Modified nucleosides in biochemistry, biotechnology and medicine:
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| 245 | 1 | 0 | |a Modified nucleosides in biochemistry, biotechnology and medicine |c ed. by Piet Herdewijn |
| 250 | |a 1. Aufl. | ||
| 264 | 1 | |a Weinheim, Bergstr |b WILEY-VCH |c 2008 | |
| 300 | |a XXVI, 658 S. |b Ill., graph. Darst. |c 240 mm x 170 mm | ||
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| 700 | 1 | |a Herdewijn, Piet |4 edt | |
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V
Contents
Preface XIX
List of Contributors XXI
Part I Biochemistry and Biophysics 1
1 Investigations on Fluorine-Labeled Ribonucleic Acids
by 19F N M R Spectroscopy 3
Christoph Kreutz and Ronald Micura
1.1 Introduction 3
1.1.1 NMR Spectroscopic Properties of the 19F Nucleus 3
1.1.1.1 General NMR Spectroscopic Properties 3
1.1.1.2 19F versus XH NMR Spectroscopy 3
1.1.1.3 Factors Affecting the 19F Chemical Shift in Biomolecules 5
1.1.1.4 Fluorine Relaxation in Biological Systems 6
1.1.1.5 Solvent-Induced Isotope Shifts of 19F NMR Resonances 7
1.1.2 19F NMR Spectroscopy of Proteins 7
1.1.2.1 Incorporation of Fluorinated Amino Acids into Proteins 7
1.1.2.2 19F NMR Spectroscopic Studies of Proteins 8
1.2 19F NMR Spectroscopy of Nucleic Acids 13
1.2.1 Nucleic Acids with Fluorinated Nucleobases 14
1.2.1.1 Transfer RNAs 14
1.2.1.2 Hhal Methyltransferase in Complex with DNA Duplexes 14
1.2.1.3 Minimal Hammerhead Ribozyme 15
1.2.1.4 HIVTARRNA 17
1.2.2 Nucleic Acids with Fluorinated Ribose Units 19
1.2.2.1 Rlinv RNA 19
1.2.2.2 RNA Secondary Structure Equilibria 21
1.2.2.3 RNA Ligand Binding 22
1.2.3 Influence of Fluorine Modifications on Nucleic Acid Structure 22
1.3 Conclusions 24
References 24
Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn
Copyright © 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim
ISBN: 978-3-527-31820-9
VI Contents
2 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine: A Major DNA Oxidation
Product 29
Jean Cadet and Paolo Di Mascio
2.1 Introduction 29
2.2 Formation of 8-Oxo-7,8-Dihydroguanine 30
2.2.1 Single Lesion 30
2.2.1.1 OH Radical 31
2.2.1.2 One-Electron Oxidation 31
2.2.1.3 Singlet Oxygen 32
2.2.2 Tandem Lesions 34
2.3 Reactivity of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine 35
2.3.1 One-Electron Oxidation 35
2.3.1.1 Secondary Oxidation Products 36
2.3.1.2 DNA-Protein Crosslinks 37
2.3.2 Singlet Oxygen 37
2.3.2.1 Nudeoside 37
2.3.2.2 Oligonudeotide 38
2.4 Formation of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine in
Cellular DNA 39
2.4.1 Methods of Measurement 39
2.4.1.1 HPLC Methods (HPLC-ECD and HPLC-MS/MS) 39
2.4.1.2 Enzymic Assays 40
2.4.2 Indirect Effects of Ionizing Radiation (OH Radical) 41
2.4.3 High-Intensity UV Laser Irradiation (One-Electron Oxidation) 41
2.4.4 UVA Photosensitization (1O2) 42
2.5 Synthesis of 8-OxodGuo and Insertion into Oligonudeotides 42
2.6 Condusions 43
References 44
3 Modified DNA Bases: Probing Base-Pair Recognition
by Polymerases 49
Eric T. Kool
3.1 Introduction 49
3.1.1 The Importance of Understanding DNA Polymerases 49
3.1.2 The Utility of Modified Nudeobases in Probing Mechanisms 50
3.1.3 The Scope of this Chapter 50
3.2 Basic Principles and Methods in Replication 51
3.2.1 The Chemistry of Polymerases 51
3.2.2 Different Classes of Polymerases 51
3.2.3 Methods Used in Polymerase Studies 52
3.3 Alternative Hydrogen-Bonding Schemes 53
3.3.1 Thioguanine-Pyridone 53
3.3.2 Benner Hydrogen-Bonding Variants 54
3.4 Non-Polar Nudeoside Isosteres 56
3.4.1 The Concept of Nucleobase Isosteres 56
Contents VII
3.4.2 Synthesis, Structure, and Physical Properties 56
3.4.3 Base-Pairing Properties 57
3.4.4 Polymerase Behavior 58
3.4.5 Other Classes of Polymerases 59
3.4.6 Summary of Watson-Crick H-Bonding Effects in Polymerase
Active Sites 60
3.5 Non-Polar Steric Probes 60
3.5.1 Isomers of Hydrocarbons Illustrate Hydrophobic "Packing" Effects 60
3.5.2 Systematic Size Variants 62
3.5.3 Systematic Shape Variants 63
3.6 Minor Groove Hydrogen Bonds in Polymerases 64
3.6.1 Base Analogues Testing Minor Groove Interactions 64
3.7 Other Non-Polar Bases and Pairs 65
3.7.1 The Quest for New Base Pairs 65
3.7.2 A Broad Variety of Heterocycles and Hydrocarbons 66
3.7.3 Benzimidazoles Continue the Debate on Steric Effects 67
3.7.4 New Pairs of Hirao and Yokoyama 67
3.8 Replication of Designed Bases in Living Cells 68
3.8.1 Effects of Hydrogen Bonding in E. coli 68
3.8.2 Effects of Nudeobase Size in E. coli 69
3.9 Conclusions and Future Prospects 70
3.9.1 What We Know About Replication 70
3.9.2 And What Remains Unknown 71
3.9.3 Future Directions 71
References 71
4 2'-Deoxyribose-Modified Nucleoside Triphosphates and their
Recognition by DNA Polymerases 75
Karl-Heinzjung and Andreas Marx
4.1 Introduction 75
4.2 Modified Nudeotides as Alternative Building Blocks to Natural
Nucleic Acids 76
4.2.1 Introduction 76
4.2.2 Nudeotides with Downsized Residues: a-L-Threose-Derived
Nudeotides 76
4.2.2.1 Introduction 76
4.2.2.2 Synthesis 77
4.2.2.3 DNA Polymerase Studies 80
4.2.3 Nudeotides with Downsized Residues: Glycerol-Derived
Nudeotides 80
4.2.3.1 Introduction 80
4.2.3.2 Synthesis 81
4.2.3.3 DNA Polymerase Studies 82
4.2.4 Nudeotides with Expanded Sugar Residues: 1,5-Anhydrohexitol
Nudeotides 82
VIII Contents
4.2.4.1 Introduction 82
4.2.4.2 Synthesis 83
4.2.4.3 Functional DNA Polymerase Studies 85
4.2.5 Nucleotides with Expanded Sugar Residues: Cydohexenyl Nudeotides 85
4.2.5.1 Introduction 85
4.2.5.2 Synthesis 86
4.2.5.3 DNA Polymerase Studies 88
4.3 DNA Polymerase Selectivity: 4'-C-Modified Nucleotides 89
4.3.1 Introduction 89
4.3.2 Design and Synthesis 90
4.3.3 DNA Polymerase Studies 91
4.4 Concluding Remarks 93
References 94
5 Pyrimidine Dimers: UV-lnduced DNA Damage 97
Shigenori \wa\
5.1 Introduction 97
5.2 Formation of Pyrimidine Dimers 98
5.2.1 Cydobutane Pyrimidine Dimers 98
5.2.2 The (6-4) Photoproducts and their Dewar Valence Isomers 101
5.2.3 Other UV Lesions 101
5.3 Chemical Synthesis of Oligonucleotides Containing Pyrimidine
Dimers 103
5.3.1 Oligonucleotides Containing a CPD 103
5.3.2 Oligonucleotides Containing the (6-4) or Dewar Photoproduct 105
5.4 Structure and Mutagenesis of Pyrimidine Dimer-Containing DNA 109
5.4.1 Tertiary Structures of Pyrimidine Dimer-Containing Duplexes 109
5.4.2 Base-Pair Formation by Pyrimidine Dimers 111
5.4.3 Mutations Induced by Pyrimidine Dimers 112
5.5 Repair of Pyrimidine Dimers in Cells 116
5.5.1 T4 Endonuclease V 116
5.5.2 Photolyases 118
5.5.3 Nucleotide Excision Repair (NER) 119
5.5.4 UV Damage Endonuclease (UVDE) 121
5.6 Bypass of Pyrimidine Dimers by DNA Polymerases 122
References 124
6 Locked Nucleic Acids: Properties, Applications, and Perspectives 133
Poul Nielsen andjesper Wengel
6.1 Introduction 133
6.2 LNA in High-Affinity Hybridization: Designing Sequences 135
6.3 Structural Studies 139
6.4 Analogues of LNA and their Structural Impact 140
6.5 LNA as Potential Therapeutics 143
6.6 LNA-Probes 147
Contents IX
6.7 Concluding Remarks 148
References 149
7 Synthesis and Properties of Oligonucleotides Incorporating
Modified Nucleobases Capable of Watson-Crick-Type Base-Pair
Formation 153
Mitsuo Sekine, Akio Ohkubo, Itaru Okamoto, and Kohji Seio
7.1 Introduction 153
7.2 Natural, Enzyme-Assisted Sophisticated Devices for Maintaining
Correct Base Recognition of Canonical Nucleobases 154
7.3 Synthesis and Properties of Oligodeoxynucleotides Incorporating
4-N-Acylated Cytosine Derivatives 155
7.4 Base-Recognition Ability of 4-N-Alkoxycarbonylcytosine Derivatives 157
7.5 Synthesis and Properties of Oligonucleotides Incorporating
4-N-Carbamoylcytosine Derivatives 159
7.6 2-Thiouracil as an Improved Nudeobase in Place of Thymine 160
7.7 Modified Adenine Bases Capable of Recognizing the Thymine Base 161
7.8 Design of Modified Guanine Bases Capable of Recognizing Cytosine 165
7.9 Conclusions 168
References 168
8 The Properties of4-Thionucleosides 173
Masataka Yokohama
8.1 Introduction 173
8.2 Synthesis of 4'-Thionudeosides 173
8.3 Synthesis of Isothionudeosides 195
8.4 Synthesis of L-Thionudeosides 196
8.5 Synthesis of Thioxonucleosides 198
8.6 Synthesis of Miscellaneous Thionudeosides 205
8.7 Biological Activity of Thionudeosides 210
8.8 Condusions 219
References 219
9 S-Adenosyl-L-methionine and Related Compounds 223
Christian Dalhoffand Elmar Weinhold
9.1 Introduction 223
9.2 The Biochemistry of AdoMet 224
9.2.1 AdoMet as a Methyl and Methylene Group Donor 224
^.l.l AdoMet as an Aminocarboxypropyl Group Donor 227
9.2.3 AdoMet as an Adenosyl Group Donor 228
9.2.4 AdoMet as a Ribosyl Group Donor 228
9.2.5 AdoMet as a Radical Source 229
9.2.6 AdoMet as an Amino Group Donor 229
9.2.7 AdoMet-Dependent Riboswitches 230
9.2.8 The Biosynthesis and Metabolism of AdoMet 230
X Contents
9.3 The Chemistry and Biochemistry of Modified AdoMet 231
9.3.1 Synthetic Approaches to AdoMet Analogues 231
9.3.2 Isotope-Labeled AdoMet 232
9.3.3 Selenium and Tellurium Analogues of AdoMet 234
9.3.4 Sulfoxide and Sulfone Analogues of AdoMet 236
9.3.5 Sinefungin 237
9.3.6 Nitrogen Analogues of AdoMet 237
9.3.7 Aziridine Analogues of AdoMet 238
9.3.8 AdoMet Analogues with Methyl Group Replacements 238
9.4 AdoMet as a Pharmaceutical 240
9.5 Concluding Remarks 241
References 242
Part II Biotechnology 249
10 5-Substituted Nucleosides in Biochemistry and Biotechnology 251
Mohammad Ahmadian and Donald E. Bergstrom
10.1 Introduction 251
10.2 Synthesis 252
10.2.1 Organopalladium Coupling Reactions 252
10.2.2 Strategies for Post-Oligonucleoride-Synthesis Modification
through Pyrimidine C-5 253
10.3 Incorporation of C-5-Substituted Pyrimidine Nucleotides into
Nucleic Acids through Modified Nucleotide 5'-Triphosphates 255
10.3.1 The Early Studies 255
10.3.2 Incorporation of Diverse Functionality into DNA 257
10.3.3 T7 RNA Polymerase-Mediated Synthesis of Modified RNA 262
10.3.4 Incorporation of C-5-Appended Fluorophores 262
10.4 C-5 Substituents that Stabilize DNA Duplexes 264
10.5 Photochemistry 269
10.6 Conclusions 271
References 271
11 Universal Base Analogues and their Applications to Biotechnology 277
Kathleen Too and David Loakes
11.1 Introduction 277
11.2 General Methods of Synthesis 278
11.3 Properties of Universal Bases 282
11.4 Structure, Stacking, and Stabilization 283
11.5 Hydrogen-Bonding Universal Base Analogues 287
11.6 Applications of Universal Base Analogues 290
11.7 Triphosphate Derivatives 295
11.8 Therapeutic Applications 298
References 300
Contents XI
Part III Medicinal Chemistry 305
12 The Properties of Locked Methanocarba Nucleosides in Biochemistry,
Biotechnology, and Medicinal Chemistry 307
Victor E. Marquez
12.1 Introduction 307
12.2 Structural Representation 308
12.2.1 The Bicyclo[3.1.0]hexane Template 308
12.2.2 Pseudoboat versus Pseudochair Conformations 309
12.3 Synthesis of Locked Nucleosides 309
12.3.1 North (N) Conformer Mimics 311
12.3.1.1 Dideoxyribonucleoside Analogues 311
12.3.1.2 2'-Deoxyribonucleoside Analogues 312
12.3.1.3 Ribonucleoside Analogues 318
12.3.2 South (S) Conformer Mimics 320
12.3.2.1 2'-Deoxyribonudeoside Analogues 320
12.3.2.2 Ribonucleoside Analogues 321
12.3.3 Synthesis of N- and S-Methanocarba AZT Analogues 323
12.3.4 Synthesis of Bicyclo[3.1.0]hexene Nucleosides 324
12.3.5 Reshuffling of Groups on a Bicyclo[3.1.0]hexane
Template 326
12.3.6 Bicyclo[3.1.0]hexane Pseudosugars as Surrogates of Abasic
Nucleosides 327
12.4 Synthesis of Oligodeoxynucleotides (ODNs) Containing Locked
Nucleosides 328
12.4.1 The Dickerson-Drew (DD) Dodecamer 330
12.5 Molecular Targets, ligand Properties, and Binding
Modes 331
12.5.1 Kinases and Polymerases 331
12.5.2 HIV Reverse Transcriptase 335
12.5.3 DNA Methyltransferase 337
12.6 Concluding Remarks 339
References 339
13 Synthesis, Chemical Properties and Biological Activities of Cyclic
Bis(3'-5')diguanylic Acid (c-di-CMP) and its Analogues 343
Mamoru Hyodo and Yoshihiro Hayakawa
13.1 Introduction 343
13.2 Synthesis of c-di-GMP and its Analogues 345
13.2.1 Synthesis of c-di-GMP 345
13.2.2 Synthesis of Artificial Analogues of c-di-GMP 347
13.3 Chemical Properties of c-di-GMP and its Analogues 348
13.3.1 Stability and Chemical Properties of c-di-GMP under Acidic, Basic,
and Physiological Conditions 348
13.3.2 Polymorphism of c-di-GMP in Aqueous Solutions 349
XII Contents
13.4 Bioactivities of c-di-GMP and its Analogues 351
13.4.1 Activity of c-di-GMP on Biofilm Formation 352
13.4.1.1 Inhibition of Biofilm Formation and Prevention of Bacterial
Infection of S. aureus in vitro 352
13.4.1.2 Activity as an Immunostimulatory Molecule 353
13.4.1.3 Activity on Biofilm Formation and Virulence Emergence of
P. aeruginosa 357
13.4.2 Inhibition of Proliferation of Human Colon Cancer Cells with
c-di-GMP 357
13.4.3 Biological Activity of c-dGpGp 358
13.5 Conclusions 359
References 361
14 Siderophore Biosynthesis Inhibitors 365
Courtney C. Aldrich and Ravindranadh V. Somu
14.1 Introduction 365
14.2 Synthesis, Physico-Chemical Properties, Metabolism, Mechanism
of Action, and Biological Activity 365
14.2.1 Synthesis 365
14.2.2 Physico-Chemical Properties 366
14.2.3 Metabolism 367
14.2.4 Toxitity 367
14.2.5 Biochemical Target 368
14.2.6 Mechanism of Action 369
14.2.7 Biological Activity 369
14.3 Background of Siderophores: Molecular Target and Rationale
for Inhibitor Design 370
14.4 ligand Properties/Binding Mode 374
14.4.1 Nature of the Linker 375
14.4.2 Importance of the Aryl Ring 379
14.4.3 Role of the Ribose 382
14.4.4 Impact of the Nucleobase 385
14.5 Conclusions 388
References 388
15 Synthesis and Biological Activity of Selected Carbocyclic
Nucleosides 393
Adam Mieczkowski and Luigi A. Agrofoglio
15.1 Introduction 393
15.2 A-5021, Synguanol, and Cyclopropane Derivatives 395
15.3 Lobucavir and Cydobutane Nudeoside Derivatives 398
15.4 Carbovir and 2',3'-Unsaturated Nudeoside Derivatives 405
15.5 Locked Nudeosides 413
15.6 Condusions 420
References 420
Contents XIII
16 4'-C-Ethynyl-2'-Deoxynucleosides 425
Hiroshi Ohrui
16.1 Introduction 425
16.2 Murine Toxicity of Purine 4'EdNs 426
16.3 4'EdA Derivatives Stable to Adenosine Deaminase, and their
Biological Properties 427
16.4 4'-C-Ethynylnucleosides without 3'-OH 429
16.4.1 2',3'-Dideoxy-4'-C-ethynylnucleoside 429
16.4.2 2',3'-Didehydrodideoxy-4'-C-ethynylnucleosides 429
16.4.3 Carbocyclic and Other Heterocyclic Analogues of
4'-C-ethynylnucleoside 431
References 431
17 Modified Nucleosides as Selective Modulators of Adenosine Receptors
for Therapeutic Use 433
Kenneth A. Jacobson, Bhalchandra V. Joshi, Ben Wang, Athena Klutz,
Yoonkyung Kim, Andrei A. Ivanov, Artem Melman, and Zhan-Cuo Cao
17.1 Introduction 433
17.2 Molecular Targets and Binding Modes 434
17.3 AR Agonists as Clinical Candidates 434
17.3.1 Modified Nucleosides as A1 AR Agonists 435
17.3.2 Modified Nucleosides as A2a AR Agonists 437
17.3.3 Modified Nucleosides as A2b AR Agonists 439
17.3.4 Modified nucleosides as A3 AR ligands 441
17.4 Summary 444
References 444
18 The Design of Forodesine HCI and Other Purine Nucleoside
Phosphorylase Inhibitors 451
Philip E. Morris and Vivekanand P. Kamath
18.1 Introduction 451
18.2 Purine Nucleoside Phosphorylase Enzyme Structure 452
18.2.1 Purine-Binding Site 453
18.2.2 Phosphate-Binding Site 454
18.2.3 Sugar-Binding Site 454
18.3 First-Generation PNP Inhibitors: Substrate Analogues 454
18.3.1 Chemistry of First-Generation PNP Inhibitors 458
18.4 Second-Generation PNP Inhibitors: Transition-State
Inhibitors 460
18.4.1 Chemistry of Second-Generation PNP Inhibitors 461
18.4.2 Convergent Synthesis of Forodesine HCI 463
18.5 Third-Generation PNP Inhibitors: Transition-State
Inhibitors 467
18.5.1 Chemistry of BCX-4208 467
References 469
XIV Contents
19 Formycins and their Analogues: Purine Nucleoside
Phosphorylase Inhibitors and their Potential Application
in Immunosuppression and Cancer 473
Agnieszka Bzowska
19.1 Introduction 473
19.2 Chemical Structure of Formycins and their Analogues 475
19.2.1 Formycin A and B, Oxoformycin B 475
19.2.2 Structural Modifications of Formycins 476
19.2.2.1 N-Methyl and N-Substituted Analogues 476
19.2.2.2 Other Base-Modified Analogues 478
19.2.2.3 Sugar-Modified Analogues 478
19.2.3 Formycin Phosphates and Polyformycin Phosphates 478
19.3 Spectral Properties of Formycins 479
19.4 Sources of Formycins 483
19.4.1 Natural Sources and Biosynthesis 483
19.4.2 Synthesis 483
19.5 The Biological Activity of Formycins: A Brief Summary 485
19.6 Formycins and Analogues as Purine Nucleoside Phosphorylase
Inhibitors 488
19.6.1 Molecular Target of Formycins: Purine Nucleoside
Phosphorylase (PNP) 488
19.6.2 Formycins and Analogues in Studies of the Molecular Mechanism
of Catalysis: The 3-D Structure of PNPs 489
19.6.2.1 Low-Molecular-Mass PNPs 490
19.6.2.2 High-Molecular-Mass PNPs 492
19.6.3 PNP Deficiency and the Potential Role of PNP Inhibitors 495
19.6.4 Formycins and Analogues as Inhibitors of Mammalian PNPs 496
19.7 Formycins as Inhibitors of Parasitic PNPs and Hydrolases 500
19.8 Actual and Potential Applications of Formycins 501
19.8.1 Formycin and Analogues in Assays of Enzyme Activity 501
19.8.2 Formycin and Analogues as Protein Iigands for X-Ray Structural
Studies 502
19.8.3 Formycins and Analogues as Molecular Probes 502
19.8.4 Formycins as Iigands in Affinity Chromatography 503
19.8.5 Formycin B as a Tool to Study Nucleoside Transport 504
References 504
20 1-(3-C-Ethynyl-p-D-ribo-pentofuranosyl)cytosine (ECyd) 511
Akira Matsuda
20.1 Introduction 511
20.2 Synthesis of ECyd and its Analogues 511
20.3 Cytotoxic Activity and Structure-Activity Relationships of ECyd
Analogues In Vitro, and In Vitro Antitumor Activity 513
20.4 Structural Features of ECyd and 4'-Thio-ECyd 513
20.5 Metabolism and Mechanism of Action 517
Contents XV
20.6 An Apoptotic Pathway Involving the Action of ECyd 519
20.7 Combination of ECyd with Low-Dose X-Irradiation 519
20.8 ECyd is Effective against Gemcitabine-Resistant Human Pancreatic
Cancer Cells 520
20.9 Conclusions 521
References 521
21 Syntheses and Biological Activity of Neplanocin and Analogues 525
Dilip K. Tosh, Hea Ok Kim, Shantanu Pal, Jeong A. Lee,
and Lak Shin Jeong
21.1 Introduction 525
21.2 New Methodologies in the Synthesis of Neplanocin A 527
21.3 Modifications on Neplanocin A and Aristeromycin 532
21.3.1 C2' Modification 533
21.3.2 C3' Modification 536
21.3.3 C4' Modification 538
213 A C5' Modification 540
21.3.5 C6' Modification 550
21.3.6 Base Modification 552
21.3.7 Miscellaneous 559
21.4 Conclusions 563
References 563
22 Clitocine and Its Analogues 567
Hyunik Shin and Changhee Min
22.1 Clitocine: Isolation, Synthesis, and Biological Activity 567
22.1.1 Isolation 567
22.1.2 Synthesis 567
22.1.3 Biological Activity 569
22.2 Clitocine Analogues 571
22.2.1 Aglycone Modifications 571
22.2.2 Carbocydic Analogues 573
22.2.3 Acyclic Analogues 576
22.2.4 5'-Amino Analogues 578
References 583
Part IV Antitu morals and Antivirals 585
23 Capecitabine Preclinical Studies: From Discovery to Translational
Research 587
Hideo Ishitsuka and Nobuo Shimma
23.1 Introduction 587
23.2 Drug Design and Discovery of Capecitabine 588
23.2.1 5'-DFUR as a Lead Compound of Capecitabine 588
XVI Contents
23.2.2 5'-DFCR Derivatives 589
23.2.3 A^-Acyl-S'-DFCR Derivatives 589
23.2.4 N^Alkoxycarbonyl-S'-DFCR Derivatives 590
23.3 Preclinical Studies 590
23.3.1 Tumor-Selective Delivery of the Active 5-FU 590
23.3.2 Anti-Tumor Activities 592
23.3.3 Dose Fractionation and Schedule 592
23.3.4 Safety (Dose Range and Mild Myelotoxicity) 593
23.4 Translational Research for Optimizing Capecitabine Efficacy 593
23.4.1 Factors that Influence Capecitabine Efficacy 593
23.4.2 Combination Therapy with Rational Partners 594
23.4.2.1 Combination with TP Up-Regulators 594
23.4.2.2 Combination with DPD Down-Regulators 594
23.4.3 Personalized Therapy of Rational Patient Populations 596
23.5 Conclusions 597
References 598
24 Tenofovir and Adefovir as Antiviral Agents 601
Tomas Cihlar, William E. Delaney IV, and Richard Mackman
24.1 Introduction 601
24.2 Synthesis 602
24.2.1 Adefovir and Adefovir Dipivoxil 603
24.2.2 Tenofovir and Tenofovir Disoproxil Fumarate 605
24.3 Mechanism of Action 606
24.3.1 Membrane Transport and Intracellular Metabolism 606
24.3.2 Inhibition of Viral Polymerases 608
24.3.3 Spectrum of Antiviral Activity 609
24.4 Activity in Animal Models 612
24.4.1 Models for Retroviral Infections 612
24.4.2 Models for Hepadnavirus Infections 613
24.4.3 Herpes Models 614
24.5 Clinical Experience 614
24.5.1 Tenofovir Disoproxil Fumarate (Viread1*) 614
24.5.2 Adefovir Dipivoxil (Hepsera") 616
24.6 Drug Resistance 618
24.6.1 HIV Resistance 618
24.6.2 HBV Resistance 619
24.7 Novel Antiviral Nucleotides and Nucleotide Prodrugs 619
24.8 Conclusions 621
References 622
Contents XVII
25 Clofarabine: From Design to Approval 631
John A. Secrist III, Jaideep V. Thottassery, and William B. Parker
25.1 Introduction 631
25.2 Clofarabine: The Background 632
25.3 The Beginnings 632
25.4 The Next Generation of Compounds 635
25.5 Mechanism of Action of Clofarabine 639
25.5.1 Transport and Metabolism to Active Metabolites 639
25.5.2 Inhibition of DNA Synthesis 640
25.5.3 Induction of Apoptosis 641
25.5.4 Activity against Non-Proliferating Cancer Cells 642
25.6 Clofarabine to the Clinic 643
25.6.1 Clinical Trials and Approval 643
25.7 Summary and Comments 644
References 644
Index 647 |
| adam_txt |
V
Contents
Preface XIX
List of Contributors XXI
Part I Biochemistry and Biophysics 1
1 Investigations on Fluorine-Labeled Ribonucleic Acids
by 19F N M R Spectroscopy 3
Christoph Kreutz and Ronald Micura
1.1 Introduction 3
1.1.1 NMR Spectroscopic Properties of the 19F Nucleus 3
1.1.1.1 General NMR Spectroscopic Properties 3
1.1.1.2 19F versus XH NMR Spectroscopy 3
1.1.1.3 Factors Affecting the 19F Chemical Shift in Biomolecules 5
1.1.1.4 Fluorine Relaxation in Biological Systems 6
1.1.1.5 Solvent-Induced Isotope Shifts of 19F NMR Resonances 7
1.1.2 19F NMR Spectroscopy of Proteins 7
1.1.2.1 Incorporation of Fluorinated Amino Acids into Proteins 7
1.1.2.2 19F NMR Spectroscopic Studies of Proteins 8
1.2 19F NMR Spectroscopy of Nucleic Acids 13
1.2.1 Nucleic Acids with Fluorinated Nucleobases 14
1.2.1.1 Transfer RNAs 14
1.2.1.2 Hhal Methyltransferase in Complex with DNA Duplexes 14
1.2.1.3 Minimal Hammerhead Ribozyme 15
1.2.1.4 HIVTARRNA 17
1.2.2 Nucleic Acids with Fluorinated Ribose Units 19
1.2.2.1 Rlinv RNA 19
1.2.2.2 RNA Secondary Structure Equilibria 21
1.2.2.3 RNA Ligand Binding 22
1.2.3 Influence of Fluorine Modifications on Nucleic Acid Structure 22
1.3 Conclusions 24
References 24
Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn
Copyright © 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim
ISBN: 978-3-527-31820-9
VI Contents
2 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine: A Major DNA Oxidation
Product 29
Jean Cadet and Paolo Di Mascio
2.1 Introduction 29
2.2 Formation of 8-Oxo-7,8-Dihydroguanine 30
2.2.1 Single Lesion 30
2.2.1.1 OH Radical 31
2.2.1.2 One-Electron Oxidation 31
2.2.1.3 Singlet Oxygen 32
2.2.2 Tandem Lesions 34
2.3 Reactivity of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine 35
2.3.1 One-Electron Oxidation 35
2.3.1.1 Secondary Oxidation Products 36
2.3.1.2 DNA-Protein Crosslinks 37
2.3.2 Singlet Oxygen 37
2.3.2.1 Nudeoside 37
2.3.2.2 Oligonudeotide 38
2.4 Formation of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine in
Cellular DNA 39
2.4.1 Methods of Measurement 39
2.4.1.1 HPLC Methods (HPLC-ECD and HPLC-MS/MS) 39
2.4.1.2 Enzymic Assays 40
2.4.2 Indirect Effects of Ionizing Radiation (OH Radical) 41
2.4.3 High-Intensity UV Laser Irradiation (One-Electron Oxidation) 41
2.4.4 UVA Photosensitization (1O2) 42
2.5 Synthesis of 8-OxodGuo and Insertion into Oligonudeotides 42
2.6 Condusions 43
References 44
3 Modified DNA Bases: Probing Base-Pair Recognition
by Polymerases 49
Eric T. Kool
3.1 Introduction 49
3.1.1 The Importance of Understanding DNA Polymerases 49
3.1.2 The Utility of Modified Nudeobases in Probing Mechanisms 50
3.1.3 The Scope of this Chapter 50
3.2 Basic Principles and Methods in Replication 51
3.2.1 The Chemistry of Polymerases 51
3.2.2 Different Classes of Polymerases 51
3.2.3 Methods Used in Polymerase Studies 52
3.3 Alternative Hydrogen-Bonding Schemes 53
3.3.1 Thioguanine-Pyridone 53
3.3.2 Benner Hydrogen-Bonding Variants 54
3.4 Non-Polar Nudeoside Isosteres 56
3.4.1 The Concept of Nucleobase Isosteres 56
Contents VII
3.4.2 Synthesis, Structure, and Physical Properties 56
3.4.3 Base-Pairing Properties 57
3.4.4 Polymerase Behavior 58
3.4.5 Other Classes of Polymerases 59
3.4.6 Summary of Watson-Crick H-Bonding Effects in Polymerase
Active Sites 60
3.5 Non-Polar Steric Probes 60
3.5.1 Isomers of Hydrocarbons Illustrate Hydrophobic "Packing" Effects 60
3.5.2 Systematic Size Variants 62
3.5.3 Systematic Shape Variants 63
3.6 Minor Groove Hydrogen Bonds in Polymerases 64
3.6.1 Base Analogues Testing Minor Groove Interactions 64
3.7 Other Non-Polar Bases and Pairs 65
3.7.1 The Quest for New Base Pairs 65
3.7.2 A Broad Variety of Heterocycles and Hydrocarbons 66
3.7.3 Benzimidazoles Continue the Debate on Steric Effects 67
3.7.4 New Pairs of Hirao and Yokoyama 67
3.8 Replication of Designed Bases in Living Cells 68
3.8.1 Effects of Hydrogen Bonding in E. coli 68
3.8.2 Effects of Nudeobase Size in E. coli 69
3.9 Conclusions and Future Prospects 70
3.9.1 What We Know About Replication 70
3.9.2 And What Remains Unknown 71
3.9.3 Future Directions 71
References 71
4 2'-Deoxyribose-Modified Nucleoside Triphosphates and their
Recognition by DNA Polymerases 75
Karl-Heinzjung and Andreas Marx
4.1 Introduction 75
4.2 Modified Nudeotides as Alternative Building Blocks to Natural
Nucleic Acids 76
4.2.1 Introduction 76
4.2.2 Nudeotides with Downsized Residues: a-L-Threose-Derived
Nudeotides 76
4.2.2.1 Introduction 76
4.2.2.2 Synthesis 77
4.2.2.3 DNA Polymerase Studies 80
4.2.3 Nudeotides with Downsized Residues: Glycerol-Derived
Nudeotides 80
4.2.3.1 Introduction 80
4.2.3.2 Synthesis 81
4.2.3.3 DNA Polymerase Studies 82
4.2.4 Nudeotides with Expanded Sugar Residues: 1,5-Anhydrohexitol
Nudeotides 82
VIII Contents
4.2.4.1 Introduction 82
4.2.4.2 Synthesis 83
4.2.4.3 Functional DNA Polymerase Studies 85
4.2.5 Nucleotides with Expanded Sugar Residues: Cydohexenyl Nudeotides 85
4.2.5.1 Introduction 85
4.2.5.2 Synthesis 86
4.2.5.3 DNA Polymerase Studies 88
4.3 DNA Polymerase Selectivity: 4'-C-Modified Nucleotides 89
4.3.1 Introduction 89
4.3.2 Design and Synthesis 90
4.3.3 DNA Polymerase Studies 91
4.4 Concluding Remarks 93
References 94
5 Pyrimidine Dimers: UV-lnduced DNA Damage 97
Shigenori \wa\
5.1 Introduction 97
5.2 Formation of Pyrimidine Dimers 98
5.2.1 Cydobutane Pyrimidine Dimers 98
5.2.2 The (6-4) Photoproducts and their Dewar Valence Isomers 101
5.2.3 Other UV Lesions 101
5.3 Chemical Synthesis of Oligonucleotides Containing Pyrimidine
Dimers 103
5.3.1 Oligonucleotides Containing a CPD 103
5.3.2 Oligonucleotides Containing the (6-4) or Dewar Photoproduct 105
5.4 Structure and Mutagenesis of Pyrimidine Dimer-Containing DNA 109
5.4.1 Tertiary Structures of Pyrimidine Dimer-Containing Duplexes 109
5.4.2 Base-Pair Formation by Pyrimidine Dimers 111
5.4.3 Mutations Induced by Pyrimidine Dimers 112
5.5 Repair of Pyrimidine Dimers in Cells 116
5.5.1 T4 Endonuclease V 116
5.5.2 Photolyases 118
5.5.3 Nucleotide Excision Repair (NER) 119
5.5.4 UV Damage Endonuclease (UVDE) 121
5.6 Bypass of Pyrimidine Dimers by DNA Polymerases 122
References 124
6 Locked Nucleic Acids: Properties, Applications, and Perspectives 133
Poul Nielsen andjesper Wengel
6.1 Introduction 133
6.2 LNA in High-Affinity Hybridization: Designing Sequences 135
6.3 Structural Studies 139
6.4 Analogues of LNA and their Structural Impact 140
6.5 LNA as Potential Therapeutics 143
6.6 LNA-Probes 147
Contents IX
6.7 Concluding Remarks 148
References 149
7 Synthesis and Properties of Oligonucleotides Incorporating
Modified Nucleobases Capable of Watson-Crick-Type Base-Pair
Formation 153
Mitsuo Sekine, Akio Ohkubo, Itaru Okamoto, and Kohji Seio
7.1 Introduction 153
7.2 Natural, Enzyme-Assisted Sophisticated Devices for Maintaining
Correct Base Recognition of Canonical Nucleobases 154
7.3 Synthesis and Properties of Oligodeoxynucleotides Incorporating
4-N-Acylated Cytosine Derivatives 155
7.4 Base-Recognition Ability of 4-N-Alkoxycarbonylcytosine Derivatives 157
7.5 Synthesis and Properties of Oligonucleotides Incorporating
4-N-Carbamoylcytosine Derivatives 159
7.6 2-Thiouracil as an Improved Nudeobase in Place of Thymine 160
7.7 Modified Adenine Bases Capable of Recognizing the Thymine Base 161
7.8 Design of Modified Guanine Bases Capable of Recognizing Cytosine 165
7.9 Conclusions 168
References 168
8 The Properties of4-Thionucleosides 173
Masataka Yokohama
8.1 Introduction 173
8.2 Synthesis of 4'-Thionudeosides 173
8.3 Synthesis of Isothionudeosides 195
8.4 Synthesis of L-Thionudeosides 196
8.5 Synthesis of Thioxonucleosides 198
8.6 Synthesis of Miscellaneous Thionudeosides 205
8.7 Biological Activity of Thionudeosides 210
8.8 Condusions 219
References 219
9 S-Adenosyl-L-methionine and Related Compounds 223
Christian Dalhoffand Elmar Weinhold
9.1 Introduction 223
9.2 The Biochemistry of AdoMet 224
9.2.1 AdoMet as a Methyl and Methylene Group Donor 224
^.l.l AdoMet as an Aminocarboxypropyl Group Donor 227
9.2.3 AdoMet as an Adenosyl Group Donor 228
9.2.4 AdoMet as a Ribosyl Group Donor 228
9.2.5 AdoMet as a Radical Source 229
9.2.6 AdoMet as an Amino Group Donor 229
9.2.7 AdoMet-Dependent Riboswitches 230
9.2.8 The Biosynthesis and Metabolism of AdoMet 230
X Contents
9.3 The Chemistry and Biochemistry of Modified AdoMet 231
9.3.1 Synthetic Approaches to AdoMet Analogues 231
9.3.2 Isotope-Labeled AdoMet 232
9.3.3 Selenium and Tellurium Analogues of AdoMet 234
9.3.4 Sulfoxide and Sulfone Analogues of AdoMet 236
9.3.5 Sinefungin 237
9.3.6 Nitrogen Analogues of AdoMet 237
9.3.7 Aziridine Analogues of AdoMet 238
9.3.8 AdoMet Analogues with Methyl Group Replacements 238
9.4 AdoMet as a Pharmaceutical 240
9.5 Concluding Remarks 241
References 242
Part II Biotechnology 249
10 5-Substituted Nucleosides in Biochemistry and Biotechnology 251
Mohammad Ahmadian and Donald E. Bergstrom
10.1 Introduction 251
10.2 Synthesis 252
10.2.1 Organopalladium Coupling Reactions 252
10.2.2 Strategies for Post-Oligonucleoride-Synthesis Modification
through Pyrimidine C-5 253
10.3 Incorporation of C-5-Substituted Pyrimidine Nucleotides into
Nucleic Acids through Modified Nucleotide 5'-Triphosphates 255
10.3.1 The Early Studies 255
10.3.2 Incorporation of Diverse Functionality into DNA 257
10.3.3 T7 RNA Polymerase-Mediated Synthesis of Modified RNA 262
10.3.4 Incorporation of C-5-Appended Fluorophores 262
10.4 C-5 Substituents that Stabilize DNA Duplexes 264
10.5 Photochemistry 269
10.6 Conclusions 271
References 271
11 Universal Base Analogues and their Applications to Biotechnology 277
Kathleen Too and David Loakes
11.1 Introduction 277
11.2 General Methods of Synthesis 278
11.3 Properties of Universal Bases 282
11.4 Structure, Stacking, and Stabilization 283
11.5 Hydrogen-Bonding Universal Base Analogues 287
11.6 Applications of Universal Base Analogues 290
11.7 Triphosphate Derivatives 295
11.8 Therapeutic Applications 298
References 300
Contents XI
Part III Medicinal Chemistry 305
12 The Properties of Locked Methanocarba Nucleosides in Biochemistry,
Biotechnology, and Medicinal Chemistry 307
Victor E. Marquez
12.1 Introduction 307
12.2 Structural Representation 308
12.2.1 The Bicyclo[3.1.0]hexane Template 308
12.2.2 Pseudoboat versus Pseudochair Conformations 309
12.3 Synthesis of Locked Nucleosides 309
12.3.1 North (N) Conformer Mimics 311
12.3.1.1 Dideoxyribonucleoside Analogues 311
12.3.1.2 2'-Deoxyribonucleoside Analogues 312
12.3.1.3 Ribonucleoside Analogues 318
12.3.2 South (S) Conformer Mimics 320
12.3.2.1 2'-Deoxyribonudeoside Analogues 320
12.3.2.2 Ribonucleoside Analogues 321
12.3.3 Synthesis of N- and S-Methanocarba AZT Analogues 323
12.3.4 Synthesis of Bicyclo[3.1.0]hexene Nucleosides 324
12.3.5 Reshuffling of Groups on a Bicyclo[3.1.0]hexane
Template 326
12.3.6 Bicyclo[3.1.0]hexane Pseudosugars as Surrogates of Abasic
Nucleosides 327
12.4 Synthesis of Oligodeoxynucleotides (ODNs) Containing Locked
Nucleosides 328
12.4.1 The Dickerson-Drew (DD) Dodecamer 330
12.5 Molecular Targets, ligand Properties, and Binding
Modes 331
12.5.1 Kinases and Polymerases 331
12.5.2 HIV Reverse Transcriptase 335
12.5.3 DNA Methyltransferase 337
12.6 Concluding Remarks 339
References 339
13 Synthesis, Chemical Properties and Biological Activities of Cyclic
Bis(3'-5')diguanylic Acid (c-di-CMP) and its Analogues 343
Mamoru Hyodo and Yoshihiro Hayakawa
13.1 Introduction 343
13.2 Synthesis of c-di-GMP and its Analogues 345
13.2.1 Synthesis of c-di-GMP 345
13.2.2 Synthesis of Artificial Analogues of c-di-GMP 347
13.3 Chemical Properties of c-di-GMP and its Analogues 348
13.3.1 Stability and Chemical Properties of c-di-GMP under Acidic, Basic,
and Physiological Conditions 348
13.3.2 Polymorphism of c-di-GMP in Aqueous Solutions 349
XII Contents
13.4 Bioactivities of c-di-GMP and its Analogues 351
13.4.1 Activity of c-di-GMP on Biofilm Formation 352
13.4.1.1 Inhibition of Biofilm Formation and Prevention of Bacterial
Infection of S. aureus in vitro 352
13.4.1.2 Activity as an Immunostimulatory Molecule 353
13.4.1.3 Activity on Biofilm Formation and Virulence Emergence of
P. aeruginosa 357
13.4.2 Inhibition of Proliferation of Human Colon Cancer Cells with
c-di-GMP 357
13.4.3 Biological Activity of c-dGpGp 358
13.5 Conclusions 359
References 361
14 Siderophore Biosynthesis Inhibitors 365
Courtney C. Aldrich and Ravindranadh V. Somu
14.1 Introduction 365
14.2 Synthesis, Physico-Chemical Properties, Metabolism, Mechanism
of Action, and Biological Activity 365
14.2.1 Synthesis 365
14.2.2 Physico-Chemical Properties 366
14.2.3 Metabolism 367
14.2.4 Toxitity 367
14.2.5 Biochemical Target 368
14.2.6 Mechanism of Action 369
14.2.7 Biological Activity 369
14.3 Background of Siderophores: Molecular Target and Rationale
for Inhibitor Design 370
14.4 ligand Properties/Binding Mode 374
14.4.1 Nature of the Linker 375
14.4.2 Importance of the Aryl Ring 379
14.4.3 Role of the Ribose 382
14.4.4 Impact of the Nucleobase 385
14.5 Conclusions 388
References 388
15 Synthesis and Biological Activity of Selected Carbocyclic
Nucleosides 393
Adam Mieczkowski and Luigi A. Agrofoglio
15.1 Introduction 393
15.2 A-5021, Synguanol, and Cyclopropane Derivatives 395
15.3 Lobucavir and Cydobutane Nudeoside Derivatives 398
15.4 Carbovir and 2',3'-Unsaturated Nudeoside Derivatives 405
15.5 Locked Nudeosides 413
15.6 Condusions 420
References 420
Contents XIII
16 4'-C-Ethynyl-2'-Deoxynucleosides 425
Hiroshi Ohrui
16.1 Introduction 425
16.2 Murine Toxicity of Purine 4'EdNs 426
16.3 4'EdA Derivatives Stable to Adenosine Deaminase, and their
Biological Properties 427
16.4 4'-C-Ethynylnucleosides without 3'-OH 429
16.4.1 2',3'-Dideoxy-4'-C-ethynylnucleoside 429
16.4.2 2',3'-Didehydrodideoxy-4'-C-ethynylnucleosides 429
16.4.3 Carbocyclic and Other Heterocyclic Analogues of
4'-C-ethynylnucleoside 431
References 431
17 Modified Nucleosides as Selective Modulators of Adenosine Receptors
for Therapeutic Use 433
Kenneth A. Jacobson, Bhalchandra V. Joshi, Ben Wang, Athena Klutz,
Yoonkyung Kim, Andrei A. Ivanov, Artem Melman, and Zhan-Cuo Cao
17.1 Introduction 433
17.2 Molecular Targets and Binding Modes 434
17.3 AR Agonists as Clinical Candidates 434
17.3.1 Modified Nucleosides as A1 AR Agonists 435
17.3.2 Modified Nucleosides as A2a AR Agonists 437
17.3.3 Modified Nucleosides as A2b AR Agonists 439
17.3.4 Modified nucleosides as A3 AR ligands 441
17.4 Summary 444
References 444
18 The Design of Forodesine HCI and Other Purine Nucleoside
Phosphorylase Inhibitors 451
Philip E. Morris and Vivekanand P. Kamath
18.1 Introduction 451
18.2 Purine Nucleoside Phosphorylase Enzyme Structure 452
18.2.1 Purine-Binding Site 453
18.2.2 Phosphate-Binding Site 454
18.2.3 Sugar-Binding Site 454
18.3 First-Generation PNP Inhibitors: Substrate Analogues 454
18.3.1 Chemistry of First-Generation PNP Inhibitors 458
18.4 Second-Generation PNP Inhibitors: Transition-State
Inhibitors 460
18.4.1 Chemistry of Second-Generation PNP Inhibitors 461
18.4.2 Convergent Synthesis of Forodesine HCI 463
18.5 Third-Generation PNP Inhibitors: Transition-State
Inhibitors 467
18.5.1 Chemistry of BCX-4208 467
References 469
XIV Contents
19 Formycins and their Analogues: Purine Nucleoside
Phosphorylase Inhibitors and their Potential Application
in Immunosuppression and Cancer 473
Agnieszka Bzowska
19.1 Introduction 473
19.2 Chemical Structure of Formycins and their Analogues 475
19.2.1 Formycin A and B, Oxoformycin B 475
19.2.2 Structural Modifications of Formycins 476
19.2.2.1 N-Methyl and N-Substituted Analogues 476
19.2.2.2 Other Base-Modified Analogues 478
19.2.2.3 Sugar-Modified Analogues 478
19.2.3 Formycin Phosphates and Polyformycin Phosphates 478
19.3 Spectral Properties of Formycins 479
19.4 Sources of Formycins 483
19.4.1 Natural Sources and Biosynthesis 483
19.4.2 Synthesis 483
19.5 The Biological Activity of Formycins: A Brief Summary 485
19.6 Formycins and Analogues as Purine Nucleoside Phosphorylase
Inhibitors 488
19.6.1 Molecular Target of Formycins: Purine Nucleoside
Phosphorylase (PNP) 488
19.6.2 Formycins and Analogues in Studies of the Molecular Mechanism
of Catalysis: The 3-D Structure of PNPs 489
19.6.2.1 Low-Molecular-Mass PNPs 490
19.6.2.2 High-Molecular-Mass PNPs 492
19.6.3 PNP Deficiency and the Potential Role of PNP Inhibitors 495
19.6.4 Formycins and Analogues as Inhibitors of Mammalian PNPs 496
19.7 Formycins as Inhibitors of Parasitic PNPs and Hydrolases 500
19.8 Actual and Potential Applications of Formycins 501
19.8.1 Formycin and Analogues in Assays of Enzyme Activity 501
19.8.2 Formycin and Analogues as Protein Iigands for X-Ray Structural
Studies 502
19.8.3 Formycins and Analogues as Molecular Probes 502
19.8.4 Formycins as Iigands in Affinity Chromatography 503
19.8.5 Formycin B as a Tool to Study Nucleoside Transport 504
References 504
20 1-(3-C-Ethynyl-p-D-ribo-pentofuranosyl)cytosine (ECyd) 511
Akira Matsuda
20.1 Introduction 511
20.2 Synthesis of ECyd and its Analogues 511
20.3 Cytotoxic Activity and Structure-Activity Relationships of ECyd
Analogues In Vitro, and In Vitro Antitumor Activity 513
20.4 Structural Features of ECyd and 4'-Thio-ECyd 513
20.5 Metabolism and Mechanism of Action 517
Contents XV
20.6 An Apoptotic Pathway Involving the Action of ECyd 519
20.7 Combination of ECyd with Low-Dose X-Irradiation 519
20.8 ECyd is Effective against Gemcitabine-Resistant Human Pancreatic
Cancer Cells 520
20.9 Conclusions 521
References 521
21 Syntheses and Biological Activity of Neplanocin and Analogues 525
Dilip K. Tosh, Hea Ok Kim, Shantanu Pal, Jeong A. Lee,
and Lak Shin Jeong
21.1 Introduction 525
21.2 New Methodologies in the Synthesis of Neplanocin A 527
21.3 Modifications on Neplanocin A and Aristeromycin 532
21.3.1 C2' Modification 533
21.3.2 C3' Modification 536
21.3.3 C4' Modification 538
213 A C5' Modification 540
21.3.5 C6' Modification 550
21.3.6 Base Modification 552
21.3.7 Miscellaneous 559
21.4 Conclusions 563
References 563
22 Clitocine and Its Analogues 567
Hyunik Shin and Changhee Min
22.1 Clitocine: Isolation, Synthesis, and Biological Activity 567
22.1.1 Isolation 567
22.1.2 Synthesis 567
22.1.3 Biological Activity 569
22.2 Clitocine Analogues 571
22.2.1 Aglycone Modifications 571
22.2.2 Carbocydic Analogues 573
22.2.3 Acyclic Analogues 576
22.2.4 5'-Amino Analogues 578
References 583
Part IV Antitu morals and Antivirals 585
23 Capecitabine Preclinical Studies: From Discovery to Translational
Research 587
Hideo Ishitsuka and Nobuo Shimma
23.1 Introduction 587
23.2 Drug Design and Discovery of Capecitabine 588
23.2.1 5'-DFUR as a Lead Compound of Capecitabine 588
XVI Contents
23.2.2 5'-DFCR Derivatives 589
23.2.3 A^-Acyl-S'-DFCR Derivatives 589
23.2.4 N^Alkoxycarbonyl-S'-DFCR Derivatives 590
23.3 Preclinical Studies 590
23.3.1 Tumor-Selective Delivery of the Active 5-FU 590
23.3.2 Anti-Tumor Activities 592
23.3.3 Dose Fractionation and Schedule 592
23.3.4 Safety (Dose Range and Mild Myelotoxicity) 593
23.4 Translational Research for Optimizing Capecitabine Efficacy 593
23.4.1 Factors that Influence Capecitabine Efficacy 593
23.4.2 Combination Therapy with Rational Partners 594
23.4.2.1 Combination with TP Up-Regulators 594
23.4.2.2 Combination with DPD Down-Regulators 594
23.4.3 Personalized Therapy of Rational Patient Populations 596
23.5 Conclusions 597
References 598
24 Tenofovir and Adefovir as Antiviral Agents 601
Tomas Cihlar, William E. Delaney IV, and Richard Mackman
24.1 Introduction 601
24.2 Synthesis 602
24.2.1 Adefovir and Adefovir Dipivoxil 603
24.2.2 Tenofovir and Tenofovir Disoproxil Fumarate 605
24.3 Mechanism of Action 606
24.3.1 Membrane Transport and Intracellular Metabolism 606
24.3.2 Inhibition of Viral Polymerases 608
24.3.3 Spectrum of Antiviral Activity 609
24.4 Activity in Animal Models 612
24.4.1 Models for Retroviral Infections 612
24.4.2 Models for Hepadnavirus Infections 613
24.4.3 Herpes Models 614
24.5 Clinical Experience 614
24.5.1 Tenofovir Disoproxil Fumarate (Viread1*) 614
24.5.2 Adefovir Dipivoxil (Hepsera") 616
24.6 Drug Resistance 618
24.6.1 HIV Resistance 618
24.6.2 HBV Resistance 619
24.7 Novel Antiviral Nucleotides and Nucleotide Prodrugs 619
24.8 Conclusions 621
References 622
Contents XVII
25 Clofarabine: From Design to Approval 631
John A. Secrist III, Jaideep V. Thottassery, and William B. Parker
25.1 Introduction 631
25.2 Clofarabine: The Background 632
25.3 The Beginnings 632
25.4 The Next Generation of Compounds 635
25.5 Mechanism of Action of Clofarabine 639
25.5.1 Transport and Metabolism to Active Metabolites 639
25.5.2 Inhibition of DNA Synthesis 640
25.5.3 Induction of Apoptosis 641
25.5.4 Activity against Non-Proliferating Cancer Cells 642
25.6 Clofarabine to the Clinic 643
25.6.1 Clinical Trials and Approval 643
25.7 Summary and Comments 644
References 644
Index 647 |
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| author2 | Herdewijn, Piet |
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| author_facet | Herdewijn, Piet |
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| bvnumber | BV035027866 |
| classification_rvk | VK 8570 WD 5365 |
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| dewey-full | 572.85 |
| dewey-hundreds | 500 - Natural sciences and mathematics |
| dewey-ones | 572 - Biochemistry |
| dewey-raw | 572.85 |
| dewey-search | 572.85 |
| dewey-sort | 3572.85 |
| dewey-tens | 570 - Biology |
| discipline | Chemie / Pharmazie Biologie |
| discipline_str_mv | Chemie / Pharmazie Biologie |
| edition | 1. Aufl. |
| format | Book |
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| id | DE-604.BV035027866 |
| illustrated | Illustrated |
| index_date | 2024-07-02T21:48:42Z |
| indexdate | 2024-07-20T09:48:27Z |
| institution | BVB |
| isbn | 9783527318209 3527318208 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-016696889 |
| oclc_num | 248619570 |
| open_access_boolean | |
| owner | DE-19 DE-BY-UBM DE-11 |
| owner_facet | DE-19 DE-BY-UBM DE-11 |
| physical | XXVI, 658 S. Ill., graph. Darst. 240 mm x 170 mm |
| publishDate | 2008 |
| publishDateSearch | 2008 |
| publishDateSort | 2008 |
| publisher | WILEY-VCH |
| record_format | marc |
| spelling | Modified nucleosides in biochemistry, biotechnology and medicine ed. by Piet Herdewijn 1. Aufl. Weinheim, Bergstr WILEY-VCH 2008 XXVI, 658 S. Ill., graph. Darst. 240 mm x 170 mm txt rdacontent n rdamedia nc rdacarrier Nucleotide (DE-588)4135085-6 gnd rswk-swf Nucleotide (DE-588)4135085-6 s DE-604 Herdewijn, Piet edt text/html http://deposit.dnb.de/cgi-bin/dokserv?id=2973589&prov=M&dok_var=1&dok_ext=htm Inhaltstext HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016696889&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Modified nucleosides in biochemistry, biotechnology and medicine Nucleotide (DE-588)4135085-6 gnd |
| subject_GND | (DE-588)4135085-6 |
| title | Modified nucleosides in biochemistry, biotechnology and medicine |
| title_auth | Modified nucleosides in biochemistry, biotechnology and medicine |
| title_exact_search | Modified nucleosides in biochemistry, biotechnology and medicine |
| title_exact_search_txtP | Modified nucleosides in biochemistry, biotechnology and medicine |
| title_full | Modified nucleosides in biochemistry, biotechnology and medicine ed. by Piet Herdewijn |
| title_fullStr | Modified nucleosides in biochemistry, biotechnology and medicine ed. by Piet Herdewijn |
| title_full_unstemmed | Modified nucleosides in biochemistry, biotechnology and medicine ed. by Piet Herdewijn |
| title_short | Modified nucleosides in biochemistry, biotechnology and medicine |
| title_sort | modified nucleosides in biochemistry biotechnology and medicine |
| topic | Nucleotide (DE-588)4135085-6 gnd |
| topic_facet | Nucleotide |
| url | http://deposit.dnb.de/cgi-bin/dokserv?id=2973589&prov=M&dok_var=1&dok_ext=htm http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016696889&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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