Foreword xiii
Introduction xv
About the Contributors xix
Part I Challenges Specific to Macrocycles 1
1 Contemporary Macrocyclization Technologies 3
Serge Zaretsky and Andrei K. Yudin
1.1 Introduction 3
1.2 Challenges Inherent to the Synthesis of Macrocycles 3
1.3 Challenges in Macrocycle Characterization 6
1.4 Macrocyclization Methods 8
1.5 Cyclization on the Solid Phase 14
1.6 Summary 17
References 18
2 A Practical Guide to Structural Aspects of Macrocycles (NMR, X]Ray, and Modeling) 25
David J. Craik, Quentin Kaas and Conan K. Wang
2.1 Background 25
2.2 Experimental Studies of Macrocycles 31
2.3 Molecular Modeling of Macrocyclic Peptides 38
2.4 Summary 46
Acknowledgments 47
References 47
3 Designing Orally Bioavailable Peptide and Peptoid Macrocycles 59
David A. Price, Alan M. Mathiowetz and Spiros Liras
3.1 Introduction 59
3.2 Improving Peptide Plasma Half]Life 60
3.3 Absorption, Bioavailability, and Methods for Predicting Absorption 61
3.4 In Silico Modeling 70
3.5 Future Directions 71
References 72
Part II Classes of Macrocycles and Their Potential for Drug Discovery 77
4 Natural and Nature]Inspired Macrocycles: A Chemoinformatic Overview and Relevant Examples 79
Ludger A. Wessjohann, Richard Bartelt and Wolfgang Brandt
4.1 Introduction to Natural Macrocycles as Drugs and Drug Leads 79
4.2 Biosynthetic Pathways, Natural Role, and Biotechnological Access 79
4.3 QSAR and Chemoinformatic Analyses of Common Features 84
4.4 Case Studies: Selected Natural Macrocycles of Special Relevance in Medicinal Chemistry 88
References 91
5 Bioactive and Membrane]Permeable Cyclic Peptide Natural Products 101
Andrew T. Bockus and R. Scott Lokey
5.1 Introduction 101
5.2 Structural Motifs and Permeability of Cyclic Peptide Natural Products 101
5.3 Conformations of Passively Permeable Bioactive Cyclic Peptide Natural Products 103
5.4 Recently Discovered Bioactive Cyclic Peptide Natural Products 108
5.5 Conclusions 125
References 125
6 Chemical Approaches to Macrocycle Libraries 133
Ziqing Qian, Patrick G. Dougherty and Dehua Pei
6.1 Introduction 133
6.2 Challenges Associated with Macrocyclic One]Bead]One-Compound Libraries 134
6.3 Deconvolution of Macrocyclic Libraries 134
6.4 Peptide]Encoded Macrocyclic Libraries 136
6.5 DNA] Encoded Macrocyclic Libraries 142
6.6 Parallel Synthesis of Macrocyclic Libraries 142
6.7 Diversity] Oriented Synthesis 145
6.8 Perspective 147
6.9 Conclusion 149
References 150
7 Biological and Hybrid Biological/Chemical Strategies in Diversity Generation of Peptidic Macrocycles 155
Francesca Vitali and Rudi Fasan
7.1 Introduction 155
7.2 Cyclic Peptide Libraries on Phage Particles 155
7.3 Macrocyclic Peptide Libraries via In Vitro Translation 166
7.4 Emerging Strategies for the Combinatorial Synthesis of Hybrid Macrocycles In Vitro and in Cells 171
7.5 Comparative Analysis of Technologies 175
7.6 Conclusions 178
References 178
8 Macrocycles for Protein–Protein Interactions 185
Eilidh Leitch and Ali Tavassoli
8.1 Introduction 185
8.2 Library Approaches to Macrocyclic PPI Inhibitors 186
8.3 Structural Mimicry 192
8.4 Multi] Cycles for PPIs 197
8.5 The Future for Targeting PPIs with Macrocycles 197
References 200
Part III The Synthetic Toolbox for Macrocycles 205
9 Synthetic Strategies for Macrocyclic Peptides 207
Eric Biron, Simon Vezina]Dawod and François Bedard
9.1 Introduction to Peptide Macrocyclization 207
9.2 One Size Does Not Fit All: Factors to Consider During Synthesis Design 209
9.3 Peptide Macrocyclization in Solution 213
9.4 Peptide Macrocyclization on Solid Support 220
9.5 Peptide Macrocyclization by Disulfide Bond Formation 226
9.6 Conclusion 229
References 230
10 Ring]Closing Metathesis]Based Methods in Chemical Biology: Building a Natural Product Inspired Macrocyclic Toolbox to Tackle Protein–Protein Interactions 243
Jagan Gaddam, Naveen Kumar Mallurwar, Saidulu Konda, Mahender Khatravath, Madhu Aeluri, Prasenjit Mitra and Prabhat Arya
10.1 Introduction 243
10.2 Protein– Protein Interactions: Challenges and Opportunities 243
10.3 Natural Products as Modulators of Protein–Protein Interactions 243
10.4 Introduction to Ring]Closing Metathesis 244
10.5 Selected Examples of Synthetic Macrocyclic Probes Using RCM]Based Approaches 246
10.6 Summary 259
References 259
11 The Synthesis of Peptide-Based Macrocycles by Huisgen Cycloaddition 265
Ashok D. Pehere and Andrew D. Abell
11.1 Introduction 265
11.2 Dipolar Cycloaddition Reactions 266
11.3 Macrocyclic Peptidomimetics 267
11.4 Macrocyclic β]Strand Mimetics as Cysteine Protease Inhibitors 273
11.5 Conclusion 275
References 277
12 Palladium]Catalyzed Synthesis of Macrocycles 281
Thomas O. Ronson, William P. Unsworth and Ian J. S. Fairlamb
12.1 Introduction 281
12.2 Stille Reaction 281
12.3 Suzuki– Miyaura Reaction 285
12.4 Heck Reaction 288
12.5 Sonogashira Reaction 290
12.6 Tsuji– Trost Reaction 293
12.7 Other Reactions 295
12.8 Conclusion 298
References 298
13 Alternative Strategies for the Construction of Macrocycles 307
Jeffrey Santandrea, Anne]Catherine Bedard, Mylene de Leseleuc, Michaël Raymond and Shawn K. Collins
13.1 Introduction 307
13.2 Alternative Methods for Macrocyclization Involving Carbon–Carbon Bond Formation 307
13.3 Alternative Methods for Macrocyclization Involving Carbon–Carbon Bond Formation: Ring Expansion and Photochemical Methods 320
13.4 Alternative Methods for Macrocyclization Involving Carbon–Oxygen Bond Formation 322
13.5 Alternative Methods for Macrocyclization Involving Carbon–Nitrogen Bond Formation 327
13.6 Alternative Methods for Macrocyclization Involving Carbon–Sulfur Bond Formation 328
13.7 Conclusion and Summary 331
References 332
14 Macrocycles from Multicomponent Reactions 339
Ludger A. Wessjohann, Ricardo A. W. Neves Filho, Alfredo R. Puentes and Micjel Chavez Morejon
14.1 Introduction 339
14.2 General Aspects of Multicomponent Reactions (MCRs) in Macrocycle Syntheses 344
14.3 Concluding Remarks and Future Perspectives 369
References 371
15 Synthetic Approaches Used in the Scale]Up of Macrocyclic Clinical Candidates 377
Jongrock Kong
15.1 Introduction 377
15.2 Background 377
15.3 Literature Examples 378
15.4 Conclusions 406
References 406
Part IV Macrocycles in Drug Development: Case Studies 411
16 Overview of Macrocycles in Clinical Development and Clinically Used 413
Silvia Stotani and Fabrizio Giordanetto
16.1 Introduction 413
16.2 Datasets Generation 413
16.3 Marketed Macrocyclic Drugs 414
16.4 Macrocycles in Clinical Studies 422
16.5 De Novo Designed Macrocycles 429
16.6 Overview and Conclusions 436
Appendix 16.A 437
16.A.1 Methods 437
References 490
17 The Discovery of Macrocyclic IAP Inhibitors for the Treatment of Cancer 501
Nicholas K. Terrett
17.1 Introduction 501
17.2 DNA]Programmed Chemistry Macrocycle Libraries 502
17.3 A New Macrocycle Ring Structure 504
17.4 Design and Profiling of Bivalent Macrocycles 506
17.5 Improving the Profile of the Bivalent Macrocycles 510
17.6 Selection of the Optimal Bivalent Macrocyclic IAP Antagonist 512
17.7 Summary 515
Acknowledgments 515
References 516
18 Discovery and Pharmacokinetic–Pharmacodynamic Evaluation of an Orally Available Novel Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase and c]Ros Oncogene 1 519
Shinji Yamazaki, Justine L. Lam and Ted W. Johnson
18.1 Introduction 519
18.2 Discovery and Synthesis 520
18.3 Evaluation of Pharmacokinetic Properties Including CNS Penetration 531
18.4 Evaluation of Pharmacokinetic–Pharmacodynamic (PKPD) Profiles 536
18.5 Conclusion 540
References 540
19 Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II): Development of TZP]102 545
Hamid R. Hoveyda, Graeme L. Fraser, Eric Marsault, Rene Gagnon and Mark L. Peterson
19.1 Introduction 545
19.2 Advanced AA3 and Tether SAR 548
19.3 Structural Studies 554
19.4 Conclusions 554
Acknowledgments 555
References 556
20 Solithromycin: Fourth]Generation Macrolide Antibiotic 559
David Pereira, Sara Wu, Shingai Majuru, Stephen E. Schneider and Lovy Pradeep
20.1 Introduction 559
20.2 Structure–Activity Relationship (SAR) of Ketolides and Selection of Solithromycin 559
20.3 Mechanism of Action 564
20.4 Overcoming the Ketek Effect 568
20.5 Manufacture of Solithromycin 569
20.6 Polymorphism 569
20.7 Pharmaceutical Development 569
20.8 Clinical Data 574
20.9 Summary 574
References 574
Index 579
