Peptidomimetics in Organic and Medicinal Chemistry

Andrea Trabocchi Department of Chemistry “Ugo Schiff”, University of Florence, Italy Antonio Guarna Department of Chemistry “Ugo Schiff”, University of Florence, Italy

Preface xiii

Abbreviations xvii

Part I The Basics of Peptidomimetics 1

1. The Basics of Peptidomimetics 3

1.1 Introduction 3

1.2 Definition and Classification 5

1.3 Strategic Approaches to Peptidomimetic Design 7

1.3.1 Modification of Amino Acids 8

1.3.2 Compounds with Global Restrictions 9

1.3.3 Molecular Scaffolds Mimicking the Peptidic Backbone 10

1.4 Successful Examples of Peptidomimetic Drugs 12

1.4.1 ACE Inhibitors 13

1.4.2 Thrombin Inhibitors 13

1.5 Conclusion 16

References 16

2. Synthetic Approaches towards Peptidomimetic Design 19

2.1 Introduction 19

2.2 Local Modifications 20

2.2.1 Single Amino Acid Modifications 23

2.2.2 Dipeptide Isosteres 26

2.2.3 Retro-inverso Peptides 29

2.2.4 N-Methylation of Peptides 30

2.2.5 Azapeptides 31

2.2.6 Peptoids 31

2.3 Global Restrictions through Cyclic Peptidomimetics 32

2.4 Peptidomimetic Scaffolds 34

2.5 Conclusions 35

References 35

Part II Synthetic Methods and Molecules 37

3. Peptidomimetic Bioisosteres 39

3.1 Introduction 39

3.2 Peptide Bond Isosteres 40

3.2.1 Thioamides 41

3.2.2 Esters 41

3.2.3 Alkenes and Fluoroalkenes 41

3.2.4 Transition-State Isosteres 42

3.3 Side-Chain Isosteres 45

3.3.1 Guanidine Isosteres in Arginine Peptidomimetics 45

3.3.2 Isosteres of Aspartic Acid and Glutamic Acid 49

3.3.3 Tethered α-Amino Acids: Constraining the χ-Space 53

3.4 Dipeptide Isosteres 59

3.4.1 δ-Amino Acids 63

3.5 Tripeptide Isosteres 67

3.6 Conclusion 68

References 69

4. Solid-Phase Synthesis and Combinatorial Approaches to Peptidomimetics 75

4.1 Introduction 75

4.2 Solid-Phase Synthesis of Peptidomimetics 76

4.2.1 Scaffolds from α-Amino Acids 76

4.2.2 Scaffolds from Amino Aldehyde Intermediates 85

4.2.3 Pyrrolidine-Containing Scaffolds 89

4.3 Conclusion 94

References 95

5. Click Chemistry: The Triazole Ring as a Privileged Peptidomimetic Scaffold 99

5.1 Introduction 99

5.1.1 CuAAC Reaction 100

5.1.2 Triazole Ring as a Peptidomimetic Isostere 101

5.2 Triazole-Containing Peptidomimetics Elaborated through ‘Click Chemistry’ 102

5.2.1 Macrocycles 102

5.2.2 Oligomers and Foldamers 107

5.3 Relevant Applications in Drug Discovery 110

5.3.1 AChE Inhibitors 110

5.3.2 HIV Protease Inhibitors 111

5.3.3 MMP Inhibitors 114

5.3.4 Integrin Ligands 115

5.4 Conclusions 118

Acknowledgements 119

References 119

6. Peptoids 123

6.1 Introduction and Basics of Peptoids 123

6.2 Synthetic Methods 126

6.3 Macrocyclic Peptoids 129

6.4 Conformational Analysis of Folded Peptoids 130

6.5 Application of Peptoids as Antimicrobial Peptidomimetics 132

6.6 Conclusions 134

References 134

7. Sugar Amino Acids 137

7.1 Introduction 137

7.2 α-SAAs 138

7.2.1 Furanoid α-SAAs 138

7.2.2 Pyranoid α-SAAs 142

7.3 β-SAAs 144

7.3.1 Furanoid β-SAAs 144

7.3.2 Pyranoid β-SAAs 147

7.4 γ-SAAs 148

7.5 δ-SAAs 150

7.5.1 Furanoid δ-SAAs 150

7.5.2 Pyranoid δ-SAAs 154

7.6 Representative Applications in Medicinal Chemistry 159

7.7 Conclusions 162

References 162

8. Cyclic α-Amino Acids as Proline Mimetics 165

8.1 Introduction 165

8.2 Cyclic α-Amino Acids 166

8.2.1 3-Substituted Proline Derivatives 167

8.2.2 4-Substituted Proline Derivatives 168

8.2.3 5-Substituted Proline Derivatives 169

8.2.4 Other Heterocyclic Proline Analogues 171

8.3 Bicyclic α-Amino Acids 174

8.3.1 β/γ-Ring Junction 175

8.3.2 α/γ-Ring Junction 178

8.3.3 γ/δ-Ring Junction 179

8.3.4 α/δ-Ring Junction 180

8.3.5 β/δ-Ring Junction 182

8.3.6 N/β-Ring Junction 183

8.3.7 Pipecolic-Based Bicyclic α-Amino Acids 183

8.3.8 Morpholine-Based Bicyclic α-Amino Acids 187

8.4 Conclusions 189

References 189

9. β-Turn Peptidomimetics 191

9.1 Introduction 191

9.2 Definition and Classification of β-Turns 192

9.3 Conformational Analysis 194

9.4 β-Turn Peptidomimetics 196

9.4.1 Proline Analogues in β-Turn Peptidomimetics 197

9.4.2 δ-Amino Acids as Reverse-Turn Inducers 200

9.4.3 Molecular Scaffolds as β-Turn Peptidomimetics 209

9.5 Conclusions 214

References 215

10. Peptidomimetic Foldamers 219

10.1 Introduction 219

10.2 Classification 220

10.3 Peptoids 221

10.4 β-Peptides: First Systematic Conformational Studies 221

10.5 Hybrid Foldamers 226

10.6 From Structural to Functional Foldamers 227

10.6.1 Peptoids as Foldameric Antimicrobial Peptidomimetics 227

10.6.2 Foldamers Targeting Bcl-x L Antiapoptotic Proteins 227

10.7 Conclusions 228

References 228

Part III Applications in Medicinal Chemistry 231

11. Case Study 1: Peptidomimetic HIV Protease Inhibitors 233

11.1 Introduction 233

11.2 The HIV-1 Virus 233

11.2.1 HIV-1 Protease 234

11.3 Antiretroviral Therapy 238

11.4 Drug Resistance 239

11.4.1 Mechanisms of Resistance to Protease Inhibitors 239

11.5 HIV-1 Protease Inhibitors 240

11.5.1 Transition-State Analogues 240

11.5.2 Peptidomimetic Drugs 241

11.5.3 Next-Generation Cyclic Peptidomimetic Inhibitors 245

11.6 Conclusions 255

Acknowledgements 255

References 256

12. Case Study 2: Peptidomimetic Ligands for αVβ3 Integrin 259

12.1 Introduction 259

12.2 Peptide-Based Peptidomimetic Integrin Ligands 262

12.3 Scaffold-Based Peptidomimetic Integrin Ligands 270

12.4 Conclusions 280

References 280

Index 283