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Alma Mater Studiorum –– Università Di Bologna Alma Mater Studiorum –– Università di Bologna DOTTORATO DI RICERCA IN Scienze Chimiche Ciclo XXIV Settore Concorsuale di afferenza: CHIM/06 Settore Scientifico disciplinare: CHIMICA ORGANICA TITOLO TESI Synthesis of Modified Amino Acids and Insertion in Peptides and Mimetics. Structural Aspects and Impact on Biological Activity. Presentata da: De Marco Rossella Coordinatore Dottorato Relatore Prof. Adriana Bigi Prof. Luca Gentilucci Esame finale anno 2012 1 Synthesis of Modified Amino Acids and Insertion in Peptides and Mimetics. Structural Aspects and Impact on Biological Activity. by Rossella De Marco 2012 2 To My Self 3 Table of Contents Cap 1. Chemical Modifications Designed to Improve Peptide Stability 1. Introduction 1.2. Enzymatic Degradation of Peptides 1.3. Structure Modifications to Improve Peptide Stability 1.3.1.Pseudopeptides 1.3.2. Reduced Peptide Bonds 1.3.3. Azapeptides 1.3.4. Retro-Inverso Peptides 1.3.5. Peptoids 1.4. Incorporation of Non-Natural Amino Acids 1.4.1. D-Amino Acids 1.4.2. N-Alkylated Amino Acids 1.4.3. α-Substituted α-Amino-Acids 1.4.4. β-Substituted α-Amino Acids 1.4.5. Proline analogues 1.4.6. β-Amino-Acids 1.5. Cyclization 1.6. β-Turn-Mimetics 1.7. Conclusion References Chapter 2. Cyclopeptide Analogs for Generating New Molecular and 3D Diversity. 2. Introduction 2. 1. Matherial and Methods 2.2. General Methods. 2.3. General Procedure for Peptide Coupling 2.3.1. Boc group deprotection 2.3.2. Fmoc group deprotection 2.3.3. Cbz and benzyl group deprotection 2.3.4. General Procedure for Peptide Cyclization 2.4. Conformation Analysis 2.5.Results 2.6. VT-1H-NMR 2.7. 2D-ROESY 4 2.8. Discussion 2.9. Conclusions References Chapter 3. Synthesis and Conformational Analysis of Cyclotetrapeptide Mimetic β-Turn Templates and Validation as 3D Scaffolds. 3. Introduction 3.1. Experimental section 3.1.1. General methods 3.1.2. Synthesis of 6 3.1.3. Synthesis of 9 3.1.4. Peptide cleavage 3.1.5. Cyclization 3.2. Conformational analysis 3.3. Cell adhesion assay 3.4. Supporting Information References Chapter 4. Antiangiogenic Effect of Dual/Selective α5β1/αvβ3 Integrin Antagonists Designed on Partially Modified Retro-Inverso Cyclotetrapeptide Mimetics. 4. Introduction 4.1. Results 4.1.1. Inhibition of Cell Adhesion 4.1.2. Effect of Integrin Antagonists on in Vitro Elicited by Basic Fibroblast Grotw Factor (bFGF) 4.1.3. α5β1/αvβ3 Integrin Antagonists Do Not Affect Endothelial Cell Viability 4.1.4. Conformational Analysis of 2 and 3 in Solution 4.2. Molecular Docking 4.3. Discussion 4.4. Conclusions 4.5. Experimental Section 4.5.1. General Methods 4.5.2. Representative Synthetic Procedures and Analytical Characterization of PMRI RGD Mimetics 2 and 3. 4.5.3. 14 {c[βPheψ(NHCO)Asp(Ot-Bu)ψ(NHCO)Gly-Arg(Mtr)]} 4.5.4. 2 {c[βPheψ(NHCO)Aspψ(NHCO)Gly-Arg]} 4.5.5. 3 {c[(R)-βPheψ(NHCO)Aspψ(NHCO)Gly-Arg]} 4.6. Pharmacological Assays 4.6.1. Materials for Biossays 5 4.6.2. Cell Culture 4.6.3. Cell Adhesion Assays 4.6.3. Flow Cytometry Assays 4.6.4. In Vitro Tubular Formation of HUVEC 4.7. Conformational Analysis 4.7.1. Molecular Docking 4.7.3. Protein Setup 4.7.4. Docking 4.8. Supporting Information References Chapter 5. Molecular docking of opioid peptides and analogues, a powerful tool for the design of selective agonists and antagonists, and for the investigation of atypical ligand-receptor interactions. 5. Introduction 5.1. Structure and functions of the opioid receptors, and representative opioid ligands 5.2. Insights into the interactions between ligands and receptors 5.3. Principles of molecular docking. 5.4. Exploring the determinants of ligand affinity and selectivity: comparative docking studies 5.5. The docking of ligands lacking of the cationic amino group 5.5.1. Salvinorins 5.5.2. 6,6-Bicyclic enkephalin mimetics 5.5.3. Dhp-peptide 5.5.4. Fentanyl “carba”-analogues 5.6. The D-Trp-Phe β-turn MOR pharmacophoric motif References Chapter 6. The Inverse Type II β-Turn on D-Trp-Phe, a Pharmacophoric Motif for MOR Agonist. 6. Introduction 6.1. Results 6.1.2. Cyclopeptide Design 6.1.3. Cyclopeptide Synthesis 6.1.3. Binding Affinity to the Cloned Human Opioid Receptors 6.1.4. Effects on Forskolin-Stimulated cAMP Production 6.2. Conformational Analysis 6.3. Molecular Backbone 6.4. Molecular Docking 6.5. Discussion 6.6. Conclusions 6 6.7. Experimental section 6.7.1. Chemistry 6.7.2. General Methods 6.7.3. Peptide Synthesis 6.7.4. Peptide Cleavage 6.7.5. Peptide Cyclization 6.8 Biology 6.8.1. Receptor Binding Assays to Cloned Human DOR and KOR 6.8.2. Determination of Inhibition of Cyclic AMP Accumulation 6.9. Conformational Analysis 6.9.1. Computational Methods 6.9.2. Molecular Docking 6.9.3. Hybrid QM/MM 6.9.4. Supporting Information References Chapter 7. A simple route towards peptide analogues containing substituted (S)- or (R)-tryptophans. 7. Introduction 7.1. Results and Discussion 7.2. Conclusions 7.3. Supporting Information References Chapter 8. Synthesis of Constrained Peptidomimetics Containing 2-Oxo-1,3-oxazolidine-4-carboxylic Acids. 8. Introduction 8.1. Results and Discussion 8.2. Conclusions 8.3. Experimental Section References Chapter 9. Expedient Synthesis of Pseudo-Pro-Containing Peptides 9. Introduction 9.1. Results and discussion 9.1.1. Optimization of the Reaction Conditions 9.1.2. Synthesis of di-Oxd-peptides 9.2. Conformational Aspects of the Oxd peptides 9.3. Conclusions 7 9.4. Experimental part 9.4.1. Peptide Synthesis 9.4.2. Mono-Oxd-peptide Synthesis 9.4.3. Di-Oxd-peptide Synthesis 9.4.4. Di-Oxd-peptide Solid-Phase Synthesis 9.5. Theoretical Computations 9.5.1. Conformational Analysis 9.5.2.. Circular Dichroism 9.5.3. NMR Analysis 9.5.4. Roesy and Molecular Dynamics 9.6. Supporting information References Conclusions Curriculum Vitae List of Publications 8 Abbreviations and acronyms CNS = Central nervous system BBB = Blood-brain barrier ACE = Angiotensin-converting enzyme ADMET = Absorption distribution metabolism excretion toxicity SPPS = Solid phase peptide synthesis SAR = Structure-activity relationship RGD = Arg-Gly-Asp CCK = Cholecystokinin LHRH = Luteinizing hormone-releasing hormone TRH = Thyrotropin releasing hormone PEG = Polyethylene glycol PMRI = Partially modified retro inverso RCM = Ring-closing methatesis Boc = Tert-butyloxycarbonyl Fmoc = 9H-fluoren-9-ylmethoxycarbonyl EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBt = Hydroxybenzotriazole PG = Protecting group Bz = Benzyl DIC = N,N'-diisopropylcarbodiimide DEAD = Diethylazodicarboxylate Cbz = Benzyloxycarbonyl Dpp = Diphenylphosphinamide LDA = Lithium diisopropylamide Salen = Salicylic aldehyde ethylenediamine A* = Chiral auxiliary TMS = Trimethylsilyl PyBOP = Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate DIEA = Diisopropylethylamine TFA = Trifluoroacetic acid Bom = Benzyloxymethyl Pip = Pipecolic acid or piperidine TEA = triethylamine DPPA = diphenylphosphorylazide DCM= dichlorometane DMA = dimethylamine 9 THF = tetrahydrofuran DMF = dimethylformamide EM = endomorphin MOR, DOR, KOR, -, δ- ,k- = opioid receptor, respectively EL = extracellular loop TMH = transmembrane helix 2D, 3D = two-, three-dimensional, respectively HBTU = 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate DMSO = dimethyl sulfoxide RP = reversed-phase ES-MS = electrospray ionization mass spectrometry SE = standard error DAMGO = H-T yr-D-Ala-Gly-N-MePhe-glyol DPDPE = [D-Pen2,D-Pen5]-enkephalin JOM-6 = Tyr-c(S-Et-S)[D-Cys-Phe-D-Pen]NH2 MD = molecular dynamics Dock = molecular docking DO = docking orientation VT = variable temperature AMBER = assisted model building with energy refinement TIP3P = transferrable intermolecular potential three point DAD = diode array detector HMBC = heteronuclear multiple-bond coherence HSQC = heteronuclear single-quantum coherence rt = room temperature CPK = Corey, Pauling, and Koltun CCP4 = Collaborative Computational Project 4 PBS = phosphate-buffered saline bFGF = basic fibroblast growth factor CTP = cyclotetrapeptide K562 = human erythroleukemic cells SK-MEL-24 = human malignant melanoma cells HUVEC = human umbilical vein endothelial cells BSA = bovine serum albumin ECM = extracellular matrix S.E.M. = standard error of mean ANOVA = analysis of variance test RMSD = root mean square deviation 10 MIDAS = metal-ion-dependent adhesion site ODS = octadecyl silane EDTA = ethylenediaminetetraacetic acid MEM = minimum essential medium RPMI = Roswell park Memorial Institute FBS = fetal bovine serum PBS = phosphate buffered saline PMA = phorbol 12-myristate 13-acetate PI = propidium iodide. 11 Chapter 1 Chemical Modifications Designed to Improve Peptide Stability 1. Introduction Peptides are amino acid derived compounds containing at least one amide (peptide) bound. Conventionally, peptides up to 20 amino acids are named oligopeptides, while the term polypeptatide refers to peptides up to 100 amino acids. From the structural point of view, peptides encompass diverse types such as linear, cyclic peptides, depsipeptides, and peptides modified with diverse nonpeptide moietes including phosphoryl groups or carbohydrate, polyketides or terpenoids, etc [1]. The evolution of enzymatic synthesis, recombinant DNA technology, and automated synthetic methodologies in particular SPPS, allow for the production of large libraries of diverse peptides characterized by a range of pharmacological effects. Peptide or peptidomimetic drugs are currently utilized for the
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