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NNT : 2016SACLS544 THESE DE DOCTORAT DE L’UNIVERSITE PARIS-SACLAY PREPAREE A “UNIVERSITE PARIS-SUD FACULTE DE PHARMACIE” ECOLE DOCTORALE N° 569 Innovation thérapeutique : du fondamental à l'appliqué Spécialité de doctorat : Chimie thérapeutique Par Nicolo Michele Tonali Mimes synthétiques de feuillets bêta: conception, synthèse et évaluation de leur capacité à moduler l'agrégation du peptide bêta-amyloïde 1-42. Thèse présentée et soutenue à Châtenay-Malabry, le 24 Novembre 2016 : Composition du Jury : M. Aitken, David Professeur, Université Paris-sud Président M. Maillard, Ludovic Maître de Conférences, Université de Montpellier Rapporteur M. Guichard, Gilles Directeur de recherche, Université de Bordeaux Rapporteur M. Lequin, Olivier Professeur, Université Pierre et Marie Curie Examinateur Mme Ongeri, Sandrine Professeur, Université Paris-sud Directrice de thèse Mme Kaffy, Julia Maître de Conférences , Université Paris-sud Co-encadrante Synthetic mimics of β-sheets: design, synthesis and evaluation of their ability to modulate the aggregation of the β-amyloid 1-42 peptide Nicolo Tonali 2 Contents 1 Introduction 13 1.1 Three-dimensional structure of polypeptides and proteins . 13 1.1.1 Secondary structure . 15 1.1.2 Tertiary structure . 22 1.1.3 Quaternary structure . 23 1.2 Alzheimer’s disease . 23 1.2.1 Amyloidosis and neurodegenerative disease . 23 1.2.2 Physiopathology of Alzheimer’s disease . 28 1.2.3 The hypotheses of the cause of the disease . 30 1.3 Therapeutical strategies in development to target Aβ 1-42 peptide . 44 1.3.1 Enzyme inhibitors . 45 1.3.2 Immunotherapy . 48 1.3.3 Aβ homeostasis . 49 1.3.4 Modulators of Aβ aggregation . 50 1.4 General conception of the hairpin mimics design . 65 2 β-hairpin mimics containing the piperidine-pyrrolidine scaf- fold and rationally designed peptide sequences 69 2.1 Design of the β-hairpin mimics . 69 2.2 Synthesis of the piperidine-pyrrolidine scaffold . 72 2.3 Synthesis of β-hairpins . 76 2.4 Conformational studies . 77 2.4.1 Circular Dichroism (CD) . 79 2.4.2 Nuclear Magnetic Resonance (NMR) . 80 2.5 Evaluation of β-hairpin ability to inhibit Aβ 1-42 aggregation 85 2.5.1 Thioflavin T fluorescence spectroscopy (ThT) . 85 2.5.2 Transmission electron microscopy (TEM) . 90 2.5.3 Capillary electrophoresis (CE) . 92 2.5.4 Cell viability assay . 96 2.6 Conclusion . 100 3 4 CONTENTS 3 β-hairpin mimics containing the piperidine-pyrrolidine scaf- fold and the 5-acetamido-2-methoxybenzohydrazide peptidomimetic derivative unit 101 3.1 Design of the β-hairpin mimics . 101 3.1.1 Previous results in the laboratory . 101 3.1.2 β-hairpin mimics based on the Tosyl scaffold and the 5-amino-2-methoxybenzhydrazide unit . 104 3.1.3 Modulation of the protective group of the β-turn scaffold105 3.2 Synthesis of the β-hairpin mimics . 107 3.2.1 Synthesis of compounds 3.1 and 3.2 . 107 3.2.2 Trials of Tosyl cleavage of scaffold 2.5 . 109 3.2.3 Synthesis of the Nosyl scaffold 3.11 . 110 3.2.4 Synthesis of compound 3.5 . 114 3.2.5 Synthesis of the Boc scaffold 3.20 . 116 3.2.6 Synthesis of compounds 3.3 and 3.4 . 118 3.3 Evaluation of the β-hairpin mimics . 120 3.4 Conformational analysis of the β-hairpin mimics 3.1 and 3.2 129 3.5 Conclusions . 142 4 β-hairpin mimic containing the piperidine-pyrrolidine scaf- fold and a fluorinated peptidomimetic derivate unit 145 4.1 Design of the fluorinated β-hairpin mimic . 145 4.1.1 The importance of fluorine in bioorganic and medicinal chemistry . 145 4.1.2 Design of the fluorinated β-strand peptidomimetic . 147 4.1.3 Design of the fluorinated β-hairpin . 151 4.2 Synthesis of the fluorinated β-hairpin mimic . 151 4.2.1 Synthesis of the fluorinated β-strand peptidomimetic . 151 4.2.2 Synthesis of compound 4.4 and of the fluorinated β- hairpin 4.3 . 161 4.3 Evaluation of the fluorinated β-strand 4.2 by ThT fluorescence assay . 162 4.4 Conclusions and perspectives . 165 5 β-hairpin mimics containing the piperidine-pyrrolidine scaf- fold and azatide β-strand peptidomimetics 167 5.1 Design of the azatide peptidomimetics and the β-hairpin mimics167 5.1.1 State of the art . 167 5.1.2 Objectives . 171 5.2 Synthesis of the azatide peptidomimetics . 173 5.3 Conformational studies . 184 5.3.1 State of the art . 186 5.3.2 General procedures for the conformational analyses . 193 5.3.3 Structural constituents of a 2:1 [Aza/α]-tripeptide . 194 CONTENTS 5 5.3.4 Conformational analyses of compound 5.1 . 196 5.3.5 Conformational analyses of the Val-Ala-Val tripeptide analogues . 202 5.3.6 Conformational analyses of aGly-aGly-Val-CONH2 . 230 5.4 Conclusion and perspectives . 234 6 Experimental part 239 6 CONTENTS List of Abbreviations Aβ Amyloid β AA Amino acid Ac Acetyl Ac2O Acetic anhydride ACN Acetonitrile AcOH Acetic acid ADME Absorption, distribution, metabolism, and excretion AICD Amyloid precursor protein intracellular domain ApoE Apolipoprotein E APP Amyloid precursor protein APTS p-Toluenesulfonic acid BACE β-secretase inhibitor Bn Benzyl Boc tert-butyloxycarbonyl Boc2O Di-tert-butyl dicarbonate BSBp β-sheet breaker peptide C-PIB Pittsburgh compound B CA Clan CA cysteine proteases Cbz Carboxybenzyl CD Circular dichroism CD Clan CD cysteine proteases 7 8 CONTENTS CDI 1’-Carbonyldiimidazole CE Capillary electrophoresis CNS Central nervous system COSY Correlation spectroscopy COX Cyclooxygenase CSD Chemical shift deviation CTF C-terminal fragment Cyclo Cyclohexane DCM Dichloromethane DFT Density functional theory DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-diméthylformamide DMSO Dimethyl sulfoxide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EGCG Epigallocatechin-3-gallate EM Electron microscopy eq. Equivalent Et2O Diethyl ether EtOAc Ethyl acetate FDA Food and drug administration Fmoc Fluorenylmethyloxycarbonyl Fmoc-Osu Fmoc N-hydroxysuccinimide For Formyl FTIR Fourier transform infrared HCl Hydrochloric acid HFIP Hexafluoroisopropanol CONTENTS 9 HIV-1 PR Human Immunodeficiency Virus 1 protease HMBC Heteronuclear multiple-bond correlation spectroscopy HOAt 1-Hydroxy-7-azabenzotriazole HOBt Hydroxybenzotriazole HPLC High-performance liquid chromatography HRMS High resolution mass spectrometry HSQC Heteronuclear Single Quantum Coherence I.D. Internal diameter IDP Intrinsically disordered protein iPrOH Isopropanol IR Infrared L-CPL Left-handed circularly polarised light LC-MS Liquid chromatography-mass spectrometry LDH Lactate dehydrogenase LTD Long-term depression LTP Long-term potentiation M-TTR monomeric variant of transthyretin MAP Microtubule associated protein MCMM Monte Carlo Multiple Minima Me Methyl MeOH Methanol MM Molecular modelling MO Molecular orbital MRI Magnetic resonance imaging MW Molecular weight NBO Natural Bond Orbital NMDA N-methyl-D-aspartate receptor 10 CONTENTS NMM N-Methylmorpholine NMR Nuclear magnetic resonance NOESY Nuclear Overhauser effect spectroscopy Nos Nosyl NSAIDs Non-steroidal anti-inflammatory drugs PDA Photodiode Array Detector PET Positron emission tomography PhSH Thiophenol Py Pyridine R-CPL Right-handed circularly polarised light Rf Retardation factor ROESY Rotating-frame nuclear Overhauser effect correlation spectroscopy SAA Serum amyloid A SAR Structure activity relationship SDS-PAGE Sodium Dodecyl Sulphate-PolyAcrylamide Gel Electrophoresis SREs Self-recognition elements TDA Taylor dispersion analysis TEA Triethylamine TEM Transmission electron microscopy THF Tetrahydrofuran ThT Thioflavin T TLC Thin-layer chromatography TOCSY Total correlation spectroscopy Tos Tosyl UV Ultraviolet Acknowledgement First, I would like to thank my thesis supervisor Sandrine Ongeri to have always been present during these three years, for giving me the opportunity to grow scientifically. Thanks for your professionalism and for all the time you devoted to me to best perform my thesis but also thank you for the human support and for being too a big help in daily life on a personal level. Thanks to Julia Kaffy for being an important co-supervisor and always being available to discuss and give good advice. I want to thank the members of the jury who accepted to judge my work. This thesis has been possible thanks to numerous collaborations with several laboratories, who have welcomed and formed me. I would like to thank all the members of these laboratories to be available to welcome me. I would especially like to thank Myriam Taverna, Dimitri and Nacéra (Protéines et Nanotechnologies Séparatives en Sciences, Institut Galien de Paris Sud, UMR-CNRS 8612, Université Paris Sud) for their invaluable support during my months, spent learning the capillary electrophoresis. The laboratory of Maria Luisa Gelmi (DISFARM Sezione di Chimica Generale e Organica ”A. Marchesini”, Università Degli studi di Milano, Milano, Italy) welcomed me very well during my two months in visiting scholar. Thanks to Carine Van Heijenoort (Dept Chimie et Biologie Structurales et Analytiques CNRS, ICSN Gif sur Yvette France) for allowing us to perform the conformational analysis by NMR in Gif sur Yvette. Thanks to Olivier Lequin and Isabelle Correia for being a great support during the month spent to perform the conformational analysis by NMR on the azatide peptidomimetics. Thank you for your patience and for your expertise. Thanks to Camille Dejean for the contribution to the various NMR analysis of the synthesized compounds and thanks to Karine Leblanc for your time that allowed me to analyze the purity and the mass of all the molecules synthesized in the course of this thesis. During these three years I had the opportunity to meet and know people who have become part of my life. Jean Louis thanks for your continued support, for chats together and the many advice. Thanks to Jordi for your sympathy in the laboratory and for all the moments spent together. 11 Thank you so much Guillaume for all the help you have given me to create a well-paged manuscript but above all thanks very much for your professionalism and for your deep knowledge in all areas.
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  • Design and Syntheses of Gramicidin S Analogs, Cyclo(-X-Leu-XD

    Design and Syntheses of Gramicidin S Analogs, Cyclo(-X-Leu-XD

    The Journal of Antibiotics (2011) 64, 583–585 & 2011 Japan Antibiotics Research Association All rights reserved 0021-8820/11 $32.00 www.nature.com/ja NOTE Design and syntheses of gramicidin S analogs, cyclo(-X-Leu-X-D-Phe-Pro-)2 (X¼His, Lys, Orn, Dab and Dap) Makoto Tamaki1, Kenta Fujinuma1, Takuji Harada1, Kazumasa Takanashi1, Mitsuno Shindo2, Masahiro Kimura2 and Yoshiki Uchida2 The Journal of Antibiotics (2011) 64, 583–585; doi:10.1038/ja.2011.43; published online 25 May 2011 Keywords: gramicidin S; polycationic analog; structure-activity relationship; synthesis 1,1¢ 2,2¢ 3,3¢ 4,4¢ 5,5¢ 1–3 Gramicidin S (GS), cyclo(-Val -Orn -Leu -D-Phe -Pro -)2, solid phase peptide synthesis on oxime resin (loading of oxime group: is a potent cyclopeptide antibiotic isolated from Bacillus brevis.Its 0.35 mmol gÀ1 resins) (Scheme 1).8 Yresidue(Y¼His(3-Bom), Lys(Z), secondary structure has been established as an antiparallel b-sheet Orn(Z), Dab(Z) and Dap(Z)) as a C-terminal amino acid residue was conformation with amphiphilicity.4,5 The conformation is charac- used based on the propensity of the biosynthetic precursor of GS teristically featured with the orientation of side chains in such a way to form a conformation highly favorable for head–tail cyclization.2,3 that the charged Orn side chains are situated on one side of the The cyclization-cleavage of H-D-Phe-Pro-Y-Leu-Y-D-Phe-Pro-Y-Leu- molecule and the hydrophobic Val and Leu side chains are situated on Y-oxime from the resin was performed in 1,4-dioxane with 2 equiv the other side.
  • Group in Amine Protection and Activation Patrice Ribière, Valérie Declerck, Jean Martinez, Frédéric Lamaty

    Group in Amine Protection and Activation Patrice Ribière, Valérie Declerck, Jean Martinez, Frédéric Lamaty

    2-(Trimethylsilyl)ethanesulfonyl (or SES) Group in Amine Protection and activation Patrice Ribière, Valérie Declerck, Jean Martinez, Frédéric Lamaty To cite this version: Patrice Ribière, Valérie Declerck, Jean Martinez, Frédéric Lamaty. 2-(Trimethylsilyl)ethanesulfonyl (or SES) Group in Amine Protection and activation. Chemical Reviews, American Chemical Society, 2006, 106, pp.2249-2269. hal-00116881 HAL Id: hal-00116881 https://hal.archives-ouvertes.fr/hal-00116881 Submitted on 18 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Chem. Rev. 2006, 106, 2249−2269 2249 2-(Trimethylsilyl)ethanesulfonyl (or SES) Group in Amine Protection and Activation Patrice Ribie`re, Vale´rie Declerck, Jean Martinez, and Fre´de´ric Lamaty* Laboratoire des Aminoacides, Peptides et Prote´ines (LAPP), CNRS-Universite´s Montpellier 1 et 2, Place Euge`ne Bataillon, 34095 Montpellier Cedex 5, France Received July 25, 2005 Contents 7. SES Protection on Polymeric Support 2266 8. Conclusion 2268 1. Introduction 2249 9. Abbreviations 2268 2. SES−Cl in Synthesis 2250 10. References 2268 2.1. Synthesis of Sulfonyl Chloride 2250 2.2. Protection of Amines 2250 3. Direct Introduction of 2251 2-(Trimethylsilyl)ethanesulfonamide in Synthesis 1.