Chi-Huey Wong 
Carbohydrate-based Drug Discovery [PDF ebook] 

Volume 1

Preface xxv

List of Contributors xxvii

1 Synthetic Methodologies 1
Chikako Saotome and Osamu Kanie

1.1 Introduction 1

1.2 Tactical Analysis for Overall Synthetic Efficiency 1

1.3 Methodological Improvements 2

1.4 Accessibility 11

1.5 Concluding Remarks 32

1.6 References 33

2 Complex Carbohydrate Synthesis 37
Makoto Kiso, Hideharu Ishida, and Hiromune Ando

2.1 Introduction 37

2.2 Synthetic Gangliosides 38

2.3 Toxin Receptor 50

2.4 Summary and Perspectives 52

2.5 References 52

3 The Chemistry of Sialic Acid 55
Geert-Jan Boons and Alexei V. Demchenko

3.1 Introduction 55

3.2 Chemical and Enzymatic Synthesis of Sialic Acids 56

3.3 Chemical Glycosidation of Sialic Acids 59

3.4 Enzymatic Glycosidations of Sialic Acids 83

3.5 Synthesis of C- and S-Glycosides of Sialic Acid 91

3.6 Modifications at N-5 94

3.7 References 95

4 Solid-Phase Oligosaccharide Synthesis 103
Peter H. Seeberger

4.1 Introduction 103

4.2 Pioneering Efforts in Solid-Phase Oligosaccharide Synthesis 104

4.3 Synthetic Strategies 105

4.4 Support Materials 107

4.5 Linkers 108

4.6 Synthesis of Oligosaccharides on Solid Support by Use of Different Glycosylating Agents 112

4.7 Automated Solid-Phase Oligosaccharide Synthesis 118

4.8 Conclusion and Outlook 124

4.9 References 125

5 Solution and Polymer-Supported Synthesis of Carbohydrates 129
Shin-Ichiro Nishimura

5.1 Introduction 129

5.2 Mimicking Glycoprotein Biosynthetic Systems 130

5.3 References 136

6 Enzymatic Synthesis of Oligosaccharides
Jianbo Zhang, Jun Shao, Prezemk Kowal, and Peng George Wang

6.1 Introduction 137

6.2 Sugar Nucleotide Biosynthetic Pathways 140

6.3 Enzymatic Oligosaccharide Synthesis Processes 151

6.4 Future Directions 162

6.5 References 162

7 Glycopeptides and Glycoproteins: Synthetic Chemistry and Biology 169
Oliver Seitz

7.1 Introduction 169

7.2 The Glycosidic Linkage 169

7.3 The Challenges of Glycopeptide Synthesis 171

7.4 Synthesis of Preformed Glycosyl Amino Acids 173

7.5 Synthesis of Glycopeptides 181

7.6 Biological and Biophysical Studies 200

7.7 Summary and Outlook 208

7.8 References 209

8 Synthesis of Complex Carbohydrates: Everninomicin 13, 384-1 215
K. C. Nicolaou, Helen J. Mitchell, and Scott A. Snyder

8.1 Introduction 215

8.2 Retrosynthetic Analysis and Strategy 218

8.3 Total Synthesis of Everninomicin 13, 384-1 (1) 223

8.4 Conclusion 249

8.5 References 250

9 Chemical Synthesis of Asparagine-Linked Glycoprotein Oligosaccharides: Recent Examples 253
Yukishige Ito and Ichiro Matsuo

9.1 Introduction 253

9.2 Synthesis of Asn-Linked Oligosaccharides: Basic Principles 257

9.3 Chemical Synthesis of Complex Oligosaccharides 261

9.4 References 278

10 Chemistry and Biochemistry of Asparagine-Linked Protein Glycosylation 281
Barbara Imperiali and Vincent W.-F. Tai

10.1 Protein Glycosylation 281

10.2 Small-Molecule Probes of the Biochemistry of Oligosaccharyl Transferase 283

10.3 Conclusions 301

10.4 References 301

11 Conformational Analysis of C-Glycosides and Related Compounds: Programming Conformational Profiles of C- and O-Glycosides 305
Peter G. Goekjian, Alexander Wei, and Yoshito Kishi

11.1 Introduction 305

11.2 Stereoelectronic Effects and te exo-Anomeric Conformation 306

11.3 Conformational Analysis of C-Glycosides: C-Monoglycosides 309

11.4 1, 4-Linked C-Disaccharides: the Importance of syn-Pentane Interactions 314

11.5 Prediction of Conformational Preference and Experimental Validation 318

11.6 Programming Oligosaccharide Conformation 322

11.7 Conformational Design of C-Trisaccharides based on a Human Blood Group Antigen 323

11.8 Conformational Design: Relationship to Biological Activity 330

11.9 Concluding Remarks 336

11.10 Acknowledgements 337

11.11 References 337

12 Synthetic Lipid A Antagonists for Sepsis Treatment 341
William J. Christ, Lynn D. Hawkins, Michael D. Lewis, and Yoshito Kishi

12.1 Background 341

12.2 Hypothesis and Approach 342

12.3 Conclusion 351

12.4 Acknowledgement 353

12.5 References 353

13 Polysialic Acid Vaccines 357
Harold J. Jennings

13.1 Introduction 357

13.2 Group C Meningococcal Vaccines 358

13.3 Group B Meningococcal Vaccines 362

13.4 Chemically Modified Group B Meningococcal Vaccines 366

13.5 Cancer Vaccines 371

13.6 Acknowledgements 375

13.7 References 375

14 Synthetic Carbohydrate-Based Vaccines 381
Stacy J. Keding and Samuel J. Danishefsky

14.1 Introduction 381

14.2 Cancer Vaccines 382

14.3 Bacterial Polysaccharide Vaccines 397

14.4 Synthetic Parasitic Polysaccharide Conjugate Vaccine 402

14.5 Conclusions 403

14.6 References 403

15 Chemistry, Biochemistry, and Pharmaceutical Potentials of Glycosaminoglycans and Related Saccharides 407
Tasneem Islam and Robert J. Linhardt

15.1 Introduction 407

15.2 Dermatan and Chondroitin Sulfates 417

15.3 Hyaluronan 419

15.4 Keratan Sulfate 423

15.5 Other Acidic Polysaccharides 425

15.6 Pharmaceutical Potential and Challenges 430

15.7 Conclusion 432

15.8 References 433

16 A New Generation of Antithrombotics Based on Synthetic Oligosaccharides 441
Maurice Petitou and Jean-Marc Herbert

16.1 Introduction 441

16.2 Heparin and Its Mechanism of Action as an Antithrombotic Agent 442

16.3 Synthetic Pentasaccharides, Selective Factor Xa Inhibitors, are Antithrombotic Agents 446

16.4 Synthetic Thrombin-Inhibiting Oligosaccharides: The Next Generation? 452

16.5 The Mechanism of Antithrombin Activation by Synthetic Oligosaccharides 456

16.6 Conclusion and Perspectives 456

16.7 References 457

Volume 2

17 Sequencing of Oligosaccharides and Glycoproteins 461
Stuart M. Haslam, Kay-Hooi Khoo, and Anne Dell

17.1 Mass Spectrometry 462

17.2 MS-Based Sequencing Strategies 466

17.3 Glycan Sequencing and Structural Determination – A Case Study 470

17.4 Mammalian Glycomics 475

17.5 Some Special Case Strategies 477

17.6 References 481

18 Preparation of Heterocyclic 2-Deoxystreptamine Aminoglycoside Analogues and Characterization of their Interaction with RNAs by Use of Electrospray Ionization Mass Spectrometry 483
Richard H. Griffey, Steven A. Hofstadler, and Eric E. Swayze

18.1 Introduction 483

18.2 ESI-MS for Characterization of Aminoglycoside-RNA Interactions 484

18.3 Preparation of Heterocyclic 2-Deoxystreptamines and Binding to a 16S A Site RNA Model 490

18.4 Preparation, Binding, and Biological Activity of Substituted Paromomycin Derivatives 495

18.5 Future Prospects 498

18.6 Acknowledgements 498

18.7 References 498

19 Glycosylation Analysis of a Recombinant P-Selectin Antagonist by High-p H Anion-Exchange Chromatography with Pulsed Electrochemical Detection (HPAEC/PED) 501
Mark R. Hardy and Richard J. Cornell

19.1 Introduction 501

19.2 Use of HPAEC/PED in the Development of Biopharmaceuticals 502

19.3 Biology of P-Selectin 503

19.4 HPAEC/PED as an Adjunct to r PSGL-Ig Process Development 504

19.5 Results and Discussion 508

19.6 Summary 515

19.7 Acknowledgements 516

19.8 References 516

20 Analytical Techniques for the Characterization and Sequencing of Glycosaminoglycans 517
Ram Sasisekharan, Zachary Shriver, Mallik Sundaram, and Ganesh Venkataraman

20.1 Introduction to GAG Linear Complex Polysaccharides 517

20.2 Depolymerization of Nascent GAG Chains 521

20.4 Analytical Tools Used in the Structural Characterization of GAGs 527

20.5 Future Directions 536

20.6 Acknowledgements 537

20.7 References 537

21 Thermodynamic Models of the Multivalency Effect 541
Pavel I. Kitov and David R. Bundle

21.1 Introduction 541

21.2 Concept of Distribution Free Energy 542

21.3 Multivalent Receptor vs. Monovalent Ligand 546

21.4 Multivalent Receptor vs. Multivalent Ligand 551

21.5 Topological Classification of Multivalent Systems 553

21.6 Determination of Microscopic Binding Parameters by Molecular Modeling 555

21.7 Determination of Microscopic Binding Parameters from Binding Data 561

21.8 Thermodynamic Analysis of Multivalent Interaction 562

21.9 Conclusions 570

21.10 Mathematical Appendix 570

21.10.1 Calculation of Statistical Coefficients 570

21.10.2 Multivalent Receptor and Monovalent Ligand 571

21.10.3 Multivalent Binding with Linear and Circular Topology 571

21.10.4 Multivalent Binding with Radial Topology 572

21.10.5 Derivation of Eq. (24) 572

21.11 References 573

22 Synthetic Multivalent Carbohydrate Ligands as Effectors or Inhibitors of Biological Processes 575
Laura L. Kiessling, Jason K. Pontrello, and Michael C. Schuster

22.1 Introduction 575

22.2 Multivalent Carbohydrate Ligands as Inhibitors 581

22.3 Multivalent Carbohydrate Ligands as Effectors 596

22.4 Conclusions 605

22.5 References 605

23 Glycosyltransferase Inhibitors 609
Karl-Heinz Jung and Richard R. Schmidt

23.1 Introduction 609

23.2 Glycosyltransferases Utilizing NDP-Sugar Donors 610

23.3 Glycosyltransferases Utilizing NMP-Sugar Donors 641

23.4 Bisubstrate Analogues as Inhibitors 648

23.5 Conclusion 653

23.6 References 654

24 RNA-Aminoglycoside Interactions 661
Haim Weizman and Yitzhak Tor

24.1 RNA as an Emerging Therapeutic Target 661

24.2 Aminoglycoside Antibiotics: Past and Present 664

24.3 Aminoglycosides as RNA Binders 666

24.4 Identifying RNA Targets and Developing Binding Assays 670

24.5 Dimeric Aminoglycosides 673

24.6 Aminoglycoside-Intercalator Conjugates 675

24.7 Guanidinoglycosides 677

24.8 Summary and Outlook 679

24.9 Acknowledgements 680

24.10 References 680

25 Glycosylated Natural Products 685
Jon S. Thorson and Thomas Vogt

25.1 Introduction 685

25.2 A Summary of Bioactive Glycosylated Secondary Metabolites 686

25.3 Conclusions 707

25.4 References 707

26 Novel Enzymatic Mechanisms in the Biosynthesis of Unusual Sugars 713
Alexander Wong, Xuemei He, and Hung-Wen Liu

26.1 Introduction 713

26.2 Biosynthesis of Deoxysugars 714

26.3 Biosynthesis of Aminosugars 725

26.4 Biosynthesis of Branched-Chain Sugars 730

26.5 Epimerization Reactions 734

26.6 Rearrangement of Hexose Skeletons: UDP-Galactopyranose Mutase-Catalyzed Biosynthesis of Galactofuranose 738

26.7 Summary 740

26.8 Acknowledgements 741

26.9 References 741

27 Neoglycolipids: Identification of Functional Carbohydrate Epitopes 747
Ten Feizi, Alexander M. Lawson, and Wengang Chai

27.1 Rationale for Developing Neoglycolipids as Oligosaccharide Probes 747

27.2 The First and Second Generation Neoglycolipids 749

27.3 Mass Spectrometry of Neoglycolipids 750

27.4 Scope of the Neoglycolipid Technology 752

27.5 Oligosaccharide Microarrays 755

27.6 Summary and Perspectives 757

27.7 Acknowledgement 757

27.8 References 757

28 A Preamble to Aglycone Reconstruction for Membrane-Presented Glycolipid Mimics 761
Murugesapillai Mylvaganam and Clifford A. Lingwood

28.1 Introduction 761

28.2 The Role of Ceramide Subtype Composition 762

28.3 Effects of Ceramide Subtype Composition in the Binding of Gb3Cer to Verotoxins 764

28.4 Hypothesis Regarding Lipid Replacement Structural Motifs (LRSMs) 766

28.5 Effect of Replacement of GSL Fatty Acyl Chains with Rigid, Non-Planar Hydrophobic Groups 768

28.6 Ada-Gb3Cer, a Functional Mimic of Membrane Presented Gb3Cer for VT Binding 769

28.7 Ceramide Subtype-Dependent Binding of Heat Shock Protein Hsp70 to Sulfogalactosyl Ceramide 772

28.8 Adamantyl-Acyl Ceramide is a Functional Replacement for a Ceramide-Cholesterol Composition: A Study with HIV Coat Protein gp120 775

28.9 Acknowledgement 777

28.10 References 777

29 Small Molecule Inhibitors of the Sulfotransferases 781
Dawn E. Verdugo, Lars C. Pedersen, and Carolyn R. Bertozzi

29.1 Introduction: Sulfotransferases and the Biology of Sulfation 781

29.2 EST as a Model ST for Inhibitor Design 783

29.3 Inhibition of Representative Golgi-Resident Sulfotransferases: GST-2, GST-3, and TPST-2 792

29.4 Assays for High-Throughput Screening of STs 794

29.5 New Directions in Inhibitor Discovery 796

29.6 Conclusions 796

29.7 Acknowledgements 796

29.8 References 797

30 Carbohydrate-Based Treatment of Cancer Metastasis 803
Reiji Kannagi

30.1 Implication of Carbohydrate Determinants in Cancer Metastasis 803

30.2 Tumor Angiogenesis and Cancer-Endothelial Interaction 808

30.3 Use of Monoclonal Antibodies for Inhibition of Cancer Cell-Endothelial Interaction 809

30.4 Inhibitors of Selectin-Mediated Cell Adhesion 812

30.5 Regulation of Selectin Expression on Endothelial Cells 814

30.6 Enhanced Expression of Sialyl Lex and Sialyl Lea in Malignant Cells and its Modulation 816

30.7 References 824

31 N-Acetylneuraminic Acid Derivatives and Mimetics as Anti-Influenza Agents 831
Robin Thomson and Mark von Itzstein

31.1 Introduction 831

31.2 Structure-Based Design of Inhibitors of Influenza Virus Sialidase 836

31.3 Structure/Activity Relationship Studies of N-Acetylneuraminic Acid-Based Influenza Virus Sialidase Inhibitors 840

31.4 Concluding Remarks 856

31.5 Acknowledgements 856

31.6 References 857

32 Modified and Modifying Sugars as a New Tool for the Development of Therapeutic Agents – The Biochemically Engineered N-Acyl Side Chain of Sialic Acid: Biological Implications and Possible Uses in Medicine 863
Rüdiger Horstkorte, Oliver T. Keppler, and Werner Reutter

32.1 Introduction 863

32.2 N-Acyl Side Chain-Modified Precursors of Sialic Acid 865

32.3 Outlook 871

32.4 Acknowledgements 872

32.5 Abbreviations 872

32.6 References 872

33 Modified and Modifying Sugars as a New Tool for the Development of Therapeutic Agents – Glycosidated Phospholipids as a New Type of Antiproliferative Agents 875
Kerstin Danker, Annette Fischer, and Werner Reutter

33.1 Introduction 875

33.2 Structures of Synthetic Glycosidated Phospholipid Analogues 876

33.3 Antiproliferative Effect and Cytotoxicity of Glycosidated Phospholipid Analogues in Cell Culture Systems 876

33.4 Effect of Glycosidated Phospholipid Analogues on Cell Matrix Adhesion 878

33.5 Mechanisms of Action 879

33.6 Outlook and New Developments 880

33.7 Acknowledgements 881

33.8 References 881

34 Glycoside Primers and Inhibitors of Glycosylation 883
Jillian R. Brown, Mark M. Fuster, and Jeffrey D. Esko

34.1 Introduction 883

34.2 Glycoside-Based Substrates 883

34.3 Glycoside Primers – Xylosides 884

34.4 Other Types of Primers 885

34.5 Glycosides as Metabolic Decoys 888

34.6 Analogues 890

34.7 References 892

35 Carbohydrate-Based Drug Discovery in the Battle Against Bacterial Infections: New Opportunities Arising from Programmable One-Pot Oligosaccharide Synthesis 899
Thomas K. Ritter and Chi-Huey Wong

35.1 Introduction 899

35.2 Cell-Surface Carbohydrates 900

35.3 Peptidoglycan 904

35.4 Macrolide Antibiotics 913

35.5 Aminoglycosides 917

35.6 Programmable One-Pot Oligosaccharide Synthesis 922

35.7 Summary 927

35.8 References 928

Subject Index 933

Professor Chi-Huey Wong received his B.S. and M.S. degrees from National Taiwan University, and Ph.D. in Chemistry (with George Whitesides) from Massachusetts Institute of Technology in 1982. He started his independent career as Assistant Professor of Chemistry at Texas A&M University in 1983, where he became Full Professor in 1987. He has been Professor and Ernest W. Hahn Chair in Chemistry at the Scripps Research Institute since 1989 and is also a member of the Skaggs Institute for Chemical Biology since 1996.
Professor Wong is a member of the U.S. National Academy of Sciences and the American Academy of Arts and Sciences. He is a recipient of The Searle Scholar Award in Biomedical Sciences (1985), the Presidential Young Investigator Award in Chemistry (1986), the American Chemical Society A.C. Cope Scholar Award (1993), the Roy Whistler Award of the International Carbohydrate Organization (1994), the American Chemical Society Harrison Howe Award in Chemistry (1998) and the Claude S. Hudson Award in Carbohydrate Chemistry (1999), the International Enzyme Engineering Award (1999) and the Presidential Green Chemistry Challenge Award (2000). He is a member of Academia Sinica, Taipei (1994), the American Academy of Arts and Sciences (1996) and the US National Academy of Sciences (2002). He serves as editor-in-chief of Bioorganic and Medicinal Chemistry and is an executive board member of the Tetrahedron Publications. He was head of the Frontier Research Program on Glycotechnology at RIKEN (Institute of Physical and Chemical Research, Japan) (1991-1999) and is currently a scientific advisor of the Max-Planck Institute, a board member of the U.S. National Research Council on Chemical Sciences and Technology, and is a founding scientist of Optimer Pharmaceuticals, Inc. He is author and co-author of over 450 publications, 60 patents and several books.
His current interests are in the areas of bioorganic and synthetic chemistry and biocatalysis, including development of new synthetic chemistry based on enzymatic and chemo-enzymatic reactions, synthetic approach to carbohydrate-mediated biological recognition, design and synthesis of mechanism-based inhibitors of enzymes, RNA and carbohydrate receptors, development of oligosaccharide and aminoglycoside microarrays for high-throughput screening and the study of reaction mechanisms.