Peptidomimetics In Organic And Medicinal Chemistry by Andrea Trabocchi and Antonio Guarna

6857c59e89b8b4f-261x361.jpg Author Andrea Trabocchi and Antonio Guarna
Isbn 9781119950608
File size 14.1 Mb
Year 2014
Pages 332
Language English
File format PDF
Category chemistry


Peptidomimetics in Organic and Medicinal Chemistry Peptidomimetics in Organic and Medicinal Chemistry The Art of Transforming Peptides in Drugs ANDREA TRABOCCHI Department of Chemistry “Ugo Schiff”, University of Florence, Italy ANTONIO GUARNA Department of Chemistry “Ugo Schiff”, University of Florence, Italy This edition first published 2014 © 2014 John Wiley & Sons, Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom. If professional advice or other expert assistance is required, the services of a competent professional should be sought The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Trabocchi, Andrea, author. Peptidomimetics in organic and medicinal chemistry / Dr. Andrea Trabocchi and Professor Antonio Guarna. pages cm Includes bibliographical references and index. ISBN 978-1-119-95060-8 (hardback) 1. Peptide drugs. 2. Proteins–Therapeutic use. 3. Drugs–Design. I. Guarna, Antonio, author. II. Title. RS431.P38T73 2014 615.1′ 9–dc23 2013048681 A catalogue record for this book is available from the British Library. ISBN: 9781119950608 Typeset in 10/12pt TimesLTStd by Laserwords Private Limited, Chennai, India 1 2014 Dedicated to our families: Nicoletta and Tommaso Lory, Francesco, Sara and Tommaso Contents Preface Abbreviations xiii xvii PART I The Basics of Peptidomimetics 1 1. The Basics of Peptidomimetics 1.1 Introduction 1.2 Definition and Classification 1.3 Strategic Approaches to Peptidomimetic Design 1.3.1 Modification of Amino Acids 1.3.2 Compounds with Global Restrictions 1.3.3 Molecular Scaffolds Mimicking the Peptidic Backbone 1.4 Successful Examples of Peptidomimetic Drugs 1.4.1 ACE Inhibitors 1.4.2 Thrombin Inhibitors 1.5 Conclusion References 3 3 5 7 8 9 10 12 13 13 16 16 2. Synthetic Approaches towards Peptidomimetic Design 2.1 Introduction 2.2 Local Modifications 2.2.1 Single Amino Acid Modifications 2.2.2 Dipeptide Isosteres 2.2.3 Retro-inverso Peptides 2.2.4 N-Methylation of Peptides 2.2.5 Azapeptides 2.2.6 Peptoids 2.3 Global Restrictions through Cyclic Peptidomimetics 2.4 Peptidomimetic Scaffolds 2.5 Conclusions References 19 19 20 23 26 29 30 31 31 32 34 35 35 viii Contents PART II Synthetic Methods and Molecules 37 3. Peptidomimetic Bioisosteres 3.1 Introduction 3.2 Peptide Bond Isosteres 3.2.1 Thioamides 3.2.2 Esters 3.2.3 Alkenes and Fluoroalkenes 3.2.4 Transition-State Isosteres 3.3 Side-Chain Isosteres 3.3.1 Guanidine Isosteres in Arginine Peptidomimetics 3.3.2 Isosteres of Aspartic Acid and Glutamic Acid 3.3.3 Tethered α-Amino Acids: Constraining the χ-Space 3.4 Dipeptide Isosteres 3.4.1 δ-Amino Acids 3.5 Tripeptide Isosteres 3.6 Conclusion References 39 39 40 41 41 41 42 45 45 49 53 59 63 67 68 69 4. Solid-Phase Synthesis and Combinatorial Approaches to Peptidomimetics 4.1 Introduction 4.2 Solid-Phase Synthesis of Peptidomimetics 4.2.1 Scaffolds from α-Amino Acids 4.2.2 Scaffolds from Amino Aldehyde Intermediates 4.2.3 Pyrrolidine-Containing Scaffolds 4.3 Conclusion References 75 75 76 76 85 89 94 95 5. Click Chemistry: The Triazole Ring as a Privileged Peptidomimetic Scaffold 5.1 Introduction 5.1.1 CuAAC Reaction 5.1.2 Triazole Ring as a Peptidomimetic Isostere 5.2 Triazole-Containing Peptidomimetics Elaborated through ‘Click Chemistry’ 5.2.1 Macrocycles 5.2.2 Oligomers and Foldamers 5.3 Relevant Applications in Drug Discovery 5.3.1 AChE Inhibitors 5.3.2 HIV Protease Inhibitors 5.3.3 MMP Inhibitors 5.3.4 Integrin Ligands 5.4 Conclusions Acknowledgements References 99 99 100 101 102 102 107 110 110 111 114 115 118 119 119 Contents ix 6. Peptoids 6.1 Introduction and Basics of Peptoids 6.2 Synthetic Methods 6.3 Macrocyclic Peptoids 6.4 Conformational Analysis of Folded Peptoids 6.5 Application of Peptoids as Antimicrobial Peptidomimetics 6.6 Conclusions References 123 123 126 129 130 7. Sugar Amino Acids 7.1 Introduction 7.2 α-SAAs 7.2.1 Furanoid α-SAAs 7.2.2 Pyranoid α-SAAs 7.3 β-SAAs 7.3.1 Furanoid β-SAAs 7.3.2 Pyranoid β-SAAs 7.4 γ-SAAs 7.5 δ-SAAs 7.5.1 Furanoid δ-SAAs 7.5.2 Pyranoid δ-SAAs 7.6 Representative Applications in Medicinal Chemistry 7.7 Conclusions References 137 137 138 138 142 144 144 147 148 150 150 154 159 162 162 8. Cyclic 𝛂-Amino Acids as Proline Mimetics 8.1 Introduction 8.2 Cyclic α-Amino Acids 8.2.1 3-Substituted Proline Derivatives 8.2.2 4-Substituted Proline Derivatives 8.2.3 5-Substituted Proline Derivatives 8.2.4 Other Heterocyclic Proline Analogues 8.3 Bicyclic α-Amino Acids 8.3.1 β/γ-Ring Junction 8.3.2 α/γ-Ring Junction 8.3.3 γ/δ-Ring Junction 8.3.4 α/δ-Ring Junction 8.3.5 β/δ-Ring Junction 8.3.6 N/β-Ring Junction 8.3.7 Pipecolic-Based Bicyclic α-Amino Acids 8.3.8 Morpholine-Based Bicyclic α-Amino Acids 8.4 Conclusions References 165 165 166 167 168 169 171 174 175 178 179 180 182 183 183 187 189 189 132 134 134 x Contents 9. 𝛃-Turn Peptidomimetics 9.1 Introduction 9.2 Definition and Classification of β-Turns 9.3 Conformational Analysis 9.4 β-Turn Peptidomimetics 9.4.1 Proline Analogues in β-Turn Peptidomimetics 9.4.2 δ-Amino Acids as Reverse-Turn Inducers 9.4.3 Molecular Scaffolds as β-Turn Peptidomimetics 9.5 Conclusions References 191 191 192 194 196 197 200 209 214 215 10. Peptidomimetic Foldamers 10.1 Introduction 10.2 Classification 10.3 Peptoids 10.4 β-Peptides: First Systematic Conformational Studies 10.5 Hybrid Foldamers 10.6 From Structural to Functional Foldamers 10.6.1 Peptoids as Foldameric Antimicrobial Peptidomimetics 10.6.2 Foldamers Targeting Bcl-xL Antiapoptotic Proteins 10.7 Conclusions References 219 219 220 221 221 226 227 227 227 228 228 PART III Applications in Medicinal Chemistry 11. Case Study 1: Peptidomimetic HIV Protease Inhibitors 11.1 Introduction 11.2 The HIV-1 Virus 11.2.1 HIV-1 Protease 11.3 Antiretroviral Therapy 11.4 Drug Resistance 11.4.1 Mechanisms of Resistance to Protease Inhibitors 11.5 HIV-1 Protease Inhibitors 11.5.1 Transition-State Analogues 11.5.2 Peptidomimetic Drugs 11.5.3 Next-Generation Cyclic Peptidomimetic Inhibitors 11.6 Conclusions Acknowledgements References 231 233 233 233 234 238 239 239 240 240 241 245 255 255 256 Contents xi 12. Case Study 2: Peptidomimetic Ligands for 𝛂𝐯 𝛃𝟑 Integrin 12.1 Introduction 12.2 Peptide-Based Peptidomimetic Integrin Ligands 12.3 Scaffold-Based Peptidomimetic Integrin Ligands 12.4 Conclusions References 259 259 262 270 280 280 Index 283 Preface Peptidomimetic design and synthesis are powerful and well-established tools for the generation of small-molecule-based drugs acting as enzyme inhibitors or receptor ligands. Several decades since the introduction of the concept of peptidomimetics, this approach is still timely in drug discovery, owing to the never-ending interest in developing novel drugs derived from bioactive peptides and protein fragments. In fact, the field of small molecules encompassing the panorama of peptide drugs is covered by the generation of peptidomimetics with the aim of reducing the conformational flexibility and the peptide character, so as to improve the potency and selectivity, and to achieve hit compounds possessing optimal bioactivity and improved pharmacokinetics profile. Over the years the basic concepts and approaches to peptidomimetic compounds have evolved to diverse compounds and synthetic strategies, spanning from combinatorial chemistry to solid-phase synthesis and heterocyclic chemistry. In this respect, research efforts within organic and medicinal chemistry have produced novel peptidomimetic entries of improved technology with the aim of generating diverse arrays of enzyme inhibitors and receptor ligands. Specifically, several synthetic approaches have been proposed, which can be broadly divided into local and global modifications of the parent peptide, together with the generation of scaffold-based peptidomimetics possessing reduced or absent peptide character, though maintaining the structural features identified by the pharmacophore. Moreover, interest in larger peptidomimetics, such as foldamers and macrocycles, is growing, especially with a view to developing novel antimicrobial therapeutics, and to identifying bioactive compounds addressing protein–protein interactions. This book is intended to give a comprehensive view of peptidomimetics and their classification based on common structural features, and to discuss the most successful synthetic approaches underlying the building of bioactive compounds of ‘peptidomimetic nature’ based on the structure of natural bioactive peptides. Moreover, selected case studies in relevant biomedical areas are presented to illustrate the relevance of peptidomimetics in the hit-to-lead process towards drug development. The book has been organized into three main parts: the first one describes the basics of peptidomimetics, followed by a comprehensive overview of synthetic methods and molecules and, finally, selected applications in medicinal chemistry are presented. Part I encompasses the basic concepts underlying the development of peptidomimetic compounds, including their classification, and describes diverse strategic approaches to peptidomimetic design, such as the modification of amino acids, and the introduction of global restrictions to a target bioactive peptide, and also discusses successful examples of xiv Preface peptidomimetic drugs, such as ACE inhibitors and thrombin inhibitors. These concepts are covered in more detail in the subsequent chapter. In particular, Chapter 2 reports the approaches to local and global modifications, the classification of single amino acid modifications, including the presentation of key peptide isosteres, and the principles of peptidomimetic scaffold design. In Part II, synthetic methods and molecules of peptidomimetic character are reported in detail. Chapter 3 presents synthetic approaches to peptidomimetic bioisosteres, including peptide bond isosteres and transition-state isosteres, which have found wide application in drug discovery as protease inhibitors. This chapter discusses both side-chain and dipeptide isosteres. Chapter 4 reports the relevance of solid-phase synthesis and combinatorial chemistry as straightforward approaches towards the generation of libraries of peptidomimetics. Click chemistry is presented in Chapter 5 as a powerful concept addressing modern peptidomimetic compounds, taking advantage of the triazole ring as a privileged peptidomimetic scaffold, in terms of developing novel peptidomimetic inhibitors in drug discovery. The special case of peptoids as peptidomimetics containing peptide bond isosteres is described in Chapter 6. The last chapters of this part (Chapters 7–10) discuss the major area of peptidomimetic scaffolds, which is connected to the generation of unnatural amino acids. Specifically, Chapter 7 explores the family of sugar amino acids, which belongs to an important class of scaffolds with high density of stereocentres and functional groups, while Chapter 8 gives a picture of cyclic amino acids as proline surrogates, particularly addressing diverse ring size and tethers in the building of cyclic chemotypes. Some of these compounds are also discussed in Chapter 9, which deals with the subclass of β-turn peptidomimetics that play a crucial role in many biological recognition systems and protein–protein interactions. Chapter 10 concludes Part II by addressing the field of foldamers, where peptidomimetics occupy a prominent role given their similar profile to that of peptides, which fold into helices, sheets and strands. This timely issue is relevant in addressing ‘difficult-to-target’ proteins, which are of major concern in therapeutic areas where target proteins interacting with large surface contacts are involved. Finally, Part III presents significant applications in medicinal chemistry, specifically reporting research in the fields of HIV protease inhibitors and integrin ligands as key studies aiming to give a picture of the important role of peptidomimetic chemistry in past, present and future biomedical research. The topic of peptidomimetic HIV protease inhibitors is reported in Chapter 11, describing the principles underlying the selection of HIV protease as a key therapeutic target, and discussing both peptidomimetic drugs out in the market and novel peptidomimetic scaffolds as promising lead compound addressing drug-resistant strains. Chapter 12 reports on the concepts essential to peptidomimetic ligands for interacting with αv β3 integrin, which is a relevant target for cancer research, and discusses both peptide-based and scaffold-based as two diverse approaches to peptidomimetic integrin ligands. These presentations have been conceived for a broad readership, and should interest not only those readers who currently work in the field of organic and medicinal chemistry addressing drug discovery but also those who are considering this approach in the field chemical biology, taking advantage of peptidomimetic compounds as small-molecule chemical probes to provide important tools for dynamically interrogating biological Preface xv systems and for investigating potential drug targets. We hope that these chapters will stimulate further advances in the ever-developing field of peptidomimetics. Andrea Trabocchi Antonio Guarna Florence, July 2013 Abbreviations AC6C ACE ACHC AChE ACPC Acpca Aib Aic AIDS AIP AMPs APV Ate ATV azPro BAL BBI Bcl-xL BGS Boc BTAa BTG BTPP Cbz CCR5 CD mCPBA cGMP CNS CuAAC CXCR4 DCC DCM de DFT DIC α-aminocyclohexane carboxylic acid angiotensin-converting enzyme aminocyclohexane carboxylic acid acetylcholinesterase aminocyclopentane carboxylic acid γ-aminocyclopentane carboxylic acid 2-amino-isobutyric acid 2-aminoindan-2-carboxylic acid acquired immunodeficiency syndrome autoinducing peptides antimicrobial peptides Amprenavir 2-aminotetralin-2-carboxylic acid Atazanavir azaproline backbone amide linker Bowman–Birk inhibitor B-cell lymphoma-extra large bicycle from glyceraldehyde and serine t-butoxycarbonyl bicycle from tartaric acid and amino acid bicyclic from tartaric acid and glycine t-butylimino-tri(pyrrolidino)-phosphorane benzyloxycarbonyl CC chemokine receptor 5 circular dichroism m-chloroperbenzoic acid cyclic guanine monophosphate central nervous system Cu-catalysed azide alkyne cycloaddition CXC chemokine receptor type 4 N,N′ -dicyclohexylcarbodiimide dichloromethane diastereomeric excess density functional theory N,N′ -diisopropylcarbodiimide xviii Abbreviations DIEA DKP DMF DNA DOPA DOS DPPA DRV Dtc EGF Fmoc FPV FRET GABA GPCRs HATU HCV HIV HPLC HSP HSQC HUVEC IDV IR Lac LC-MS LF LHMDS LHRH LPV MC/SD mCPBA MCRs MD MIDAS miniAMP MMPs Mor MTT Nal NFV NGF NMR NOESY NPR-A N,N-diisopropylethylamine 2,5-diketopiperazine N,N-dimethylformamide deoxyribonucleic acid 3,4-dihydroxyphenylalanine diversity-oriented synthesis diphenylphosphoryl azide Darunavir 5,5-dimethylthiazolidine-4-carboxylic acid epidermal growth factor fluorenylmethyloxycarbonyl fosamprenavir fluorescence resonance energy transfer γ-aminobutyric acid G protein-coupled receptors N,N,N′ ,N′ -tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate hepatitis C virus human immunodeficiency virus high-performance liquid chromatography heat shock protein heteronuclear single quantum coherence spectroscopy human umbilical cord vein endothelial cell Indinavir infrared spectroscopy lactic acid liquid chromatography–mass spectrometry lethal factor lithium bis(trimethylsilyl)amide luteinizing hormone releasing hormone Lopinavir Monte Carlo/stochastic dynamics 3-chloroperoxybenzoic acid melanocortin receptors molecular dynamics metal ion-dependent adhesion site mini atrial natriuretic polypeptide matrix metalloproteases morpholine 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide naphthylalanine Nelfinavir nerve growth factor nuclear magnetic resonance nuclear Overhauser effect spectroscopy natriuretic peptide receptor A

Author Andrea Trabocchi and Antonio Guarna Isbn 9781119950608 File size 14.1 Mb Year 2014 Pages 332 Language English File format PDF Category Chemistry Book Description: FacebookTwitterGoogle+TumblrDiggMySpaceShare A peptidomimetic is a small protein-like chain designed to mimic a peptide with adjusted molecular properties such as enhanced stability or biological activity. It is a very powerful approach for the generation of small-molecule-based drugs as enzyme inhibitors or receptor ligands. Peptidomimetics in Organic and Medicinal Chemistry outlines the concepts and synthetic strategies underlying the building of bioactive compounds of a peptidomimetic nature. Topics covered include the chemistry of unnatural amino acids, peptide- and scaffold-based peptidomimetics, amino acid-side chain isosteres, backbone isosteres, dipeptide isosteres, beta-turn peptidomimetics, proline-mimetics as turn inducers, cyclic scaffolds, amino acid surrogates, and scaffolds for combinatorial chemistry of peptidomimetics. Case studies in the hit-to-lead process, such as the development of integrin ligands and thrombin inhibitors, illustrate the successful application of peptidomimetics in drug discovery.       Download (14.1 Mb) Enantioselective Synthesis of Beta-Amino Acids Synthetic Receptors For Biomolecules: Design Principles And Applications Bioorganic Synthesis: An Introduction Electrochemistry I (Topics in Current Chemistry) Functionalised N-Heterocyclic Carbene Complexes Load more posts

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