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Experimental Section N° d’ordre : 4542 THÈSE PRÉSENTÉE A L’UNIVERSITÉ BORDEAUX 1 ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES Par Daniela Melanie DELANNOY LOPEZ POUR OBTENIR LE GRADE DE DOCTEUR SPÉCIALITÉ : CHIMIE ORGANIQUE Synthèse de dérivés de polyphénols bioactifs pour l’étude de leurs interactions avec des protéines Directeur de recherche : Pr. Stéphane Quideau Soutenue le : 02 Juillet 2012 Après avis de : Mme RENARD, C. Directrice de Recherche, INRA-Avignon Rapporteur M. MONTI J. Professeur Universite de Bordeaux 2 Rapporteur Devant la commission d’examen formée de : Mme RENARD, C. Directrice de Recherche, INRA-Avignon Rapporteur M. MONTI J. Professeur Universite de Bordeaux 2 Rapporteur M. GENOT E. Group leader, IECB Université Bordeaux 2 Présidente M. Di Primo C. Chargé de recherche, Université Bordeaux Examinateur M. DEFFIEUX, D. Maître de conférence, Université Bordeaux 1 Co-directeur de thèse M. QUIDEAU, S. Professeur, Université Bordeaux 1 Directeur de thèse Table of Contents Acknowledgements…………………………………………………………………...………5 Résumé en français…………………………………..……………………………………….8 List of communications………………………….………………………………………….12 Introduction……………..…………………………………………………………………...13 Chapter I. Polyphenol-Protein Interactions ........................................................................ 16 Ia. Polyphenols ................................................................................................................... 17 Ia.1 Physico-chemical properties of polyphenols ............................................................... 24 Ia.2 Antioxidant/Pro-oxidant Activity ................................................................................. 25 Ia.3 Tanning Action ............................................................................................................. 26 Ib. Polyphenols and Proteins Interactions .......................................................................... 27 Ib.1 Brief generalities about proteins ................................................................................... 27 Ib.2 Polyphenols-Protein Complex Precipitation ................................................................ 28 Ib.3 Polyphenols-Proteins and Specific Interactions ........................................................... 31 Ib.3.1 F0F1-ATPase/ATP synthase protein- resveratrol .............................................................. 31 Ib.3.2 Anthocyanidin synthase-flavonoids ................................................................................... 33 Ib.3.3 -Amyloid peptide-flavonoids ........................................................................................... 35 Ib.3.4 Topoisomerase II-ellagitannins .......................................................................................... 37 Ib.3.5 Squalene epoxidase and proteasome activity vs. catechin .................................................. 38 Ib.3.6 Herpes simplex virus-ellagitannins .................................................................................... 39 Ib.3.7 Actin-ellagitannins ............................................................................................................. 39 Ic. Techniques used to Study Polyphenol-Protein Interaction ........................................... 40 Ic.1 Commonly used techniques to measure protein-ligand interaction ............................. 40 Ic.2 SPR as an alternative technique in the study of polyphenol-protein interaction ......... 41 Ic.3 Classical SPR experiment vs. reverse SPR experiment ............................................... 42 Id. Polyphenol-fluorescent adducts and their use in cellulo studies. .................................. 45 Chapter II. Polyphenol Derivatization for Surface Plasmon Resonance Studies ............ 50 IIa. Design of Polyphenol-Biotin Conjugates. ..................................................................... 51 IIb. Hemisynthesis of Vescalagin- and Vescalin-Biotin Conjugates. .................................. 52 IIc. Hemisynthesis of Catechin- and Epicatechin- Biotin Conjugates. ............................... 56 IIc.1 C-Ring derivatization of catechin (1a) and epicatechin (1b) ....................................... 57 IIc.1.1 Approach without the use of protecting groups on the catechin skeleton .......................... 58 IIc.1.2 Approach using protecting groups on the catechin skeleton .............................................. 60 IIc.2 A-Ring derivatization of catechin (1a) and epicatechin (1b) ...................................... 69 IId. Hemisynthesis of B-Type Procyanidins Biotin Conjugates .............................................. 72 IId.1 F-Ring derivatization of B-type procyanidin .............................................................. 72 IId.1.1 Hemisynthesis of per-O-TBDMS B-type procyanidin derivatives .................................... 72 IId.2 A-Ring derivatization of B-type procyanidin ............................................................. 78 IIe. Conclusion ......................................................................................................................... 80 Chapter III. Polyphenol-Protein Interaction Studies by Surface Plasmon Resonance ... 81 IIIa. Generalities about the analysis of intermolecular interactions by SPR. .......................... 82 IIIc. Polyphenol-Protein Interaction Studies ........................................................................... 84 IIIc.1 Topoisomerase II (TopII vs. Vescalagin/ Vescalin/Catechin ............................ 84 IIIc.2. Other proteins vs. Vescalin/Vescalagin/Catechin .................................................... 91 IIIc.3 Actin vs. Vescalagin .................................................................................................. 95 IIIc.4. ANS vs. Catechin ..................................................................................................... 99 Chapter IV. Fluorescent Labeling of Vescalagin and Bioassays ..................................... 106 IVa. Design of Vescalagin-Fluorescent Conjugate ............................................................. 107 IVa.1 At which position of the vescalagin skeleton should we anchor the fluorescent tag? ............................................................................................................................................ 107 IVa.2 What kind of fluorescent tag should we use? ........................................................... 108 IVa.3 What kind of linker should we use? ......................................................................... 109 IVb. Hemisynthesis of Vescalagin-Fluorescein Conjugate. ................................................ 111 IVb.1 Hemisynthesis of vescalagin-Fluorescein Conjugate I ............................................ 112 IVb.2 Hemisynthesis of vescalagin-Fluorescein Conjugate II ........................................... 114 IVb.3 Hemisynthesis of vescalagin-Fluorescein Conjugate III ......................................... 117 3 IVc. Hemisynthesis of vescalin-Fluorescein Conjugate ........................................................ 121 IVd. Actin-vescalagin interaction studies: application of vescalagin-fluorescein derivative 122 IVd.1 In vitro assays ........................................................................................................... 122 IVd.2 In cellulo assays ....................................................................................................... 123 IVe. Conclusions ................................................................................................................. 125 General Conclusion…………………………..…………………………………………….125 Chapter V. Experimental Section ....................................................................................... 127 Va. Materials and methods ................................................................................................ 128 Vb. Purification and analysis ............................................................................................. 128 Vc. Synthetic procedures ................................................................................................... 130 Vd. Surface plasmon resonance procedures ........................................................................... 206 Appendix ............................................................................................................................... 210 Generalities about SPR detection system for intermolecular interaction studies ............... 211 Sensorgrams: proteins injected on to the reference streptavidin surface ........................... 216 ANS activity assays ............................................................................................................ 217 References ............................................................................................................................. 221 4 Acknowledgements This work was possible thanks to the funding of La Fundacion Gran Mariscal Fundayacucho-Convenio Alianza Francesa, Caracas-Venezuela. I would like to thank this organization for giving me the opportunity to learn in such an interdisciplinary and multicultural environment through the financing of the 3 year doctorate. But also, for the supplementary 6 months granted, which allowed me to finish my formation and to obtain satisfactory results that will allow us to write a publication concerning the last two years and a half of work. This work was carried out under the direction of Stéphane Quideau in the Synthèse et Activite
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