Diversity-Oriented Synthesis

ISBN-13: 9781118145654 / Angielski / Twarda / 2013 / 664 str.

Andrea Trabocchi

Opis

Discover an enhanced synthetic approach to developing and screening chemical compound libraries Diversity-oriented synthesis is a new paradigm for developing large collections of structurally diverse small molecules as probes to investigate biological pathways. This book presents the most effective methods in diversity-oriented synthesis for creating small molecule collections. It offers tested and proven strategies for developing diversity-oriented synthetic libraries and screening methods for identifying ligands. Lastly, it explores some promising new applications based on diversity-oriented synthesis that have the potential to dramatically advance studies in drug discovery and chemical biology. Diversity-Oriented Synthesis begins with an introductory chapter that explores the basics, including a discussion of the relationship between diversity-oriented synthesis and classic combinatorial chemistry. Divided into four parts, the book:

• Offers key chemical methods for the generation of small molecules using diversity-oriented principles, including peptidomimetics and macrocycles
• Expands on the concept of diversity-oriented synthesis by describing chemical libraries
• Provides modern approaches to screening diversity-oriented synthetic libraries, including high-throughput and high-content screening, small molecule microarrays, and smart screening assays
• Presents the applications of diversity-oriented synthetic libraries and small molecules in drug discovery and chemical biology, reporting the results of key studies and forecasting the role of diversity-oriented synthesis in future biomedical research

This book has been written and edited by leading international experts in organic synthesis and its applications. Their contributions are based on a thorough review of the current literature as well as their own firsthand experience developing synthetic methods and applications. Clearly written and extensively referenced, Diversity-Oriented Synthesis introduces novices to this highly promising field of research and serves as a springboard for experts to advance their own research studies and develop new applications.

This book reviews diversity–oriented synthesis (DOS), a leading and dynamic area in organic chemistry and drug discovery. It first covers key chemical methods for the generation of small molecules according to DOS principles as well as important classes of molecules generated through DOS approaches.

Spis treści

CONTRIBUTORS xv

FOREWORD xix

PREFACE xxi

ABBREVIATIONS xxv

1 The Basics of Diversity–Oriented Synthesis 1
Kieron M. G. O′Connell, Warren R. J. D. Galloway, and David R. Spring

1.1 Introduction, 1

1.2 What Is Diversity–Oriented Synthesis?, 1

1.3 Small Molecules and Biology, 2

1.4 Comparing DOS, TOS, and Combinatorial Chemistry: Focused Library Synthesis, 4

1.5 Molecular Diversity, 5

1.6 Molecular Diversity and Chemical Space, 8

1.7 Synthetic Strategies for Creating Molecular Diversity, 8

1.8 Reagent–Based Approaches to Diversity Generation, 11

1.9 Substrate–Based Approach to Skeletal Diversity Generation, 19

1.10 Other Build/Couple/Pair Examples, 19

1.11 Concluding Remarks, 24

PART I CHEMICAL METHODOLOGY IN DIVERSITY–ORIENTED SYNTHESIS

2 Strategic Applications of Multicomponent Reactions in Diversity–Oriented Synthesis 29
John M. Knapp, Mark J. Kurth, Jared T. Shaw, and Ashkaan Younai

2.1 Introduction, 29

2.2 MCR Products for HTS, 31

2.3 MCRs as Starting Points for DOS, 39

2.4 Conclusions, 55

3 Cycloaddition Reactions in Diversity–Oriented Synthesis 59
Giovanni Muncipinto

3.1 Introduction, 59

3.2 [4+2] Cycloaddition Reactions, 60

3.3 1,3–Dipolar Cycloaddition Reactions, 70

3.4 Miscellaneous Cycloadditions, 83

3.5 Conclusions, 91

4 Phosphine Organocatalysis as a Platform for Diversity–Oriented Synthesis 97
Zhiming Wang and Ohyun Kwon

4.1 Introduction, 97

4.2 DOS Using Phosphine Organocatalysis, 100

4.3 Skeletal Diversity Based on a Phosphine Catalysis/Combinatorial Scaffolding Strategy, 116

4.4 A DOS Library Based on Phosphine Organocatalysis: Biological Screening, Analog Synthesis, and Structure Activity Relationship Analysis, 121

4.5 Conclusions, 129

5 Domino Reactions in Library Synthesis 135
Matthew G. LaPorte, John R. Goodell, Sammi Tsegay, and Peter Wipf

5.1 Introduction, 135

5.2 Pericyclic Domino Reactions, 136

5.3 Anionic Domino Reactions, 150

5.4 Transition–Metal–Mediated Domino Reactions, 159

5.5 Radical Domino Reactions, 165

5.6 Conclusions, 174

6 Diversity–Oriented Synthesis of Amino Acid Derived Scaffolds and Peptidomimetics: A Perspective 177
Andrea Trabocchi

6.1 Introduction, 177

6.2 Definition and Classification of Peptidomimetics, 179

6.3 Early Combinatorial Approaches to Peptidomimetic Scaffolds, 180

6.4 Amino Acid Derived Scaffolds, 183

6.5 Macrocyclic Peptidomimetic Scaffolds, 194

6.6 Conclusions, 197

7 Solid–Phase Synthesis Enabling Chemical Diversity 201
Nadezda Canka¡rova and Viktor Krch¡nak

7.1 Introduction, 201

7.2 Skeletal Diversity, 203

7.3 Stereochemical Diversity, 234

7.4 Appendage Diversity, 238

7.5 Build/Couple/Pair Strategy, 239

7.6 Scaffold Hopping, 243

7.7 Conclusions, 249

8 Macrocycles as Templates for Diversity Generation in Drug Discovery 253
Eric Marsault

8.1 Introduction, 253

8.2 Challenges Associated with Macrocycles, 254

8.3 Macrocyclic Peptides, 259

8.4 Peptidomimetic Macrocycles, 265

8.5 Diversity–Oriented Strategies Based on Nonpeptidic Natural Product Scaffolds, 273

8.6 Conclusions, 281

PART II CHEMICAL LIBRARIES AND DIVERSITY–ORIENTED SYNTHESIS

9 Diversity–Oriented Synthesis of Natural Product Like Libraries 291
Mark Dow, Francesco Marchetti, and Adam Nelson

9.1 Introduction, 291

9.2 Libraries Inspired by Natural Product Scaffolds, 292

9.3 Folding Pathways in the Synthesis of Natural Product Like Libraries, 297

9.4 Branching Pathways in the Synthesis of Natural Product Like Libraries, 305

9.5 Oligomer–Based Approaches to Natural Product Like Libraries, 312

9.6 Summary, 320

10 Chemoinformatic Characterization of the Chemical Space and Molecular Diversity of Compound Libraries 325
Jose Luis Medina–Franco

10.1 Introduction, 325

10.2 Concept of Chemical Space, 326

10.3 General Aspects of Chemoinformatic Methods to Analyze the Chemical Space, 327

10.4 Chemoinformatic–Based Analysis of Libraries using Different Representations, 328

10.5 Recent Trends in Computational Approaches to Characterize Compound Libraries, 344

10.6 Concluding Remarks, 345

11 DNA–Encoded Chemical Libraries 353
Luca Mannocci

11.1 Introduction, 353

11.2 DNA–Encoded Chemical Libraries, 357

11.3 Selection and Decoding, 386

11.4 Drug Discovery by DNA–Encoded Chemical Libraries, 388

11.5 DNA–Encoded Chemical Libraries: Prospects and Outlook, 391

11.6 Conclusions, 393

PART III SCREENING METHODS AND LEAD IDENTIFICATION

12 Experimental Approaches to Rapid Identification, Profiling, and Characterization of Specific Biological Effects of DOS Compounds 403
Eduard A. Sergienko and Susanne Heynen–Genel

12.1 Introduction, 403

12.2 Basic Principles of HTS, 405

12.3 Common Assay Methods and Techniques, 415

12.4 Future Perspectives, 428

13 Small–Molecule Microarrays 431
Hongyan Sun

13.1 Introduction, 431

13.2 Chemical Library Design and Synthesis, 432

13.3 Fabrication of SMMs, 438

13.4 Applications of SMM, 446

13.5 Summary and Outlook, 451

14 Yeast as a Model in High–Throughput Screening of Small–Molecule Libraries 455
Irene Stefanini, Carlotta De Filippo, and Duccio Cavalieri

14.1 Introduction, 455

14.2 Chemical Genetics and S. cerevisiae, 461

14.3 Chemical Genomics and S. cerevisiae, 471

14.4 Conclusions: The Route of Drug Discovery with the Budding Yeast, 477

15 Virtual Screening Methods 483
Jurgen Bajorath

15.1 Introduction, 483

15.2 Basic Virtual Screening Concepts, 484

15.3 Molecular Similarity in Virtual Screening, 487

15.4 Spectrum of Virtual Screening Approaches, 489

15.5 Docking, 490

15.6 Similarity Searching, 491

15.7 Compound Classification, 496

15.8 Machine Learning, 498

15.9 Conclusions, 501

16 Structure Activity Relationship Data Analysis: Activity Landscapes and Activity Cliffs 507
Jurgen Bajorath

16.1 Introduction, 507

16.2 Numerical SAR Analysis Functions, 508

16.3 Principles and Intrinsic Limitations of Activity Landscape Design, 511

16.4 Activity Landscape Representations, 513

16.5 Defining and Identifying Activity Cliffs, 520

16.6 Activity Cliff Survey, 525

16.7 Activity Cliffs and SAR Information, 526

16.8 Concluding Remarks, 528

PART IV APPLICATIONS IN CHEMICAL BIOLOGY AND DRUG DISCOVERY

17 Diversity–Oriented Synthesis and Drug Development: Facilitating the Discovery of Novel Probes and Therapeutics 535
Jeremy R. Duvall, Eamon Comer, and Sivaraman Dandapani

17.1 Introduction, 535

17.2 Case Study 1: Inhibition of Cytokine–Induced –cell Apoptosis, 540

17.3 Case Study 2: Identification of Antimalarials, 548

17.4 Case Study 3: Targeting Protein Protein and Protein DNA Interactions, 558

17.5 Conclusions, 570

18 DOS–Derived Small–Molecule Probes in Chemical Biology 575
Nicholas Hill, Lingyan Du, and Qiu Wang

18.1 Introduction, 575

18.2 DOS–Derived Small–Molecule Probes, 576

18.3 Developing Small–Molecule Probes of Complex Biological Pathways, 576

18.4 Expanding the Collection of Important Biological Probes, 595

18.5 Developing Probes for Therapeutically Desirable Phenotypes, 603

18.6 Natural Product Inspired Small–Molecule Probes Developed from DOS and Biology–Oriented Synthesis, 606

18.7 Summary and Outlook, 611

References, 611

INDEX 619

O autorze

ANDREA TRABOCCHI, PhD, is Assistant Professor of Organic Chemistry at the University of Florence. Dr. Trabocchi leads research in diversity–oriented synthesis, peptidomimetic chem–istry, chemical genetics, and conformational analysis.

Blurb

Discover an enhanced synthetic approach to developing and screening chemical compound libraries

Diversity–oriented synthesis is a new paradigm for developing large collections of structurally diverse small molecules as probes to investigate biological pathways. This book presents the most effective methods in diversity–oriented synthesis for creating small molecule collections. It offers tested and proven strategies for developing diversity–oriented synthetic libraries and screening methods for identifying ligands. Lastly, it explores some promising new applications based on diversity–oriented synthesis that have the potential to dramatically advance studies in drug discovery and chemical biology.

Diversity–Oriented Synthesis begins with an introductory chapter that explores the basics, including a discussion of the relationship between diversity–oriented synthesis and classic combinatorial chemistry. Divided into four parts, the book:

• Offers key chemical methods for the generation of small molecules using diversity–oriented principles, including peptidomimetics and macrocycles
• Expands on the concept of diversity–oriented synthesis by describing chemical libraries
• Provides modern approaches to screening diversity–oriented synthetic libraries, including high–throughput and high–content screening, small molecule microarrays, and smart screening assays
• Presents the applications of diversity–oriented synthetic libraries and small molecules in drug discovery and chemical biology, reporting the results of key studies and forecasting the role of diversity–oriented synthesis in future biomedical research

This book has been written and edited by leading international experts in organic synthesis and its applications. Their contributions are based on a thorough review of the current literature as well as their own firsthand experience developing synthetic methods and applications.

Clearly written and extensively referenced, Diversity–Oriented Synthesis introduces novices to this highly promising field of research and serves as a springboard for experts to advance their own research studies and develop new applications.