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
