A Foucaultian analysis of power relations in child protection case work with youth and families

This thesis takes some steps in examining the child protection system from a position that is rarely discussed. Specifically, I explore how Foucault's concept of disciplinary power can be used to demonstrate how power operates within the client/worker relationship. This relationship is shown to be quite complex with power flowing bidirectionally, rather than hierarchically. Instead of viewing power imbalances as a function of state control, I show how the client/worker relationship is constituted by the worker, the client, the organization and the social body. A postmodern auto ethnography is used to document my journey as I expose the disciplinary practices and instruments that I was subject to and used with my clients. 2 Given that the child protection system is constantly shifting and changing in order to improve its ability to safeguard children a greater emphasis is required to examine how workers operate within this complex, overwhelming and multi-dimensional world. This thesis has shown that by engaging in a reflexive examination of my position of power different approaches to making intervention beneficial to all involved become available. This is important if child protection work aims to work with clients rather than on clients.

Enhancing personal effectiveness : the impacts of Costa Rica Outward Bound on students in an independent school in southwestern Ontario

This project examines students in a private school in southwestern Ontario on a 17 -day Costa Rica Outward Bound Rainforest multielement course. The study attempted to discover whether voluntary teenage participants could increase their self-perceptions of life effectiveness by participating in a 17-day expedition. A total of9 students participated in the study. The experimental design that was implemented was a mixed methods design. Participants filled in a Life Effectiveness Questionnaire (LEQ) at four predesignated times during the study. These time intervals occurred (a) before the trip commenced, (b) the first day of the trip, ( c) the last day of the trip, and (d) 1 month after the trip ended. Fieldnotes and recordings from informal group debriefing sessions were also used to gather information. Data collected in this study were analyzed in a variety of ways by the researcher. Analyses that were run on the data included the Friedman test for covariance, means, medians, and the Wilcoxon Pairs Test. The questionnaires were analyzed quantitatively, and the fieldnotes were analyzed qualitatively. Nonparametric statistical analysis was implemented as a result of the small group size of participants. Both sets of data were grouped and discussed according to similarities and differences. The data indicate that voluntary teenage participants experience significant changes over time in the areas of time management, social competency, emotional control, active initiative, and self-confidence. The types of outcomes from this study illustrate that Outward Bound-type opportunities should be offered to teenagers in Ontario schools as a means to bring about self-development.

Investigation of motivation strategies used by school teachers for workplace engagement

The purpose of this study was to explore the strategies that elementary school teachers use to be engaged in their work. Participation was solicited from a random sample of schools stratified by location (i.e., urban, inner city, and rural) of a large school board. The study used an anonymous quantitative/qualitative questionnaire. The survey tool was based upon Kahn's (1990) psychological engagement framework, which presents the foundation of availability of self, meaningfulness of work, and safety while at work. Forty-one surveys were analyzed descriptively including a subgroup of self-rated highly engaged teachers. Teachers tended to favour physical and emotional strategies compared to cognitive type strategies, with the exception of the highly engaged subgroup. The theme of preferred strategies reflected a setting outside the school/workplace, that is, a preference for horne based strategies. The study's main contribution highlights the teachers' sense of importance for physical and emotional health in a profession that is heavily focused in the cognitive domain. This may influence administrative and teacher discourse regarding workplace engagement with strategies to help reduce stress and to maintain and increase teacher engagement.

ORGANOSILICON BIOTECHNOLOGY: A BIO-INSPIRED APPROACH TO THE HYDROLYSIS OF ALKOXYSILANES and THE LIPASE-CATALYZED SYNTHESIS OF SILOXANE-CONTAINING POLYESTERS AND POLYAMIDES

The first part of this thesis studied the capacity of amino acids and enzymes to catalyze the hydrolysis and condensation of tetraethoxysilane and phenyltrimethoxysilane. Selected amino acids were shown to accelerate the hydrolysis and condensation of tetraethoxysilane under ambient temperature, pressure and at neutral pH (pH 7±0.02). The nature of the side chain of the amino acid was important in promoting hydrolysis and condensation. Several proteases were shown to have a capacity to hydrolyze tri- and tet-ra- alkoxysilanes under the same mild reaction conditions. The second part of this thesis employed an immobilized Candida antarctica lipase B (Novozym-435, N435) to produce siloxane-containing polyesters, polyamides, and polyester amides under solvent-free conditions. Enzymatic activity was shown to be temperature dependent, increasing until enzyme denaturation became the dominant pro-cess, which typically occurred between 120-130ᵒC. The residual activity of N435 was, on average, greater than 90%, when used in the synthesis of disiloxane-containing polyesters, regardless of the polymerization temperature except at the very highest temperatures, 140-150ᵒC. A study of the thermal tolerance of N435 determined that, over ten reaction cycles, there was a decrease in the initial rate of polymerization with each consecutive use of the catalyst. No change in the degree of monomer conversion after a 24 hour reaction cycle was found.

Exploring Gifted Adults' Perception of Giftedness in their Pursuit of Graduate Education

This qualitative study explores 8 gifted adults' perceptions of their own giftedness and how those perceptions influenced their pursuit of graduate education as revealed by retrospective interviews. This study serves to inform the existing literature surrounding giftedness especially as it relates to gifted individuals across the lifespan and their experiences and perceptions of education at all levels. This study also provides insight into the emotional impact being labeled gifted has on an individual's self-concept and academic identity. The major themes that emerged using the interpretive phenomenological analysis method (Smith & Osborn, 2003) were discussed under five main headings: Evolution of Giftedness, Success and Failure, Expectations, Effort, and Doubt and Proof. An adaptation of the listening guide method (Gilligan, Spencer, Weinberg, & Bertsch, 2003) was used to provide a unique and personal perspective of the phenomenon of giftedness and revealed the feelings behind the themes that emerged in the interpretive phenomenological analysis method. Specifically; this study illuminates the lack of evolution that an individual's understanding and perception of giftedness undergoes across the lifespan, and the impact such a static and school-bound understanding has on gifted adults' self-concept. It also reveals the influence that gifted individuals' innate need to achieve has on their academic aspirations and their perceptions of themselves as gifted. Furthermore, it reveals how important the understanding and internalization of failure can be on the self-concept of gifted individuals, and that this issue needs immediate attention at all levels of education.

Parent and Peer Factors Relating to Adolescent Antisocial Behaviour: Investigating the Moderating Role of Temperament

The purpose of this study was to examine whether certain temperament characteristics (fearfulness, surgency, frustration, and effortful control) moderate the association between authoritative parenting dimensions (psychological autonomy granting, acceptance-involvement, and monitoring knowledge) or friends' antisocial behaviour, and self-reported antisocial behaviour among adolescents. Questionnaires on adolescent temperament and authoritative parenting were completed by 484 mothers and their adolescent children (54.8% female). In addition, the adolescents responded to measures regarding friends' antisocial behavior and their own antisocial behaviour. Adolescent participants ranged between 13 and 17 years of age (M = 14.96 years, SD = 1.39) and lived in a region of southern Ontario. As predicted, the results indicated that effortful control moderated the association between parental monitoring knowledge and adolescent antisocial behaviour. Also, as predicted, effortful control moderated the relation between friends' antisocial behaviour and adolescents' self-reports of antisocial behaviour although the relation was sex-specific to girls. Unexpected results included a significant monitoring knowledge by frustration by sex interaction, and a significant friends' antisocial behaviour by age interaction. In general, the findings were consistent with the expectation that the relation of parenting and peer factors to antisocial behaviour would depend on adolescents' temperamental predispositions. However, effortful control, which contributes to individual differences in self-regulation abilities, served this moderating role to a greater extent than the measures of temperamental reactivity, including fearfulness, surgency and frustration-proneness. Implications of these results are discussed with reference to parenting or classroom-based interventions that may be especially helpful for adolescents with poor self-regulation abilities.

The Synthesis and Coordination Chemistry of Two Families of Polydentate Ligands - Exploring Their Potential for the Preparation of Molecule-Based Magnets

The synthesis and studies of two classes of poly dentate ligands are presented as two projects. In project 1, four new carboxamide ligands have been synthesised via the condensation of 2,2',6,6'-tetrachloroformyl-4,4'-bipyridine or 2,6-dichloroformyl pyridine together with heterocyclic amines containing pyridine or pyrazole substituents. The coordination chemistry of these ligands has been investigated and studies have shown that with a Cu(II) salt, two carboxamide ligands LJ and L2 afford large clusters with stoichiometries [Cu8(L1)4Cl16].CHCl3.5H2O.7CH3OH (I) and [Cu9(L2)6Cl6].CH3OH.5H2O.(C2H5)3N (II) respectively. [molecular diagram availabel in pdf]. X-ray diffraction studies of cluster (I) reveal that it has approximate S4 symmetry and is comprised of four ligands and eight copper (II) centers. Here, coordination takes place via amide 0 atoms, and pyrazole nitrogens. This complex is the first reported example of an octanuclear copper cluster with a saddle-shaped structure. The second cluster comprises nine copper ions that are arranged in a cyclic array. Each ligand coordinates three copper centers and each copper ion shares two ligands to connect six ligands with nine copper ions. The amide nitrogens are completely deprotonated and both amide Nand 0 atoms coordinate the metal centres. The cluster has three-fold symmetry. There are six chloride ions, three of which are bridging two neighbouring Cu(II) centres. Magnetic studies of (I) and (II) reveal that both clusters display weak antiferromagnetic interactions between neighbouring Cu(II) centers at low temperature. In the second project, three complexes with stoichiometries [Fe[N302](SCN)2]2 (III), R,R-[Fe[N3O2](SCN)2 (IV) and R,R-]Fe[N3O2](CN)2] (V) were prepared and characterized, where [N302] is a pentadentate macrocycle. Complex (III) was prepared via the metal templated Schiff-base condensation of 2,2',6,6'-tetraacetyl-4,4'-bipyridine together with 3,6-dioxaoctane-I,8-diamine and comprises of a dimeric macro cycle where the two Fe(II) centres are in a pentagonal-bipyramidal environment with the [N302] ligands occupying the equatorial plane and two axial NCS ligands. Complexes (IV) and (V) were prepared via the condensation of 2,6-diacetylpyridine together with a chiral diamine in the presence of FeCh. The synthetic strategy for the preparation of the chiral diamine (4R,5R)-4,5-diphenyl-3,6-dioxa-I,8-octane-diamine was elucidated. The chirality of both macrocycles (IV) and (V) was probed by circular dichroism spectroscopy. The crystal structure of (IV) at 200 K contains two independent molecules in the unit cell, both of which contain a hepta-coordinated Fe(II) and axial NCS ligands. Variable temperature magnetic susceptibility and structural studies are consistent with a high spin Fe(II) complex and show no evidence of any spin crossover behaviour. In contrast, the bis cyanide derivative (V) crystallizes with two independent molecules in the unit cell, both of which have different coordination geometries consistent with different spin states for the two Fe(II) centres. At 250 K, the molecular structure of (V) shows the presence of both 7- and a 6-coordinate Fe(II) complexes in the crystal lattice. As the temperature is lowered, the molecules undergo a structural change and at 100 K the structural data is consistent with a 6- and 5-coordinate Fe(II) complex in the unit cell. Magnetic studies confirm that this complex undergoes a gradual, thermal, spin crossover transition in the solid state. Photomagnetic measurements indicate this is the first chiral Fe (II) sea complex to exhibit a LIESST.

Social Economy and Developmental Disabilities: An Employment Option that Promotes a Form of Authentic Work and Fosters Social Inclusion

Typical employment options for people with developmental disabilities are insufficient. Most employment opportunities that are community-based provide typical workplace and geographical inclusion but tend not to support social inclusion and "belonging". This study explored the innovative employment alternative of social businesses and considered this form of employment for persons with a developmental disability as a viable avenue for meaningful work and social inclusion. A total of six business partners with a developmental disability were interviewed; two partners from three separate worker owned businesses. The partners' descriptions of their job and their workplace composed the interpretative findings. The social businesses provided an avenue for this group of people who tend to be segregated in isolated workshops or marginalized in mainstream work environments and who feel a sense of being "outsiders" to participate in meaningful work in community settings. This group of partners described their job as authentic "work" and discussed the many skills and the work ethic learned from their employment opportunity. In addition to the instrumental aspects of the job, the partners also discussed the group autonomy and self-determination of being their own "bosses". The partners confidently expressed feeling valued, understood in the context of others with similar life experiences, attached to the workplace and connected to a larger community as important outcomes of their businesses. These criteria of social inclusion (Hall, 2010) were complemented by teamwork, friendship and ultimately, with a feeling of being genuine "insiders". Replication of this innovative employment model would be recommended for groups of marginalized people with DD in other geographic areas.

Part Time University Teaching in Ontario: A Self-Study

This qualitative self-study explored the disappointment I felt as a part-time university teacher in a mid-sized, primarily undergraduate Ontario university, where I experienced difficulty integrating my beliefs about teaching into my practice of teaching. The purpose of this qualitative study was to inquire into why it was difficult for me, representative of a part-time university teacher in a mid-sized, primarily undergraduate university, to enact the critical pedagogical practices I espoused in my teaching philosophy. The secondary purpose was to apply the findings of the study to reframe my university teaching practice in a way that met my need to enact my beliefs about university teaching while complying with the broader geo-political conditions of part-time university teaching in Ontario (Loughran, 2006; Russell & Loughran, 2007). This study is grounded in the sociological theoretical framework of critical pedagogy (Freire, 1970; Giroux, 1988, 2010; McLaren, 2003) and the methodological framework of The Self-Study of Teacher Education Practices (S-STEP). This study combined the methods of Brookfield’s (1995; 2002) critically reflective practice and Cole and Knowles (2000) practice of reflexive inquiry with Creswell’s (2005) methods of thematic analysis to answer the research question: Why is it difficult for me to enact my beliefs about university teaching as a part-time teacher in an Ontario university? Findings suggest the geo-political contexts of part-time university teaching work can impact a teacher’s ability to enact his/her beliefs about teaching within his/her practice of teaching.

Whose Voice Is Present?: An Examination of Power and Privilege in Service-Learning in Ontario Universities

This research paper examines themes of power and privilege that occur within service-learning as described by 3 Ontario universities on their service-learning websites. Due to size and time restrictions, this paper was able to examine only 3 Ontario universities: Brock, Wilfrid Laurier, and Lakehead. The purpose of this study is geared towards service-learning practitioners in order for the universities and students to become more self-aware of their immense place of privilege within the service-learning context. Qualitative narrative analysis research methods were employed in this purposeful sample to examine how each university’s story of service-learning reflected themes of power and privilege. The research found that each university posed a unique narrative of service-learning representing various stakeholders’ voices and presence in different ways on their website. Brock largely focuses on faculty and student voices. Laurier intentionally attempts to include all three stakeholder voices, although still favours students and the university as an audience over the community. Lakehead’s unique program includes a plethora of voices and intends much of their information for the community members, students, and the university. The implications of this research demonstrate that universities have a large amount of power and privilege, which is carried through to the students within the service-learning partnership.

The γ-tocopherol-like family of N-methyltransferases: A taxonomically clustered gene family encoding enzymes responsible for N-methylation of monoterpene indole alkaloids

The plant family Apocynaceae accumulates thousands of monoterpene indole alkaloids (MIAs) which originate, biosynthetically, from the common secoiridoid intermediate, strictosidine, that is formed from the condensation of tryptophan and secologanin molecules. MIAs demonstrate remarkable structural diversity and have pharmaceutically valuable biological activities. For example; a subunit of the potent anti-neoplastic molecules vincristine and vinblastine is the aspidosperma alkaloid, vindoline. Vindoline accumulates to trace levels under natural conditions. Research programs have determined that there is significant developmental and light regulation involved in the biosynthesis of this MIA. Furthermore, the biosynthetic pathway leading to vindoline is split among at least five independent cell types. Little is known of how intermediates are shuttled between these cell types. The late stage events in vindoline biosynthesis involve six enzymatic steps from tabersonine. The fourth biochemical step, in this pathway, is an indole N-methylation performed by a recently identified N-methyltransfearse (NMT). For almost twenty years the gene encoding this NMT had eluded discovery; however, in 2010 Liscombe et al. reported the identification of a γ-tocopherol C-methyltransferase homologue capable of indole N-methylating 2,3-dihydrotabersonine and Virus Induced Gene Silencing (VIGS) suppression of the messenger has since proven its involvement in vindoline biosynthesis. Recent large scale sequencing initiatives, performed on non-model medicinal plant transcriptomes, has permitted identification of candidate genes, presumably involved, in MIA biosynthesis never seen before in plant specialized metabolism research. Probing the transcriptome assemblies of Catharanthus roseus (L.)G.Don, Vinca minor L., Rauwolfia serpentine (L.)Benth ex Kurz, Tabernaemontana elegans, and Amsonia hubrichtii, with the nucleotide sequence of the N-methyltransferase involved in vindoline biosynthesis, revealed eight new homologous methyltransferases. This thesis describes the identification, molecular cloning, recombinant expression and biochemical characterization of two picrinine NMTs, one from V. minor and one from R. serpentina, a perivine NMT from C. roseus, and an ajmaline NMT from R. serpentina. While these TLMTs were expressed and functional in planta, they were active at relatively low levels and their N-methylated alkaloid products were not apparent our from alkaloid isolates of the plants. It appears that, for the most part, these TLMTs, participate in apparently silent biochemical pathways, awaiting the appropriate developmental and environmental cues for activity.

Using First Nations Children's Literature in the Classroom: Portfolio of Learning

A portfolio was developed to encourage teachers of Aboriginal children to include First Nations mentor texts into their daily teaching practices. The artifacts within the portfolio have been produced in accordance with guiding beliefs about how students, specifically First Nations students, learn. The portfolio supports the notion that Aboriginal children need to encounter representations of their own culture, histories and beliefs within the literature in order to be successful in school. The use of First Nations children’s literature in the classroom was explored with an emphasis on how using this literature will assist in improving literacy levels and the self-esteem of First Nations students.

Individual and social determinants of multiple chronic disease behavioural risk factors in Canadian children and adolescents

Contexte: Les facteurs de risque comportementaux, notamment l’inactivité physique, le comportement sédentaire, le tabagisme, la consommation d’alcool et le surpoids sont les principales causes modifiables de maladies chroniques telles que le cancer, les maladies cardiovasculaires et le diabète. Ces facteurs de risque se manifestent également de façon concomitante chez l’individu et entraînent des risques accrus de morbidité et de mortalité. Bien que les facteurs de risque comportementaux aient été largement étudiés, la distribution, les patrons d’agrégation et les déterminants de multiples facteurs de risque comportementaux sont peu connus, surtout chez les enfants et les adolescents. Objectifs: Cette thèse vise 1) à décrire la prévalence et les patrons d’agrégation de multiples facteurs de risque comportementaux des maladies chroniques chez les enfants et adolescents canadiens; 2) à explorer les corrélats individuels, sociaux et scolaires de multiples facteurs de risque comportementaux chez les enfants et adolescents canadiens; et 3) à évaluer, selon le modèle conceptuel de l’étude, l’influence longitudinale d’un ensemble de variables distales (c’est-à-dire des variables situées à une distance intermédiaire des comportements à risque) de type individuel (estime de soi, sentiment de réussite), social (relations sociales, comportements des parents/pairs) et scolaire (engagement collectif à la réussite, compréhension des règles), ainsi que de variables ultimes (c’est-à-dire des variables situées à une distance éloignée des comportements à risque) de type individuel (traits de personnalité, caractéristiques démographiques), social (caractéristiques socio-économiques des parents) et scolaire (type d’école, environnement favorable, climat disciplinaire) sur le taux d’occurrence de multiples facteurs de risque comportementaux chez les enfants et adolescents canadiens. Méthodes: Des données transversales (n = 4724) à partir du cycle 4 (2000-2001) de l’Enquête longitudinale nationale sur les enfants et les jeunes (ELNEJ) ont été utilisées pour décrire la prévalence et les patrons d’agrégation de multiples facteurs de risque comportementaux chez les jeunes canadiens âgés de 10-17 ans. L’agrégation des facteurs de risque a été examinée en utilisant une méthode du ratio de cas observés sur les cas attendus. La régression logistique ordinale a été utilisée pour explorer les corrélats de multiples facteurs de risque comportementaux dans un échantillon transversal (n = 1747) de jeunes canadiens âgés de 10-15 ans du cycle 4 (2000-2001) de l’ELNEJ. Des données prospectives (n = 1135) à partir des cycle 4 (2000-2001), cycle 5 (2002-2003) et cycle 6 (2004-2005) de l’ELNEJ ont été utilisées pour évaluer l’influence longitudinale des variables distales et ultimes (tel que décrit ci-haut dans les objectifs) sur le taux d’occurrence de multiples facteurs de risque comportementaux chez les jeunes canadiens âgés de 10-15 ans; cette analyse a été effectuée à l’aide des modèles de Poisson longitudinaux. Résultats: Soixante-cinq pour cent des jeunes canadiens ont rapporté avoir deux ou plus de facteurs de risque comportementaux, comparativement à seulement 10% des jeunes avec aucun facteur de risque. Les facteurs de risque comportementaux se sont agrégés en de multiples combinaisons. Plus précisément, l’occurrence simultanée des cinq facteurs de risque était 120% plus élevée chez les garçons (ratio observé/attendu (O/E) = 2.20, intervalle de confiance (IC) 95%: 1.31-3.09) et 94% plus élevée chez les filles (ratio O/E = 1.94, IC 95%: 1.24-2.64) qu’attendu. L’âge (rapport de cotes (RC) = 1.95, IC 95%: 1.21-3.13), ayant un parent fumeur (RC = 1.49, IC 95%: 1.09-2.03), ayant rapporté que la majorité/tous de ses pairs consommaient du tabac (RC = 7.31, IC 95%: 4.00-13.35) ou buvaient de l’alcool (RC = 3.77, IC 95%: 2.18-6.53), et vivant dans une famille monoparentale (RC = 1.94, IC 95%: 1.31-2.88) ont été positivement associés aux multiples comportements à risque. Les jeunes ayant une forte estime de soi (RC = 0.92, IC 95%: 0.85-0.99) ainsi que les jeunes dont un des parents avait un niveau d’éducation postsecondaire (RC = 0.58, IC 95%: 0.41-0.82) étaient moins susceptibles d’avoir de multiples facteurs de risque comportementaux. Enfin, les variables de type social distal (tabagisme des parents et des pairs, consommation d’alcool par les pairs) (Log du rapport de vraisemblance (LLR) = 187.86, degrés de liberté = 8, P < 0,001) et individuel distal (estime de soi) (LLR = 76.94, degrés de liberté = 4, P < 0,001) ont significativement influencé le taux d’occurrence de multiples facteurs de risque comportementaux. Les variables de type individuel ultime (âge, sexe, anxiété) et social ultime (niveau d’éducation du parent, revenu du ménage, structure de la famille) ont eu une influence moins prononcée sur le taux de cooccurrence des facteurs de risque comportementaux chez les jeunes. Conclusion: Les résultats suggèrent que les interventions de santé publique devraient principalement cibler les déterminants de type individuel distal (tel que l’estime de soi) ainsi que social distal (tels que le tabagisme des parents et des pairs et la consommation d’alcool par les pairs) pour prévenir et/ou réduire l’occurrence de multiples facteurs de risque comportementaux chez les enfants et les adolescents. Cependant, puisque les variables de type distal (telles que les caractéristiques psychosociales des jeunes et comportements des parents/pairs) peuvent être influencées par des variables de type ultime (telles que les caractéristiques démographiques et socioéconomiques), les programmes et politiques de prévention devraient également viser à améliorer les conditions socioéconomiques des jeunes, particulièrement celles des enfants et des adolescents des familles les plus démunies.

Semisynthetic aminoglycoside antibiotics : toward biomimetic synthesis, evasion of bacterial resistance and reduced toxicity

Les antibiotiques aminoglycosidiques sont des agents bactéricides de grande valeur et d’efficacité à large spectre contre les pathogènes Gram-positifs et Gram-négatifs, dont plusieurs membres naturels et semisynthétiques sont importants dans l’histoire clinique depuis 1950. Des travaux crystallographiques sur le ribosome, récompensés par le prix Nobel, ont démontré comment leurs diverses structures polyaminées sont adaptées pour cibler une hélice d’ARN dans le centre de codage de la sous-unité 30S du ribosome bactérien. Leur interférence avec l’affinité et la cinétique des étapes de sélection et vérification des tARN induit la synthèse de protéines à basse fidélité, et l’inhibition de la translocation, établissant un cercle vicieux d’accumulation d’antibiotique et de stress sur la membrane. En réponse à ces pressions, les pathogènes bactériens ont évolué et disséminé une panoplie de mécanismes de résistance enzymatiques et d’expulsion : tels que les N acétyltransférases, les O phosphotransférases et les O nucleotidyltransférases qui ciblent les groupements hydroxyle et amino sur le coeur des aminoglycosides; des méthyl-transférases, qui ciblent le site de liaison ribosomale; et des pompes d’expulsion actives pour l’élimination sélective des aminoglycosides, qui sont utilisés par les souches Gram-négatives. Les pathogènes les plus problématiques, qui présentent aujourd’hui une forte résilience envers la majorité des classes d’antibiotiques sur le bord de la pan-résistance ont été nommés des bactéries ESKAPE, une mnémonique pour Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa et Enterobacteriaceae. La distribution globale des souches avec des mécanismes de résistance envers les standards cliniques aminoglycosides, tels que la tobramycine, l’amikacine et la gentamicine, est comprise entre 20 et 60% des isolées cliniques. Ainsi, les aminoglycosides du type 4,6-disubstitués-2-deoxystreptamine sont inadéquats comme thérapies anti-infectieuses à large spectre. Cependant, la famille des aminoglycosides 4,5-disubstitués, incluant la butirosine, la neomycine et la paromomycine, dont la structure plus complexe, pourrait constituter une alternative. Des collègues dans le groupe Hanessian et collaborateurs d’Achaogen Inc. ont démontré que certains analogues de la paraomomycine et neomycine, modifiés par désoxygénation sur les positions 3’ et 4’, et par substitution avec la chaîne N1-α-hydroxy-γ-aminobutyramide (HABA) provenant de la butirosine, pourrait produire des antibiotiques très prometteurs. Le Chapitre 4 de cette dissertation présente la conception et le développement d’une stratégie semi-synthétique pour produire des nouveaux aminoglycosides améliorés du type 4,5 disubstitués, inspiré par des modifications biosynthétiques de la sisomicine, qui frustrent les mécanismes de résistance bactérienne distribuées globalement. Cette voie de synthèse dépend d’une réaction d’hydrogénolyse de type Tsuji catalysée par palladium, d’abord développée sur des modèles monosaccharides puis subséquemment appliquée pour générer un ensemble d’aminoglycosides hybrides entre la neomycine et la sisomicine. Les études structure-activité des divers analogues de cette nouvelle classe ont été évaluées sur une gamme de 26 souches bactériennes exprimant des mécanismes de résistance enzymatique et d’expulsion qui englobe l’ensemble des pathogènes ESKAPE. Deux des antibiotiques hybrides ont une couverture antibacterienne excellente, et cette étude a mis en évidence des candidats prometteurs pour le développement préclinique. La thérapie avec les antibiotiques aminoglycosidiques est toujours associée à une probabilité de complications néphrotoxiques. Le potentiel de toxicité de chaque aminoglycoside peut être largement corrélé avec le nombre de groupements amino et de désoxygénations. Une hypothèse de longue date dans le domaine indique que les interactions principales sont effectuées par des sels des groupements ammonium, donc l’ajustement des paramètres de pKa pourrait provoquer une dissociation plus rapide avec leurs cibles, une clairance plus efficace et globalement des analogues moins néphrotoxiques. Le Chapitre 5 de cette dissertation présente la conception et la synthèse asymétrique de chaînes N1 HABA β substitutées par mono- et bis-fluoration. Des chaînes qui possèdent des γ-N pKa dans l’intervalle entre 10 et 7.5 ont été appliquées sur une neomycine tétra-désoxygénée pour produire des antibiotiques avancés. Malgré la réduction considérable du γ N pKa, le large spectre bactéricide n’a pas été significativement affecté pour les analogues fluorés isosteriques. De plus, des études structure-toxicité évaluées avec une analyse d’apoptose propriétaire d’Achaogen ont démontré que la nouvelle chaîne β,β difluoro-N1-HABA est moins nocive sur un modèle de cellules de rein humain HK2 et elle est prometteuse pour le développement d’antibiotiques du type neomycine avec des propriétés thérapeutiques améliorées. Le chapitre final de cette dissertation présente la proposition et validation d’une synthèse biomimétique par assemblage spontané du aminoglycoside 66-40C, un dimère C2 symétrique bis-imine macrocyclique à 16 membres. La structure proposée du macrocycle a été affinée par spectroscopie nucléaire à un système trans,trans-bis-azadiène anti-parallèle. Des calculs indiquent que l’effet anomérique de la liaison α glycosidique entre les anneaux A et B fournit la pré-organisation pour le monomère 6’ aldéhydo sisomicine et favorise le produit macrocyclique observé. L’assemblage spontané dans l’eau a été étudié par la dimérisation de trois divers analogues et par des expériences d’entre croisement qui ont démontré la généralité et la stabilité du motif macrocyclique de l'aminoglycoside 66-40C.

Poly(ethylene-co-acrylic acid) random copolymers : amphiphilic properties and self-assembly in aqueous medium

Les travaux de recherche présentés ici avaient pour objectif principal la synthèse de copolymères statistiques à base d’éthylène et d’acide acrylique (AA). Pour cela, la déprotection des groupements esters d’un copolymère statistique précurseur, le poly(éthylène-co-(tert-butyl)acrylate), a été effectuée par hydrolyse à l’aide d’iodure de triméthylsilyle. La synthèse de ce précurseur est réalisée par polymérisation catalytique en présence d’un système à base de Palladium (Pd). Le deuxième objectif a été d’étudier et de caractériser des polymères synthétisés à l’état solide et en suspension colloïdale. Plusieurs copolymères précurseurs comprenant différents pourcentages molaires en tert-butyl acrylate (4 à 12% molaires) ont été synthétisés avec succès, puis déprotégés par hydrolyse pour obtenir des poly(éthylène-coacide acrylique) (pE-co-AA) avec différentes compositions. Seuls les copolymères comprenant 10% molaire ou plus de AA sont solubles dans le Tétrahydrofurane (THF) et uniquement dans ce solvant. De telles solutions peuvent être dialysées dans l’eau, ce qui conduit à un échange lent entre cette dernière et le THF, et l’autoassemblage du copolymère dans l’eau peut ensuite être étudié. C’est ainsi qu’ont pu être observées des nanoparticules stables dans le temps dont le comportement est sensible au pH et à la température. Les polymères synthétisés ont été caractérisés par Résonance Magnétique Nucléaire (RMN) ainsi que par spectroscopie Infra-Rouge (IR), avant et après déprotection. Les pourcentages molaires d’AA ont été déterminés par combinaison des résultats de RMN et ii de titrages conductimètriques. A l’état solide, les échantillons ont été analysés par Calorimétrie différentielle à balayage (DSC) et par Diffraction des rayons X. Les solutions colloïdales des polymères pE-co-AA ont été caractérisées par Diffusion dynamique de la lumière et par la DSC-haute sensibilité. De la microscopie électronique à transmission (TEM) a permis de visualiser la forme et la taille des nanoparticules.