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PDF 01 These Reniers Main Institutional Repository - Research Portal Dépôt Institutionnel - Portail de la Recherche University of Namurresearchportal.unamur.be THESIS / THÈSE DOCTOR OF SCIENCES Rational design, synthesis, molecular modeling and evaluation of -carboline and 5H-indeno[1,2-c]pyridazin-5-one derivatives as potential MAO and IDO inhibitors Author(s) - Auteur(s) : Reniers, Jérémy Award date: 2011 SupervisorAwarding - institution:Co-Supervisor / Promoteur - Co-Promoteur : University of Namur Unit of theoretical and structural physico-chemistry Link to publication Publication date - Date de publication : Permanent link - Permalien : Rights / License - Licence de droit d’auteur : General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately Bibliothèqueand investigate Universitaire your claim. Moretus Plantin Facultés Universitaires Notre-Dame de la Paix Rational design, synthesis, molecular modeling and evaluation of -carboline and 5H-indeno[1,2-c]pyridazin-5-one derivatives as potential MAO and IDO inhibitors Faculté des Sciences DÉPARTEMENT DE CHIMIE Dissertation présentée par Jérémy RENIERS en vue de l’obtention du grade de Docteur en Sciences Octobre 2011 FUNDP Faculté des Sciences Département de Chimie Rational design, synthesis, molecular modeling and evaluation of -carboline and 5H-indeno[1,2-c]pyridazin-5-one derivatives as potential MAO and IDO inhibitors Dissertation présentée par Jérémy RENIERS en vue de l’obtention du grade de Docteur en Sciences Composition du jury : Prof. S. Vincent (FUNDP, Namur, président du jury) Prof. R. Kiss (ULB, Bruxelles) Prof. C. Michiels (FUNDP, Namur) Dr. R. Frédérick (FUNDP, Namur) Prof. J. Wouters (FUNDP, Namur, promoteur) 2011 © Presses universitaires de Namur & Jérémy Reniers Rempart de la Vierge, 13 B - 5000 Namur (Belgique) Toute reproduction d'un extrait quelconque de ce livre, hors des limites restrictives prévues par la loi, par quelque procédé que ce soit, et notamment par photocopie ou scanner, est strictement interdite pour tous pays. Imprimé en Belgique ISBN : 978-2-87037 -734-5 Dépôt légal: D / 2011 / 1881 / 39 Facultés Universitaires Notre-Dame de la Paix Faculté des Sciences Rue de Bruxelles 61 - 5000 Namur, Belgique Conception rationnelle, synthèse, modélisation moléculaire et évaluation de dérivés - carbolines et 5H-indéno[1,2-c]pyridazin-5-ones comme inhibiteurs potentiels de la MAO et d’IDO Par Jérémy Reniers Résumé: La monoamine oxydase A (MAO-A) et –B (MAO-B) sont des cibles intéressantes pour une large gamme de thérapies contre des pathologies telles que la dépression, l’anxiété et les maladies de Parkinson et d’Alzheimer. La plupart des inhibiteurs actuels mènent à des effets secondaires par un manque d’affinité et de sélectivité envers une des isoformes. Récemment, les structures cristallographiques de hMAO-A et –B en complexe avec des inhibiteurs ont ouvert le chemin vers la découverte de nouveaux inhibiteurs plus sélectifs et plus puissants. En conséquence, l’objectif principal de ce travail, fut la conception de nouveaux inhibiteurs plus puissants, réversibles et sélectifs de MAO-A ou –B à partir des motifs β-carbolines et 5H-indéno[1,2-c]pyridazin-5-ones respectivement, en suivant une stratégie classique comprenant une approche expérimentale (synthèse et évaluation biologique) et théorique (modélisation moléculaire). Les pouvoirs d’inhibition sur la MAO ont montré que la substitution du groupe méthoxy de l’harmine par des groupes plus lipophiles augmente l’inhibition de MAO-A. Des études sur les 5H-indéno[1,2-c]pyridazin-5- ones substituées à la fois aux positions 3 et 8 par des groupes lipophiles ont montré que la substitution en position 3 influence significativement les propriétés d’inhibition de la MAO- B. De plus, l’implication à travers une même voie métabolique et la similarité dans les propriétés structurales de la MAO avec l’indoléamine 2,3-dioxygénase (IDO) et la lysine spécifique déméthylase 1 (LSD1) respectivement, nous ont amené à l’investigation des -carbolines et 5H-indéno[1,2-c]pyridazin-5-ones comme inhibiteurs potentiels d’IDO et de LSD1. Cependant, les deux series n’inhibent pas ces deux systèmes enzymatiques et sont donc sélectives de MAO. Finalement, en partant de la même stratégie utilisée pour la MAO, nous nous sommes aussi intéressés à la synthèse de deux nouvelles -carbolines substitutées en position 3 par des groupements aminés et directement dérivées du 3-butyl--carboline, un inhibiteur connu d’IDO. Ces deux composés présentent en effet une charge positive à pH physiologique laquelle pourrait établir une interaction coulombienne supplémentaire avec le 7-propionate de l’hème comparé au 3-butyl--carboline. Cependant, les premiers résultats tendent à démontrer que l’introduction d’une charge positive abolit l’inhibition d’IDO. Dissertation doctorale en Sciences 4 octobre 2011 Laboratoire de Chimie Biologique Structurale (Prof. J. Wouters) Promoteur: Prof. J. Wouters Facultés Universitaires Notre-Dame de la Paix Faculté des Sciences Rue de Bruxelles 61 - 5000 Namur, Belgium Rational design, synthesis, molecular modeling and evaluation of -carboline and 5H-indeno[1,2-c]pyridazin-5-one derivatives as potential MAO and IDO inhibitors By Jérémy Reniers Abstract: Monoamine oxidase A (MAO-A) and –B (MAO-B) are attractive targets for a broad range of treatments against pathologies including depression, anxiety disorders, Parkinson’s and Alzheimer’s diseases. Most current MAO inhibitors lead to side effects by a lack of affinity and selectivity towards one of the isoforms. Recently, the crystal structures of hMAO- A and –B in complex with inhibitors opened the way towards the discovery of new, more selective and potent inhibitors. Thus, the main objective of this work, was the design of new, more potent, reversible and selective MAO-A or –B inhibitors derived from β-carboline and 5H-indeno[1,2-c]pyridazin-5-one scaffolds respectively, following a classical strategy including experimental (synthesis and biological evaluation) and theoretical (molecular modeling) approaches. The MAO inhibitory potencies showed that the replacement of the methoxy group of harmine by more lipophilic groups increases the inhibition for MAO-A. Studies on 5H-indeno[1,2-c]pyridazin-5-one scaffold bearing lipophilic groups in the 3 and 8- positions showed that the substitution in the 3-position dramatically influences the MAO-B- inhibiting properties. Furthermore, the involvement through a same metabolic pathway and the similarity in the structural properties of MAO with indoleamine 2,3-dioxygenase (IDO) and lysine specific demethylase 1 (LSD1) respectively, led us to the investigation of the -carboline and 5H- indeno[1,2-c]pyridazin-5-one derivatives as potential IDO and LSD1 inhibitors. However, the two series show no inhibition of those two enzymes and are thus selective of MAO. Finally, starting from the same strategy used for MAO, we are also interested in the synthesis of two new 3-substituted--carboline derivatives with amino groups and directly derived from 3-butyl--carboline, a known IDO inhibitor. Indeed, these two compounds display a positive charge at physiological pH which might establish an additional coulomb interaction with 7- propionate of the heme compared to 3-butyl--carboline. Howerver, first results tend to demonstrate that the introduction of a positive charge abolishes the inhibition of IDO. Ph.D. thesis in Sciences October 4, 2011 Laboratoire de Chimie Biologique Structurale (Prof. J. Wouters) Advisor: Prof. J. Wouters Au terme de ces quatre années de thèse passées au sein du laboratoire de Chimie Biologique Structurale, je tiens à exprimer mes remerciements les plus sincères à toutes les personnes qui ont contribué, de près ou de loin, par leur aide et/ou leur soutien, à l'élaboration de ce travail, parmi eux : - Tout d’abord, je voudrais remercier le Professeur Johan Wouters pour m’avoir accueilli dans son laboratoire. Je tiens aussi à le remercier pour ses conseils judicieux et pour son attention lesquels m’ont permis d’acquérir de l’expérience et d’enrichir mes connaissances tout au long de ces quatre années. Finalement, un immense merci pour toute la confiance qu’il m’a accordée ainsi que pour m’avoir donné la chance d’explorer ma thèse à travers différents domaines de la chimie. - Je tiens à exprimer toute ma gratitude au Professeur Stéphane Vincent pour l’expérience de la chimie des sucres et de la chimie organique qu’il m’a enseignée au cours de mon mémoire laquelle m’a permis de développer une rigueur dans ma démarche scientifique et d’acquérir une autonomie. Celles-ci ont été très importantes pour ma thèse et je le remercie aussi pour m’avoir permis d’utiliser ses installations et matériels au cours de ces années. - Je remercie le Professeur Bernard Masereel du Département de Pharmacie pour m’avoir permis d’utiliser ses installations et matériels au cours de ces quatre années. - Je suis tout particulièrement reconnaissant à Séverine Robert pour l’aide qu’elle m’a fournie pour la mise au point du test enzymatique sur les monoamines oxydases. - Je tiens ensuite à adresser mes remerciements à tous les chercheurs du laboratoire CBS et du CBO pour leur bonne humeur ainsi que pour leurs conseils tout au long de la réalisation de cette thèse. - Je remercie Bernadette Norberg pour l’aide qu’elle m’a apportée afin de me former à la résolution de structures cristallines.
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