New Trends in Synthetic Medicinal Chemistry. (Methods and Principles in Medicinal Chemistry, Volume 7)

The long-awaited volume on synthetic chemistry in the series "Methods and Principles in Medicinal Chemistry" is now available. In the pharmaceutical industry, computational methods play a major role in the discovery and development of new drugs. Yet, the SYNTHESIS of these compounds still remains the most crucial topic in drug design.

Written by an internationally renowned team of authors and editors from academia and industry, this volume describes all recent developments in organic synthetic methodology which are essential for pharmaceutical research. The most modern synthetic developments of pharmacologically interesting compounds (carbohydrates and nucleotides) as well as important synthetic methods such as combinatorial chemistry, solid-phase reactions, bioassisted organic synthesis and asymmetric synthesis are critically discussed.

Special emphasis is given to a hands-on practical approach which enables researchers to apply the featured methods immediately to their specific problems. Also, the detailed presentation of the topic and the selection of references will be of help to any researcher working in the laboratory.

Organic Synthesis and Medicinal Chemistry

Series Design in Synthetic Chemistry

Combinatorial Chemistry

Tubes and Cubes, Chips and Tips: Tools for Solid-Phase Organic Synthesis

Stereoselective Synthesis of Enantiomerically Pure Drugs

Resolution of Enantiomers of Chiral Drugs

Biocatalyzed Reactions

Selective Glycosilation Reactions and Their Use in Medicinal Chemistry

Chemistry of Antisense Oligonucleotides

Table of Contents

Preface V

List of Contributors VII

1 Organic Synthesis and Medicinal Chemistry

• F. Gualtieri 1

1.1 Setting the Scene 1

1.2 Classical and Bio-assisted Organic Synthesis 2

1.3 New Strategies 9

1.4 Oligomers 12

1.5 Conclusion 15

• References 15

2 Series Design in Synthetic Chemistry

• Sergio Clementi, Gabriele Cruciani, Manuel Pastor and Torbjörn Lundstedt 17

2.1 Introduction 18

2.2 The Design Approach 19

2.2.1 The Multivariate Approach 20

2.2.2 Design in Latent Variables 20

2.2.3 Factorial Designs 21

2.2.4 D-optimal Designs 23

2.2.5 Cluster Designs 25

2.3 Optimization 26

2.3.1 The CARSO Procedure 26

2.4 Disjoint Principal Properties 27

2.5 Combinatorial Chemistry 28

2.6 Examples 30

2.6.1 Applications of design in PPs for QSAR studies 30

2.6.2 Example on General Application of Series Design Techniques 31

2.6.3 Combinatorial Chemistry: A Design Example 34

2.7 Conclusions 35

• References 36

3 Combinatorial Chemistry

• Valery V. Antonenko, Nicolay V. Kulikov and Reza Mortezaei 39

3.1 Needs of the Drug Discovery Process 39

3.2 Split/Pool Method for Creating Combinatorial Libraries 40

3.3 Encoded Synthetic Libraries 42

3.3.1 Chemically Encoded Synthetic Libraries 42

3.3.1.1 Oligonucleotide Tags 43

3.3.1.2 Peptide Tags 44

3.3.1.3 Haloaromatic Binary Coding 44

3.3.1.4 Secondary Amine Binary Coding 46

3.3.1.5 Mass Encoding 49

3.3.2 Non-Chemical Encoding Methods 50

3.3.2.1 Radio Frequency Tags 50

3.3.2.2 Laser Encoding 52

3.4 Parallel Synthesis and Positional Encoding 53

3.4.1 Light-Directed Synthesis 53

3.4.2 Spot-Synthesis on Membranes 59

3.4.3 Manual Methods for Resin-Based Parallel Synthesis 60

3.4.3.1 HiTOPS System 60

3.4.4 Synthesis on Macroscopic Polymer Supports 63

3.4.4.1 Synthesis on Multipins 63

3.4.4.2 Parallel Synthesis in "Tea Bags" 64

3.4.4.3 Synthesis on Cellulose and Other Laminar Supports 64

3.5 Tools for Increasing Productivity in Combinatorial Chemistry 64

3.5.1 Instruments for Solution Chemistry 65

3.5.1.1 MultiReactorTM (RoboSynthon, Inc.) 65

3.5.1.2 STEM Reacto-StationsTM (STEM Corporation) 66

3.5.2 Manual and Semiautomated Instruments for Solid-Phase Chemistry 68

3.5.2.1 Quest 210 (Argonaut Technologies) 68

3.5.2.2 APOS 1200 System (Rapp Polymer GmbH) 69

3.5.2.3 ReacTech Synthesizer (Advanced ChemTech) 71

3.5.2.4 SAS (MultiSynTech GmbH) 71

3.5.2.5 Systems Based on 96-Well Microtiter Format 71

3.5.3 Automatic Systems for Solid-Phase Synthesis 72

3.5.3.1 Automated RAMTM Synthesizer (Bohdan Automation, Inc.) 72

3.5.3.2 NautilusTM 2400 Synthesizer (Argonaut Technologies, Inc.) 73

3.5.3.3 TridentTM Synthesizer (Argonaut Technologies, Inc.) 74

3.5.3.4 Syro II Synthesizer (MultiSynTech GmbH) 75

3.5.3.5 Advanced ChemTech Synthesizers 75

3.5.4 HP 7686 Solution-Phase Synthesizer (Hewlett Packard) 75

• References 77

4 Tubes and Cubes, Chips and Tips: Tools for Solid-Phase Organic Synthesis

• A.W. Czarnik 81

4.1 Introduction 81

4.2 Tubes: The Diversomer Project 82

4.3 Cubes: Matrix Chemistry 85

4.4 Chips: Radiofrequency-Tagged Microreactors 88

4.5 Tips: Self-Assembled, Randomly-Ordered Microarrays 92

4.6 Conclusion 94

• References 95

5 Stereoselective Synthesis of Enantiomerically Pure Drugs

• Maurizio Benaglia, Mauro Cinquini and Franco Cozzi 97

5.1 Introduction 98

5.2 Classification of the Methods for the Preparation of Enantiomerically Pure Compounds 98

5.2.1 Definition of Stereoselective Synthesis 98

5.2.2 Classification 100

5.2.2.1 Stoichiometric Methods 100

5.2.2.1.1 Chiral Non-Racemic Substrates 100

5.2.2.1.2 Chiral Auxiliary Modified Substrates 102

5.2.2.1.3 Chiral Non-Racemic Agents 104

5.2.2.2 Kinetic Resolution 106

5.2.2.3 Multiple Stereoselection 108

5.2.2.4 Catalytic Methods 111

5.3 Examples of Stereoselective Synthesis of Drugs 113

5.3.1 Synthesis of Sanfetrinem 113

5.3.2 Synthesis of MK-0507 115

5.3.3 Synthesis of Naproxen (Chiral Auxiliary Approach) 118

5.3.4 Synthesis of Diltiazem 118

5.3.5 Synthesis of MK-0287 120

5.3.6 Synthesis of L-738,372 and L-743,726 121

5.3.7 Synthesis of (S)-Propranolol 122

5.3.8 Synthesis of an HIV-Protease Inhibitor 124

5.3.9 Synthesis of Mibefradil 125

5.3.10 Synthesis of Naproxen and Ibuprofen (by C-H Bond Formation) 125

5.3.11 Synthesis of a Carbapenem and Penem Precursor 127

5.3.12 Synthesis of Sertraline 128

5.3.13 Synthesis of Dextromethorphan 129

5.3.14 Synthesis of (1S, 2R)-1-Aminoindanol 131

5.3.15 Synthesis of a Fragment of the HIV-Protease Inhibitor Ro-31-8959 133

5.3.16 Synthesis of (2R, 3S)-Phenylisoserine, Precursor of the Taxol and Taxotere Side Chains 133

5.3.17 Synthesis of Naproxen (by C-C Bond Formation) 134

5.4 Outlook and Conclusions 136

• References 136

6 Resolution of Enantiomers of Chiral Drugs

• Gottfried Blaschke and Bezhan Chankvetadze 139

6. 1 Introduction 139

6. 2 Crystallization 141

6.2.1 Spontaneous Crystallization 141

6.2.2 Diastereomeric Crystallization 141

6. 3 Kinetic Resolution 144

6. 4 Chromatographic Techniques 147

6.4.1 Gas Chromatography 147

6.4.2 High-Performance Liquid Chromatography 150

6.4.2.1 Indirect HPLC Enantioseparations 150

6.4.2.2 HPLC Enantioseparations using Chiral Additives to the Mobile Phase 151

6.4.2.3 Direct HPLC Enantioseparations 151

6.4.2.4 Preparative Resolution of Enantiomers in LC 153

6.4.2.4.1 Elution Batch Chromatography 154

6.4.2.4.2 Closed-Loop Recycling Chromatography 156

6.4.2.4.3 Simulated Moving Bed Chromatography 159

6.4.3 Supercritical (Subcritical) Fluid Chromatography 164

6.5 Electromigration Techniques 164

6.6 Racemization 166

6.7 Method Selection Strategy 167

• References 169

7 Biocatalyzed Reactions

• Oreste Ghisalba 175

7.1 Introduction: Biotechnology and Biocatalysis 175

7.2 Advantages of Biocatalysis 176

7.3 Application Range of Biocatalysis 177

7.4 Screening for Biocatalysts 182

7.5 Technical Aspects of Biocatalysis 185

7.6 Biocatalysis in Research and Development: On the Road to New Bioprocesses 191

7.7 Large-scale Biocatalysis 204

7.7.1 Immobilized Enzymes 206

7.7.2 Immobilized (Resting) Mecrobial Cells 207

7.7.3 Additional Established Bioprocesses Documented by Case Studies 208

7.8 Outlook 213

• References 214

8 Selective Glycosidation Reactions and their Use in Medicinal Chemistry

• Giuseppe Capozzi, Stefano Menichetti and Cristina Nativi 221

8.1 Introduction 221

8.2 Selective Protection of Carbohydrates 222

8.2.1 Acetal Derivatives 223

8.2.2 Activation via Stannoxanes 224

8.2.3 Silyl Derivatives 226

8.2.4 Experimental Procedures 227

8.3 O-Glycosidation Reactions 229

8.3.1 The Koenigs-Knorr and Related Methods 229

8.3.2 The Glycal Method 233

8.3.3 The Trichloroacetimidate Method 238

8.3.4 The n-Pentenyl Method 242

8.3.5 2-Deoxy Glycosides 245

8.3.6 Experimental Procedures 250

8.4 Conclusion 255

• References 255

9 Chemistry of Antisense Oligonucleotides

• Christian R. Noe and Lucius Kaufhold 261

9.1 Introductory Remarks 262

9.2 Historical Aspects 262

9.2.1 Nucleic Acids and Molecular Biology in Drug Research 262

9.2.2 Gene Therapy 264

9.3 Scope of the Article 264

9.4 Criteria in Development of Antisense Drugs 265

9.4.1 Structural Aspects 265

9.4.2 Definition of "antisense" and Size of Oligonucleotides 267

9.4.3 Molecular Targets of Antisense Action 268

9.5 Solid Support Synthesis of Oligonucleotides 269

9.5.1 Building Blocks 270

9.5.2 Solid Support 271

9.5.3 Cycle of Synthesis via the Phosphoramidite Method 272

9.5.4 Specific Measures for Efficient Deprotection 275

9.5.5 Synthesis in "Large Scale" 277

9.5.6 5?3?Synthesis 277

9.6 Oligonucleotides with Modifications of the Nucleotide-Linkage 277

9.6.1 Phosphorothioates 278

9.6.2 Phosphorodithioates 280

9.6.3 Methylphosphonates 281

9.6.4 Phosphoric Acid Triesters 281

9.6.5 Phosphoramidates 282

9.6.6 Phosphoroboronates 283

9.6.7 Non-Phosphorus Linkages 283

9.7 Modifications of the Nucleoside 285

9.7.1 2?Modification of the Sugar Moiety 285

9.7.2 Modified Bases 288

9.8 Purification and Characterization of Oligonucleotides 291

9.8.1 Ion-Exchange Chromatography 291

9.9 Analysis of Oligonucleotides 292

9.9.1 Capillary Electrophoresis 292

9.9.2 Mass Spectrometry 295

9.9.3 31P-NMR 295

9.9.4 UV Spectroscopy 296

9.9.5 ORD Spectroscopy 297

9.9.6 Crystal Structures of Oligonucleotides 298

9.10 Antisense Compounds Exhibiting "Major" Modifications 298

9.10.1 Peptide Nucleic Acids 298

9.10.2 Morpholino Oligomers 299

9.10.3 Modification at the Anomeric Center 300

9.10.4 Three-Atom 2?5?Linkages 301

9.11 The Triple-Helix Concept 302

9.11.1 Modified Oligonucleotides in Triple Helix Formation 304

9.11.2 Minor Groove Recognition by Peptides 304

9.12 Synthetic Methods for Ligand Attachment 305

9.12.1 Attachment to Nucleobases 306

9.12.2 Attachment to the Sugar 307

9.12.3 Attachment to the Phosphate Bridge 307

9.13 Ligands as Enhancers of Antisense Action: Effectors 308

9.13.1 Tricyclic Rings Linked to Oligonucleotides 308

9.13.2 Chelators Linked to Oligonucleotides 310

9.13.3 Zwitterionic Oligonucleotides 311

9.14 Modification of Biological Effects of Oligonucleotides: Modulators 312

9.14.1 Phosphorylation of Oligonucleotides 312

9.14.2 Base-Modified Nucleotides at Degenerated Sites 312

9.14.3 Natural Abasic DNA-Nucleotides and Tetrahydrofuran-Spacers 314

9.14.4 Inhibitors of Enzymatic Degradation 314

9.15 Ligands for Localization of Oligonucleotides: Detectors 314

9.15.1 Biotinylation of Oligonucleotides 315

9.15.2 2,4-Dinitrophenyl Groups in Oligonucleotides 316

9.15.3 Fluorescein-Linked Oligonucleotides 316

9.15.4 1,N6-Ethenopurines as Fluorophores 317

9.15.5 Halogenated Pyrimidines and Purines as Photo Cross-Linkers 318

9.15.6 Applications of Radioactive Oligonucleotides 318

9.15.7 Immobilization and Array-Techniques 318

9.16 Catalytically Active Antisense Compounds 320

9.16.1 Group I Introns 320

9.16.2 RNase P 321

9.16.3 Viroids and Virusoids (Hammerhead Ribozymes) 321

9.16.4 RNase H: Chimeric Oligonucleotides 322

9.17 Drug Delivery 323

9.17.1 Cellular Uptake and Intracellular Fate of Oligonucleotides 323

9.17.2 Oligonucleotide Ligands for Improved Drug Delivery 323

9.17.3 Liposomes 325

9.17.4 Nanoparticles 326

9.17.5 Virus Capsids 327

9.18 Standards of Antisense Drug Development 327

9.19 Therapeutic Targets 330

9.20 State and Tendencies of Industrial Antisense Drug Development 330

9.21 Concluding Remarks 335

• References 335
• Index 347

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