Dissertation/ Thesis
Total synthesis and biological evaluation of natural inhibitor of DYRK1A kinase ; Synthèse totale et évaluation biologique d’un inhibiteur d’origine naturelle de la kinase DYRK1A
| العنوان: | Total synthesis and biological evaluation of natural inhibitor of DYRK1A kinase ; Synthèse totale et évaluation biologique d’un inhibiteur d’origine naturelle de la kinase DYRK1A |
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| المؤلفون: | Lucas, Romain |
| المساهمون: | Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS), Université René Descartes - Paris V, Hervé Galons |
| المصدر: | https://theses.hal.science/tel-02894510 ; Chimie thérapeutique. Université René Descartes - Paris V, 2014. Français. ⟨NNT : 2014PA05P613⟩. |
| بيانات النشر: | HAL CCSD |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Kinase, DYRK1A, Natural compound, Dihydrostilbene, Down syndrome, Alzheimer, Composé naturel, Dihydrostilbène, Trisomie 21, [CHIM.THER]Chemical Sciences/Medicinal Chemistry |
| الوصف: | This thesis focuses on the synthesis of RCZ, a natural compound isolated from the plant Scorzonera radiata. During a high-throughput screening, this compound has demonstrated, on a large panel of kinases, a high and unusual degree of selectivity against the kinase DYRK1A. On a structural point of view, the compound is a glycosylated dihydrostlibene, which also bears two phenols and an acetyl group. Recently, a link between the deregulation of the kinase DYRK1A with Down syndrom and some neurodegenerative diseases such as Alzheimer disease has been established. In order to perform the synthesis of this compound, three approaches were undertaken. In these approaches, the acetyl group was built through a Sonogashira coupling followed by a mercury salt catalyzed hydration of the acetylenic group. Also, the stilbene scaffold was always obtained by Wittig condensdation. In the first approach, an isomer was obtained with approximately a ten times less potent inhibitory activity against DYRK1A than RCZ. By the use of different protective groups the final compound RCZ was successfully obtained. In conclusion, a total and efficient synthesis of RCZ has been constructed in 15 steps. This work opens future perspective in the design of new inhibitors based on the determination of the crystal structure of the RCZ-DYRK2 complex. ; Les travaux de la thèse se sont articulés autour de la synthèse totale d’un composé naturel isolé à partir de la plante Scorzoneraradiata, la RCZ. Lors d’un criblage sur un panel de kinases, dont la kinase DYRK1A, les résultats ont montré la très grande sélectivité de ce composé avec une action d’inhibition sur DYRK1A (IC50 = 220 nM). De nombreuses études disponibles dans la littérature ont établi le lien entre la dérégulation de la protéine DYRK1A avec le syndrome de Down (trisomie 21) et certaines maladies neurodégénératives tel que la maladie d’Alzheimer. En vue de l’obtention de ce composé prometteur présentant un squelette dihydrostilbène porteur d’une fonction cétone et d’un groupement ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| اللغة: | French |
| Relation: | NNT: 2014PA05P613; tel-02894510; https://theses.hal.science/tel-02894510; https://theses.hal.science/tel-02894510/document; https://theses.hal.science/tel-02894510/file/va_Lucas_Romain.pdf |
| الاتاحة: | https://theses.hal.science/tel-02894510 https://theses.hal.science/tel-02894510/document https://theses.hal.science/tel-02894510/file/va_Lucas_Romain.pdf |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.F3E6BFA7 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |