Modélisations moléculaires réalisés avec le logiciel HyperChem 8. / L’effet de différentes alkylations sur l’activité biologique et la stabilité enzymatique d’un peptide linéaire L, énantiomère du modulateur allostérique des récepteurs prostaglandine F2α ont été étudiés. Dans une étude antérieure, le peptide D PDC-31 avait montré un potentiel d’inhibition des contractions du myomètre et permettait de retarder l’accouchement dans des modèles animaux et humains. Il est possible que le peptide L possède une activité semblable, mais les protéases, abondantes dans le tissu myométrial, le dégradent probablement avant qu’il ne puisse atteindre le site actif. La synthèse peptidique sur support solide suivie d’une amination réductive a permis d’obtenir différents peptides portant différentes chaines alkyle et PEG N-terminales. La protection de l’amine terminale par un groupement ortho-nitrobenzène sulfonyle suivie par une réaction de Mitsunobu a permis l’obtention d’un analogue portant une chaine farnesyle. Malgré le fait que ni l’analogue PEGylé, ni l’analogue farnesylé n’aient montrés la moindre activité, certains analogues alkylés se sont avérés actifs dans l’essai tissulaire de contractions myométriales. Le peptide L portant une chaine dodecyle s’est avéré posséder une activité statistiquement significative et reproductible. Qui plus est, l’analogue D du peptide possédant une chaine de 12 carbones s’est avéré posséder une activité inférieure à l’analogue L portant la même chaine, ce qui représente une perte d’activité significative par rapport au peptide D nonmodifié (PDC-31). / The application of hydrophobic grafts to prolong the biological activity of rapidly metabolized peptides has been explored by modification of the L-peptide of the prostaglandin F2α receptor modulator PDC-31. The all-D peptide PDC-31 has previously been shown to inhibit myometrial contractions and delay labour in various animal models as well as in humans. The L-peptide may have activity; however, proteases, which are abundant in myometrial tissue, may likely degrade the peptide before it is capable of showing activity. Solid-phase peptide synthesis followed by Nterminal modification by reductive aminations with different aldehydes provided linear aliphatic alkyl and PEG-grafted peptide analogs. Alternatively, ortho-nitrobenzensulfonylation of the peptide followed by Mitsunobu alkylation with farnesol and deprotection gave a farnesylated analog. Although the PEG and fanesylated analogs exhibited no activity, certain N-alkyl analogs exhibited inhibitory activity on myometrial contractions, with the most active analog possessing a dodecyl chain. Moreover, the N-dodecyl analog of PDC-31, exhibited lower activity than its L-counterpart in the myometrial contraction assay, and with reduced potency relative to its unmodified structure.

La naissance avant terme constitue un important problème de santé périnatale partout dans le monde. Chaque année près de 15 millions de bébés naissent prématurément. Notre laboratoire s’intéresse depuis une décennie à la conception et le développement de nouvelles classes thérapeutiques (appelés agents tocolytiques) capables d’inhiber les contractions utérines et prolonger le temps de gestation. Due à son implication directe dans le déclanchement des contractions utérines, la prostaglandine F2α (FP) est devenue notre cible de choix. Le PDC 113.824 et aza-glycinyl-proline sont apparus comme des inhibiteurs allostériques puissants du récepteur de la prostaglandine F2α, capables de prolonger la durée de gestation chez les souris. Le travail réalisé au cours de ce mémoire a pour objectif d’étudier le tour β nécessaire pour la reconnaissance sur le récepteur de la prostaglandine F2α. Dans la conception de mime peptidique sélectif efficace et puissant, le repliement β est un élément structural essentiel pour le maintien ou l’amélioration de l’activité du mime peptidique. Les études conformationelles du PDC113.824 et l’aza-glycinyl-proline montrent que les squelettes centraux de ces mimes peptidiques pourraient adopter essentiellement un tour β de type I ou II`, ce qui suggère l’implication des deux types de tours dans l’activité biologique. La synthèse de mimes peptidiques adoptant le tour β de type I et II` est devenue une stratégie logique dans la recherche de nouveaux agents tocolytiques. Au cours de ces études quatre analogues du PDC113.824 ont été synthétisés, un azabicyclo[5.3.0]alkanone et un dipeptide macrocyclique (mimes du tours β de type I) pour étudier l’implication du tour β type I. Par la suite la synthèse de glycinyl-proline et le D-alaninyl-proline (des mimes du tour β du type II`) a été réalisée afin de valider l’implication du tour β type II` dans la reconnaissance sur le récepteur. Nous avons utilisé une stratégie de synthèse efficace pour obtenir les deux analogues (azabicyclo [5.3.0]alkanone et dipeptides macrocycles) à partir d’un intermédiaire commun, en procédant par une cyclisation transannulaire diastéréosélective du tétra-peptide. / Preterm birth is a major perinatal health problem. Worldwide each year, more than one baby on ten is born premature, accounting for approximately 15 million babies per year. Pursuing molecules that can delay labour, so called tocolytics, we have targeted the prostaglandin F2α receptor (FP), because of its intimate involvement with the stimulation of uterine contractions leading to birth and preterm birth. Our laboratory has previously demonstrated that PDC-113.824 and azapeptide can modulate FP function by an allosteric mechanism featuring biased signalling, and can delay labour in a mouse model. The objective of the present work is to study the active turn geometry responsible for the modulatory effects of our lead tocolytic agents on the prostaglandin F2α receptor. Crystal structure and computational analyses of indolizidin-2-one amino acid and aza-glycinyl-proline components have shown them to adopt geometry that mimic ideal type I and II’ β-turns suggesting the potential involvement of such turns in the biological activity. To study the relevance of a type I β-turn on activity, we have prepared analogs possessing macrocyclic and pyrroloazepinone dipeptide mimics, because of their reported propensities to mimic type I β-turns. The syntheses of analogs possessing glycinyl-proline and D-alaninyl-proline were conducted to validate the involvement of a type II` β-turn in receptor recognition. In addition, we reported an efficient strategy for preparing the macrocyclic and pyrroloazepinone dipeptide mimics from a common intermediate using a diastereoselective transannular cyclization on a tetrapeptide precursor.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / It is well established that locally produced factors exert pivotal roles during dominant follicle selection, oocyte maturation, ovulation and luteolysis. However, the identification of these factors and pathways involved in these processes are not yet established. In the present study, we focused on the in vivo bovine models to study reproductive physiology, which were used to identify receptors and intracellular signaling pathways involved in follicle selection and luteolysis. In the first study, it was reviewed the in vivo models used in our lab, describing and discussing the different bovine models and techniques currently used to study ovarian physiology in this mono-ovulatory specie. In a second study, it was evaluated the expression of estrogen receptors (ESRs) before (day 2 of follicular wave), during (day 3) and after (day 4) follicular deviation in cattle. ESR1 and ESR2 transcripts levels were higher in dominant (F1) than subordinate (F2) follicle after follicular deviation. FSH treatment maintained mRNA levels of both ESR1 and ESR2 in F2 follicles at similar levels observed in F1 follicles. Intrafollicular injection of 100 μM fulvestrant (an antagonist of ESRs) inhibited follicular growth and decreased CYP19A1 mRNA levels. Transcript levels of both ESR1 and ESR2 were not affected by fulvestrant injection. In the third study, our objective was to demonstrate the role of the transcription factor signal transducer and activator of transcription 3 (STAT3) and the nuclear receptor 5A2 (NR5A2) in luteolysis. Luteal and blood samples were collected from separate groups of cows on Day 10 of the estrous cycle 0, 2, 12, 24, and 48 hours after prostaglandin F2 alpha (PGF) treatment. Serum progesterone concentrations decreased (P < 0.05) within 2h and the histological examination of the corpus luteum at 24 and 48h after PGF treatment confirmed functional and morphological luteolysis, respectively. The abundance of STAR mRNA and protein decreased at 12h after PGF treatment. The abundance of NR5A2 mRNA and protein decreased (P < 0.05) at 12 and 24h post-PGF, respectively. Levels of STAT3 mRNA remained constant (P > 0.05) throughout the time-points evaluated. However, the abundance of phosphorylated isoform of STAT3, normalized to total STAT3, increased reaching a peak at 12h and remaining high until 48h after PGF treatment. In conclusion, bovine in vivo models provide a valuable system to study reproductive events under physiological endocrine environment while keeping intact the communication between follicular cells through autocrine and paracrine signaling, without the need to perform ovariectomy or euthanaze the animals. Our results suggest that both ESR1 and ESR2 are regulated during follicular deviation and dominance and in response to FSH treatment in cattle, ESRs are required for normal gene expression and development of the dominant follicle. PGF treatment results in decreased expression of the nuclear receptor NR5A2 and activation of STAT3 by phosphorylation in bovine luteal cells. / É bem estabelecido que fatores produzidos localmente exercem papel essencial durante a seleção do folículo dominante, maturação oocitária, ovulação e luteólise. No entanto, os fatores e vias envolvidas nestes processos não estão totalmente estabelecidos. No presente estudo, enfatizou-se o uso de modelos bovinos in vivo para o estudo da fisiologia reprodutiva, sendo aqui utilizados para identificar receptores e vias de sinalização intracelular envolvidas na seleção do folículo e luteólise. No primeiro estudo, revisaram-se os modelos in vivo utilizados em nosso laboratório, descreveram-se e discutiram-se os diferentes modelos em bovinos e técnicas atualmente utilizadas para estudar fisiologia ovariana nesta espécie monovulatória. Em um segundo estudo, avaliou-se a expressão de receptores de estradiol (ESRS) antes (dia 2 da onda folicular), durante (dia 3) e após (dia 4) a divergência folicular em bovinos. Os níveis dos transcritos ESR1 e ESR2 foram maiores no folículo dominante (F1) que no subordinado (F2) após a divergência folicular. O tratamento com FSH manteve os níveis de RNAm de ambos ESR1 e ESR2 nos folículos F2 em níveis semelhantes aos observados em folículos F1. A injeção intrafolicular de 100 uM de fulvestrant (um antagonista de ESRs) inibiu o crescimento folicular e causou uma diminuição dos níveis de RNAm de CYP19A1. Os níveis de transcritos, tanto para ESR1 e ESR2, não foram afetados pela injeção de fulvestrant. Num terceiro estudo, o nosso objetivo foi demonstrar o papel do Transdutor de sinais e ativador de transcrição 3 (STAT3) e do receptor nuclear 5A2 (NR5A2) na luteólise. Amostras de corpo lúteo (CL) e sangue foram coletadas dos grupos de vacas 0, 2, 12, 24 e 48 horas após o tratamento com prostaglandina F2 alpha (PGF) no dia 10 do ciclo estral. A concentração de progesterona sérica diminuiu (P < 0.05) em 2 horas e o exame histológico do CL às 24h e 48h após o tratamento com PGF confirmou a ocorrência de luteólise funcional e morfológica, respectivamente. A abundância de RNAm e proteína de STAR diminuiu às 12h após o tratamento com PGF. A abundância de RNAm e proteína de NR5A2 diminuiu (P < 0.05) às 12 e 24 horas pós-PGF, respectivamente. Os níveis de RNAm de STAT3 permaneceram constantes (P> 0.05) ao longo do tempo avaliado. No entanto, a abundância da isoforma fosforilada de STAT3, normalizados para STAT3 total, aumentou, atingindo um pico às 12h e permaneceu elevada até 48h após o tratamento com PGF. Em conclusão, os modelos bovinos in vivo fornecem um sistema valioso para estudar os eventos reprodutivos sob ambiente fisiológico, mantendo intacta a comunicação entre as células foliculares através de sinalização autócrina e parácrina, reduzindo a necessidade de realizar ovariectomia ou realizar a eutanásia dos animais. Nossos resultados sugerem que tanto ESR1 como ESR2 são regulados durante a divergência e dominância folicular em bovinos e em resposta ao tratamento com FSH, e ESRs são necessários para a expressão gênica e para o desenvolvimento do folículo dominante. O tratamento com PGF resulta em diminuição da expressão do receptor nuclear NR5A2 e ativação de STAT3 por fosforilação em células luteais bovinas.

<p>Inflammation and oxidative stress may be involved in atherogenesis. This thesis describes clinical studies of prostaglandin F_2α (PGF_2α), an inflammatory mediator, and the isoprostane 8-iso-PGF_2α, a reliable indicator of oxidative stress, and cytokine-related inflammatory mediators and indicators in healthy subjects and in a population-based cohort of Swedish men. </p><p>PGF_2α and 8-iso-PGF_2α formation in healthy subjects varied considerably between days with a mean intra-individual coefficient of variation of 41 % and 42 %, respectively. A morning urine sample reflected the basal level of 8-iso-PGF_2α formation as accurately as a 24-hour urine collection, and represents a more practical alternative to the 24-hour urine collection in clinical studies. PGF_2α formation (as measured by urinary 15-keto-dihydro-PGF_2α) was increased in patients with type 2 diabetes and in smokers independent of other cardiovascular risk factors. These results indicated an on-going cyclooxygenase (COX)-mediated inflammatory reaction related to these conditions. Further, an increased formation of isoprostanes (as measured by urinary 8-iso-PGF_2α) was found in patients with type 2 diabetes and in smokers, indicating a high level of oxidative stress in these men. The smokers had also increased levels of the cytokine interleukin-6, indicating an on-going cytokine-related inflammatory reaction. The inflammatory indicators C-reactive protein and serum amyloid A were related to overweight but not independently associated to type 2 diabetes. High levels of serum selenium in middle-aged men predicted reduced formation of PGF_2α and 8-iso-PGF_2α 27 years later.</p><p>In summary, low-grade, chronic COX-mediated and possibly cytokine-related inflammation, and oxidative stress, seem to be joint features of type 2 diabetes and smoking, two major risk factors of atherosclerosis, in elderly men. Inflammation and oxidative stress may represent a possible common pathogenetic link between established risk factors for atherosclerosis and atherogenesis.</p>

Inflammation and oxidative stress may be involved in atherogenesis. This thesis describes clinical studies of prostaglandin F2α (PGF2α), an inflammatory mediator, and the isoprostane 8-iso-PGF2α, a reliable indicator of oxidative stress, and cytokine-related inflammatory mediators and indicators in healthy subjects and in a population-based cohort of Swedish men. PGF2α and 8-iso-PGF2α formation in healthy subjects varied considerably between days with a mean intra-individual coefficient of variation of 41 % and 42 %, respectively. A morning urine sample reflected the basal level of 8-iso-PGF2α formation as accurately as a 24-hour urine collection, and represents a more practical alternative to the 24-hour urine collection in clinical studies. PGF2α formation (as measured by urinary 15-keto-dihydro-PGF2α) was increased in patients with type 2 diabetes and in smokers independent of other cardiovascular risk factors. These results indicated an on-going cyclooxygenase (COX)-mediated inflammatory reaction related to these conditions. Further, an increased formation of isoprostanes (as measured by urinary 8-iso-PGF2α) was found in patients with type 2 diabetes and in smokers, indicating a high level of oxidative stress in these men. The smokers had also increased levels of the cytokine interleukin-6, indicating an on-going cytokine-related inflammatory reaction. The inflammatory indicators C-reactive protein and serum amyloid A were related to overweight but not independently associated to type 2 diabetes. High levels of serum selenium in middle-aged men predicted reduced formation of PGF2α and 8-iso-PGF2α 27 years later. In summary, low-grade, chronic COX-mediated and possibly cytokine-related inflammation, and oxidative stress, seem to be joint features of type 2 diabetes and smoking, two major risk factors of atherosclerosis, in elderly men. Inflammation and oxidative stress may represent a possible common pathogenetic link between established risk factors for atherosclerosis and atherogenesis.

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.