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Book Details
Abstract
Synthetic chemistry plays a central role in many areas of chemical biology; utilising recent case studies, the goal of Chemical and Biological Synthesis is to highlight the full impact that the preparation of novel reagents can have in chemical biology. Covering the synthetic approaches that can be applied across the whole field of chemical biology, this book provides synthetic chemists with the broader context to which their work contributes and the biological questions that can be addressed through it. An ideal guide for postgraduate students and researchers in synthetic organic chemistry and chemical biology, Chemical and Biological Synthesis introduces synthetic techniques and methods to those who wish to incorporate synthesis for the first time in their biology-focused research programmes.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Contents | v | ||
| Section 1: Synthetic Approaches to Enable Small-molecule Probe Discovery | 1 | ||
| Chapter 1 Synthetic Tools for the Elucidation of Biological Mechanisms | 3 | ||
| 1.1 Context | 3 | ||
| 1.2 Synthetic Approaches to Enable Small-molecule Probe Discovery | 4 | ||
| 1.3 Synthetic Approaches to Classes of Modified Biomolecule | 5 | ||
| 1.4 Summary | 6 | ||
| References | 6 | ||
| Chapter 2 The Application of Diversity-oriented Synthesis in Chemical Biology | 8 | ||
| 2.1 Introduction | 8 | ||
| 2.1.1 Small Molecule Screening Collections | 9 | ||
| 2.1.2 Sources of Complex and Diverse Libraries | 12 | ||
| 2.1.3 Synthetic Strategies for the Construction of Complex and Diverse Libraries: Diversity-oriented Synthesis | 14 | ||
| 2.2 Application of Diversity-oriented Synthesis for the Identification of Small Molecule Modulators | 18 | ||
| 2.2.1 Structural Diversity and Phenotypic Screening | 18 | ||
| 2.2.2 The Role of DOS in Target Validationthrough the Discovery of New Chemical Probes | 25 | ||
| 2.3 Conclusions and Outlook | 37 | ||
| Acknowledgements | 38 | ||
| References | 38 | ||
| Chapter 3 Biology-oriented Synthesis | 45 | ||
| 3.1 Introduction | 45 | ||
| 3.2 Structural Classification of Natural Products, Protein Structure Similarity Clustering and Scaffold Hunter | 47 | ||
| 3.3 Implications and Opportunities for Biology-oriented Synthesis | 50 | ||
| 3.4 Applications of Biology-oriented Synthesis | 52 | ||
| 3.4.1 Chemical-structure-and Bioactivity-guided Approaches | 52 | ||
| 3.4.2 Protein-structure-clustering-guided Approaches | 57 | ||
| 3.4.3 Natural-product-derived-fragment-based Approaches | 61 | ||
| 3.5 Conclusions and Outlook | 68 | ||
| References | 69 | ||
| Chapter 4 Lead- and Fragment-oriented Synthesis | 74 | ||
| 4.1 Introduction | 74 | ||
| 4.1.1 Introduction to Lead-oriented Synthesis | 75 | ||
| 4.1.2 Introduction to Fragment-oriented Synthesis | 77 | ||
| 4.2 Lead-oriented Synthesis | 79 | ||
| 4.2.1 Diverse and Novel Scaffolds for Lead-oriented Synthesis | 79 | ||
| 4.2.2 New Synthetic Methods for Lead-oriented Synthesis | 87 | ||
| 4.2.3 Natural Products as Inspiration for Lead-like Libraries | 91 | ||
| 4.2.4 The European Lead Factory | 93 | ||
| 4.3 Fragment-oriented Synthesis | 94 | ||
| 4.4 Conclusions | 107 | ||
| References | 108 | ||
| Chapter 5 Principles and Applications of Fragment-based Drug Discovery for Chemical Probes | 114 | ||
| 5.1 Introduction | 114 | ||
| 5.1.1 What Is a Chemical Probe? | 114 | ||
| 5.1.2 Chemical Probe Characteristics | 115 | ||
| 5.1.3 Fragment Library Design | 116 | ||
| 5.1.4 Screening Methods/Fragment Elaboration | 116 | ||
| 5.2 Case Studies | 117 | ||
| 5.2.1 A-1155463 (BCL-XL) | 117 | ||
| 5.2.2 CCT244747 (CHK1) | 118 | ||
| 5.2.3 GSK2334470 (PDK1) | 120 | ||
| 5.2.4 PFI-3 (SMARCA2/4 and PB1) | 123 | ||
| 5.2.5 BI-9564 (BRD9) | 125 | ||
| 5.2.6 Astex DDR1 Kinase Inhibitor (DDR1/DDR2) | 128 | ||
| 5.3 Outlook | 129 | ||
| Abbreviations | 130 | ||
| References | 131 | ||
| Chapter 6 Function-driven Discovery of Bioactive Small Molecules | 138 | ||
| 6.1 Context | 138 | ||
| 6.1.1 Chemical Approaches That Underpin Bioactive Small-molecule Discovery | 139 | ||
| 6.1.2 Evolution of Biosynthetic Pathways to Natural Products | 139 | ||
| 6.1.3 Scope of This Chapter | 140 | ||
| 6.2 Synthetic Fermentation | 140 | ||
| 6.2.1 Discovery of a Protease Inhibitor | 141 | ||
| 6.2.2 Conclusion | 141 | ||
| 6.3 Activity-directed Synthesis | 144 | ||
| 6.3.1 Discovery of Androgen Receptor Agonists Using Intramolecular Reactions | 145 | ||
| 6.3.2 Discovery of Androgen Receptor Agonists Using Intermolecular Reactions | 148 | ||
| 6.3.3 Conclusion | 151 | ||
| 6.4 Outlook | 151 | ||
| References | 151 | ||
| Chapter 7 DNA-encoded Library Technology (ELT) | 153 | ||
| 7.1 Introduction | 153 | ||
| 7.2 Overview of the ELT Process | 154 | ||
| 7.3 DEL Design and on-DNA Reaction Development | 156 | ||
| 7.3.1 On-DNA Reaction Development | 156 | ||
| 7.3.2 DEL Design and Production | 161 | ||
| 7.4 ELT Selections and Data Analysis | 164 | ||
| 7.5 Post Selection Chemistry (PSC) | 167 | ||
| 7.6 Examples of Probes Derived from DELs | 172 | ||
| 7.6.1 Protein Arginine Deiminase 4-Inhibitor | 172 | ||
| 7.6.2 Allosteric Wip1 Phosphatase Inhibitor | 174 | ||
| 7.6.3 PDE12 Inhibitor | 176 | ||
| 7.6.4 RIP3 Kinase Inhibitor | 176 | ||
| 7.6.5 BACTm Inhibitor | 177 | ||
| References | 177 | ||
| Chapter 8 Engineering Chemistry to Enable Bioactive Small Molecule Discovery | 184 | ||
| 8.1 Preamble | 184 | ||
| 8.2 Technologies for Machine-assisted Synthesis | 186 | ||
| 8.2.1 Machine Vision | 186 | ||
| 8.2.2 Process Analytical Technology (PAT) | 188 | ||
| 8.3 Integration of Synthesis with Biological Evaluation | 194 | ||
| 8.4 Technologies for the Automated Synthesis of Bioactive Compounds | 196 | ||
| 8.4.1 Immobilized Systems | 197 | ||
| 8.4.2 Flow Chemistry | 200 | ||
| 8.5 Advanced Automation | 207 | ||
| 8.6 Future Outlook | 214 | ||
| References | 214 | ||
| Section 2: Synthetic Approaches to Classes of Modified Biomolecule | 219 | ||
| Chapter 9 Genetically Encoded Cyclic Peptide Libraries | 221 | ||
| 9.1 Introduction | 221 | ||
| 9.2 SICLOPPS | 223 | ||
| 9.2.1 SICLOPPS in Prokaryotic Cells | 226 | ||
| 9.2.2 SICLOPPS in Eukaryotic Cells | 228 | ||
| 9.3 Phage Display | 229 | ||
| 9.3.1 Applications of Phage Display in Drug Discovery | 231 | ||
| 9.4 mRNA Display | 235 | ||
| 9.5 Concluding Remarks | 239 | ||
| References | 239 | ||
| Chapter 10 Modern Methods for the Synthesis of Carbohydrates | 243 | ||
| 10.1 Introduction | 243 | ||
| 10.2 Glycosylation: The Basics | 244 | ||
| 10.3 Stereoselectivity in Glycosylation Reactions | 244 | ||
| 10.4 Solvent and Protecting Group Strategies for Controlling Stereoselective Glycosylation | 248 | ||
| 10.5 Organocatalyst-mediated Glycosylations | 250 | ||
| 10.6 Automated Oligosaccharide Synthesis | 254 | ||
| 10.7 Pushing the Limits of Solution-phase Synthesis | 262 | ||
| 10.8 Conclusion | 269 | ||
| References | 269 | ||
| Chapter 11 Precursor-directed Biosynthesis and Semi-synthesis of Natural Products | 275 | ||
| 11.1 Introduction | 275 | ||
| 11.2 Strategies for Coupling of Biosynthesis and Chemical Synthesis | 276 | ||
| 11.2.1 Combinatorial Biosynthesis | 278 | ||
| 11.2.2 Precursor-directed Biosynthesis | 278 | ||
| 11.2.3 Mutasynthesis | 278 | ||
| 11.2.4 Semi-synthesis | 278 | ||
| 11.3 Leveraging Assembly Line Biosynthetic Systems for Polyketide and Non-ribosomal Peptide Diversification | 279 | ||
| 11.3.1 Overview of Assembly Line Biosynthesis | 279 | ||
| 11.3.2 A Model for Biosynthetic Engineering: 6-Deoxyerythronolide B Synthase (DEBS) | 281 | ||
| 11.3.3 Precursor-directed Biosynthesis andMutasynthesis of Unnatural Complex Polyketides | 284 | ||
| 11.3.4 Semi-synthesis of Complex Unnatural Polyketides | 288 | ||
| 11.3.5 Precursor-directed Biosynthesis andMutasynthesis of Unnatural Non-ribosomal Peptides | 290 | ||
| 11.4 Leveraging Non-templated Biosynthetic Systems for Natural Product Diversification | 291 | ||
| 11.4.1 Overview of Non-templated Biosynthesis of Natural Products | 291 | ||
| 11.4.2 Unnatural Aromatic Polyketides via Type III PKSs | 294 | ||
| 11.4.3 Diversification of RiPPs | 295 | ||
| 11.4.4 Terpene Diversification | 297 | ||
| 11.4.5 Alkaloid Diversification | 299 | ||
| 11.4.6 Diversification of Natural Product Glycosides | 300 | ||
| 11.5 Summary and Outlook | 301 | ||
| Acknowledgements | 302 | ||
| References | 302 | ||
| Chapter 12 Site-specific Protein Modification and Bio-orthogonal Chemistry | 313 | ||
| 12.1 Modification of Native Amino Acids | 313 | ||
| 12.1.1 Modification of Lysine, Serine and Threonine | 314 | ||
| 12.1.2 Modification of Cysteine | 317 | ||
| 12.1.3 Modification of Tyrosine, Tryptophan and Methionine | 322 | ||
| 12.2 Bio-orthogonal Chemistry | 324 | ||
| 12.2.1 Staudinger Ligation and CuAAC | 324 | ||
| 12.2.2 SPAAC and SPANC | 327 | ||
| 12.2.3 Inverse Electron-demand Diels–Alder Reactions (IEDDA) and Photoclick | 327 | ||
| 12.3 Strategies to Incorporate Amino-acids Containing Reactive Groups | 328 | ||
| 12.3.1 Metabolite Suppression | 328 | ||
| 12.3.2 Amber Suppression | 329 | ||
| 12.4 Enzymatic Protein Modification | 330 | ||
| 12.4.1 Modification Using Post-Translational Modification Enzymes | 330 | ||
| 12.4.2 Post-translational Modification | 331 | ||
| 12.4.3 Modification Using Transpeptidases | 342 | ||
| 12.4.4 Other Ligating Enzymes | 346 | ||
| 12.5 Conclusions | 346 | ||
| References | 347 | ||
| Chapter 13 Chemical Protein Synthesis: Strategies and Biological Applications | 357 | ||
| 13.1 Introduction | 357 | ||
| 13.2 Overview of Chemical Protein Synthesis | 358 | ||
| 13.2.1 Bottom Up: Solid-phase Peptide Synthesis | 358 | ||
| 13.2.2 Convergent Protein Synthesis with Native Chemical Ligation | 360 | ||
| 13.2.3 Semi-synthesis: Coupling ChemicalSynthesis with Recombinant Technology | 365 | ||
| 13.3 General Applications of Synthetic Protein Chemistry | 369 | ||
| 13.3.1 Precise Installation of Probes | 369 | ||
| 13.3.2 Access to Post-translationally Modified Proteins | 371 | ||
| 13.3.3 Synthesis of Unusual and Artificial Structures | 374 | ||
| 13.4 Case Studies: Biological Insights Through Synthetic Protein Chemistry | 376 | ||
| 13.4.1 HIV Protease—Probing Structure, Mechanism and Asymmetry | 376 | ||
| 13.4.2 Erythropoietin: Understanding and Manipulating Protein Serum Lifetime | 378 | ||
| 13.4.3 GTPases: Mechanism of Membrane Attachment of Molecular Address Tags | 381 | ||
| 13.4.4 Regulation of Regulators: Synthesis of Phosphorylated Kinases and Phosphatases | 383 | ||
| 13.4.5 Histones: The Geometry of Positive-feedback Loops | 387 | ||
| 13.5 Concluding Remarks | 389 | ||
| Acknowledgements | 390 | ||
| References | 390 | ||
| Subject Index | 398 |