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. The concept of diversity-oriented synthesis is then expanded to the description of chemical libraries. The book also examines modern approaches for screening DOS libraries and concludes with significant applications of DOS libraries and small molecules in the fields of drug discovery and chemical…mehr
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. The concept of diversity-oriented synthesis is then expanded to the description of chemical libraries. The book also examines modern approaches for screening DOS libraries and concludes with significant applications of DOS libraries and small molecules in the fields of drug discovery and chemical biology.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.
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.
Inhaltsangabe
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
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
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