 and Pt(bpib)Cl¬2 show a trans-chelating geometry around the metal centre. Frozen solutions of [Cu(bpib)2]+ and Pd(bpib)Cl2 display MCLT phosphorescence. Finally the atropisomeric ligands bpib and bbib were examined as sensors to determine the enantiomeric excess of Zn(2-bromo-3-methylbutyrate)2 by CD spectroscopy. CD and fluorescent titration experiments verified that these ligands have selective interactions with different Zn(II) carboxylates. DFT computations showed that diastereomeric excess caused by chiral discrimination leads to the CD spectral-response of the atropisomeric ligands toward chiral Zn(II) carboxylates. / Thesis (Ph.D, Chemistry) -- Queen's University, 2008-09-25 09:54:21.464

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen found in unburned tobacco and tobacco smoke. To exert its carcinogenic effect, NNK is metabolically activated to reactive intermediates that can damage DNA by alkylation or pyridyloxobutylation. NNK also has the ability to induce DNA oxidation and alter DNA repair activities that can result in deficient repair and potentially exacerbate carcinogenesis. Base excision repair (BER) is a ubiquitous DNA repair system that mainly repairs oxidative DNA damage. The goal of this study was to determine the effect of NNK on DNA oxidation status and BER activity in A/J mouse lung and liver. Female mice were treated with 10 µmol of NNK i.p. and lung and liver were isolated 1, 2 and 24 hours post administration. DNA was isolated from lung and liver, and the formation of 8-hydroxydeoxyguanosine (8-OHdG, a biomarker of DNA oxidation) was assessed by high-performance liquid chromatography with electrochemical detection. At 1, 2 and 24 hours in both murine lung and liver, there was no statistically significant difference in 8-OHdG levels (n = 4, P > 0.05) between control and NNK-treated mice. To assess BER, cell-free whole tissue nuclear protein extracts from liver and lung were prepared and incubated with a plasmid substrate containing oxidative DNA damage. In vivo treatment with NNK did not alter BER activity in lung or liver compared to control mice (n=3 or 4, P > 0.05). These experiments indicate that acute treatment with a tumourigenic dose of NNK does not significantly stimulate oxidative DNA damage or significantly alter BER activity in murine lung and liver. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2011-04-28 17:42:08.172

Thèse (Ph.D)--Université Laval, 2001. / Titre de l'écran-titre (visionné le 22 mars 2004). Bibliogr. Présenté aussi en version papier.

Thèse (M.Sc.) -- Université Laval, 1997. / Bibliogr.: f. 74-84. Publ. aussi en version électronique.

The earliest landmark in computer technology was construction of the Electronic Numerial Integrator and Computer, ENIAC. Computational switching was performed with vacuum tubes and relays, rather large in size, making this computer rather unwieldy. The next milestone came with the integration of transistors into computers as the switching component. Since then, transistors have been miniaturised dramatically, resulting in the amount of components integrated on a computer chip increasing logarithmically with time. The components are nowadays so small and so densely packed that problems with leak currents and cross-talk can arise and the lower limit for transistor size will soon be reached. In order to meet increasing demands on the size and performance of electronics, a new paradigm is due – the molecular electronics approach. Oligothiophenes have been shown to possess the physical and chemical characteristics required for electron/energy transport in molecular systems. However oligothiophenes must be electronically coupled to other components within a molecular circuit for them to be functional. In this work, different modes of incorporation of [2,2’]-bipyridinyl functionalities onto the ends of prototypic oligothiophene wires have been examined. The bipyridine connectors allow complexation to metal centres which can then function as a source or sink of electrons in the circuit. Ruthenium tris-bipyridine complexes, in particular, possess interesting electrochemical and photophysical characteristics, making them suitable for use in molecular electronics. This thesis reports synthetic strategies to a range of novel ligands based on the [2,2’]-bipyridinyl system, together with a study of the redox and fluorescence properties of their ruthenium tris-bipyridine complexes. The mode of connection between the chelating bipyridine and the first member of the oligothiophene chain was found to have a profound effect upon the fluorescence lifetimes and intensities of the resulting complexes. The discovery of complexes exhibiting long and intense fluorescence (a requirement for directed electron/energy transfer within molecular networks) thus forms an important design element in future prototypes.

According to the famous axiom known as Moore’s Law the number of transistors that can be etched on a given piece of silicon, and therefore the computing power, will double every 18 to 24 months. For the last 40 years Moore’s prediction has held true as computers have grown more and more powerful. However, around 2020 hardware manufac-turers will have reached the physical limits of silicon. A proposed solution to this dilemma is molecular electronics. Within this field researchers are attempting to develop individual organic molecules and metal complexes that can act as molecular equivalents of electronic components such as diodes, transistors and capacitors. By utilizing molecular electronics to construct the next generation of computers processors with 100,000 times as many components on the same surface area could potentially be created. We have synthesized a range of new pyridyl thienopyridine ligands and compared the electrochemical and photophysical properties of their corresponding Ru(II) complexes with that with the Ru(II) complexes of a variety of ligands based on 6-thiophen-2-yl-2,2´-bipyridine and 4-thiophen-2-yl-2,2´-bipyridine. While the electrochemistry of the Ru(II) complexes were similar to that of unsubstituted [Ru(bpy)3]2+, substantial differences in luminescence lifetimes were found. Our findings show that, due to steric interactions with the auxiliary bipy-ridyl ligands, luminescence is quenched in Ru(II) complexes that in-corporate the 6-thiophen-2-yl-2,2´-bipyridine motif, while it is on par with the luminescence of [Ru(bpy)3]2+ in the Ru(II) complexes of the pyridyl thienopyridine ligands. The luminescence of the Ru(II) com-plexes based on the 4-thiophen-2-yl-2,2´-bipyridine motif was en-hanced compared to [Ru(bpy)3]2+ which indicates that complexes of this category are the most favourable for energy/electron-transfer sys-tems. At the core of molecular electronics are the search for molecular ON/OFF switches. We have synthesized a reversible double cyclome-tallated switch based on the Ru(tpy) complex of 3,8-bis-(6-thiophen-2-yl-pyridin-2-yl)-[4,7]phenanthroline. Upon treatment with acid/base the complex can be switched between the cyclometallated and the S-bonded form. This prototype has potentially three different states which opens the path to systems based on ternary computer logic.

Alveolar macrophages (AM) play an important role in pulmonary homeostasis by their cellular functions which include inflammatory mediator production and cytotoxic activity. Epithelial cells are known for their role as a physical barrier, gas exchange and ion and fluid transport. However, they can also initiate the pulmonary immune response by secreting many inflammatory mediators. The functions of these two cell types are affected by cigarette smoke, which is composed of more than 4 000 compounds, 20 of which are known to be pulmonary carcinogens. One of these carcinogens, 4-(methylnitrosamino)-l- (3-pyridyl)-l-butanone (NNK), has a strong specificity for pulmonary tissues. This compound also has an immunomodulatory effect on AM mediator production. Many metabolic pathways of NNK performed by AM may be responsible for the immunomodulatory effects observed. We investigated these pathways to characterize the major one implicated in the effects of NNK on AM. We also studied the implication of NNK on cytotoxic activity of AM against tumoral cells. Knowing the importance of epithelial cells in the pulmonary immune response, we investigated the effect of NNK on these cells at the bronchial and alveolar level and identified the major pathway implicated. Our study showed that the a-methylhydroxylation pathway is responsible for the immunomodulatory effects on AM and epithelial cells. NNK, like cigarette smoke, inhibits AM cytotoxicity. This study indicates that NNK modulates cellular function of both AM and epithelial cells. Cell-cell communication between these two cell types being a leading event in the pulmonary immune response, we investigated the effect of NNK on this communication. This study, specific to NNK's modulatory effect on immune response, shows the global effect of NNK at the pulmonary level. This study also reports that NNK carcinogenic mechanism may involved the inhibition of defence pulmonary mechanisms in addition to forming DNA adducts. / Plusieurs cellules pulmonaires, dont les macrophages alvéolaires (MA) et les cellules épithéliales, peuvent être affectées par une exposition à la fumée de cigarette. Les MA sont responsables de l'intégrité immunologique du poumon de par leurs nombreuses fonctions dont la production de médiateurs inflammatoires et leur activité cytotoxique. Les cellules épithéliales sont reconnues pour leur rôle de barrière physique, les échanges gazeux ainsi que le transport ionique et liquidien, mais elles peuvent aussi initier la réponse immune pulmonaire en sécrétant différents médiateurs inflammatoires. La fumée de cigarette contient plus de 4000 composants, dont une vingtaine sont des cancérigènes pulmonaires, dont la 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK). Plusieurs voies d'activation métabolique de la NNK sont présentes chez les MA et peuvent expliquer l'effet immunomodulatoire de ce cancérigène sur ces cellules. Nous avons caractérisé la voie d'activation métabolique majeure de la NNK impliquée dans la modulation de ce composé chez les MA en plus d'étudier son effet sur l'activité cytotoxique des MA envers les cellules tumorales. En plus de déterminer la voie principale d'activation métabolique de la NNK chez les cellules épithéliales, nous avons aussi investi gué l'effet de la NNK sur la production de médiateurs inflammatoires par les cellules épithéliales bronchiques et alvéolaires,. Cette étude démontre que la voie d'a-méthylhydroxylation de la NNK est responsable de l'effet immunomodulateur de celle-ci sur les MA et sur les cellules épithéliales. La NNK, comme la fumée de cigarette, inhibe l'activité cytotoxique des MA. Cette inhibition pourrait contribuer à la survie et à la prolifération des cellules tumorales. La communication cellule-cellule entre les MA et les cellules épithéliales joue un grand rôle dans l'initiation de la réponse immune pulmonaire. Pour démontrer l'effet de synergie de cette communication sur la production de cytokines dans les co-cultures, nous avons exposé des co-cultures de MA et de cellules épithéliales alvéolaires à la NNK. Cette étude, spécifique au pouvoir immunomodulatoire de la NNK sur la réponse immune, précise davantage l'effet global que ce composé peut avoir au niveau pulmonaire. Cette étude indique que la NNK pourrait contribuer au développement des cellules tumorales en inhibant les défenses cellulaires de l'organisme face à ces cellules en plus d'induire la formation d'adduits d'ADN et l'inhibition de la réparation de l'ADN.

An active football season during the fall acclimation period tests the traffic tolerance of bermudagrass. Exogenous applications of synthetic cytokinins or cytokinin-enhancing plant growth regulators (PGRs), such as trinexapac-ethyl, may improve the traffic tolerance of "Patriot" and "Tifsport" hybrid berudagrasses (Cynodon dactylon var. dactylon x Cynodon transvaalensis). This study was designed to mimic the agronomic practices and traffic stresses experienced at Virginia Tech's Worsham Field. Starting in September 2005, treatments were applied with a differential-slip traffic simulator. Following a traffic treatment, plots received an application of one of three PGRs: 6-Benzyladenine (6-BA), 2-Chloro-4-pyridyl-phenylurea (CPPU) or trinexapac-ethyl (TE). Physiological and morphological responses such as total non-structural carbohydrates and turf density were measured. Previous researchers have shown that increased tissue cytokinins are related to increased tiller density, delay of senescence and enhanced photochemical efficiency. For these reasons, the application of cytokinin enhancing PGRs may have potential to increase bermudagrass traffic tolerance. Patriot's aggressive growth and excellent cold hardiness are predicted to result in better overall traffic tolerance and repair as compared to Tifsport. / Master of Science

Deux nouvelles familles de complexes de cuivre(I) cationiques, de formules [Cu(NHC)(N^N)][X] et [Cu(P^P)(N^N)][PF6], ont été synthétisées avec des ligands 2,2’ bis pyridyl pontés, chélates à six chaînons, facilement modulables. Ces complexes présentent des émissions à l’état solide centrées entre 455 et 520 nm (bleu à vert), avec de larges décalages de Stokes et des rendements quantiques pouvant atteindre 0,86. De plus, l’émission via un phénomène de fluorescence retardée activée thermiquement (TADF) a été prouvée pour les complexes [Cu(NHC)(N^N)][X]. Les premiers scintillateurs plastiques dopés avec des complexes de cuivre(I) détectant les radiations nucléaires de type gammas ont été obtenus avec des complexes de formule générale [Cu(P^P)(N^N)][PF6]. Les complexes de formule [Cu(NHC)(N^N)][X] ont permis l’obtention des premières Cellules Electrochimiques Luminescentes (LECs) émettant dans le bleu et incorporant des complexes de cuivre(I). Enfin, les complexes de formule [Cu(NHC)(N^N)][X] à ligand 2,2’ dipyridylamine présentent une activité cytotoxique envers différentes lignées de cellules cancéreuses et apportent la possibilité d’une action ciblée sur les cellules tumorales via l’ajout d’un vecteur. La polyvalence de ces complexes de cuivre(I) repose sur les ligands 2,2’-bis-pyridyl pontés, chélates à six chaînons, dont la synthèse est facile d’accès et les propriétés électroniques et structurales sont modulables. / New cationic copper(I) complexes of general formula [Cu(NHC)(N^N)][X] and [Cu(P^P)(N^N)][PF6] were developed with 6-membered-ring 2,2’-bis-pyridyl derivatives as ligand. These complexes exhibited blue (420 nm) to green (520 nm) emissions in solid state, with large Stokes shifts and photoluminescence quantum yields up to 0.86. Furthermore, the emission of the [Cu(NHC)(N^N)][X] complexes via a thermally activated delayed fluorescence (TADF) was demonstrated. The first plastic scintillators incorporating copper(I) complexes and detecting gamma radiations were obtained with [Cu(P^P)(N^N)][PF6] complexes. Application of the [Cu(NHC)(N^N)][X] complexes to the LEC technology led to the first copper(I)-based blue emitting device. In the last chapter, we also demonstrated that copper(I) complexes [Cu(NHC)(N^N)][X] bearing a 2,2’-dipyridylamine as N^N ligand exhibited high cytotoxycity against different cancer cells lines. These complexes paved the way for the design of a new type of copper(I) anti-cancer agents with the opportunity to increase the selectivity against cancer cells via a vectorization of the N^N ligand. The versatility of these copper(I) complexes demonstrated in this work relied on the easy to handle and highly modular 2,2’-bis-pyridyl ligands.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is believed to play a role in human lung cancer induced by tobacco smoking. NNK biotransformation may involve the enzymes prostaglandin H synthase (PHS)-1, PHS-2 and cytochrome 450 (CYP) 2F. PHS activity is thought to be important in extrahepatic tissues, where CYP activity is low. The CYP2F subfamily contains a single functional enzyme in humans (CYP2F1) and goats (CYP2F3); these enzymes are preferentially expressed in the lung, with little or no expression in other organs. The role of these enzymes in the pulmonary biotransformation of NNK was investigated. 4.2 µM [5-3H]NNK was incubated with human lung microsomes under NADPH-dependent and arachidonic acid-dependent conditions. Metabolites reflective of NNK α-carbon hydroxylation, N-oxidation and carbonyl reduction were detected in the presence of NADPH, and metabolite levels for all three biotransformation pathways were lower in the presence of arachidonic acid compared with NADPH (p<0.05, N=4). Incubation of microsomes with the PHS-1 selective inhibitor SC-560 and the PHS-2 selective inhibitor NS-398 did not change NNK biotransformation either in the presence of NADPH or in the presence of arachidonic acid (p>0.05, N=4). Incubation of [5-3H]NNK with ovine PHS-1 or PHS-2 did not result in formation of α-carbon hydroxylation or N­-oxidation metabolites; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was measurable only in the presence of PHS-2. Incubation of goat recombinant CYP2F3 with [5-3H]NNK resulted in formation of keto acid, keto alcohol and NNK-N-oxide (65.0%, 17.5% and 30.0% (µmol enzyme)-1 minute-1, respectively). Metabolite formation was inhibited by 3-methylindole (3-MI), a mechanism-based inactivator of CYP2F3. Based on an N value of 3, incubation of human lung microsomes with 3-MI inhibited N-oxidation (p<0.05) but did not alter NNK bioactivation or carbonyl reduction (p>0.05). However, when metabolite formation was examined in lung microsomes from different individuals, decreases in NNK biotransformation (ranging from 19.6 to 68.5%) were observed and were more pronounced in some patients than others, suggesting inter-individual variability in CYP2F1 activity. These studies demonstrate the ability of CYP2F to biotransform NNK and suggest inter-individual variability in the importance of CYP2F1 for this activity in human lung. They also strongly argue against the involvement of PHS enzymes. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2007-12-30 16:12:58.228