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Novel Phenoxazine Dyes: Laccase-Mediated Synthesis, Physico-Chemical Properties and Applications

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Novel Phenoxazine Dyes: Laccase-Mediated Synthesis, Physico-Chemical Properties and Applications Université catholique de Louvain Faculté des Sciences Unité de chimie organique et médicinale Promoteur: Prof. J. Marchand-Brynaert Novel Phenoxazine Dyes: Laccase-Mediated Synthesis, Physico-Chemical Properties and Applications February 2010 2 Members of the jury: Prof. J. F. GOHY (Université catholique de Louvain, president of the jury) Prof. G. IACAZIO (Laboratoire de Bioinorganique Structurale, Université Paul Cézanne-Aix-Marseille III, France) Prof. P. J. COURTOY (De Duve Institute, Université catholique de Louvain) Prof. J. MARCHAND-BRYNAERT (Université catholique de Louvain, supervisor) Prof. M. DEVILLERS (Université catholique de Louvain) Prof. B. ELIAS (Université catholique de Louvain) Prof. R. ROBIETTE (Université catholique de Louvain) 3 4 Acknowledgements This work would not have been possible without the support of many people. First of all I would like to thank my supervisor, Prof. J. Marchand-Brynaert, who welcomed me again, after 3 years of an insightful journey in the pharmaceutical industry, and gave me the opportunity to perform a research work in the extremely interesting and challenging domain of biocatalysis. Without her precious confidence, constant support and helpful guidelines, this work would have never seen neither the beginning nor the end. I have a special thought for the Dr. Sophie Vanhulle and for her family. Sophie Vanhulle, unfortunately deceased in September 2009, had a vision which resulted in the SOPHIED project that she initiated and in which she kindly welcomed me. Without this research project, this thesis would not have been possible. I also thank my committee members, Prof. Gohy, Prof. Iacazio, Prof. Devillers, Prof. Courtoy, Prof. Elias and the Prof. Robiette for the helpful suggestions. During this project I had the chance to work with a number of competent, kind and very helpful peoples that I would like to specially thanks: Ludovic Billottet, Ludovic D‟Auria, Estelle Enaud and the members of the Microbiology Unit, Van Tran- Trieu for training me in the science of HPLC, Bernard Tinant for his insightful help in X-ray structures analysis, Sabrina Devouge and Chantal Delaet for who I‟m deeply indebted for their constant help in administrative tasks. All the NMR team, i.e. Cecile Leduff, Alain Jancquart, but also the „mass team‟, i.e. Raoul Rozenberg and Alexandre Spote, for their help and training in the LC-MS/MS2 analysis. 5 I would like to thanks also the members of the group ORGJ: “the old ones” yet younger than myself for their helpful discussions, their energy and joy and the all fun activities we shared outside the lab. This goes especially for Frédéric, Benoit, Vincent, Martin and Xavier. I also thank the younger ones for cheering the lab atmosphere, sometime at their expense. I thank my apprentice, Murielle and a former co-worker Olivier who did learn me how to teach to “younger one”. A special thought goes to my family, especially my parents for giving me the love of science and their constant support, but also to my friends for their support and their affection. 6 RESUME Les Laccases font partie de la famille des oxydases à cuivre, enzymes principalement impliquées dans de nombreuses voies de biosynthèse chez les champignons. Parmi les isozymes répertoriés, une laccase a permis de réaliser avec succès la formation in vitro d‟un pigment d‟origine naturelle dénommé « acide cinnabarinique ». Ce composé comprend un motif hétérocyclique identique à celui du groupement chromophore de l‟Actinomycin D qui s‟avère être un puissant agent antitumoral d‟origine fongique. Le motif hétérocyclique commun dénommé 2-amino-3H-phenoxazin-3-one, possède un potentiel avéré pour une application telle que le marquage par fluorescence dans le domaine de la biologie cellulaire et/ou moléculaire. Une excellente solubilité en milieux aqueux représente une caractéristique incontournable pour de telles applications biologiques. Dés lors, de nouvelles voies de synthèses présentant simultanément originalité et efficacité doivent être continuellement élaborées afin de produire de nouveaux marqueurs fluorescents hydrophiles inspirés de pigments naturels. Dans le cadre d‟un projet de recherche européen nommé SOPHIED, nous avons élaboré la synthèse biomimétique de nouveaux colorants de type aminophenoxazinone possédant une solubilité en milieux aqueux modulable grâce aux groupements fonctionnels présents sur ceux-ci. Notre voie de synthèse implique une étape clé de cascade oxydante pour un total de six électrons initiée par un bio- catalyseur, une laccase. Nos blocs de constructions, des molécules de type aminophénols présentant des groupements fonctionnels dérivés d‟acides sulfoniques et phosphoniques, ont été synthétisés avec un contrôle total de la régio-sélectivité. Ces substrats hydrophiles ont été transformés par une laccase en nouveaux colorants fluorescents avec une complète sélectivité et d‟excellents rendements. 7 Une investigation des potentialités et limitations de notre synthèse bio-catalytique a permis de suggérer une proposition mécanistique pour la cascade oxydante, principalement une variante de celle communément acceptée pour la production de pigments naturels. Néanmoins, bien que cette proposition ait le mérite d‟expliquer certains de nos résultats plutôt surprenant, elle reste une suggestion et en aucun cas une quelconque affirmation. Les propriétés de fluorescence de ces composés hétérocycliques ont été évaluées et testés comme marqueurs fluorescents de structures cellulaires vivantes. Grâce à cette application, un de ces hétérocycles s‟est révélé prometteur en tant que traceur pour endocytose avec une localisation intracellulaire finale dans les lysosomes. Finalement, la découverte accidentelle d‟une cyclisation intramoléculaire due à un effet activant des groupes fonctionnels acides, type sulfonique et phosphorique, dans nos substrats aromatiques à mené à une brève investigation d‟une voie alternative de synthèse de benzoxazoles car ce motif structural est largement représenté dans diverses molécules bioactives d‟origine naturelle ou synthétique. 8 ABSTRACT Laccases are members of the multicopper oxidase family which are involved in numerous biosynthetic pathways in fungi. Among these, one laccase has been shown to produce in vitro a natural pigment, namely the cinnabarinic acid, which is related to the actinomycin chromophore. The core structure of this chromophore, i.e 2-amino-3H-phenoxazin-3-one, was found to possess a marked potential for the fluorescent labelling in the field of molecular biology. As water-solubility is one of the critical features for biological application, efficient and original synthetic routes are needed to provide new hydrophilic fluorophores inspired from natural pigments. In the frame of the European research project SOPHIED, we have investigated the biomimetic synthesis of novel aminophenoxazinone dyes featuring tuneable water-solubility. Our synthetic route involves a key step of biocatalysed oxidative cascade with a total of 6e- oxidation mediated by a laccase. Sulfonylated and phosphorylated aminophenol building-blocks were synthesised with a total regioselectivity control and further processed as water-soluble substrates by our biocatalyst to afford novel fluorophores. The investigation of the scope and limitations of our biocatalytic process led to a new mechanistic proposal for the key step of oxidative cyclisation initiated by the laccase. Fluorescent properties of these heterocyclic scaffolds were evaluated and further assayed in a live-cell imaging application. This results in the discovery of a promising fluorophore, presumably a bulk endocytic tracer with targeting by default to lysosomes. Lastly the serendipitous discovery of an intramolecular cyclisation due to a neighbouring substituent effect of the acidic group (SO3H and PO(OH)2) in our aminophenol derivatives led to the development of an alternative synthetic route towards novel benzoxazole derivatives of potential interest in medicinal chemistry. 9 Abbreviations list 2-HMA : 2-hydroxymetanilic acid 3ASA : 3-aminosalicylic acid 3HAA : 3-hydroxyanthranilic acid 3HOA : 3-hydroxyorthanilic acid aa : amino acid ABTS : 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid Acac : Acetyl acetonate AcOEt : Ethyl acetate Actinocin : derivatives with the same chromophore as actinomycin D AIBN : Azo-bis(1-amidinopropane) APCI : Atmospheric pressure chemical ionisation APX : 2-aminophenoxazine Aq : Aqueous ATR : Attenuated total reflection Bn : Benzyl BTIB : bis(trifluoroacetoxy)iodobenzene BuLi : Butyllithium CA : cinnabarinic acid CAN : Ceric ammonium nitrate CHO : Chinese Hamster Ovary CI : Chemical ionisation CV : Cyclic voltametry CVs : Cyclic voltamograms DBU : 1,8-Diazabicyclo[5.4.0]undec-7-ene 10 DCE : Ethylene chloride DCM : Methylene chloride DDQ : 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEPTQ : Distorsionless Enhancement by Polarization Transfer Including the Detection of Quaternary Nuclei DIEA : Diisopropylethylamine DME : 1,2-dimethoxy ethane DMEM/F12 : Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12 DMF : Dimethylformamide DMG : Directing metallation group DMSO : Dimethylsulfoxide DMVP : Dimethylvinylphosphonate DPPA : diphenyl phosphoryl azide DPQ : Diphenoquinone EI : Electronic Impact Eq : Equivalents ESIPT : Excited state electron proton transfer ET : Electron Transfer EtOH : Ethanol FT-IR : Fourier transformed infrared GFP : Green Fluorescent Protein GSA : guaiacol sulfonic acid Hbpx : 2-(2‟-Hydroxyl-phenyl)benzoxazole HMBC : Heteronuclear Multiple Bond Correlation
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