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Docteur De L'universite De La Mediterranee UNIVERSITE DE LA MEDITERRANEE AIX-MARSEILLE II Faculté des Sciences de Luminy 163, avenue de Luminy 13288 MARSEILLE Cedex 9 N° attribué par la bibliothèque THESE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE DE LA MEDITERRANEE Discipline : Chimie Organique Présentée et soutenue publiquement Par Alain César Biraboneye Le 02 /02 /2011 INNOVATION MOLECULAIRE A VISEE THERAPEUTIQUE : CONCEPTION, SYNTHESE ET EVALUATION BIOLOGIQUE DE NOUVEAUX DERIVES CONTRE L’ISCHEMIE CEREBRALE Directeur de thèse: Professeur Jean-Louis KRAUS JURY M. Jean-Yves WINUM Maître de conférences, UMR 5247 CNRS, Montpellier Rapporteur M. Jean DESSOLIN Chargé de recherche, UMR 5248 CNRS, Bordeaux Rapporteur M. Christian ROUSSEL Professeur, UMR 6263 CNRS Marseille Examinateur M. Jean Louis KRAUS Professeur, UMR 6216 CNRS Marseille Directeur de Thèse i T Ät Å°ÅÉ|Üx wx Åt zÜtÇwx á‚âÜ? wx ÅÉÇ Ñ¢Üx xà wx àÉâá Äxá Å|ÄÄ|xÜá wxá |ÇÇÉvxÇàá ÅÉÜà á ÑxÇwtÇà Äx z°ÇÉv|wx DLLGA ii Remerciements Ce travail de recherche a été effectué dans le Laboratoire de Chimie Biomoléculaire, CNRS, IBDML-UMR-6216 situé sur le Campus de Luminy. Je remercie le Pr. Jean Louis KRAUS pour m’avoir accueilli dans son laboratoire. Ce travail n’aurait pas pu se faire sans son aide précieuse, sa patience, ses compétences en chimie-biologie et son professionnalisme. Ses encouragements, associés aux moyens matériels dont j’ai disposé, m’ont permis de mener à bien la recherche présentée dans ce rapport. Je le remercie également pour m’avoir permis de valoriser ces travaux de thèse par la publication de plusieurs articles scientifiques. C’est pourquoi je lui exprime ma plus grande gratitude. Je remercie plus particulièrement Dr. Jean-Yves WINUM et Dr. Jean DESSOLIN d’avoir accepté la charge d’être rapporteurs de ce travail.Pr. Christian ROUSSEL me fait l’honneur en acceptant de participer au jury de cette thèse. Je leur exprime ma plus grande gratitude et mon plus profond respect. J’adresse aussi mes remerciements au Dr. Pamela MAHER et au Dr. Slavica KRANTIC pour avoir réalisé les tests biologiques. Je remercie aussi Dr.Valérie MONNIER pour avoir effectué les spectres de masses. Je remercie également le Dr. Sébastien Madonna et le Dr. Patrick Secondo dont les précieux conseils et le soutient moral m’ont beaucoup aidé au cours de ma thèse. Je présente enfin mes amitiés à tous les étudiants qui ont travaillé dans ce laboratoire, durant cette période, et à tous les doctorants ou ex-doctorants de notre laboratoire, que j’ai eu le plaisir de rencontrer, Dr. Laras Younes, Dr. Amandine Rolland, Vincent Moret et Clément Weck. Ils ont fait de cette thèse un travail très intéressant et agréable et m’ont beaucoup apporté sur le plan humain. Enfin, merci à tous ceux qui par un mot ou un geste m’ont rendu un service au cours de ces dernières années. Je tiens à terminer en remerciant les membres de ma famille et mes amis. iii Liste de Figures Figure 1. Mortalité par accident cérébraux vasculaire dans le monde. Figure 2. Représentation schématique du polygone artériel de Willis. Figure 3. Mécanismes de franchissement de la BHE. Figure 4. Différentes causes d’AVC. Figure 5. Les dommages cérébraux qui se produisent pendant l'ischémie cérébrale. Figure 6. Représentation schématique de la pénombre. Figure 7. Cinétique des mécanismes impliqués dans l'ischémie cérébrale. Figure 8. Principaux intervenants dans l’homéostasie neuronale du calcium. Figure 9. Rôle initiateur du calcium sur les principaux mécanismes cellulaires mis en jeu au cours de l’ischémie cérébrale. Figure10. Implication du monoxyde d’azote (NO) dans les mécanismes cellulaires au cours de l’ischémie cérébrale. Figure11. Implication de la mitochondrie dans le développement de l’apoptose au cours de l’ischémie cérébrale. Figure12. Nouvelles entités chimiques acceptées par la FDA (courbe bleue) et investissements en R&D aux Etats-Unis (courbe rouge) entre 1996 et 2003. Figure 13. Quelques isostères monovalents. Figure 14. Exemples des isostères classiques divalents. Figure 15. Analogie structurale du tétrazole avec l’acide carboxylique. Figure 16. AP5 Antagoniste du récepteur NMDA. Figure 17. ATPO comme antagoniste du récepteur AMPA. Figure 18. Structure de 1,2,4 oxadiazolidine-3,5-dione. Figure 19. Quisqualamine (à gauche) et GABA (à droite). Figure 20. Structure de GM1 (monosialotetrahexosylganglioside). Figure 21. Structure d’acide gras. Figure 22. Nomenclature des acides gras. Figure 23. Conformation linéaire d’un acide gras saturé. Figure 24. La structure simplifiée de « GM1-like » analogue. Figure 25. La structure générale des composés cibles. Figure 26. Molécules cibles analogues portant des résidus sérine, cystéine et tyrosine. Figure 27. Quelques structures des agents de couplage. Figure 28. Molécules ciblées : bioisostères phosphoniques. Figure 29. Les molécules ciblées iv Figure 30. Molécules ciblées portant le résidu thiazolidine-2,4-dione. Figure 31. Les structures de molécules Ciblées comportant le motif acide ascorbique. Figure 32. Sites d’action des protéines Ser/Thr et Tyr kinases Figure 33. La représentation schématique des cascades ischémiques impliquant les MAPK et leurs rôles dans les mécanismes cellulaires. Figure 34. Schéma réactionnel de modifications chimiques conduisant à l'introduction d'un groupement carboxylique. Figure 35. Cytotoxicité de l’IAA sur les cellules HT22. Figure 36. Structure moléculaire du TTC. Figure 37. Courbe dose-réponse de neuroprotection des cellules HT22 par divers acides gras contre la toxicité de l’IAA. Figure 38. La fisétine (3, 7,3’,4’-tétrahydroxyflavone) le produit de référence. Figure 39. Représentation comparatif des valeurs EC50. Figure 40. Courbes représentatifs montrant la neuroprotection de quelques composés contre la toxicité de l’IAA sur les cellules HT22. Figure 41. Effet neuroprotecteur des composés 2 et 8 sur les tranches de cerveau lésées par 1 µM le glutamate. Figure 42. Effets de composés sur c-Jun et la phosphorylation MAPAPK2. Figure 43. Effets de composés sur JNK and p38 MAPK phosphorylation. Figure 44. Effets de composés sur la phosphorylation d’ERK. Liste de tableaux Tableau 1. Estimation du nombre de cas d’AVC en France. Tableau 2. Quelques composés qui ont échoué au stade d’évaluation clinique de l’ischémie cérébrale. Tableau 3. logP de bioisostères de l’acide carboxylique. Tableau 4. Présentation de quelques structures privilégiées issue de la littérature. Tableau 5. Groupe d’isostère selon « Langmuir ». Tableau 6. Loi de déplacement des protons de Grimm. Tableau 7. Isostères bases sur le nombre d’électrons périphériques. Tableau 8. La famille des bioisostères classiques. Tableau 9. «Les bioisostères non classiques ». Tableau 10. Les bioisostères de la liaison amide. v Tableau 11. Les Bioisostères de l’acide carboxylique sur lesquels on a constitué une chimiothèque. Tableau 12. La similarité entre le tétrazole et l’acide carboxylique. Tableau 13. Valeurs des Perméations (PD50) des acides carboxyliques saturés et insaturés à travers de membranes de vésicules de dihexadecyl phosphates et Leurs logP. Tableau 14. Résultats des analogues portant des résidus sérine, couplés à des acides gras. Tableau 15. Résultats des analogues portant des résidus tyrosine couplés à des acides gras. Tableau 16. Résultats des analogues portant des résidus cystéine couplés à des acides gras. Tableau 17. Résultats de la saponification (analogues portant le résidu sérine). Tableau 18. Résultats de la saponification (analogues portant le résidu tyrosine). Tableau 19. Résultats de la Saponification (analogues portant le résidu cystéine). Tableau 20. Les résultats obtenus de la molécule 36 et 37. Tableau 21. Les résultats obtenus pour les oximes. Tableau 22. Les résultats obtenus pour les hydroxylamines. Tableau 23. Les résultats obtenus pour les N-hydroxurées. Tableau 24. Les résultats obtenus pour les produits cyclisés. Tableau 25. Les rendements obtenus. Tableau 26. Les rendements obtenus du composé 74 à 83. Tableau 27. Résultats du produit de référence la fisétine. Tableau 28. Résultats des analogues portant de résidu sérine, couplés à des acides gras. Tableau 29. Résultats des analogues portant des résidus tyrosine couplés à des acides gras. Tableau 30. Résultats des analogues portant des résidus cystéine couplés à des acides gras. Tableau 31. Résultats des analogues portant de bioisostères tétrazole 33 et phosphonique 40 et 41 couplés à des acides gras. Tableau 32. Résultats des analogues de N-alkyl oximes. Tableau 33. Résultats des analogues de N-alkyl hydroxylamines. Tableau 34. Résultats des analogues de N-alkyl hydroxylamine éthyle formylcarbamate et N- octadecylhydroxylamine éthyle thioformylcarbamate. Tableau 35. Résultats des analogues de 2-Alkyl-1,2, 4-oxadiazolidine-3,5-dione et 2-alkyl-3-thioxo-1, 2,4-oxadiazolidin-5 none. Tableau 36. Résultats des analogues acides gras couplés à l’acide ascorbique. Tableau 37. Effet de la neuroprotection des composés 60, 55, 46, 56, et 62 sur JNK, p38 MAP kinase et l’activation de l’ERK. vi Liste des Abréviations Partie Chimique Partie Biologique Å Angström Aβ Peptide β-amyloïde AA Acide Arachidonique ACE Angiotensin Converting Enzyme Ac Acétyle ADMET Absorption, Distribution, Métabolisme, Excrétion et Toxicité AcOEt Acétate d’éthyle ADN Acide désoxyribonucléique AcOH Acide acétique AIF Facteur induisant l‘Apoptose AC2O Anhydride acétique AMPA-R Récepteur α-amino-3-hydroxy-5-méthyl-4- AGPI Acide gras polyinsaturés isoxazole propionate Atm Atmosphère APAF-1 Apoptosis activating factor-1 Bn Benzyl Arg Arginine Boc2O Ditert-butyldicarbonate ARN Acide ribonucléique
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