L’accouchement prématuré est un problème de santé publique dans le monde et notamment dans les pays économiquement développés avec un taux variant entre 7 et 12 % des naissances. Le diagnostic du risque d’accouchement prématuré est difficile à faire et les outils à notre disposition ont peu évolué ces dernières années. La contraction utérine est la conséquence directe de l’activité électrique au niveau du myomètre. Le type de contraction est lié à l’importance de l’excitabilité cellulaire et de sa diffusion à l’ensemble du myomètre. Le recueil et l’analyse de cette activité électrique par des électrodes de surface est aujourd’hui le seul moyen non invasif d’étudier, pendant la grossesse, les mécanismes qui sont à l’origine de la contraction. L’enregistrement de l’électromyogramme utérin ou électrohystérogramme (EHG) est donc prometteur pour réaliser un diagnostic et une surveillance des femmes à risque d’accouchement prématuré. Dans ce travail de thèse 3 études cliniques ont été réalisées. Dans la première, j’ai étudié différentes électrodes de surface permettant d’enregistrer les signaux électriques. Je propose à la fin de cette première partie un système d’électrodes pour permettre à la fois un enregistrement de qualité et une pose aisée compatible avec une application clinique. Dans la deuxième étude j’ai étudié la détection automatique des contractions par l’EHG avec des résultats encourageants pour l’application clinique et notamment en ambulatoire. Enfin dans la troisième étude j’ai étudié la prédiction du risque d’accouchement prématuré par l’analyse de paramètres électriques issus de l’EHG. Les résultats obtenus permettent d’améliorer la prédiction du risque d’accouchement prématuré par rapport aux outils utilisés en routine. / Premature birth is a public health problem in the world, particularly in economically developed countries with a rate varying between 7% and 12% of births. The diagnosis of the risk of premature labor is difficult to make and the tools at our disposal have changed little in recent years. Uterine contraction is a direct consequence of electrical activity at the level of the myometrium. The type of contraction is related to the importance of cell excitability and its diffusion to the entire myometrium. The analysis of this electrical activity by surface electrodes is currently the only non-invasive way to study the mechanisms that are at the origin of the contraction. The recording of the uterine electromyogram or electrohysterogram (EHG) is therefore promising for the diagnosis and surveillance of women at risk of preterm birth. In this thesis work 3 clinical studies have been carried out. In the first clinical study, different surface electrodes to record electrical signals were tested. I propose at the end of this first part a system of electrodes to allow at the same time a recording of quality and an easy pose compatible with a clinical application. In the second study , the automatic detection of contractions by the El-IG was studied with encouraging results for the clinical application and especially in ambulatory. Finally, in the third clinical experiment, I studied the prediction of the risk of premature delivery by the analysis of electrical parameters extracted from the EHG. The results obtained make it possible to improve the prediction of the risk of premature delivery compared to the tools used routinely.

The doctoral dissertacion is focused on the role of inflammation in the pathogenesis of preterm labor. In the first part, we describe the current view on pathophysiology of preterm labor. In the second part, we evaluated the relationship of specific markers of inflammation and endothelial dysfunction to preterm birth and fetal inflammatory response. The most important findings of our study was that we found decreased levels of MMP-2 and decreased levels of sRAGE in women with preterm labor in comparison with the control group of pregnant women. Similarly, we found decreased levels of MMP-2 in women with subsequent diagnosed fetal inflammatory response. sRAGE is currently ranked among patttern recognition receptors. In the case of sRAGE we followed the results of our pilot project, it can be assumed that the its low level are connected with tissue damage. We confirmed that it can play an important role in the pathogenesis of preterm labor. We assume abnormal regulatory mechanisms of the production of MMP-2. In both cases, however, further studies are required to elucidate the functional significance of our results.

The doctoral dissertacion is focused on the role of inflammation in the pathogenesis of preterm labor. In the first part, we describe the current view on pathophysiology of preterm labor. In the second part, we evaluated the relationship of specific markers of inflammation and endothelial dysfunction to preterm birth and fetal inflammatory response. The most important findings of our study was that we found decreased levels of MMP-2 and decreased levels of sRAGE in women with preterm labor in comparison with the control group of pregnant women. Similarly, we found decreased levels of MMP-2 in women with subsequent diagnosed fetal inflammatory response. sRAGE is currently ranked among patttern recognition receptors. In the case of sRAGE we followed the results of our pilot project, it can be assumed that the its low level are connected with tissue damage. We confirmed that it can play an important role in the pathogenesis of preterm labor. We assume abnormal regulatory mechanisms of the production of MMP-2. In both cases, however, further studies are required to elucidate the functional significance of our results.

An energy transition can be defined as the adoption of a new primary energy system. As such, it is a structural change that implies a broad shift in technologies and behaviors in order to replace one source of energy with another. Energy transitions motivated by economic, climate, and/or health goals are taking place everywhere in the world. Air pollution, a consequence of fossil fuel-based and solid fuel-based energy use among other sources, is the largest environmental health risk accounting for 6.4 million premature deaths annually. Given the health implications of our energy systems and the social drivers of energy use, access, and burden, energy transitions have the potential to impact health outcomes and associated disparities in a context-dependent manner. The research presented in this dissertation has two objectives: 1) to evaluate the distribution of benefits from energy transitions in the United States (US) and in Ghana; 2) to identify and characterize health outcomes that are relevant to these transitions but are currently understudied. Chapters 2 and 3 are anchored in the US energy policy context. Chapter 2 focuses on the transition away from coal as the primary source of energy in the US and its implications for particulate matter pollution and preterm births. Leveraging a novel dispersion model, I assessed the association between coal PM2.5 and preterm birth rates along with effect modification by race/ethnicity. We observed a positive non-linear relationship between coal PM2.5 and preterm birth rate, which plateaued at higher levels of pollution. The findings of this study suggest that the transition away from coal may have reduced preterm birth rates in the US, but that the association was stronger among non-Hispanic White women compared to non-Hispanic Black women. In Chapter 3, I use a mixed-methods framework to evaluate the first pilot of gas-to-electric stove transition in low-income housing in the US. Through a collaboration with a community-based environmental justice group in New York City, we monitored indoor air quality in participants homes pre- and post-intervention, conducted controlled cooking tests, and carried out focus groups to characterize their experience. Post-intervention, daily NO2 concentrations were 46.3% (95% CI: -67.8%, -10.3%) lower in the intervention arm compared to the control arm. Participants were unanimously pleased with the transition, which had simultaneously improved their cooking experience and partially addressed energy insecurity concerns that plagued their building. Chapters 4 and 5 contribute to the characterization of the health implications associated with Ghana’s commitment to increase access to liquified petroleum gas (LPG) nationally. In Chapter 4, we aimed to describe the country-level incidence of severe cooking-related burns by fuel type in use and to identify effect modifiers. We conducted a nationally representative (n = 7,389) household energy use survey in all 16 regions of Ghana. The incidence rate (95% CI) of cooking-related burns per 1000 person-years among working age females was 8.3 (7.2; 12.0) per 1000 person-years, which was 8 times higher than that of working age males. Among adults, the odds of experiencing a cooking-related burn were doubled among solid fuel users compared to primary LPG users. In Chapter 5, we aimed to understand the effect of an LPG intervention on personal exposure to household air pollution in a peri-urban setting of Ghana and to characterize the distribution of benefits between male and female household members quantitatively and qualitatively. The difference-in-differences results suggested a reduction in exposure to carbon monoxide due to the intervention (-14.2%, 95% CI: -44.1%, 31.6%), which might have benefited male and female participants to the same extent. Importantly, focus group discussions suggested that the ability that LPG affords to cook “on demand” could negatively impact intra-household dynamics and expectations in a way that has not been previously documented. Taken together, our findings from two distinct socioeconomic contexts, highlight the non-uniform distribution of benefits from energy transitions, especially when benefits that are not mediated by air pollution are considered. These results contribute to the understanding that social drivers of inequities should be integrated in the design of energy policies and interventions aimed at generating equitable outcomes. Future directions include a detailed characterization of the context-dependent relative contributions of indoor and outdoor air pollution sources as well as a more systematic integration of quantitative and qualitative methods in policy evaluation.

Preterm birth (PTB), defined as birth before 37 weeks of gestation, is the leading cause of neonatal morbidity, and survivors can face lifelong medical difficulties. PTB remains a clinical challenge worldwide, with rates of PTB rising in all countries with reliable data. A lack in understanding of the mechanisms that lead to PTB has made developing diagnostics and therapeutics challenging, and existing ones are often ineffective. For a successful pregnancy, the major reproductive organs and surrounding tissues must sustain the growing loads of pregnancy. The cervix is one of these major reproductive organs. The cervix sits at the base of the uterus and has a versatile mechanical function in pregnancy. First, it must stay closed during gestation while the fetus develops; second, the cervix must remodel sufficiently and timely to dilate and allow delivery. The proper timing and extent of remodeling are critical for a healthy pregnancy. Improper cervical remodeling is a final common pathway to PTB and is the tissue of focus in this thesis. To improve our ability to identify when a PTB birth will occur and ultimately be able to treat those at risk, this thesis will identify the mechanical role of three extracellular matrix (ECM) components at various gestational ages and evaluate the ability of two major hormones to alter cervix function. Using experimental techniques (large-deformation tensile testing, digital-image correlation, imaging, biochemical) and theoretical and computational techniques (constitutive modeling, finite element analysis), the mechanical behavior of whole mouse cervices will be characterized in wild type, genetic knockout, and hormone-treated animals. First, the loss of both Class-I small leucine rich proteoglycans (SLRPs), decorin and biglycan, is detrimental to cervix function in late gestation. When the cervix should be most compliant and extensible, cervices without decorin and biglycan cannot stretch and are as stiff as the nonpregnant cervix. The loss of these proteoglycans also slows the cervix’s stress dissipation mechanism in late gestation, which could put the cervix at increased risk for damage. The mechanism of stiffening and lost viscoelasticity indicates the fibril crosslinking associated with SLRPs is a structural mechanism of the ECM contributing to cervical remodeling. Second, the loss of hyaluronic acid diminishes the cervix’s mechanical function at every gestational age tested. For nonpregnant to mid-gestational age, the cervix is softer than normal. Though by late gestation, the loss of hyaluronic acid stiffens the cervix; this is at a point when the cervix should be at its softest. The loss of hyaluronic acid also decreases the cervix’s protective stress dissipation mechanism in late gestation. There is limited knowledge of the interaction of collagen, elastic fibers, and hyaluronic acid in the cervix. The significant mechanical role of hyaluronic acid in the cervix warrants exploration of the structural mechanisms of these functional changes. Third, the loss of endogenous hormones stiffens the tissue and increases extensibility compared to the nonpregnant cervix. The administration of estrogen recovers large amounts of extensibility (beyond the stretch level of a late gestation cervix), stiffens the tissue (such that it is stiffer than a nonpregnant cervix), and recovers a significant amount of cervix strength. Fourth, relaxin increases cervix extensibility in mid-gestation and endows the cervix with viscoelastic ability in late gestation. Altogether, understanding the correlation between these extracellular matrix components, hormones, and functional changes of the cervix is fundamental to teasing out mechanisms of cervical remodeling and developing improved PTB diagnostics and therapeutics.

O presente trabalho teve como proposta estudar as representações sociais para mulheres com diagnóstico de gestação de alto risco em decorrência tanto de doenças pré-existentes quanto de doenças adquiridas durante o período gestacional. Foram entrevistadas 100 mulheres na faixa etária dos 18 aos 42 anos, assim divididas em termos de quadros clínicos: 09 com Diabetes mellitus tipo I associada à gestação; 08 com Diabetes mellitus tipo II associada à gestação; 06 com Hipertensão arterial crônica associada à gestação; 16 com Diabetes gestacional; 18 com Rotura Prematura de Membrana; 20 com Trabalho de Parto Prematuro e 23 com Hipertensão induzida pela gestação. Essas gestantes estavam hospitalizadas para monitoração da gestação no Hospital Maternidade-Escola de Vila Nova Cachoeirinha Dr. Mário de Moraes Altenfelder Silva, localizado na região norte da cidade de São Paulo. A metodologia utilizada foi a qualitativa, com respaldo da teoria das representações sociais, e a estratégia metodológica para a análise das entrevistas foi o Discurso do Sujeito Coletivo. Diferentes representações sociais foram extraídas dos depoimentos e classificadas em quatro grupos temáticos: o primeiro grupo temático trouxe representações a respeito da forma como ocorreu a gestação (se foi planejada ou não); o segundo grupo temático trouxe representações sociais relacionadas aos sentimentos das gestantes ao vivenciarem o diagnóstico do alto risco, por consequência disso a necessidade de hospitalização e suas vivências no contexto hospitalar. As representações sociais do terceiro grupo temático estiveram relacionadas ao significado da maternidade e do filho no contexto do alto risco. E o quarto grupo temático trouxe representações dos sentimentos do companheiro e da família ao vivenciarem junto à gestante o diagnóstico de risco e a hospitalização. Podemos considerar a existência de uma multiplicidade de significados para a maternidade no contexto da gestação de alto risco, onde dois grupos de representações emergiram nos grupos temáticos: um deles trazendo representações relacionadas tanto ao contexto de baixo quanto ao de alto risco e outro trazendo representações que sofrem influência dos quadros clínicos diagnosticados em gestações de alto risco. Por meio dos discursos das entrevistadas foi possível verificar o impacto da gestação de alto risco para a gestante, seu companheiro e sua família, levando-nos a compreender melhor seus medos, desejos e expectativas, o que possibilita uma reflexão a respeito da promoção da integralidade das ações de saúde da mulher no ciclo gravídico-puerperal, especialmente quando a gestação apresenta condições de risco materno-fetal / This work aimed to study the social representations for women diagnosed with high-risk pregnancy resultant from both pre-existing diseases and diseases acquired during the pregnancy period. One hundred (100) women, aged 18 to 42, were interviewed and thereafter divided according to their clinical situation: 09 with Diabetes mellitus type I associated with pregnancy; 08 with Diabetes mellitus type II associated with pregnancy; 06 with chronic arterial hypertension associated with pregnancy; 16 with pregnancy Diabetes; 18 with Premature Rupture of Membrane; 20 with Premature Labor Signs; and 23 with Specific Hypertensive Diseases of Pregnancy. These pregnant women were hospitalized for pregnancy monitoring in the Maternity-School Hospital of Vila Nova Cachoeirinha Dr. Mário de Moraes Altenfelder Silva, in the North region of the city of São Paulo. The methodology used was qualitative, with support of social representation theory, and the methodological strategy used for analyzing interviews was the Discourse of Collective Subject. Different social representations were extracted from statements and classified into four theme groups: the first theme group presented representations regarding the way pregnancy was conceived (if it was planned or not); the second theme group provided social representations related to the feelings of the pregnant women while experiencing the high-risk pregnancy diagnosis, and subsequent hospitalization and experiences in the hospital environment. The social representations of the third theme group considered the meaning of motherhood and child when in a high-risk pregnancy situation. And the fourth theme group presented the partner and the family feelings while experiencing a high-risk pregnancy diagnosis and hospitalization. Considering the existence of multiple meanings of motherhood in a high-risk pregnancy situation, we can highlight two representation groups among the theme groups: one of them with representations related to both low and high-risk pregnancy and the other presenting representations under the influence of the clinical situations diagnosed with high-risk pregnancy. Through the discourses of the interviewed women, it was possible to identify the impact of the high-risk pregnancy to the pregnant women, their partners and families, to better understand their fears, desires, and expectations, which enabled the consideration to promote actions as a whole in regard to womens health in pregnancy-puerperal cycle, especially when pregnancy presents mother-fetus risk conditions

O presente trabalho teve como proposta estudar as representações sociais para mulheres com diagnóstico de gestação de alto risco em decorrência tanto de doenças pré-existentes quanto de doenças adquiridas durante o período gestacional. Foram entrevistadas 100 mulheres na faixa etária dos 18 aos 42 anos, assim divididas em termos de quadros clínicos: 09 com Diabetes mellitus tipo I associada à gestação; 08 com Diabetes mellitus tipo II associada à gestação; 06 com Hipertensão arterial crônica associada à gestação; 16 com Diabetes gestacional; 18 com Rotura Prematura de Membrana; 20 com Trabalho de Parto Prematuro e 23 com Hipertensão induzida pela gestação. Essas gestantes estavam hospitalizadas para monitoração da gestação no Hospital Maternidade-Escola de Vila Nova Cachoeirinha Dr. Mário de Moraes Altenfelder Silva, localizado na região norte da cidade de São Paulo. A metodologia utilizada foi a qualitativa, com respaldo da teoria das representações sociais, e a estratégia metodológica para a análise das entrevistas foi o Discurso do Sujeito Coletivo. Diferentes representações sociais foram extraídas dos depoimentos e classificadas em quatro grupos temáticos: o primeiro grupo temático trouxe representações a respeito da forma como ocorreu a gestação (se foi planejada ou não); o segundo grupo temático trouxe representações sociais relacionadas aos sentimentos das gestantes ao vivenciarem o diagnóstico do alto risco, por consequência disso a necessidade de hospitalização e suas vivências no contexto hospitalar. As representações sociais do terceiro grupo temático estiveram relacionadas ao significado da maternidade e do filho no contexto do alto risco. E o quarto grupo temático trouxe representações dos sentimentos do companheiro e da família ao vivenciarem junto à gestante o diagnóstico de risco e a hospitalização. Podemos considerar a existência de uma multiplicidade de significados para a maternidade no contexto da gestação de alto risco, onde dois grupos de representações emergiram nos grupos temáticos: um deles trazendo representações relacionadas tanto ao contexto de baixo quanto ao de alto risco e outro trazendo representações que sofrem influência dos quadros clínicos diagnosticados em gestações de alto risco. Por meio dos discursos das entrevistadas foi possível verificar o impacto da gestação de alto risco para a gestante, seu companheiro e sua família, levando-nos a compreender melhor seus medos, desejos e expectativas, o que possibilita uma reflexão a respeito da promoção da integralidade das ações de saúde da mulher no ciclo gravídico-puerperal, especialmente quando a gestação apresenta condições de risco materno-fetal / This work aimed to study the social representations for women diagnosed with high-risk pregnancy resultant from both pre-existing diseases and diseases acquired during the pregnancy period. One hundred (100) women, aged 18 to 42, were interviewed and thereafter divided according to their clinical situation: 09 with Diabetes mellitus type I associated with pregnancy; 08 with Diabetes mellitus type II associated with pregnancy; 06 with chronic arterial hypertension associated with pregnancy; 16 with pregnancy Diabetes; 18 with Premature Rupture of Membrane; 20 with Premature Labor Signs; and 23 with Specific Hypertensive Diseases of Pregnancy. These pregnant women were hospitalized for pregnancy monitoring in the Maternity-School Hospital of Vila Nova Cachoeirinha Dr. Mário de Moraes Altenfelder Silva, in the North region of the city of São Paulo. The methodology used was qualitative, with support of social representation theory, and the methodological strategy used for analyzing interviews was the Discourse of Collective Subject. Different social representations were extracted from statements and classified into four theme groups: the first theme group presented representations regarding the way pregnancy was conceived (if it was planned or not); the second theme group provided social representations related to the feelings of the pregnant women while experiencing the high-risk pregnancy diagnosis, and subsequent hospitalization and experiences in the hospital environment. The social representations of the third theme group considered the meaning of motherhood and child when in a high-risk pregnancy situation. And the fourth theme group presented the partner and the family feelings while experiencing a high-risk pregnancy diagnosis and hospitalization. Considering the existence of multiple meanings of motherhood in a high-risk pregnancy situation, we can highlight two representation groups among the theme groups: one of them with representations related to both low and high-risk pregnancy and the other presenting representations under the influence of the clinical situations diagnosed with high-risk pregnancy. Through the discourses of the interviewed women, it was possible to identify the impact of the high-risk pregnancy to the pregnant women, their partners and families, to better understand their fears, desires, and expectations, which enabled the consideration to promote actions as a whole in regard to womens health in pregnancy-puerperal cycle, especially when pregnancy presents mother-fetus risk conditions

Les accouchements prématurés constituent un problème médical majeur en constante augmentation et ce, malgré tous les efforts mis en œuvre afin de contrer le déclenchement des contractions avant terme. Cette thèse relate du ''design'' rationnel d'un nouvel agent thérapeutique (i.e., tocolytique) qui serait capable de 1) arrêter les contractions, et 2) prolonger la gestation. Pour ce faire, une nouvelle cible, la prostaglandine F2α et son récepteur ont été sélectionnés et le peptidomimétisme a été choisi afin de résoudre cette problématique. L'introduction contient un historique rapide de la conception à la synthèse (''drug design'') du peptide parent, le PDC113, premier peptide a avoir démontré des aptitudes tocolytiques suffisantes pour faire du peptidomimétisme. La deuxième partie de l'introduction présente les concepts du peptidomimétisme appliqués au PDC113 qui ont permis d'accéder au PDC113.824, inhibiteur allostérique du récepteur de la prostaglandine F2α, et explique comment ce mime nous a permis d'élucider les mécanismes de signalisation intracellulaire impliqués dans la contraction musculaire lisse. Cette thèse présente la conception, la synthèse et l'étude structure-activité de mimes de repliement de tour β au sein du mime peptidique original (PDC113.824) dans lequel nous avons remplacé l'azabicycloalkane central (l'indolizidin-2-one) par une série d'autres azabicycloalcanes connus et des acides aza-aminés dont nous avons élaboré la synthèse. Dans un premier temps, une nouvelle stratégie de synthèse en solution de l'aza-glycyl-proline à partir de la diphényle hydrazone et du chloroformate de p-nitrophényle a été réalisée. Cette stratégie a permis d'éliminer les réactions secondaires de cyclisation intramoléculaires communément obtenues lors de l'introduction d'acides aza-aminés avec les protections traditionnelles de type carbamate en présence de phosgène, mais aussi de faciliter l'accès en une étape à des dérivés peptidiques du type aza-glycyle. L'élongation de l'aza-glycyl-proline en solution nous a permis d'accéder à un nouveau mime tetrapeptidique du Smac, un activateur potentiel de l'apoptose au sein de cellules cancéreuses. Par la suite, nous avons développé une stratégie de diversification sélective de l'azote α du résidu azaglycine en utilisant différents types d'halogénures d'alkyle en présence de tert-butoxyde de potassium. Afin de valider le protocole d'alkylation de l'aza-dipeptide, différents halogénures d'alkyle ont été testés. Nous avons également démontré l'utilité des aza-dipeptides résultants en tant que ''building block'' afin d'accéder à une variété d'azapeptides. En effet, l'aza-dipeptide a été déprotégée sélectivement soit en N-terminal soit en C-terminal, respectivement. D'autre part, la libération de l'amine de l'ester méthylique de l'aza-alkylglycyl-proline a conduit à une catégorie de composés à potentiel thérapeutique, les azadicétopipérazines (aza-DKP) par cyclisation intramoléculaire. Enfin, notre intérêt quant au développement d'un nouvel agent tocolytique nous a amené à développer une nouvelle voie de synthèse en solution du PDC113.824 permettant ainsi d'élucider les voies de signalisation intracellulaires du récepteur de la prostaglandine F2α. Afin de valider l'importance de la stéréochimie et d'étudier la relation structure/ activité du mime, nous avons remplacé l'indolizidin-2-one (I2aa) centrale du PDC113.824 par une série d'autres azabicycloalcanes et azadipeptides. Les azabicycloalcanes D-I2aa, quinolizidinone, et indolizidin-9-one ont été synthétisés et incorporés au sein du dit peptide ne donnant aucune activité ni in vitro ni ex vivo, validant ainsi l'importance du tour β de type II' pour le maintien de l'activité biologique du PDC113.824. Finalement, l'insertion d'une série de dérivés aza(alkyl)glycyl-prolyles a mené à de nouveaux inhibiteurs allostériques du récepteur de la PGF2α, l'un contenant l'azaglycine et l'autre, l'azaphénylalanine. Cette thèse a ainsi contribué, grâce à la conception et l'application de nouvelles méthodes de synthèse d'aza-peptides, au développement de nouveaux composés à potentiel thérapeutique afin d'inhiber le travail prématuré. / Premature birth is a steadily increasing major medical problem, in spite of efforts made to counter the onset of preterm contractions. This thesis describes the rational design of a new therapeutic agent (i.e., tocolytic) capable of 1) stopping uterine contractions, and 2) prolonging gestation. The prostaglandin F2α receptor was explored for tocolytic development and a peptidomimetic approach was developed to produce modulators of this novel target. A brief discussion introduces the impact of preterm birth and history on the design and synthesis of a peptide lead, PDC113, to address this unmet medical need. Subsequently, the peptidomimetic approach is described for converting PDC113 to the small molecule PDC113.824, which was shown to be an allosteric modulator of prostaglandin F2α receptor, which mediates intracellular signalling pathways involved in uterine contraction. This thesis presents the design, synthesis and structure-activity relationship study of the peptide mimic PDC113.824, in which we have replaced the central β-turn mimic moiety, the indolizidin-2-one amino acid, by a series of other previously reported azabicycloalcane turn mimics and novel aza-amino acids. To accomplish the latter, new solution-phase methods for synthesizing aza-glycyl-proline analogs were developed starting from diphenyl hydrazone and p-nitrophenyl chloroformate. This strategy has surmounted side reactions such as the intramolecular cyclization commonly obtained with traditional coupling reactions employing alkyl-carbazates and phosgene, facilitating access to aza-glycyl-proline derivatives by a one step reaction. The modification of the aza-glycyl-proline using conventional strategies led to a new Smac mimic (a proapoptotic molecule), with potential as a tetrapeptide activator of apoptosis in cancer cells. Subsequently, we focused on the diversification of the aza-glycine residue by selective alkylation using different alkyl halides in the presence of potassium tert-butoxide. To validate the alkylation protocol, various alkyl groups were employed, and the usefulness of the resulting aza-dipeptides as ''building blocks'' was examined. Conditions were developed for selectively unmasking the protecting groups at the N- and C-terminal of the aza-dipeptide. In addition, removal of the amine protection of aza-alkylglycyl-proline methyl ester gave access to a class of compounds with therapeutic potential, the aza-diketopiperazines (aza-DKP), by intramolecular cyclization. Finally, our interest in developing a new tocolytic agent led us to develop a new solution-phase synthetic route to PDC113.824 for elucidating the intracellular signalling pathways of prostaglandin F2α receptor. To explore the importance of stereochemistry and to study the relationship between structure and activity, we replaced the central indolizidin-2-one (I2aa) of PDC113.824 by a series of others azabicycloalcanes and aza-dipeptides. The D-I2aa, quinazolidinone and indolizidin-9-one analogs were synthesized and incorporated into the mimic; however, none exhibited activity neither in vitro nor ex vivo, thus indicating the importance of a type II' β-turn for maintaining biological activity of PDC113.824. Finally, the synthesis of a series of aza(alkyl)glycyl-prolyl analogs led to new allosteric modulators of the PGF2α receptor, one containing aza-glycine and another aza-phenylalanine. This results reported in this thesis have contributed to the development of novel agents with promise for inhibiting preterm labor by the conception and application of new methods for making aza-peptides.

Les accouchements prématurés constituent un problème médical majeur en constante augmentation et ce, malgré tous les efforts mis en œuvre afin de contrer le déclenchement des contractions avant terme. Cette thèse relate du ''design'' rationnel d'un nouvel agent thérapeutique (i.e., tocolytique) qui serait capable de 1) arrêter les contractions, et 2) prolonger la gestation. Pour ce faire, une nouvelle cible, la prostaglandine F2α et son récepteur ont été sélectionnés et le peptidomimétisme a été choisi afin de résoudre cette problématique. L'introduction contient un historique rapide de la conception à la synthèse (''drug design'') du peptide parent, le PDC113, premier peptide a avoir démontré des aptitudes tocolytiques suffisantes pour faire du peptidomimétisme. La deuxième partie de l'introduction présente les concepts du peptidomimétisme appliqués au PDC113 qui ont permis d'accéder au PDC113.824, inhibiteur allostérique du récepteur de la prostaglandine F2α, et explique comment ce mime nous a permis d'élucider les mécanismes de signalisation intracellulaire impliqués dans la contraction musculaire lisse. Cette thèse présente la conception, la synthèse et l'étude structure-activité de mimes de repliement de tour β au sein du mime peptidique original (PDC113.824) dans lequel nous avons remplacé l'azabicycloalkane central (l'indolizidin-2-one) par une série d'autres azabicycloalcanes connus et des acides aza-aminés dont nous avons élaboré la synthèse. Dans un premier temps, une nouvelle stratégie de synthèse en solution de l'aza-glycyl-proline à partir de la diphényle hydrazone et du chloroformate de p-nitrophényle a été réalisée. Cette stratégie a permis d'éliminer les réactions secondaires de cyclisation intramoléculaires communément obtenues lors de l'introduction d'acides aza-aminés avec les protections traditionnelles de type carbamate en présence de phosgène, mais aussi de faciliter l'accès en une étape à des dérivés peptidiques du type aza-glycyle. L'élongation de l'aza-glycyl-proline en solution nous a permis d'accéder à un nouveau mime tetrapeptidique du Smac, un activateur potentiel de l'apoptose au sein de cellules cancéreuses. Par la suite, nous avons développé une stratégie de diversification sélective de l'azote α du résidu azaglycine en utilisant différents types d'halogénures d'alkyle en présence de tert-butoxyde de potassium. Afin de valider le protocole d'alkylation de l'aza-dipeptide, différents halogénures d'alkyle ont été testés. Nous avons également démontré l'utilité des aza-dipeptides résultants en tant que ''building block'' afin d'accéder à une variété d'azapeptides. En effet, l'aza-dipeptide a été déprotégée sélectivement soit en N-terminal soit en C-terminal, respectivement. D'autre part, la libération de l'amine de l'ester méthylique de l'aza-alkylglycyl-proline a conduit à une catégorie de composés à potentiel thérapeutique, les azadicétopipérazines (aza-DKP) par cyclisation intramoléculaire. Enfin, notre intérêt quant au développement d'un nouvel agent tocolytique nous a amené à développer une nouvelle voie de synthèse en solution du PDC113.824 permettant ainsi d'élucider les voies de signalisation intracellulaires du récepteur de la prostaglandine F2α. Afin de valider l'importance de la stéréochimie et d'étudier la relation structure/ activité du mime, nous avons remplacé l'indolizidin-2-one (I2aa) centrale du PDC113.824 par une série d'autres azabicycloalcanes et azadipeptides. Les azabicycloalcanes D-I2aa, quinolizidinone, et indolizidin-9-one ont été synthétisés et incorporés au sein du dit peptide ne donnant aucune activité ni in vitro ni ex vivo, validant ainsi l'importance du tour β de type II' pour le maintien de l'activité biologique du PDC113.824. Finalement, l'insertion d'une série de dérivés aza(alkyl)glycyl-prolyles a mené à de nouveaux inhibiteurs allostériques du récepteur de la PGF2α, l'un contenant l'azaglycine et l'autre, l'azaphénylalanine. Cette thèse a ainsi contribué, grâce à la conception et l'application de nouvelles méthodes de synthèse d'aza-peptides, au développement de nouveaux composés à potentiel thérapeutique afin d'inhiber le travail prématuré. / Premature birth is a steadily increasing major medical problem, in spite of efforts made to counter the onset of preterm contractions. This thesis describes the rational design of a new therapeutic agent (i.e., tocolytic) capable of 1) stopping uterine contractions, and 2) prolonging gestation. The prostaglandin F2α receptor was explored for tocolytic development and a peptidomimetic approach was developed to produce modulators of this novel target. A brief discussion introduces the impact of preterm birth and history on the design and synthesis of a peptide lead, PDC113, to address this unmet medical need. Subsequently, the peptidomimetic approach is described for converting PDC113 to the small molecule PDC113.824, which was shown to be an allosteric modulator of prostaglandin F2α receptor, which mediates intracellular signalling pathways involved in uterine contraction. This thesis presents the design, synthesis and structure-activity relationship study of the peptide mimic PDC113.824, in which we have replaced the central β-turn mimic moiety, the indolizidin-2-one amino acid, by a series of other previously reported azabicycloalcane turn mimics and novel aza-amino acids. To accomplish the latter, new solution-phase methods for synthesizing aza-glycyl-proline analogs were developed starting from diphenyl hydrazone and p-nitrophenyl chloroformate. This strategy has surmounted side reactions such as the intramolecular cyclization commonly obtained with traditional coupling reactions employing alkyl-carbazates and phosgene, facilitating access to aza-glycyl-proline derivatives by a one step reaction. The modification of the aza-glycyl-proline using conventional strategies led to a new Smac mimic (a proapoptotic molecule), with potential as a tetrapeptide activator of apoptosis in cancer cells. Subsequently, we focused on the diversification of the aza-glycine residue by selective alkylation using different alkyl halides in the presence of potassium tert-butoxide. To validate the alkylation protocol, various alkyl groups were employed, and the usefulness of the resulting aza-dipeptides as ''building blocks'' was examined. Conditions were developed for selectively unmasking the protecting groups at the N- and C-terminal of the aza-dipeptide. In addition, removal of the amine protection of aza-alkylglycyl-proline methyl ester gave access to a class of compounds with therapeutic potential, the aza-diketopiperazines (aza-DKP), by intramolecular cyclization. Finally, our interest in developing a new tocolytic agent led us to develop a new solution-phase synthetic route to PDC113.824 for elucidating the intracellular signalling pathways of prostaglandin F2α receptor. To explore the importance of stereochemistry and to study the relationship between structure and activity, we replaced the central indolizidin-2-one (I2aa) of PDC113.824 by a series of others azabicycloalcanes and aza-dipeptides. The D-I2aa, quinazolidinone and indolizidin-9-one analogs were synthesized and incorporated into the mimic; however, none exhibited activity neither in vitro nor ex vivo, thus indicating the importance of a type II' β-turn for maintaining biological activity of PDC113.824. Finally, the synthesis of a series of aza(alkyl)glycyl-prolyl analogs led to new allosteric modulators of the PGF2α receptor, one containing aza-glycine and another aza-phenylalanine. This results reported in this thesis have contributed to the development of novel agents with promise for inhibiting preterm labor by the conception and application of new methods for making aza-peptides.