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  Contents  
 
  Volume 1  
  Preface XXV
  List of Contributors XXVII
1 Synthetic Methodologies
Chikako Saotome and Osamu Kanie 		1
1.1 Introduction 1
1.2 Tactical Analysis for Overall Synthetic Efficiency 1
1.3 Methodological Improvements 2
1.3.1 Chemistry 3
1.3.2 Protecting Group Manipulations 4
1.3.3 Modulation of the Reactivity of Glycosyl Donors 6
1.3.4 Block Synthesis 8
1.4 Accessibility 11
1.4.1 Solution-based Chemistry 11
1.4.2 One-Pot Glycosylation 13
1.4.3 Solid-Phase Chemistry 16
1.4.3.1 Fundamentals of Solid-Phase Oligosaccharide Synthesis 16
1.4.3.2 The Support 16
1.4.3.3 Linkers to the Support 20
1.4.3.4 Protecting Groups used in Solid-Phase Oligosaccharide Synthesis 20
1.4.3.5 Solid-Phase Oligosaccharide Synthesis 20
1.4.3.6 Monitoring of Reaction Progress 26
1.4.4 Automation 29
1.5 Concluding Remarks 32
1.6 References 33
2 Complex Carbohydrate Synthesis
Makoto Kiso, Hideharu Ishida, and Hiromune Ando 		37
2.1 Introduction 37
2.2 Synthetic Gangliosides 38
2.2.1 Gangliosides GM4 and GM3, and their Analogues and Derivatives 38
2.2.2 Sialylparagloboside (SPG) Analogues and Derivatives 40
2.2.3 Selectin Ligands 43
2.2.3.1 Sialyl Lewis x 44
2.2.3.2 Novel 6-Sulfo sLex Variants 45
2.2.4 Siglec ligands 46
2.2.4.1 Chol-1 (-Series) Gangliosides 47
2.2.4.2 Novel Sulfated Gangliosides 50
2.3 Toxin Receptor 50
2.4 Summary and Perspectives 52
2.5 References 52
3 The Chemistry of Sialic Acid
Geert-Jan Boons and Alexei V. Demchenko 		55
3.1 Introduction 55
3.2 Chemical and Enzymatic Synthesis of Sialic Acids 56
3.3 Chemical Glycosidation of Sialic Acids 59
3.3.1 Direct Chemical Sialylations 60
3.3.1.1 2-Chloro Derivatives as Glycosyl Donors 61
3.3.1.2 2-Thio Derivatives as Glycosyl Donors 62
3.3.1.3 2-Xanthates as Glycosyl Donors 69
3.3.1.3 2-Phosphites as Glycosyl Donors 71
3.3.1.4 Miscellaneous Direct Chemical Methods 71
3.3.2 Indirect Chemical Methods with the Use of a Participating Auxiliary at C-3 73
3.3.2.1 3-Bromo- and other 3-O-Auxiliaries 73
3.3.2.2 3-Thio and 3-Seleno Auxiliaries 74
3.3.3 Synthesis of (28)-Linked Sialosides 77
3.4 Enzymatic Glycosidations of Sialic Acids 83
3.4.1 Sialyltransferases 84
3.4.1.1 Metabolic Engineering of the Sialic Acid Biosynthetic Pathway 90
3.4.2 Sialidases 90
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
Peter H. Seeberger 		103
4.1 Introduction 103
4.2 Pioneering Efforts in Solid-Phase Oligosaccharide Synthesis 104
4.3 Synthetic Strategies 105
4.3.1 Immobilization of the Glycosyl Acceptor 106
4.3.2 Immobilization of the Glycosyl Donor 106
4.3.3 Bi-directional Strategy 107
4.4 Support Materials 107
4.4.1 Insoluble Supports 107
4.4.2 Soluble Supports 108
4.5 Linkers 108
4.5.1 Silyl Ethers 108
4.5.2 Acid- and Base-Labile Linkers 109
4.5.3 Thioglycoside Linkers 110
4.5.4 Linkers Cleaved by Oxidation 110
4.5.5 Photocleavable Linkers 111
4.5.6 Linkers Cleaved by Olefin Metathesis 111
4.6 Synthesis of Oligosaccharides on Solid Support by Use of Different Glycosylating Agents 112
4.6.1 1,2-Anhydrosugars -- The Glycal Assembly Approach 112
4.6.2 Glycosyl Sulfoxides 113
4.6.3 Glycosyl Trichloroacetimidates 114
4.6.4 Thioglycosides 115
4.6.5 Glycosyl Fluorides 118
4.6.6 n-Pentenyl Glycosides 118
4.6.7 Glycosyl Phosphates 118
4.7 Automated Solid-Phase Oligosaccharide Synthesis 118
4.7.1 Fundamental Considerations 119
4.7.2 Automated Synthesis with Glycosyl Trichloroacetimidates 121
4.7.3 Automated Synthesis with Glycosyl Phosphates 121
4.7.4 Automated Oligosaccharide Synthesis by Use of Different Glycosylating Agents 121
4.7.5 "Cap-Tags" to Suppress Deletion Sequences 123
4.7.6 Current State of the Art of Automated Synthesis 123
4.8 Conclusion and Outlook 124
4.9 References 125
5 Solution and Polymer-Supported Synthesis of Carbohydrates
Shin-Ichiro Nishimura 		129
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 		137
6.1 Introduction 137
6.2 Sugar Nucleotide Biosynthetic Pathways 140
6.2.1 Basic Principle 140
6.2.2 Regeneration Systems for nine Common Sugar Nucleotides 142
6.2.2.1 Regeneration Systems for UDP-Gal, UDP-Glc, UDP-GlcA and UDP-Xyl 142
6.2.2.2 Regeneration Systems for UDP-GlcNAc and UDP-GalNAc 144
6.2.2.3 Regeneration Systems for GDP-Man and GDP-Fuc 147
6.2.2.4 CMP-Neu5Ac Regeneration 149
6.2.3 Novel Energy Source in Sugar Nucleotide Regeneration 150
6.3 Enzymatic Oligosaccharide Synthesis Processes 151
6.3.1 Cell-Free Oligosaccharide Synthesis 151
6.3.1.1 Immobilized Glycosyltransferases and Water-Soluble Glycopolymer 152
6.3.1.2 "Superbeads" 154
6.3.2 Large-Scale Syntheses of Oligosaccharides with Whole Cells 156
6.3.2.1 Kyowa Hakko's Technology 157
6.3.2.2 Wang's "Superbug" 157
6.3.2.3 Other Whole Cell-Based Technologies 161
6.4 Future Directions 162
6.5 References 162
7 Glycopeptides and Glycoproteins: Synthetic Chemistry and Biology
Oliver Seitz 		169
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
7.4.1 N-Glycosides 173
7.4.2 O-Glycosides 176
7.4.2.1 O-Glycosyl Amino Acids bearing Mono- or Disaccharides 176
7.4.2.2 O-Glycosyl Amino Acids bearing Complex Carbohydrates 179
7.5 Synthesis of Glycopeptides 181
7.5.1 N-Glycopeptide Synthesis in Solution 181
7.5.2 O-Glycopeptide Synthesis in Solution 185
7.5.3 Solid-Phase Synthesis of N-Glycopeptides 188
7.5.4 Solid-Phase Synthesis of O-Glycopeptides 192
7.6 Biological and Biophysical Studies 200
7.6.1 Conformations of Glycopeptides 200
7.6.2 Glycopeptides as Substrates of Enzymes and Receptors 203
7.6.3 Glycopeptides and Cancer Immunotherapy 204
7.6.4 Glycopeptides and T Cell Recognition 206
7.7 Summary and Outlook 208
7.8 References 209
8 Synthesis of Complex Carbohydrates: Everninomicin 13,384-1
K.C. Nicolaou, Helen J. Mitchell, and Scott A. Snyder 		215
8.1 Introduction 215
8.2 Retrosynthetic Analysis and Strategy 218
8.2.1 Overview of Synthetic Strategies and Methodologies 218
8.2.2 Retrosynthetic Analysis: Overall Approach 222
8.3 Total Synthesis of Everninomicin 13,384-1 (1) 223
8.3.1 Approaches Towards the A1B(A)C Fragment 223
8.3.1.1 Initial Model Studies 223
8.3.1.2 Construction of the Building Blocks 225
8.3.1.3 Assembly and Completion of the A1B(A)C Fragment 229
8.3.2 Construction of the FGHA2 Fragment 231
8.3.2.1 First Generation Approach to the FGHA2ragment 231
8.3.2.2 Second Generation Strategy Towards the FGHA2 Fragment 232
8.3.2.3 Assembly of the FGHA2 Fragment 235
8.3.3 Construction of the DE Disaccharide 241
8.3.3.1 Retrosynthetic Analysis and Construction of Building Blocks for the DE Fragment 241
8.3.3.2 Assembly of the DE Fragment 243
8.3.3.3 Test of Strategies 244
8.3.4 Assembly of the DEFGHA2 Fragment 245
8.3.5 Completion of the Total Synthesis of Everninomicin 13,384-1 247
8.4 Conclusion 249
8.5 References 250
9 Chemical Synthesis of Asparagine-Linked Glycoprotein Oligosaccharides: Recent Examples
Yukishige Ito and Ichiro Matsuo 		253
9.1 Introduction 253
9.2 Synthesis of Asn-Linked Oligosaccharides: Basic Principles 257
9.3 Chemical Synthesis of Complex Oligosaccharides 261
9.3.1 Classical Examples 261
9.3.2 Trichloroacetimidate Approach to Complex-Type Glycan Chains 265
9.3.3 n-Pentenyl Glycosides as Glycosyl Donors 265
9.3.4 Glycal Approach to Complex Oligosaccharides 267
9.3.5 Intramolecular Aglycon Delivery Approach 269
9.3.6 New Protecting Group Strategy 273
9.3.7 Linear Synthesis of Branched Oligosaccharide 274
9.3.8 Chemoenzymatic Approach to Complex-type Glycans 275
9.4 References 278
10 Chemistry and Biochemistry of Asparagine-Linked Protein Glycosylation
Barbara Imperiali and Vincent W.-F. Tai 		281
10.1 Protein Glycosylation 281
10.1.1 Introduction 281
10.1.2 Asparagine-Linked Glycosylation and Oligosaccharyl Transferase 281
10.2 Small-Molecule Probes of the Biochemistry of Oligosaccharyl Transferase 283
10.2.1 Photoaffinity and Affinity Labeling of Oligosaccharyl Transferase 284
10.2.2 Investigation of Peptide-Based Substrate Analogues as Inhibitors of Oligosaccharyl Transferase 287
10.2.2.1 Inhibitors of N-Linked Glycosylation and Glycoprotein Processing 287
10.2.2.2 Peptide-Based Analogues and Inhibitors 288
10.2.2.3 Interim Summary 292
10.2.3 Investigation of Carbohydrate-Based Substrate Analogues as Probes of Oligosaccharyl Transferase Function 292
10.2.3.1 Possible Mechanisms for Glycosyl Transfer 294
10.2.3.2 Probing of the Mechanism of Oligosaccharyl Transferase with Potential Inhibitors 296
10.2.3.3 Interim Summary 300
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
Peter G. Goekjian, Alexander Wei, and Yoshito Kishi 		305
11.1 Introduction 305
11.2 Stereoelectronic Effects and the 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
11.8.1 C-Lactose vs. O-Lactose 331
11.8.2 Human Blood Group Trisaccharides 334
11.9 Concluding Remarks 336
11.10 Acknowledgements 337
11.11 References 337
12 Synthetic Lipid A Antagonists for Sepsis Treatment
William J. Christ, Lynn D. Hawkins, Michael D. Lewis, and Yoshito Kishi 		341
12.1 Background 341
12.2 Hypothesis and Approach 342
12.2.1 Monosaccharide Antagonists: Lipid X Analogues 343
12.2.2 Disaccharide Antagonist of Lipid A: First Generation 344
12.2.3 Disaccharide Antagonist of Lipid A: Second Generation 348
12.3 Conclusion 351
12.4 Acknowledgement 353
12.5 References 353
13 Polysialic Acid Vaccines
Harold J. Jennings 		357
13.1 Introduction 357
13.2 Group C Meningococcal Vaccines 358
13.2.1 Structure and Immunology of GCMP 358
13.2.2 Group C Conjugate Vaccines 360
13.3 Group B Meningococcal Vaccines 362
13.3.1 Structure of GBMP 362
13.3.2 Immunology of GBMP 362
13.3.3 B Polysaccharide-Protein Conjugates 363
13.3.4 Extended Helical Epitope of PSA 364
13.4 Chemically Modified GroupB Meningococcal Vaccines 366
13.4.1 N-Propionylated PSA Conjugate Vaccine 366
13.4.2 Immunology of NPr PSA 368
13.4.3 Protective Epitope mimicked by NPr PSA 370
13.4.4 Safety Concerns 370
13.5 Cancer Vaccines 371
13.5.1 PSA on Human Cells 371
13.5.2 Potential of NPr PSA as a Cancer Vaccine 373
13.6 Acknowledgements 375
13.7 References 375
14 Synthetic Carbohydrate-Based Vaccines
Stacy J. Keding and Samuel J. Danishefsky 		381
14.1 Introduction 381
14.2 Cancer Vaccines 382
14.2.1 Carrier Proteins 384
14.2.2 Lipid Carriers 392
14.2.3 T-Cell Epitopes 394
14.2.4 Dendrimers 396
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
Tasneem Islam and Robert J. Linhardt 		407
15.1 Introduction 407
15.1.1 Biological Activities 408
15.1.2 Heparin and Heparan Sulfate 409
15.1.2.1 Structure and Properties 409
15.1.2.2 Biosynthesis and Biological Functions 410
15.1.2.3 Applications of Heparin and Heparan Sulfate 411
15.2 Dermatan and Chondroitin Sulfates 417
15.2.1 Structure and Biological Role 417
15.2.2 Therapeutic Applications 418
15.2.2.1 Dermatan Sulfate 418
15.2.2.2 Chondroitin Sulfates 419
15.3 Hyaluronan 419
15.3.1 Structure and Properties 419
15.3.2 Tissue Distribution and Biosynthesis 420
15.3.3 Functions and Applications 421
15.3.3.1 Medical Applications 422
15.3.3.2 Hyaluronic Acid Biomaterials 423
15.4 Keratan Sulfate 423
15.4.1 Structure and Distribution 423
15.4.2 Chemistry and Biosynthesis of Linkage Regions 424
15.4.2.1 Keratan Sulfate on Cartilage Proteoglycans 424
15.4.2.2 Keratan Sulfate on Corneal Proteoglycans 424
15.4.3 Biological Roles of Keratan Sulfate 425
15.4.3.1 Role of KS in Macular Corneal Dystrophy 425
15.5 Other Acidic Polysaccharides 425
15.5.1 Acharan Sulfate 425
15.5.2 Fucoidins 426
15.5.3 Carrageenans 427
15.5.4 Sulfated Chitins 427
15.5.5 Dextran Sulfate 427
15.5.6 Alginates 428
15.5.7 Fully Synthetic Sulfated Molecules 428
15.5.7.1 Polymers 428
15.5.7.2 Small Sulfonated Molecules 428
15.6 Pharmaceutical Potential and Challenges 430
15.6.1 GAG-Based Agents Are Heterogenous 431
15.6.2 GAG-Based Agents and Sulfonated Analogues Have Low Bioavailability 431
15.6.3 GAGs Have a Myriad of Biological Activities 432
15.6.4 Carbohydrate-Based Drugs Are Expensive and Difficult to Prepare 432
15.7 Conclusion 432
15.8 References 433
16 A New Generation of Antithrombotics Based on Synthetic Oligosaccharides
Maurice Petitou and Jean-Marc Herbert 		441
16.1 Introduction 441
16.2 Heparin and Its Mechanism of Action as an Antithrombotic Agent 442
16.2.1 Heparin, a Complex Polysaccharide with Blood Anticoagulant Properties 442
16.2.2 Which Coagulation Factor must be Inhibited? 442
16.2.3 The Structure of Heparin in Relation to Antithrombin Activation 444
16.2.4 The Limitations of Heparin 445
16.3 Synthetic Pentasaccharides, Selective Factor Xa Inhibitors, are Antithrombotic Agents 446
16.3.1 New Synthetic Oligosaccharides Required in Order to Validate A Pharmacological" Hypothesis 446
16.3.2 A Strategy for the Synthesis of an Active Pentasaccharide 446
16.3.3 A Strategy for the Synthesis of the First Pentasaccharide 448
16.3.4 Activation of Antithrombin: Structure/Activity Relationship 449
16.3.5 Clinical Trials Results 449
16.3.6 The Second Generation of Antithrombotic Pentasaccharides 451
16.4 Synthetic Thrombin-Inhibiting Oligosaccharides: The Next Generation? 452
16.4.1 First Approach: Oligomerization of a Disaccharide 452
16.4.2 Second Approach: Molecules Containing Two Identified Domains 453
16.4.3 Introduction of a Neutral Domain 454
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
Stuart M. Haslam, Kay-Hooi Khoo, and Anne Dell 		461
17.1 Mass Spectrometry 462
17.1.1 EI-, FAB-, and MALDI-MS 462
17.1.2 ES, NanoES, and LC-MS 464
17.1.3 MS/MS and Mass Analyzers 465
17.2 MS-Based Sequencing Strategies 466
17.2.1 Chemical Derivatization 467
17.2.2 MS/MS Fragmentation Patterns 467
17.2.3 Permethylation and Sequence Assignment from Fragment Ions 468
17.3 Glycan Sequencing and Structural Determination A Case Study 470
17.3.1 GC-MS Sugar Analysis 471
17.3.2 Glycan Derivatization 471
17.3.3 FAB-MS of the Deuteroreduced Permethylated HSP Sample 473
17.3.4 ES-MS/MS 473
17.3.5 Linkage Analysis 474
17.3.6 Chemical Hydrolysis 474
17.3.7 Exo-Glycosidase Digestion 474
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
Richard H. Griffey, Steven A. Hofstadler, and Eric E. Swayze 		483
18.1 Introduction 483
18.1.1 RNA as a Target 483
18.1.2 Functional RNA Subdomains 483
18.1.3 Aminoglycosides are a Privileged Class of RNA Ligands 484
18.2 ESI-MS for Characterization of Aminoglycoside-RNA Interactions 484
18.2.1 Aminoglycoside-16S and 18S A Site RNA Models 484
18.2.2 Neomycin and TAR RNA 489
18.2.3 Interim Summary 490
18.3 Preparation of Heterocyclic 2-Deoxystreptamines and Binding to a 16S A Site RNA Model 490
18.3.1 4-Substituted 2-Deoxystreptamine Derivatives 491
18.3.2 16S rRNA Binding Affinity Study in an ESI-MS Assay 493
18.3.3 Isolation of Sugar Ring Fragments from Neomycin 494
18.4 Preparation, Binding, and Biological Activity of Substituted Paromomycin Derivatives 495
18.4.1 Synthesis of Racemic A Ring-Substituted Paromomycin Analogues 495
18.4.2 Synthesis of Chiral A Ring-Substituted Paromomycin Analogues 496
18.5 Future Prospects 498
18.6 Acknowledgements 498
18.7 References 498
19 Glycosylation Analysis of a Recombinant P-Selectin Antagonist by High-pH Anion-Exchange Chromatography with Pulsed Electrochemical Detection (HPAEC/PED)
Mark R. Hardy and Richard J. Cornell 		501
19.1 Introduction 501
19.2 Use of HPAEC/PED in the Development of Biopharmaceuticals 502
19.3 Biology of P-Selectin 503
19.3.1 Structures of PSGL-1 and rPSGL-Ig 503
19.4 HPAEC/PED as an Adjunct to rPSGL-Ig Process Development 504
19.4.1 Materials and Methods 504
19.4.2 HPAEC/PED O-Linked Oligosaccharide Profile Analysis 506
19.4.3 N-Linked Oligosaccharide Profile Analysis 507
19.5 Results and Discussion 508
19.5.1 HPAEC/PED Oligosaccharide Profile Analysis of a Developmental Batch of rPSGL-Ig 508
19.5.2 Repeatability of the O-Linked Oligosaccharide Profile Method 510
19.5.3 O-Glycosylation of rPSGL-Ig Expressed by Different Cell Lines 510
19.5.4 N-Glycosylation of rPSGL-Ig 515
19.6 Summary 515
19.7 Acknowledgements 516
19.8 References 516
20 Analytical Techniques for the Characterization and Sequencing of Glycosaminoglycans
Ram Sasisekharan, Zachary Shriver, Mallik Sundaram, and Ganesh Venkataraman 		517
20.1 Introduction to GAG Linear Complex Polysaccharides 517
20.2 Depolymerization of Nascent GAG Chains 521
20.2.1 Enzymes that Degrade GAGs 521
20.2.2 Chemical Methods for Degrading GAG Oligosaccharides 524
20.3 Detection of GAG Oligosaccharides 525
20.3.1 4,5 Bond Formation and UV Detection 525
20.3.2 Fluorescent Tagging 526
20.3.3 Metabolic Labeling 526
20.4 Analytical Tools Used in the Structural Characterization of GAGs 527
20.4.1 High Pressure Liquid Chromatography 527
20.4.1.1 Amino-Bonded Silica 528
20.4.1.2 High-Performance Gel Permeation 528
20.4.1.3 Weak and Strong Anion Exchange 528
20.4.1.4 Pellicular Anion Exchange 529
20.4.1.5 IP-RPHPLC 529
20.4.1.6 Sequencing GAGs I: HPLC Methods 529
20.4.2 Polyacrylamide Gel Electrophoresis 530
20.4.2.1 Sequencing GAGs II: PAGE Methods 530
20.4.3 Capillary Electrophoresis 530
20.4.4 NMR Spectroscopy 532
20.4.5 Mass Spectrometry 533
20.4.5.1 Sequencing GAGs III: Mass Spectrometric Methodologies 536
20.4.6 Oligosaccharide Array Technologies 536
20.5 Future Directions 536
20.6 Acknowledgements 537
20.7 References 537
21 Thermodynamic Models of the Multivalency Effect
Pavel I. Kitov and David R. Bundle 		541
21.1 Introduction 541
21.2 Concept of Distribution Free Energy 542
21.2.1 Binding Isotherm 542
21.2.2 Competitive Inhibition Isotherm 544
21.3 Multivalent Receptor vs. Monovalent Ligand 546
21.3.1 Interim Summary 549
21.4 Multivalent Receptor vs. Multivalent Ligand 551
21.5 Topological Classification of Multivalent Systems 553
21.5.1 Indifferent Presentation 553
21.5.2 Linear Presentation 554
21.5.3 Circular Presentation 554
21.5.4 Radial Presentation 554
21.6 Determination of Microscopic Binding Parameters by Molecular Modeling 555
21.6.1 Optimization of the Tether in Bivalent Pk-Trisaccharide Ligands for Shiga-Like Toxin 557
21.7 Determination of Microscopic Binding Parameters from Binding Data 561
21.8 Thermodynamic Analysis of Multivalent Interaction 562
21.8.1 Radially Arranged Multivalent Ligands for Shiga-Like Toxin 565
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
Laura L. Kiessling, Jason K. Pontrello, and Michael C. Schuster 		575
22.1 Introduction 575
22.1.1 Mechanisms of Binding of Multivalent Ligands 576
22.1.2 Investigating the Structure/Function Relationship of a Series of Ligand Classes 577
22.2 Multivalent Carbohydrate Ligands as Inhibitors 581
22.2.1 Multivalency with AB5 Toxins 581
22.2.1.1 Bundle's Decavalent Ligand for the E. coli Shiga-Like Toxin 582
22.2.1.2 Fan's Pentavalent Ligands for Cholera Toxin and the E. coli Heat-Labile Enterotoxin" 584
22.2.2 Multivalency in Anti-adhesives 587
22.2.2.1 Low Molecular Weight Multivalent Carbohydrate Inhibitors of Bacterial Adhesion 587
22.2.2.2 Polymeric Multivalent Carbohydrate Inhibitors of Influenza Virus 592
22.2.3 Multivalent Carbohydrate Ligands as Inhibitors of Immune Responses 595
22.3 Multivalent Carbohydrate Ligands as Effectors 596
22.3.1 Low Molecular Weight Multivalent Effectors 597
22.3.2 Multivalency in Targeting Strategies 599
22.3.3 Multivalent Bacterial Chemoattractants 600
22.3.4 Multivalent Ligand-Mediated Cell Aggregation 602
22.3.5 Multivalent Ligands and the Selectins 603
22.4 Conclusions 605
22.5 References 605
23 Glycosyltransferase Inhibitors
Karl-Heinz Jung and Richard R. Schmidt 		609
23.1 Introduction 609
23.2 Glycosyltransferases Utilizing NDP-Sugar Donors 610
23.2.1 Inverting Glycosyltransferases 610
23.2.1.1 -Glucosyltransferases 611
23.2.1.2 -Galactosyltransferases 616
23.2.1.3 -N-Acetylglucosaminyltransferases 620
23.2.1.4 -Fucosyltransferases 625
23.2.1.5 -Glucuronosyltransferases 632
23.2.2 Retaining Glycosyltransferases 636
23.2.2.1 -Galactosyltransferases 637
23.2.2.2 -N-Acetylgalactosaminyltransferases 640
23.3 Glycosyltransferases Utilizing NMP-Sugar Donors 641
23.3.1 (2--6)Sialyltransferases 641
23.3.2 (2--3)Sialyltransferases and a(2--8)Sialyltransferases 647
23.4 Bisubstrate Analogues as Inhibitors 648
23.5 Conclusion 653
23.6 References 654
24 RNA-Aminoglycoside Interactions
Haim Weizman and Yitzhak Tor 		661
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
Jon S. Thorson and Thomas Vogt 		685
25.1 Introduction 685
25.2 A Summary of Bioactive Glycosylated Secondary Metabolites 686
25.2.1 Agents that Interact with DNA 686
25.2.1.1 Enediynes 686
25.2.1.2 Bleomycins 688
25.2.1.3 Diazobenzofluorenes 689
25.2.1.4 Anthracyclines 689
25.2.1.5 Pluramycins 689
25.2.1.6 Aureolic Acids 690
25.2.2 Agents that Interact with RNA 692
25.2.2.1 Orthosomycins 692
25.2.2.2 Macrolides 692
25.2.2.3 Aminoglycosides 694
25.2.2.4 Amicetins 695
25.2.3 Agents that Interact with Cell Walls and Cell Membranes 695
25.2.3.1 Non-Ribosomal Peptides 695
25.2.3.2 Polyenes 697
25.2.3.3 Saccharomicins 699
25.2.4 Agents that Interact with Proteins 699
25.2.4.1 Indolocarbazoles 699
25.2.4.2 Coumarins 699
25.2.4.3 Benzoisochromanequinones 701
25.2.4.4 Avermectins 701
25.2.4.5 Angucyclines 701
25.2.4.6 Cardiac Glycosides 702
25.2.4.7 Lignans 703
25.2.4.8 Anthraquinone Glycosides 703
25.2.4.9 Ginsenosides 704
25.2.4.10 Glycoalkaloids 704
25.2.4.11 Glucosinolates 705
25.2.5 Agents that Interact with Other (or Undefined) Targets 706
25.2.5.1 Plant Phenolics 706
25.2.5.2 Mono- and Triterpenoid Glycosides 707
25.2.5.3 Plant Polymeric Natural Glycosides 707
25.3 Conclusions 707
25.4 References 707
26 Novel Enzymatic Mechanisms in the Biosynthesis of Unusual Sugars
Alexander Wong, Xuemei He, and Hung-Wen Liu 		713
26.1 Introduction 713
26.2 Biosynthesis of Deoxysugars 714
26.2.1 Eod-Catalyzed C-O Bond-Cleavage at the C-6 Position in the Biosynthesis of 6-Deoxyhexose 715
26.2.1.1 Catalytic Mechanism of Eod 715
26.2.1.2 Stereochemical Course of Eod-Catalyzed Reactions 716
26.2.2 E1- and E3-Catalyzed C-O Bond-Cleavage at the C-3 Position in the Biosynthesis of Ascarylose 717
26.2.2.1 Catalytic Properties of CDP-6-Deoxy-L-Threo-D-Glycero-4-Hexulose 3-Dehydrase (E1) 718
26.2.2.2 Catalytic Properties of CDP-6-Deoxy-L-Threo-D-Glycero-4-Hexulose 3-Dehydrase Reductase (E3) 719
26.2.2.3 Formation of Radical Intermediates During E1 and E3 Catalysis 719
26.2.3 TylX3- and TylC1-Catalyzed C-O Bond-Cleavage at the C-2 Position in the Biosynthesis of Mycarose 720
26.2.3.1 Biochemical Characterization of Enzymes Involved in C-2 Deoxygenation 721
26.2.3.2 Mechanism of C-2 Deoxygenation 721
26.2.4 DesI- and DesII-Catalyzed C-O Bond-Cleavage at the C-4 Position in the Biosynthesis of Desosamine 722
26.2.4.1 Genetic Disruption of DesI and DesII Genes 723
26.2.4.2 Proposed Mechanisms for C-4 Deoxygenation 723
26.3 Biosynthesis of Aminosugars 725
26.3.1 C-N Bond-Formation by GlmS-Catalyzed Transamidation in the Biosynthesis of Glucosamine-6-Phosphate 727
26.3.1.1 Catalytic Properties of Glucosamine-6-Phosphate Synthetase 727
26.3.1.2 The Glutaminase Activity of Glucosamine-6-Phosphate Synthetase 727
26.3.1.3 The Synthetase Activity of Glucosamine-6-Phosphate Synthetase 728
26.3.2 C-N Bond Formation by TylB-Catalyzed Transamination in the Biosynthesis of Mycaminose 729
26.4 Biosynthesis of Branched-Chain Sugars 730
26.4.1 YerE- and YerF-Catalyzed Two-Carbon Branched-Chain Attachment in the Biosynthesis of Yersiniose A 731
26.4.1.1 Biochemical Properties and Catalytic Mechanism of YerE 731
26.4.1.2 Biochemical Properties of YerF 732
26.4.2 TylC3-Catalyzed One-Carbon Branched-Chain Attachment in the Biosynthesis of Mycarose 732
26.4.2.1 Biochemical Properties and Catalytic Mechanism of TylC3 733
26.5 Epimerization Reactions 734
26.5.1 UDP-N-acetylglucosamine 2-Epimerase-Catalyzed C-2 Epimerization in the Biosynthesis of N-Acetylmannosamine 734
26.5.1.1 Catalytic Properties of UDP-N-Acetylglucosamine 2-Epimerase 734
26.5.1.2 Mechanism of C-2 Epimerization 735
26.5.2 CDP-Tyvelose 2-Epimerase-Catalyzed C-2 Epimerization in the Biosynthesis of Tyvelose 735
26.5.2.1 Biochemical Properties of CDP-Tyvelose 2-Epimerase 736
26.5.2.2 Possible Mechanisms for C-2 Epimerization 737
26.5.2.3 Distinguishing Between Mechanisms Involving C-2 or C-4 Oxidation 737
26.6 Rearrangement of Hexose Skeletons: UDP-Galactopyranose Mutase-Catalyzed Biosynthesis of Galactofuranose 738
26.6.1 Catalytic Properties of UDP-Galactopyranose Mutase 738
26.6.2 Mechanism of Ring Contraction 739
26.7 Summary 740
26.8 Acknowledgements 741
26.9 References 741
27 Neoglycolipids: Identification of Functional Carbohydrate Epitopes
Ten Feizi, Alexander M. Lawson, and Wengang Chai 		747
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
27.4.1 Novel Sulfated Ligands for the Selectins 752
27.4.2 Novel Class of O-Glycans (O-Mannosyl) in the Brain 754
27.4.3 Unique Tetrasaccharide Sequence on Heparan Sulfate 755
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
Murugesapillai Mylvaganam and Clifford A. Lingwood 		761
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
Dawn E. Verdugo, Lars C. Pedersen, and Carolyn R. Bertozzi 		781
29.1 Introduction: Sulfotransferases and the Biology of Sulfation 781
29.2 EST as a Model ST for Inhibitor Design 783
29.2.1 Inhibitors of EST Targeted Toward the PAPS Binding Site 784
29.2.2 A Bisubstrate Analogue Approach to EST Inhibition 788
29.2.3 Discovery of EST Inhibitors from a Library of PAP Analogues 789
29.2.4 Inhibition of EST by Dietary Agents and Environmental Toxins 791
29.3 Inhibition of Representative Golgi-Resident Sulfotransferases: GST-2, GST-3, and TPST-2 792
29.3.1 Heterocyclic Inhibitors of GST-2 and GST-3 792
29.3.2 Tethered Inhibitors of TPST-2 793
29.4 Assays for High-Throughput Screening of STs 794
29.4.1 A Continuous ST Assay 794
29.4.2 Immobilized Enzyme Mass Spectrometry (IEMS) Assay 795
29.4.3 A 96-Well Direct Capture Dot-Blot Assay for Carbohydrate STs 795
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
Reiji Kannagi 		803
30.1 Implication of Carbohydrate Determinants in Cancer Metastasis 803
30.1.1 Distant Hematogenous Metastasis of Cancer Cells 803
30.1.2 Multiple Organ Infiltration of Leukemic Cells 806
30.1.3 Lymph Node Infiltration Mediated by L-Selectin 807
30.1.4 Other Carbohydrate Determinants Involved in Distant Metastasis 807
30.2 Tumor Angiogenesis and Cancer-Endothelial Interaction 808
30.2.1 Possible Involvement of Selectin-Mediated Cell Adhesion in Tumor Angiogenesis 808
30.2.2 Roles of Humoral Factors and Cell Adhesion Molecules in Tumor Angiogenesis 809
30.3 Use of Monoclonal Antibodies for Inhibition of Cancer Cell-Endothelial Interaction 809
30.3.1 Diversity of Selectin Ligand Expression on Cancer Cells 809
30.3.2 Internally Fucosylated Ligands for Selectins 810
30.3.3 Sulfated Ligands for Selectins 811
30.3.4 O-Acetylation and Other Sialic Acid Modifications in Carbohydrate Ligands 812
30.4 Inhibitors of Selectin-Mediated Cell Adhesion 812
30.4.1 Use of Carbohydrate Derivatives 812
30.4.2 Use of Peptide Mimetics 813
30.5 Regulation of Selectin Expression on Endothelial Cells 814
30.5.1 Enhanced E-Selectin Expression on Vascular Beds in Cancer Patients 814
30.5.2 Factors Affecting Endothelial E-Selectin Expression in Patients with Cancers 815
30.5.3 Chemoprophylaxis of Cancer Metastasis 815
30.6 Enhanced Expression of Sialyl Lex and Sialyl Lea in Malignant Cells and its Modulation 816
30.6.1 Fucosyltransferases Involved in Sialyl Lea and Sialyl Lex Synthesis and Antisense Gene Therapy 816
30.6.2 Therapy Targeting Transcriptional Regulation of Fucosyltransferases VII and IV in Cancer and Leukemia 817
30.6.3 Cancer-Associated Alteration of Sialyltransferase Isoenzymes 818
30.6.4 Sialyltransferase and the Concept of Cancer-Associated "Incomplete Synthesis" of Carbohydrate Determinants 820
30.6.5 Sulfotransferase and Differentiation Therapy of Cancer with Histone Deacetylase Inhibitors 820
30.6.6 Effect of Sialidases and Membrane Recycling on Sialyl Lex/a Expression in Cancer 822
30.6.7 Substrate Competition with A- and B-Transferases and DNA Methylation 822
30.6.8 Altered Carbohydrate Intermediate Metabolism and Sialyl Lex/a Expression in Cancer -- Possible Relation to Warburg Theory 823
30.7 References 824
31 N-Acetylneuraminic Acid Derivatives and Mimetics as Anti-Influenza Agents
Robin Thomson and Mark von Itzstein 		831
31.1 Introduction 831
31.1.1 Influenza, the Disease 831
31.1.2 The Virus 832
31.1.3 Influenza Virus Sialidase 834
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
31.3.1 C-4 Modifications 840
31.3.2 C-5 Modifications 842
31.3.3 C-6 Modifications 843
31.3.4 Glycerol Side Chain Modifications 845
31.3.5 Glycerol Side Chain Replacement 850
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
Rüdiger Horstkorte, Oliver T. Keppler, and Werner Reutter 		863
32.1 Introduction 863
32.2 N-Acyl Side Chain-Modified Precursors of Sialic Acid 865
32.2.1 Biosynthetic Engineering of Cell Surface Sialic Acid as a Potent Tool for Study of Virus-Receptor Interactions 865
32.2.2 Immunotargeting of Tumor Cells Expressing Unnatural Polysialic Acids 868
32.2.3 Activation of Human T-Lymphocytes by ManProp 869
32.2.4 N-Acyl-Modified Sialic Acids can Stimulate Neural Cells 869
32.2.4.1 Stimulation of Glial Cells 869
32.2.4.2 Stimulation of Neurons 870
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
Kerstin Danker, Annette Fischer, and Werner Reutter 		875
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
Jillian R. Brown, Mark M. Fuster, and Jeffrey D. Esko 		883
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
Thomas K. Ritter and Chi-Huey Wong 		899
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

 
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