Diversity-Oriented Synthesis

Name: Diversity-Oriented Synthesis | Basics and Applications in Organic Synthesis, Drug Discovery, and Chemical Biology
Brand: Wiley
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Basics and Applications in Organic Synthesis, Drug Discovery, and Chemical Biology

Andrea Trabocchi(Autor*in)

Wiley (Verlag)

Erschienen am 17. Juni 2013

664 Seiten

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Beschreibung

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.

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Inhalt

Intro
DIVERSITY-ORIENTED SYNTHESIS
CONTENTS
CONTRIBUTORS
FOREWORD
PREFACE
ABBREVIATIONS
1 The Basics of Diversity-Oriented Synthesis
1.1 Introduction
1.2 What Is Diversity-Oriented Synthesis?
1.3 Small Molecules and Biology
1.4 Comparing DOS, TOS, and Combinatorial Chemistry: Focused Library Synthesis
1.5 Molecular Diversity
1.6 Molecular Diversity and Chemical Space
1.7 Synthetic Strategies for Creating Molecular Diversity
1.8 Reagent-Based Approaches to Diversity Generation
1.8.1 Use of Pluripotent Functional Groups
1.8.2 Use of Densely Functionalized Molecules
1.8.3 Twelve-fold Branching Strategy
1.9 Substrate-Based Approach to Skeletal Diversity Generation
1.10 Other Build/Couple/Pair Examples
1.11 Concluding Remarks
References
PART I CHEMICAL METHODOLOGY IN DIVERSITY-ORIENTED SYNTHESIS
2 Strategic Applications of Multicomponent Reactions in Diversity-Oriented Synthesis
2.1 Introduction
2.2 MCR Products for HTS
2.2.1 MCRs and HTS: The Real and the Virtual
2.2.2 Expanding Accessible Diversity: New MCRs
2.3 MCRs as Starting Points for DOS
2.4 Conclusions
References
3 Cycloaddition Reactions in Diversity-Oriented Synthesis
3.1 Introduction
3.2 [4+2] Cycloaddition Reactions
3.2.1 Diels-Alder Reaction
3.2.2 Inverse Electron-Demand Diels-Alder Reaction
3.3 1,3-Dipolar Cycloaddition Reactions
3.4 Miscellaneous Cycloadditions
3.5 Conclusions
References
4 Phosphine Organocatalysis as a Platform for Diversity-Oriented Synthesis
4.1 Introduction
4.2 DOS Using Phosphine Organocatalysis
4.2.1 Phosphine Organocatalysis of Allenes with Imines
4.2.2 Phosphine Organocatalysis of Allenes with Azomethine Imines
4.2.3 Phosphine Organocatalysis of Allenes with Electron-Deficient Olefins
4.2.4 Phosphine Organocatalysis of Allenes with Aldehydes
4.2.5 Phosphine Organocatalysis of Allenes with Aziridines
4.2.6 Phosphine Organocatalysis of Allenes with Dinucleophiles
4.2.7 Phosphine Organocatalysis of Acetylenes with Dinucleophiles
4.3 Skeletal Diversity Based on a Phosphine Catalysis/Combinatorial Scaffolding Strategy
4.4 A DOS Library Based on Phosphine Organocatalysis: Biological Screening, Analog Synthesis, and Structure-Activity Relationship Analysis
4.4.1 Protein Geranylgeranyltransferase Type I and Rab Inhibitors
4.4.2 Activators of Endothelium-Driven Innate Immunity of Macrophages
4.4.3 Cancer Cell Migration Assays
4.4.4 Aplexone Decreases Cellular Cholesterol Level
4.5 Conclusions
References
5 Domino Reactions in Library Synthesis
5.1 Introduction
5.2 Pericyclic Domino Reactions
5.3 Anionic Domino Reactions
5.4 Transition-Metal-Mediated Domino Reactions
5.5 Radical Domino Reactions
5.6 Conclusions
References
6 Diversity-Oriented Synthesis of Amino Acid-Derived Scaffolds and Peptidomimetics: A Perspective
6.1 Introduction
6.2 Definition and Classification of Peptidomimetics
6.3 Early Combinatorial Approaches to Peptidomimetic Scaffolds
6.4 Amino Acid-Derived Scaffolds
6.4.1 Scaffolds from-Amino Acids
6.4.2 Scaffolds Containing the Pyrrolidine Ring
6.4.3 Scaffolds from Amino Aldehyde Intermediates
6.4.4 Scaffolds from Amino Carbonyl and Sugar Derivatives
6.5 Macrocyclic Peptidomimetic Scaffolds
6.6 Conclusions
References
7 Solid-Phase Synthesis Enabling Chemical Diversity
7.1 Introduction
7.2 Skeletal Diversity
7.2.1 Reagent-Based Strategy: Branching Process
7.2.2 Substrate-Based Strategy: Folding Process
7.3 Stereochemical Diversity
7.4 Appendage Diversity
7.5 Build/Couple/Pair Strategy
7.6 Scaffold Hopping
7.7 Conclusions
References
8 Macrocycles as Templates for Diversity Generation in Drug Discovery
8.1 Introduction
8.2 Challenges Associated with Macrocycles
8.2.1 Synthetic Challenge
8.2.2 Assessment of Diversity
8.2.3 Macrocycles in Drug Discovery
8.3 Macrocyclic Peptides
8.3.1 Split-and-Pool Synthesis of Macrocyclic Peptides
8.3.2 Synthesis of Small-to-Medium-Sized Macrocycles Using Amphoteric Reagents
8.3.3 DNA-, RNA-, and Phage-Templated Synthesis of Peptidic Macrocycles
8.4 Peptidomimetic Macrocycles
8.4.1 Mimics of Peptide Secondary Structures
8.4.2 Diversity-Oriented Synthesis of Macrocyclic Peptidomimetics
8.4.3 Macrocyclic Peptoid Libraries
8.4.4 Semipeptidic Macrocycles
8.5 Diversity-Oriented Strategies Based on Nonpeptidic Natural Product Scaffolds
8.5.1 Diversification of Rapamycin
8.5.2 Diversification Strategies Based on Natural Macrolactones
8.5.3 Diversification on Macrolactam Scaffolds
8.5.4 Multicomponent Macrocyclization
8.6 Conclusions
References and Notes
PART II CHEMICAL LIBRARIES AND DIVERSITY-ORIENTED SYNTHESIS
9 Diversity-Oriented Synthesis of Natural Product-Like Libraries
9.1 Introduction
9.2 Libraries Inspired by Natural Product Scaffolds
9.3 Folding Pathways in the Synthesis of Natural Product-Like Libraries
9.4 Branching Pathways in the Synthesis of Natural Product-Like Libraries
9.5 Oligomer-Based Approaches to Natural Product-Like Libraries
9.6 Summary
References
10 Chemoinformatic Characterization of the Chemical Space and Molecular Diversity of Compound Libraries
10.1 Introduction
10.2 Concept of Chemical Space
10.3 General Aspects of Chemoinformatic Methods to Analyze the Chemical Space
10.4 Chemoinformatic-Based Analysis of Libraries using Different Representations
10.4.1 Physicochemical Properties and Medicinally Relevant Chemical Spaces
10.4.2 Molecular Complexity
10.4.3 Scaffold Analysis
10.4.4 Structure Fingerprints and Multiple Representations
10.5 Recent Trends in Computational Approaches to Characterize Compound Libraries
10.6 Concluding Remarks
References
11 DNA-Encoded Chemical Libraries
11.1 Introduction
11.1.1 Drug Discovery Today: A Formidable Challenge
11.1.2 Selecting Chemicals
11.1.3 Chapter Overview
11.2 DNA-Encoded Chemical Libraries
11.2.1 DNA Encoding
11.2.2 Single-Pharmacophore DNA-Encoded Chemical Libraries
11.2.3 Self-Assembled DNA-Encoded Chemical Libraries (Dual-Pharmacophore Libraries)
11.3 Selection and Decoding
11.3.1 In Vitro Selection Strategies
11.3.2 Decoding of DNA-Encoded Chemical Libraries
11.4 Drug Discovery by DNA-Encoded Chemical Libraries
11.5 DNA-Encoded Chemical Libraries: Prospects and Outlook
11.6 Conclusions
References
PART III SCREENING METHODS AND LEAD IDENTIFICATION
12 Experimental Approaches to Rapid Identification, Profiling, and Characterization of Specific Biological Effects of DOS Compounds
12.1 Introduction
12.2 Basic Principles of HTS
12.2.1 Specifics of HTS Assays
12.2.2 Assay Performance Measures
12.2.3 Primary Hit Selection Criteria
12.2.4 Quality Control of HTS Data
12.2.5 Stages of Lead Identification Projects
12.2.6 Special HTS Modalities
12.2.7 Principles of Assay Design
12.3 Common Assay Methods and Techniques
12.3.1 HTS Detection Approaches
12.3.2 The Great (Biological) Divide
12.3.3 Common Biochemical Screening Methods
12.3.4 Common Cell-Based Assays
12.3.5 Image-Based Screening
12.4 Future Perspectives
References
13 Small-Molecule Microarrays
13.1 Introduction
13.2 Chemical Library Design and Synthesis
13.2.1 Diversity-Oriented Synthesis
13.2.2 Other Libraries
13.3 Fabrication of SMMs
13.3.1 Noncovalent Immobilization Approach
13.3.2 Covalent Immobilization Approach
13.3.3 In Situ Synthesis Approach
13.4 Applications of SMM
13.4.1 Protein Ligand Discovery
13.4.2 Enzyme Substrate/Inhibitor Profiling
13.4.3 Other Applications
13.5 Summary and Outlook
References
14 Yeast as a Model in High-Throughput Screening of Small-Molecule Libraries
14.1 Introduction
14.1.1 The Quest for Rapid and Smart Biological Assays
14.1.2 Saccharomyces cerevisiae as a Model
14.2 Chemical Genetics and S. cerevisiae
14.2.1 Forward Chemical Genetics
14.2.2 Reverse Chemical Genetics
14.3 Chemical Genomics and S. cerevisiae
14.3.1 Competitive Growth Assay Based on Heterozygote Strains
14.3.2 Competitive Growth Assay Based on Haploid or Homozygous Strains
14.3.3 Comparative Expression Profiling
14.4 Conclusions: The Route of Drug Discovery with the Budding Yeast
References
15 Virtual Screening Methods
15.1 Introduction
15.2 Basic Virtual Screening Concepts
15.2.1 Structure- and Ligand-Based Virtual Screening
15.2.2 Scaffold Analysis
15.2.3 Methodological Complexity
15.3 Molecular Similarity in Virtual Screening
15.3.1 Local vs. Global Similarity
15.3.2 Molecular Representations
15.4 Spectrum of Virtual Screening Approaches
15.5 Docking
15.6 Similarity Searching
15.6.1 Pharmacophores
15.6.2 Two-Dimensional Fingerprints
15.7 Compound Classification
15.7.1 Chemical Reference Spaces
15.7.2 Clustering and Partitioning
15.8 Machine Learning
15.8.1 Self-Organizing Maps vs. Decision Trees
15.8.2 Support Vector Machines
15.8.3 Bayesian Methods
15.9 Conclusions
References
16 Structure-Activity Relationship Data Analysis: Activity Landscapes and Activity Cliffs
16.1 Introduction
16.2 Numerical SAR Analysis Functions
16.2.1 Structural Similarity vs. Activity Similarity
16.2.2 SAR Index
16.2.3 Per-Compound Discontinuity Score
16.2.4 Structure-Activity Landscape Index
16.3 Principles and Intrinsic Limitations of Activity Landscape Design
16.3.1 Chemical Reference Space
16.3.2 Similarity Assessment
16.4 Activity Landscape Representations
16.4.1 Three-Dimensional Models
16.4.2 SAS Maps
16.4.3 Molecular Networks
16.4.4 Compound-Centric Activity Landscape Views
16.5 Defining and Identifying Activity Cliffs
16.5.1 Similarity and Potency Criteria
16.5.2 Continuum of Activity Cliffs vs. Discrete States
16.5.3 Experimental Data
16.5.4 Different Types of Activity Cliffs
16.6 Activity Cliff Survey
16.6.1 Frequency of Cliff Formation
16.6.2 From Isolated to Coordinated Activity Cliffs
16.6.3 Preferred R-Groups and Scaffolds
16.7 Activity Cliffs and SAR Information
16.7.1 SAR Discontinuity vs. Continuity
16.7.2 Information Extraction from Activity Cliffs
16.8 Concluding Remarks
References
PART IV APPLICATIONS IN CHEMICAL BIOLOGY AND DRUG DISCOVERY
17 Diversity-Oriented Synthesis and Drug Development: Facilitating the Discovery of Novel Probes and Therapeutics
17.1 Introduction
17.2 Case Study 1: Inhibition of Cytokine-Induced -cell Apoptosis
17.3 Case Study 2: Identification of Antimalarials
17.4 Case Study 3: Targeting Protein-Protein and Protein-DNA Interactions
17.5 Conclusions
References
18 DOS-Derived Small-Molecule Probes in Chemical Biology
18.1 Introduction
18.2 DOS-Derived Small-Molecule Probes
18.3 Developing Small-Molecule Probes of Complex Biological Pathways
18.3.1 Inhibitors of Sonic Hedgehog Signaling
18.3.2 Inhibitor of the Secretory Pathway
18.4 Expanding the Collection of Important Biological Probes
18.4.1 Inhibitors of Heat Shock Protein 70: Probes with Higher Potency
18.4.2 Agonist of the Acetylcholine Muscarinic M1 Receptor: Probes with Higher Selectivity
18.4.3 Inhibitors of Protein Prenylation: Probes with Novel Structures
18.4.4 Inhibitors of Core Self-Association in Hepatitis C Virus: Probes with a Novel Mechanism
18.5 Developing Probes for Therapeutically Desirable Phenotypes
18.5.1 Inhibitors of Glucose Transport
18.5.2 Inhibitors of Osteoclastogenesis
18.6 Natural Product-Inspired Small-Molecule Probes Developed from DOS and Biology-Oriented Synthesis
18.6.1 Activator of the Wnt Pathway Derived from BIOS
18.7 Summary and Outlook
References
INDEX
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