Design, synthesis and pharmacological evaluation of protein-protein interactions inhibitors involved in cancer

Les interactions protéine-protéine interviennent dans de nombreux processus biologiques, de la communication intercellulaire à la mort programmée de la cellule. Elles représentent donc un grand nombre de cibles ayant un intérêt dans la découverte de nouveaux médicaments. Le travail présenté dans cette thèse porte sur la conception et la synthèse d’inhibiteurs d’interactions protéine-protéine responsables de la survie des cellules cancéreuses. La première partie de ce mémoire s’articule autour de l’interaction p53-HDM2. Le criblage de chimiothèques très diversifiées a permis d’identifier un hit. Des études de relation entre structure et activité ont abouti à une amélioration de l’activité du composé testé par polarisation de fluorescence sur les protéines cibles. La seconde partie est axée sur la conception de structures privilégiées synthétisées par deux réactions connues : la réaction d’Ugi qui est une réaction multicomposante dont l’un des réactifs est un isonitrile et la réaction de Meyers qui fait intervenir des biélectrophiles et des binucléophiles. L’optimisation des deux réactions en utilisant des conditions sans solvant au micro-onde ou plus classiques en microplaques, a été réalisée dans le but de synthétiser des structures privilégiées originales. Deux chimiothèques ont donc été générées afin d’enrichir les chimiothèques du laboratoire et d’augmenter le taux de succès des campagnes de criblage. Trois molécules de la chimiothèque obtenue à partir de la réaction d’Ugi ont montré une activité sur un récepteur couplé aux protéines G : TGR5. MOTS CLÉS : interactions protéine-protéine, p53/HDM2, polarisation de fluorescence, chimiothèque, structures privilégiées, Ugi, Meyers.Growing evidences indicate that a small birthweight, resulting from maternal malnutrition or others prenatal alterations, is associated with an increased neonatal morbidity and mortality and may lead to higher propensity to develop a metabolic syndrome (including type 2 diabetes, obesity, hypertension and dyslipidemia) in adulthood. However, the physiopathological mechanisms acting in utero on the programming of the offspring\\\\\\\'s metabolic profile remain confused and may implicate numerous molecules and physiological systems. Several data suggest that the placental alterations may have long-lasting consequences and could thus contribute to the programming of adult metabolic diseases. The placenta is the primary means of communication and nutrient delivery to the fetus and is also involved in fetal homeostasis. Thus, the placenta may constitute an appropriate organ for investigating how differences in maternal food consumption are sensed by the fetus along the pregnancy. Because of the increasing proportion of women eating inadequately during pregnancy and because such nutritional disturbances may have huge repercussions on adult health of the offspring, we urgently have to better understand how the placenta elaborates adaptive responses to maternal food intake modulations. My PhD aimed at identifying new placental pathways implicated in fetal growth restriction in rat, and investigated in human placental samples, the expression of these factors in pregnancies with fetal growth disturbances.As maternal malnutrition constitutes an important part in the etiology of intrauterine growth restriction (IUGR), we used an experimental model performed in rats which consists of a reduction (from 50% to 70%) of the daily maternal food intake during the gestation. These regimens lead to profound growth disturbances of the feto-placental unit revealed by drastic reductions of both placental and birth weights at term. To identify new placental pathways implicated in IUGR, we have used two different strategies: a proteomic approach and the evaluation of two proteins recently characterized in the placenta.First, we investigated the placental proteome in IUGR rats from undernourished mothers using 2D-PAGE electrophoresis and mass spectrometry identification. This strategy allowed the discovery of new pathways modulated by IUGR. Surprisingly, major modulations were observed for several proteins localized in mitochondria, suggesting specific effects of maternal undernutrition on these organelles. Thereafter, using multiple molecular, proteomic and functional analyses, we have shown that these organelles develop adaptive responses to maternal nutrient restriction that may have functional consequences on the regulation of the fetal growth. Secondly, we studied two others atypical proteins: the brain-derived neurotrophic factor and the hormone apelin. Our findings suggest that both of these factors may be implicated in the control of fetal growth at the placental level in rat and putatively in human. As actual clinical methods do not permit to diagnose precisely fetal growth disturbances, our results may permit to better understand the placental physiological pathways implicated during these pathologies and could lead to the development of markers and/or treatments in order to improve both placental functions and fetal growth

Solvent-free microwave-assisted Meyers’ lactamization

International audienceMicrowave solvent-free conditions developed for Meyers’ lactamization, a typical bielectrophile-binucleophile reaction that produces quaternary centers in a stereoselective manner, give access to Meyers’ chiral lactams in good yield and high diastereoselectivity in short times

Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches.

Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this protein, we have developed fragment-based approaches. In the current study, we combined surface plasmon resonance assay, X-ray crystallography, and ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, and in vitro and ex vivo activities of these compounds will be discussed.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches

Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this protein, we have developed fragment-based approaches. In the current study, we combined surface plasmon resonance assay, X-ray crystallography, and ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, and in vitro and ex vivo activities of these compounds will be discussed