Diversity–Oriented Synthesis: Basics and Applications in Organic Synthesis, Drug Discovery, and Chemical Biology

Discover an enhanced synthetic approach to developing andscreening chemical compound libraries

Diversity–oriented synthesis is a new paradigm for developinglarge collections of structurally diverse small molecules as probesto investigate biological pathways. This book presents the mosteffective methods in diversity–oriented synthesis for creatingsmall molecule collections. It offers tested and proven strategiesfor developing diversity–oriented synthetic libraries and screeningmethods for identifying ligands. Lastly, it explores some promisingnew applications based on diversity–oriented synthesis that havethe potential to dramatically advance studies in drug discovery andchemical biology.

Diversity–Oriented Synthesis begins with an introductorychapter that explores the basics, including a discussion of therelationship between diversity–oriented synthesis and classiccombinatorial chemistry. Divided into four parts, the book:

Offers key chemical methods for the generation of smallmolecules using diversity–oriented principles, includingpeptidomimetics and macrocycles Expands on the concept of diversity–oriented synthesis bydescribing chemical libraries Provides modern approaches to screening diversity–orientedsynthetic libraries, including high–throughput and high–contentscreening, small molecule microarrays, and smart screeningassays Presents the applications of diversity–oriented syntheticlibraries and small molecules in drug discovery and chemicalbiology, reporting the results of key studies and forecasting therole of diversity–oriented synthesis in future biomedicalresearch

This book has been written and edited by leading internationalexperts in organic synthesis and its applications. Theircontributions are based on a thorough review of the currentliterature as well as their own firsthand experience developingsynthetic methods and applications.

Clearly written and extensively referenced,Diversity–Oriented Synthesis introduces novices to thishighly promising field of research and serves as a springboard forexperts to advance their own research studies and develop newapplications.

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: FocusedLibrary 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–ORIENTEDSYNTHESIS

2 Strategic Applications of Multicomponent Reactions inDiversity–Oriented Synthesis 29
John M. Knapp, Mark J. Kurth, Jared T. Shaw, and AshkaanYounai

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 Synthesis59
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 forDiversity–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 PhosphineCatalysis/Combinatorial Scaffolding Strategy, 116

4.4 A DOS Library Based on Phosphine Organocatalysis: BiologicalScreening, Analog Synthesis, and Structure ActivityRelationship Analysis, 121

4.5 Conclusions, 129

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

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 DerivedScaffolds 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 Diversity201
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 DrugDiscovery 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 NaturalProduct Scaffolds, 273

8.6 Conclusions, 281

PART II CHEMICAL LIBRARIES AND DIVERSITY–ORIENTEDSYNTHESIS

9 Diversity–Oriented Synthesis of Natural Product LikeLibraries 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 NaturalProduct Like Libraries, 297

9.4 Branching Pathways in the Synthesis of NaturalProduct Like Libraries, 305

9.5 Oligomer–Based Approaches to Natural Product LikeLibraries, 312

9.6 Summary, 320

10 Chemoinformatic Characterization of the Chemical Space andMolecular 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 theChemical Space, 327

10.4 Chemoinformatic–Based Analysis of Libraries using DifferentRepresentations, 328

10.5 Recent Trends in Computational Approaches to CharacterizeCompound 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 ofDOS 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 ofSmall–Molecule Libraries 455
Irene Stefanini, Carlotta De Filippo, and DuccioCavalieri

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 BuddingYeast, 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 LandscapeDesign, 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 DRUGDISCOVERY

17 Diversity–Oriented Synthesis and Drug Development:Facilitating the Discovery of Novel Probes and Therapeutics535
Jeremy R. Duvall, Eamon Comer, and Sivaraman Dandapani

17.1 Introduction, 535

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

17.3 Case Study 2: Identification of Antimalarials, 548

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

17.5 Conclusions, 570

18 DOS–Derived Small–Molecule Probes in Chemical Biology575
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 BiologicalPathways, 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 ProbesDeveloped from DOS and Biology–Oriented Synthesis, 606

18.7 Summary and Outlook, 611

References, 611

INDEX 619

ANDREA TRABOCCHI, PhD, is Assistant Professor of OrganicChemistry at the University of Florence. Dr. Trabocchi leadsresearch in diversity–oriented synthesis, peptidomimeticchem–istry, chemical genetics, and conformational analysis.