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Évaluation Biologique in Vitro D'inhibiteurs De La Stéroïde Sulfatase

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Évaluation Biologique in Vitro D'inhibiteurs De La Stéroïde Sulfatase Évaluation biologique in vitro d’inhibiteurs de la stéroïde sulfatase ayant un effet SERM Mémoire Charles Ouellet Maîtrise en physiologie-endocrinologie Maître ès sciences (M.Sc.) Québec, Canada © Charles Ouellet, 2013 Résumé Initialement, les cancers du sein sont majoritairement hormonodépendants, c’est-à-dire qu’ils sont stimulés par les hormones estrogéniques endogènes. Une première approche pour traiter ce type de cancer consiste à utiliser un antiestrogène pour bloquer l’activation du récepteur des estrogènes dans le tissu mammaire. Une seconde approche consiste à inhiber la synthèse des estrogènes par l’utilisation d’inhibiteurs spécifiques pour certaines enzymes clés de la stéroïdogénèse. La stéroïde sulfatase (STS), une enzyme impliquée dans la biosynthèse des estrogènes, constituerait une importante cible thérapeutique. Dans le cadre de ce mémoire, je discuterai d’un nouveau projet de recherche qui consiste à développer des composés à double-action combinant les deux types d’approches nommées précédemment. Nous cherchons à développer une molécule non-stéroïdienne qui serait en mesure d’inhiber la STS mais également de bloquer le récepteur des estrogènes dans le tissu mammaire. Notre composé doit donc posséder un effet SERM (Selective Estrogen Receptor Modulator), c’est-à-dire de jouer le rôle d’un antagoniste dans le tissu mammaire tout en jouant le rôle d’un agoniste dans d’autres tissus (i.e. tissu osseux) où l’action des estrogènes est importante. Dans ce mémoire, j’aborderai rapidement la synthèse chimique des deux générations de composés pour m’attarder davantage sur les tests biologiques in vitro nécessaires à l’évaluation de leur potentiel à double-action. Les composés ont d’abord été testés sur la STS pour évaluer leur potentiel d’inhibition de l’enzyme. Ensuite, les composés ont été testés sur des cellules cancéreuses du sein sensibles aux estrogènes pour s’assurer qu’ils ne stimulent pas leur prolifération. Afin de vérifier l’effet SERM désiré, les composés furent testés sur des ostéoblastes pour déterminer s’ils sont en mesure d’induire leur prolifération et leur différentiation. Finalement, l’affinité pour le récepteur des estrogènes de type alpha (REα) fut également évaluée. La 2e génération de composés a produit de bons résultats car certains composés inhibent bien la STS et possèdent l’effet SERM désiré. Ce projet a donc permis de développer des composés à double-action qui pourraient être utilisés lors de futures études in vivo. iii Table des matières Résumé .................................................................................................................................. iii Table des matières .................................................................................................................. v Liste des tableaux ................................................................................................................. vii Liste des figures ..................................................................................................................... ix Liste des schémas ................................................................................................................ xiii Liste des abréviations ............................................................................................................ xv Remerciements ................................................................................................................... xvii Avant-propos ....................................................................................................................... xix Introduction ........................................................................................................................... 1 1. Cancer : Statistiques et généralités ..................................................................................... 1 2. Cancer du sein ..................................................................................................................... 1 2.1 Causes ............................................................................................................................... 2 2.2 Diagnostique ..................................................................................................................... 4 2.3 Traitements ....................................................................................................................... 5 3. Hormonothérapie ................................................................................................................ 5 3.1 Inhibiteurs de la biosynthèse des estrogènes .................................................................... 6 3.2 Antiestrogènes et SERM ................................................................................................... 6 4. Tissu osseux ........................................................................................................................ 8 4.1 Ostéogénèse ...................................................................................................................... 8 4.2 Ostéoporose ...................................................................................................................... 9 5. Stéroïdogénèse .................................................................................................................. 10 5.1 Aromatase ....................................................................................................................... 12 5.2 17β-hydroxystéroïdes déshydrogénases ......................................................................... 14 5.3 Stéroïde sulfatase ............................................................................................................ 16 6. Récepteurs des estrogènes ................................................................................................ 20 6.1 Récepteurs des estrogènes α et β : structure et mécanisme ............................................ 20 6.2 Rôles des récepteurs dans le tissu mammaire et osseux ................................................. 22 6.3 Mécanisme des SERMs .................................................................................................. 24 7. Aperçu du projet de recherche .......................................................................................... 26 Chapitre 1 ............................................................................................................................ 31 Résumé .................................................................................................................................. 32 Manuscrit « Investigation of a tetrahydroisoquinoline scaffold as dual-action steroid sulfatase inhibitors generated by parallel solid-phase synthesis » ........................................ 33 Chapitre 2 ............................................................................................................................ 59 Résumé .................................................................................................................................. 60 Manuscrit « In vitro evaluation of a steroid sulfatase inhibitor with a potential selective estrogen receptor modulator (SERM) capacity » ................................................................. 61 v Chapitre 3 ............................................................................................................................ 85 Résumé ................................................................................................................................. 86 Manuscrit « Development of sulfamate tetrahydroisoquinoline-N-substituted derivatives as potent dual-action compounds for the treatment of estrogen-dependent breast cancer » .... 87 Conclusion ......................................................................................................................... 127 Références ......................................................................................................................... 132 vi Liste des tableaux Introduction Tableau 1. Classification de la densité osseuse par l’OMS .................................................... 9 Chapitre 1 Tableau 1. Structure of the sulfamate compounds of libraries 1-EO and 2-EO and their inhibitory activity (%) for the transformation of [3H]-estrone sulfate into [3H]-estrone by STS (HEK-293 transfected cells)..................................................................40 Tableau 2. Structure of the sulfamate compounds of libraries 3-EO and 4-EO and their inhibition (%) of the transformation of [3H]-estrone sulfate into [3H]-estrone by STS (HEK-293 transfected cells)......................................................................................43 Chapitre 2 Tableau 1. IC50 values and relative binding affinities (RBA) of 6-EO-14, 8-EO-14 and reference compounds for hER훼.......................................................................................77 Chapitre 3 Tableau 1. Structure of phenolic compounds and their capacity (estrogenicity) to induce the proliferation (%) of breast cancer T-47D (ER+) cells............................................................96 vii Liste des figures Introduction Figure 1. Le rôle des gènes et de l’environnement dans le développement du cancer. ......... 2 Figure 2. Structure du fulvestrant. ......................................................................................... 7 Figure 3. Structure du tamoxifène et du raloxifène. .............................................................. 7 Figure
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